PRIMER

Lysosomal storage diseases

Frances M. Platt1*, Alessandra d’Azzo2, Beverly L. Davidson3,4, Elizabeth F. Neufeld5
and Cynthia J. Tifft6
Abstract | Lysosomal storage diseases (LSDs) are a group of over 70 diseases that are
characterized by lysosomal dysfunction, most of which are inherited as autosomal recessive
traits. These disorders are individually rare but collectively affect 1 in 5,000 live births. LSDs
typically present in infancy and childhood, although adult-​onset forms also occur. Most LSDs
have a progressive neurodegenerative clinical course, although symptoms in other organ
systems are frequent. LSD-​associated genes encode different lysosomal proteins, including
lysosomal enzymes and lysosomal membrane proteins. The lysosome is the key cellular hub for
macromolecule catabolism, recycling and signalling, and defects that impair any of these
functions cause the accumulation of undigested or partially digested macromolecules in
lysosomes (that is, ‘storage’) or impair the transport of molecules, which can result in cellular
damage. Consequently , the cellular pathogenesis of these diseases is complex and is currently
incompletely understood. Several LSDs can be treated with approved, disease-​specific therapies
that are mostly based on enzyme replacement. However, small-​molecule therapies, including
substrate reduction and chaperone therapies, have also been developed and are approved for
some LSDs, whereas gene therapy and genome editing are at advanced preclinical stages and,
for a few disorders, have already progressed to the clinic.

Lysosomal storage diseases (LSDs) are heritable (inborn) specific genetic defect and the biochemical nature of
1
Department of
errors of metabolism that affect the function of the lyso- the stored macromolecules, LSDs can also cause skeletal
Pharmacology, University of
Oxford, Oxford, UK. some. LSDs comprise a group of 70 monogenic disorders dysmorphia due to bone pathology and can be associ-
2
Department of Genetics, St.
of lysosomal catabolism, most of which are inherited as ated with developmental delay or other central nervous
Jude Children’s Research autosomal recessive traits, but three are X-​linked. These system (CNS) deficits, in addition to symptoms affect-
Hospital, Memphis, TN, USA. disorders are caused by mutations in genes encoding ing other organ systems (Fig. 1; Table 1). Patients present
3
The Raymond G. Perelman lysosomal proteins, such as lysosomal glycosidases, with a continuum of disease severity that loosely corre-
Center for Cellular and proteases, integral membrane proteins, transporters, lates with the type of mutation and residual activity of
Molecular Therapeutics,
enzyme modifiers or activators. Mutations in lysosomal the mutant protein, but they are generally classified
Children’s Hospital of
Philadelphia, Philadelphia,
genes affect the function of the encoded protein, result- on the basis of the type of disorder and the age of onset of
PA, USA. ing in lysosomal malfunction and the gradual accumu- the clinical signs as congenital or infantile (which usually
4
Department of Pathology lation of substrates inside the lysosome (that is, ‘storage’), have the most severe presentation), late-​infantile, juve-
and Laboratory Medicine, which ultimately leads to cell dysfunction and cell death. nile and adult types. Diagnosis of LSDs is based on clin-
University of Pennsylvania, Of the ~1,300 genes involved in lysosomal function, ical symptoms and confirmation of increased storage or
Philadelphia, PA, USA.
many monogenic disorders have been described, includ- genetic alterations using several diagnostic tests, includ-
5
Department of Biological ing 50 enzyme deficiencies, which can be subclassified ing enzymatic analysis and single gene sequencing7.
Chemistry, David Geffen
School of Medicine, University
according to the biochemical type of stored material However, diagnosis, especially of milder cases with
of California–Los Angeles, Los (for example, the sphingolipidoses, mucopolysacchari- longer survival, is often delayed owing to clinical symp-
Angeles, CA, USA. doses and glycoproteinoses) into 7 disorders involving toms that are characteristic of other, more common
6
Office of the Clinical Director integral membrane proteins, 12 dis­orders of lysosome- conditions. More recently, next-​generation sequenc-
and Medical Genetics Branch, related organelles (LROs) and 14 disorders involving the ing, particularly whole-​exome sequencing, is becoming
National Human Genome production of lipofuscin1–6 (Table 1). routine and might reduce the time from presentation
Research Institute, NIH,
Bethesda, MD, USA.
LSDs are genetically and clinically heterogeneous dis- to diagnosis.
orders (Fig. 1; Table 1) but frequently present as paediatric Our understanding of the pathophysiology of LSDs
*e-​mail: frances.platt@
pharm.ox.ac.uk neurodegenerative diseases that are often accompanied has undergone major advances that have identified
https://doi.org/10.1038/ by visceromegaly (the enlargement of abdominal organs multiple potential clinical intervention points. Through
s41572-018-0025-4 such as the liver and spleen)7. However, depending on the the use of animal models, various therapies have been

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Table 1 | Disorders of lysosomes and LROs

Disease (gene) Onset Primary defect Presenting symptoms Approved
(Substrate/product) therapies
Sphingolipidosesa
Fabry disease (GL A) Juvenile α-​Galactosidase A • Acroparesthesias, gastroenteritis, nephropathy , ERT and CT
(males) or adult (Globotriaosylceramide) angiokeratoma in a bathing suit distribution;
(females) or cerebrovascular disease, stroke, corneal
non-​classical opacities (males): corneal verticillata,
adult (males) acroparesthesias, cerebrovascular disease
and stroke (females)
• Left ventricular hypertrophy , cardiomyopathy
and arrhythmia; proteinuria or end-​stage renal
disease without other classical symptoms; or
cerebrovascular disease with stroke or transient
ischaemic attacks. Left ventricular hypertrophy
might be the only manifestation in some cases
(males or females)
Farber Juvenile Acid ceramidase Polyarticular arthritis, joint contractures, subcutaneous S/S
lipogranulomatosis (Ceramide) nodules, hoarse voice and cherry-​red macula
(ASAH1)
Gaucher disease: Juvenile to β Glucocerebrosidase, also • Type I: hepatosplenomegaly , pancytopenia, ERT and SRT
type I, type IIb, type IIIb adult (type I), known as β-​glucosidase bone disease, degenerative arthritis and (types I, II and III),
and perinatal lethal infantile (Glucocerebroside and elevated risk of multiple myeloma (can also be none (perinatal
formb (GBA) (type II), glucosylsphingosine) asymptomatic) lethal form)
juvenile • Type II: limited psychomotor development, bulbar
(type III) and signs including stridor and swallowing difficulty,
perinatal lethal stiffened opisthotonic posture, spasticity and trismus,
(perinatal epilepsy
lethal form) • Type III: oculomotor apraxia, abnormal horizontal
saccadic eye movements and myoclonic or
generalized epilepsy
• Perinatal lethal form: hepatosplenomegaly,
pancytopenia, skin abnormalities and non-immune
hydrops fetalis
GM1 gangliosidosis: Infantile β-​Galactosidase • Type I: hypotonia, developmental regression by S/S
type Ib, type IIb and (type I), late (GM1 ganglioside, 6 months, seizures, cherry-​red macula and severe
type IIIb (GLB1) infantile to keratan sulfate and gross motor decline
juvenile (type II) oligosaccharides) • Type II: dysarthria progressing to absent speech,
and adult ataxia progressing to loss of ambulation,
(type III) progressive cognitive decline and dysostosis
multiplex (variable)
• Type III: ataxia, dystonia, dysarthria and
parkinsonism
GM2 gangliosidosis, Infantile, β-​Hexosaminidase • Infantile: hypotonia, developmental regression S/S
Tay–Sachs diseaseb juvenile and (GM2 ganglioside, before age 1 year, macrocephaly , seizures and
(HEXA) adult glycosphingolipids and cherry-red macula
oligosaccharides) • Juvenile: progressive developmental
regression in early childhood, cerebellar
ataxia and dysarthria
• Adult: cerebellar ataxia and frequent falls
beginning in teens or twenties, dysarthria and
psychosis
GM2 gangliosidosis, Infantile, β-​Hexosaminidase • Infantile: hypotonia, developmental regression before S/S
Sandhoff diseaseb juvenile and (GM2 ganglioside, age 1 year, macrocephaly , seizures and cherry-​red
(HEXB) adult GA2 glycolipid and macula
oligosaccharides) • Juvenile: progressive developmental regression in
early childhood, cerebellar ataxia, dysarthria and
sensory neuropathy
• Adult: cerebellar ataxia and frequent falls beginning
in teens or twenties, dysarthria and psychosis
sensorineuropathy
GM2 gangliosidosis, Infantile GM2 ganglioside activator Hypotonia, developmental regression, macrocephaly , S/S
GM2 activator (GM2 ganglioside and seizures and cherry-​red macula
deficiencyb (GM2A) glycosphingolipids)
Globoid cell Infantile and Galactosylceramidase • Infantile: irritability , hypotonia, spasticity , feeding HSCT (infantile
leukodystrophy, also juvenile (Galactocerebroside and difficulties and psychomotor regression onset) and S/S
known as Krabbe psychosine) • Juvenile: variable onset and progression from
diseaseb (GALC) childhood to adulthood, muscle weakness, vision loss
and intellectual regression

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Table 1 (cont.) | Disorders of lysosomes and LROs

Disease (gene) Onset Primary defect Presenting symptoms Approved
(Substrate/product) therapies
Sphingolipidosesa (cont.)
Metachromatic Late infantile, Arylsulfatase A and • Late infantile: ataxia, weakness, loss of speech and HSCT
leukodystrophyb juvenile and prosaposin cherry-​red macula
(ARSA and PSAP) adult (Sulfatides) • Juvenile: behavioural problems and psychomotor
regression
• Adult: behavioural problems, psychiatric symptoms
and cognitive decline
Niemann–Pick Infantile Sphingomyelin • Infantile: hepatosplenomegaly , failure to thrive, S/S
disease types Ab (type A) and phosphodiesterase psychomotor regression, interstitial lung disease and
and B (SMPD1) juvenile (type B) (Sphingomyelin) cherry-​red macula
• Juvenile: hepatosplenomegaly , recurrent pulmonary
infections, thrombocytopenia, short stature and
neurological impairment
Mucopolysaccharidosesa
MPS I: Hurler Infantile α-​L-Iduronidase Coarse facial features, hepatosplenomegaly , hernias, HSCT (Hurler) and
syndromeb, (Hurler) and (Dermatan sulfate and corneal clouding, frequent otitis media, cognitive ERT (Hurler–Scheie
Hurler–Scheie juvenile heparan sulfate) decline (except attenuated forms) and dysostosis and Scheie)
syndrome and Scheie (Hurler–Scheie multiplex
syndrome (IDUA) and Scheie)
MPS II, also known as Infantile, Iduronate 2-sulfatase Coarse facial features, hepatosplenomegaly , dermal ERT
Hunter syndromeb,c juvenile (acute) (Dermatan sulfate and pebbling, frequent otitis media, hernias, no corneal
(IDS) and juvenile heparan sulfate) clouding, spinal stenosis and dysostosis multiplex
(attenuated)
MPS IIIA, also Late infantile N-​Sulfoglucosamine Behavioural difficulties, sleep disturbance, progressive S/S
known as Sanfilippo sulfohydrolase intellectual disability , coarse facial features,
syndrome Ab,c (SGSH) (Heparan sulfate) macrocephaly , hepatosplenomegaly , hernias and mild
dysostosis multiplex
MPS IIIB, also Juvenile N-​Acetyl-α-glucosaminidase Similar to MPS IIIA S/S
known as Sanfilippo (Heparan sulfate)
syndrome Bb,c
(NAGLU)
MPS IIIC, also Juvenile Heparan-​α-glucosaminide- Similar to MPS IIIA S/S
known as Sanfilippo N-​acetyltransferase
syndrome Cb,c (Heparan sulfate)
(HGSNAT)
MPS IIID, also Juvenile N-​acetylglucosamine-6- Similar to MPS IIIA S/S
known as Sanfilippo sulfatase
syndrome Db,c (GNS) (Heparan sulfate)
MPS IVA, also Late infantile N-acetylgalactosamine- Short stature, severe skeletal dysplasia, ERT
known as Morquio 6-sulfatase (Keratan sulfate hyperextensible joints, odontoid hypoplasia, corneal
syndrome A (GALNS) and chondroitin 6-sulfate) clouding and hernias
MPS IVB, also Late infantile β-​Galactosidase Similar to MPS IVA S/S
known as Morquio and juvenile (Keratan sulfate)
syndrome B (GLB1)
MPS VI, also known Late infantile Arylsulfatase B Skeletal dysplasia, short stature, contractures, ERT
as Maroteaux–Lamy and juvenile (Dermatan sulfate) macrocephaly , hernias, macroglossia,
syndrome (ARSB) hepatosplenomegaly , sleep apnoea and corneal
clouding
MPS VII, also known Infantile and β-​Glucuronidase • Infantile: hydrops fetalis ERT
as Sly diseaseb late infantile (Dermatan sulfate, heparan • Late infantile: macrocephaly , hydrocephalus,
(GUSB) sulfate and chondroitin coarse facial features, macroglossia,
6-sulfate) hepatosplenomegaly , heart valve abnormalities,
hernias, corneal clouding, recurrent otitis media,
progressive intellectual disability but not in all
patients (late infantile)
MPS IX (HYAL1) Juvenile Hyaluronidase 1 Periarticular soft tissue masses, mild short S/S
(Hyaluronan) stature, acetabular erosion and recurrent
otitis media
Glycogen storage disease (GSD)a
GSD II, also known as Infantileb and Lysosomal α-​glucosidase, • Infantile: cardiomegaly and severe hypotonia. ERT
Pompe disease (GAA) adult also known as acid maltase • Adult: muscle weakness and atrophy , including of the
(Glycogen) diaphragm

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Table 1 (cont.) | Disorders of lysosomes and LROs

Disease (gene) Onset Primary defect Presenting symptoms Approved
(Substrate/product) therapies
Glycoproteinosesa
α-​Mannosidosisb: Infantile and Lysosomal α-​mannosidase • Type I: mild skeletal deformities and cognitive ERT
type I mild, type II juvenile (Mannose-​rich impairment
moderate and type III oligosaccharides) • Type II: dysmorphic facial features, immune
severe (MAN2B1) deficiency , dysostosis multiplex, ataxia and
progressive cognitive impairment
• Type III: severe skeletal abnormalities in
early infancy , progressive psychomotor
deterioration
β-​Mannosidosisb Juvenile and β-​Mannosidase Intellectual disability and speech impairment, S/S
(MANBA) adult (Man(β1>4)N-​ angiokeratoma, hypotonia, behavioural disturbance
acetylglucosamine)
Fucosidosisb (FUCA1) Infantile, late α-l-Fucosidase Clinical spectrum ranging from severe neurological S/S
infantile and (Fucose-rich deterioration and death in childhood to milder
juvenile oligosaccharides, psychomotor deterioration, angiokeratoma, anhidrosis
glycoproteins and and dysostosis multiplex
glycolipids)
Aspartylglucos­ Juvenile Aspartoglucosaminidase Progressive intellectual disability , dysmorphic S/S
aminuriab (AGA) (Aspartylglucosamine) facial features, recurrent respiratory infections,
hepatomegaly , diarrhoea, mild dysostosis multiplex,
seizures and movement disorder into adulthood
Schindler disease: Infantile α-​N-Acetyl-​ • Type I: rapid psychomotor deterioration and seizures S/S
type Ib, also known (type I), adult galactosaminidase • Type II: mild cognitive impairment, sensorineural
as infantile-onset (type II) and (Sialylated or asialo hearing loss and angiokeratomas
neuroaxonal juvenile (type III) glycopeptides and • Type III: developmental delay , seizures,
dystrophy , type IIb glycosphingolipids) cardiomyopathy , hepatomegaly and autism spectrum
also known as disorder
Kanzaki disease,
and type IIIb,
intermediate severity
(NAGA)
Sialidosis type I, also Adult Neuraminidase-1 Gait disturbance and ataxia due to myoclonus, S/S
known as cherry-red (Sialylated oligosaccharides reduced visual acuity , cherry-​red macula, seizures and
spot myoclonus and glycopeptides) preserved cognition
syndrome (NEU1)
Sialidosis type II, Congenital, Neuraminidase-1 Hydrops fetalis, neonatal ascites, S/S
also known as infantile and (Sialylated oligosaccharides hepatosplenomegaly , spectrum of intellectual disability ,
mucolipidosis Ib juvenile and glycopeptides, L AMP1 dysostosis multiplex, coarse facial features, short
(NEU1) and amyloid precursor stature, hearing loss, hypotonia, gingival hyperplasia,
protein) flat nasal widely spaced teeth, cherry-​red macula,
myoclonus, ataxia, tremor and angiokeratoma
Galactosialidosis Early infantile, Protective protein • Early infantile: hydrops fetalis, inguinal hernia, S/S
(CTSA) late infantile, cathepsin A, and a hepatosplenomegaly , dysostosis multiplex, coarse
juvenile or secondary deficiency facial features, cardiomegaly , cherry-​red macula,
adult in β-​galactosidase renal disease
and neuraminidase-1 • Late infantile: short stature, dysostosis
(Sialylated oligosaccharides multiplex, cardiac valve abnormalities,
and glycopeptides, L AMP2 hepatosplenomegaly , coarse facial features,
and bioactive peptides) mild or no intellectual disability , hearing loss and
cherry-red macula
• Juvenile or adult: ataxia, myoclonus,
seizures, progressive intellectual disability ,
angiokeratomas, spinal anomalies, vision and
hearing loss
Lipid storage diseases
Acid lipase Infantile, Lysosomal acid lipase/ • Infantile: hepatosplenomegaly , jaundice, ERT
deficiency: Wolman juvenile and cholesteryl ester hydrolase failure to thrive, vomiting, diarrhoea,
diseaseb and adult (Cholesteryl esters, malabsorption, calcification of the adrenal
cholesterol ester triglycerides and other glands, anaemia, developmental delay and
storage disease lipids) multiorgan failure
(LIPA) • Juvenile and adult: hepatosplenomegaly , liver
fibrosis, malabsorption, high cholesterol levels and
atherosclerosis at an early age with increased risk of
heart attack or stroke

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Table 1 (cont.) | Disorders of lysosomes and LROs

Disease (gene) Onset Primary defect Presenting symptoms Approved
(Substrate/product) therapies
Post-​translational modification defects
Multiple sulfatase Infantile, late Formylglycine-​generating • Infantile: seizures, severe psychomotor retardation, S/S
deficiency (SUMF1) infantile and enzyme coarse facial features, ichthyosis, hypertrichosis,
juvenile (Sulfatides) dysostosis multiplex and hepatosplenomegaly
• Late infantile: normal early development followed by
developmental plateau then regression, ichthyosis,
dysostosis multiplex and coarse facial features
• Juvenile: typical until middle to late childhood
then plateau and psychomotor regression over a
prolonged period and ichthyosis
Mucolipidosis II α/β, Infantile N-​Acetylglucosamine- Growth deficiency beginning at birth, coarse facial S/S
I-cell diseaseb 1-phosphotransferase features, gingival hypertrophy , recurrent otitis media,
(GNPTAB) subunits α/β cardiac valvular disease, recurrent pneumonia, hernias,
(Oligosaccharides, severe psychomotor retardation, hepatosplenomegaly
glycosaminoglycans and and severe dysostosis multiplex with kyphosis,
glycosphingolipids) clubfoot and joint deformity
Mucolipodosis II α/β, Late infantile N-​Acetylglucosamine-1- Short stature, dysostosis multiplex, joint contractures, S/S
pseudo-​Hurler or juvenile phosphotransferase subunits variable intellectual disability , thickened skin and
polydystrophy α/β (Oligosaccharides, restrictive lung disease
(GNPTAB) glycosaminoglycans and
glycosphingolipids)
Mucolipidosis III γ, Juvenile or N-Acetylglucosamine-1- Short stature, aortic valve abnormalities, dysostosis S/S
variant pseudo-​ adult phosphotransferase multiplex and normal to near-​normal intelligence
Hurler polydystrophy subunit γ (Oligosaccharides,
(GNPTG) glycosaminoglycans and
glycosphingolipids)
Integral membrane protein disorders
Cystinosis (CTNS) Infantile or Cystinosin Renal tubular Fanconi syndrome, renal failure, SMT
juvenile (Cystine) failure to thrive, photophobia, corneal crystals,
hypophosphataemic rickets, light pigmentation, heat
intolerance, primary hypothyroidism and myopathy
Danon diseaseb Juvenile or L AMP2 Cardiomyopathy , myopathy , intellectual disability with S/S
(L AMP2) adult and (Cytoplasmic debris and males more severely affected than females and cardiac
sex-​linked glycogen) arrhythmia
dominant
Action Adult Lysosomal integral Tremor, action myoclonus, peripheral neuropathy , S/S
myoclonus-renal membrane protein sensorineural hearing loss and proteinuria
failure syndromeb (Unknown)
(SCARB2)
Sialic acid storage Congenital Sialin • Congenital: hydrops fetalis, developmental delay , S/S
disease: ISSDb, (ISSD) and (Sialic acids) hypotonia, failure to thrive, coarse facies, seizures,
Salla diseaseb infantile to late hepatosplenomegaly and cardiomegaly
and intermediate infantile (Salla) • Infantile to late infantile: hypotonia, intellectual
severity Salla disability , seizures, ataxia, spasticity and athetosis
diseaseb (SLC17A5)
Niemann–Pick Juvenile NPC intracellular Ataxia, vertical supranuclear gaze palsy , dystonia, SRT
disease types C1 and cholesterol transporter 1 liver disease, splenomegaly, interstitial lung disease,
C2 (NPC1 and NPC2)
b
and 2 (Cholesterol and difficulty swallowing, intellectual decline and seizures
sphingolipids)
Mucolipidosis IVb Infantile Mucolipin 1 Psychomotor delay , hypotonia, spasticity , corneal S/S
(MCOLN1) (Lipids and clouding, retinopathy , achlorhydria and iron deficiency
mucopolysaccharides) anaemia
Neuronal ceroid lipofuscinoses
CLN1: Infantile, Palmitoyl-​protein • Infantile: developmental regression by 18 months, S/S
Haltia–Santavuori juvenile or thioesterase 1 hypotonia, deceleration of head growth and cerebral
disease and INCLb adult (Lipidated thioesters and atrophy , myoclonus, epilepsy and vision loss
(PPT1) saposins A and D) • Juvenile: Intellectual decline in childhood, myoclonus,
epilepsy and vision loss
• Adult: ataxia and parkinsonism
CLN2, also known as Late infantile Tripeptidyl peptidase 1 • Late infantile: intractable epilepsy , cognitive arrest, ERT
Jansky–Bielschowsky or juvenile (Subunit c of mitochondrial myoclonus and ataxia
diseaseb (TPP1) ATP synthase) • Juvenile: severe ataxia but milder developmental
decline and myoclonus

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Table 1 (cont.) | Disorders of lysosomes and LROs

Disease (gene) Onset Primary defect Presenting symptoms Approved
(Substrate/product) therapies
Neuronal ceroid lipofuscinoses (cont.)
CLN3, also known as Juvenile Battenin Progressive visual loss, developmental regression and S/S
Batten–​Spielmeyer– (Subunit c of mitochondrial later hypokinesia including muscle rigidity and slow or
Sjogren diseaseb ATP synthase) diminished movements
(CLN3)
CLN4: Parry disease Adult Cysteine string protein • Kufs type A: marked myoclonus, progressive epilepsy , S/S
and Kufs type A (Subunit c of mitochondrial dementia, ataxia
and Bb (DNAJC5) ATP synthase) • Kufs type B: behavioural changes, dementia, facial
dyskinesia
CLN5: Finnish variant Late infantile, Ceroid-​lipofuscinosis Developmental regression, myoclonic epilepsy , ataxia S/S
late infantileb (CLN5) juvenile or neuronal protein 5 and vision loss
adult (lysosomal protein of
unknown function)
(Subunit c of mitochondrial
ATP synthase)
CLN6: Lake–​ Juvenile or Transmembrane ER protein • Juvenile: developmental regression, epilepsy , ataxia, S/S
Cavanagh or Indian adult (Kufs A) (Subunit c of mitochondrial myoclonus, dysarthria and vision loss
variantb (CLN6) ATP synthase) • Adult: ataxia, epilepsy , dysarthria and
progressive loss of intellectual function
without visual loss
CLN7: Turkish Late infantile Major facilitator superfamily Epilepsy , developmental regression, myoclonus, ataxia, S/S
variantb (MFSD8) or juvenile domain containing 8 speech impairment and vision loss
(Subunit c of mitochondrial
ATP synthase)
CLN8: northern Late infantile Protein CLN8 • Late infantile: developmental delay with S/S
epilepsy , epilepsy or juvenile (Subunit c of mitochondrial progressive myoclonus, seizures, retinopathy and
mental retardationb ATP synthase) regression
(CLN8) • Juvenile: intractable epilepsy with progressive
decline
CLN9b (N/A) Juvenile N/A Clinically indistinguishable from CLN3 but more-​rapid S/S
course
CLN10b (CTSD) Congenital, Cathepsin D • Congenital: microcephaly , neonatal epilepsy , S/S
late infantile, (Saposins A and D) respiratory insufficiency and rigidity
juvenile or • Late infantile, juvenile or adult: ataxia, visual loss and
adult cognitive decline
CLN11b (GRN) Adult Granulin Progressive visual loss, seizures, cerebellar ataxia and S/S
(Unknown) atrophy
CLN12b: Kufor–Rakeb Juvenile Cation-​transporting ATPase Mood disturbance, akinesia, rigidity and dysarthria S/S
syndrome or PARK9 13A2
(ATP13A2) (Inorganic cations)
CLN13b (CTSF) Adult (Kufs B) Cathepsin F (Unknown) Behavioural abnormalities and dementia S/S
CLN14b (KCTD7) Infantile Potassium channel Progressive myoclonic epilepsy , abnormal eye S/S
tetramerization domain movements and developmental regression
containing 7 (Unknown)
LRO disorders
Hermansky–Pudlak Infantile BLOC3 subunit 1 Oculocutaneous albinism, easy bruising, prolonged S/S
disease type 1 (HPS1) (LRO biogenesis) bleeding and pulmonary fibrosis
Hermansky–Pudlak Infantile AP-3 complex subunit β1 Oculocutaneous albinism, easy bruising and S/S
disease type 2 (HPS2) (Protein sorting) pulmonary fibrosis
Hermansky–Pudlak Infantile BLOC2 subunit 1 (Protein Oculocutaneous albinism and easy bruising S/S
disease type 3 (HPS3) sorting and/or transport)
Hermansky–Pudlak Infantile BLOC3 subunit 2 Oculocutaneous albinism, easy bruising and S/S
disease type 4 (HPS4) (LRO biogenesis) pulmonary fibrosis
Hermansky–Pudlak Infantile BLOC2 subunit 2 Oculocutaneous albinism and easy bruising S/S
disease type 5 (HPS5) (Retrograde lysosomal
trafficking)
Hermansky–Pudlak Infantile BLOC2 subunit 3 Oculocutaneous albinism and easy bruising S/S
disease type 6 (HPS6) (Retrograde lysosomal
trafficking)

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Table 1 (cont.) | Disorders of lysosomes and LROs

Disease (gene) Onset Primary defect Presenting symptoms Approved
(Substrate/product) therapies
LRO disorders (cont.)
Hermansky–Pudlak Infantile Dysbindin Oculocutaneous albinism and easy bruising S/S
disease type 7 (HPS7) (LRO biogenesis)
Hermansky–Pudlak Infantile BLOC1 subunit 3 Oculocutaneous albinism and easy bruising S/S
disease type 8 (HPS8) (HPS8)
Hermansky–Pudlak Infantile BLOC1 subunit 6 Oculocutaneous albinism and easy bruising S/S
disease type 9 (HPS9) (Vesicular trafficking)
Griscelli syndrome 1, Infantile Unconventional myosin Va, Hypopigmentation, silvery-​grey hair, developmental S/S
also known as also known as motor delay , seizures, hypotonia and visual impairment
Elejalde syndrome myosin
(MYO5A) (LRO transport)
Griscelli syndrome 2 Infantile Ras-​related protein Hypopigmentation, silvery-​grey hair, recurrent S/S
(RAB27A) Rab-27A (LRO transport) infection and haemophagocytic lymphohistiocytosis
Chédiak–Higashi Infantile, Lysosomal trafficking Recurrent infection, oculocutaneous albinism, HSCT
diseaseb (LYST) juvenile or regulator easy bruising and abnormal bleeding, progressive
adult (Size and movement of neurological problems of tremor, ataxia, peripheral
lysosomes) neuropathy and cognitive decline
BLOC, biogenesis of lysosome-​related organelles complex; CNS, central nervous system; CT, chaperone therapy ; ER , endoplasmic reticulum; ERT, enzyme
replacement therapy ; GM1, GM1-ganglioside; HSCT, haematopoietic stem cell therapy ; INCL , infantile neuronal ceroid lipofuscinosis; ISSD, infantile sialic
acid storage disease; LAMP1, lysosome-associated membrane glycoprotein 1; LROs, lysosome-​related organelles; N/A, not applicable; PARK9, Parkinson disease 9;
SMT, small-​molecule therapy ; SRT, substrate reduction therapy ; S/S, symptomatic and supportive therapy. aDenotes enzyme deficiency disorders. bDenotes
diseases that involve the CNS. cDenotes disorders with severe and attenuated forms. Presenting signs and symptoms taken from GeneReviews197, Genetics Home
Reference and clinical experience.

evaluated in vivo and have progressed to clinical trials example, CLN5 and CLN8) and other genetic isolates
and regulatory approval. Enzyme replacement therapy owing to founder effects10. These values are undoubt-
(ERT) to restore defective enzymes is the cornerstone of edly underestimates, as calculations of incidence pre-
current treatment paradigms for some LSDs, but small-​ sume that all cases are ascertained or that accurate
molecule therapies that reduce storage by inhibiting the carrier frequencies are known. Although these factors
production of the stored substrates are also approved and are known for the more severe subtypes of LSDs with
are an expanding area of drug development. Nucleic-​ infantile presentations, such as Tay–​Sachs disease in the
acid-based medicines (such as gene replacement, anti- Ashkenazi Jewish population, it might not be the case
sense oligonucleotide (ASO) therapies or gene editing) for LSDs that occur in individuals of all ethnicities, or
are also emerging. As more treatments for LSDs become juvenile-​onset and adult-​onset LSDs, whereby many
available, adding these conditions to newborn screening individuals are diagnosed up to decades after symptom
panels should speed the diagnosis, improve the clinical onset and some individuals never receive a diagnosis.
care of patients and aid in the prevention of LSDs in Despite a low incidence of individual LSDs in general,
subsequent pregnancies. the incidence can be higher in specific ethnicities, often
This Primer provides an overview of the LSDs and owing to a founder effect (Table 2). For example, aspar-
the epidemiology and genetics of these disorders as well tylglucosaminuria (one of the glycoproteinoses) is a rare
as current insights into their pathophysiology and the condition worldwide (the exact incidence is estimated as
present status of therapies. <0.2 cases per 100,000 individuals) that is common in
the Finnish population (estimated carrier frequency of
Epidemiology 2.3–3%) owing to a founder effect and genetic isolation11.
Incidence and prevalence Similarly, Hermansky–Pudlak syndrome (a LRO disor-
As a group, LSDs are common, with an estimated inci- der) is found in 1 in 500,000 individuals worldwide but
dence of 1 in 5,000 to 1 in 5,500 for LSDs that involve in ~1 in 1,800 residents of northwestern Puerto Rico12,13.
lysosomal enzyme or integral membrane protein defects;
however, individual LSDs are rare, with estimated inci- Effect of survival and treatment
dences ranging from 1 in 50,000 to 1 in 250,000 live The prevalence of an LSD is determined by the incidence
births8. The most common LSDs are Fabry disease and the average survival for that disorder. The advent
(up to 2.5 cases per 100,000 males), Gaucher disease (up to of approved therapies for some LSDs and/or more-​
2 cases per 100,000 individuals), metachromatic leu- effective supportive care for patients, most notably the
kodystrophy (up to 2.5 cases per 100,000 individuals) use of feeding tubes and better pulmonary hygiene,
and Pompe disease (up to 2.5 cases per 100,000 indivi­ have increased survival in resource-​rich countries and
duals)9. In addition, the neuronal ceroid lipofuscinoses might increase disease prevalence. Before the approval
(NCLs) are relatively common, with an incidence of of ERT, 12.3% of infants with Pompe disease survived
1 case per 100,000 individuals in the general popu- to 18 months of age, but in the initial ERT trial, all
lation, but have a higher incidence in Finland (for 18 children treated with ERT before 6 months of age were

NATUre RevIewS | DISeASe PRImeRS | Article citation ID: (2018) 4:27 7
Primer

Hair Immune deficiency Eye

HPS1, HPS2, HPS3, HPS4, HPS5, HPS6, HPS7, HPS8, MAN2B1 and RAB27A GLB1, GLA, IDUA, GALNS, ARSB, GUSB, NAGA, CTSA, CTNS,
HPS9, MYO5A, RAB27A and CTSA NPC1, NPC2, MCOLN1, HPS1, HPS2, HPS3, HPS4, HPS5, HPS6,
HPS7, HPS8, HPS9, MYO5A, LYST, CLN3, CLN5, CLN8, CLN9,
CTSD, GRN, KCTD7, NEU1, TPP1, GALC, HEXA, HEXB and GM2A
Brain
GLA, GBA, GLB1, HEXB, HEXA, GM2A, ARSA, PSAP,
SMPD1, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS,
GUSB, MAN2B1, MANBA, FUCA1, AGA, NAGA,
NEU1, CTSA, GNPTAB, LAMP2, SCARB2, SLC17A5, Thyroid Tongue
NPC1, NPC2, MCOLN1, MYO5A, LYST, PPT1, TPP1, CTNS and CTSA IDUA, IDS, ARSB and GUSB
CLN3, DNAJC5, CLN5, CLN6, MFSD8, CLN8, CLN9,
CTSD, GRN, ATP13A2, CTSF, KCTD7 and GALC
Heart
GLA, IDUA, IDS, SGSH, NAGLU, GUSB, GAA, NAGA, CTSA,
Ear GNPTAB, GNPTAG, LAMP2, SLC17A5, GLB1, CLN3 and ARSB
IDUA, IDS, GALNS, ARSB, GUSB, HYAL1, NAGA,
CTSA, GNPTAB, SCARB2 and NEU1
Hepatosplenomegaly
Lung Kidney GBA, SMPD1, IDUA, IDS, SGSH,
SMPD1, AGA, GNPTAB, NPC1, NPC2, HPS1, HPS2 GLA, CTNS, NAGLU, HGSNAT, GNS, ARSB, AGA,
and HPS4 SCARB2, NEU1 NAGA, CTSA, GNPTAB, SLC17A5,
and CTSA NPC1 and NPC2

Peripheral nervous system

GLA, HEXB, SCARB2 and LYST Coarse facies
IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GUSB, MAN2B1,
Gastrointestinal system AGA, NAGA, CTSA, GNPTAB, SLC17A5, GUSB and GALNS
GLA, ST3GAL5 and MCOLN1

Muscle Joint Skin

GAA, CTNS, LAMP2 and NEU1 ASAH1, GLB1, IDUA, GLA, ASAH1, IDS, MANBA, FUCA1,
IDS, SGSH, NAGLU, NAGA, CTSA, CTNS, HPS1, HPS2,
Haematologic HGSNAT, GNS, GALNS HPS3, HPS4, HPS5, HPS6, HPS7,
GBA, SMPD1, MCOLN1, HSP1, HSP2, HSP3, HSP4, and ARSB HPS8, HPS9, RAB27A, LYST and GBA
HSP5, HSP6, HSP7, HSP8, HSP9, RAB27A and LYST
Skeletal
Hernias GLB1, DBA, SMPD1, IDUA, IDS, SGSH, NAGLU, HGSNAT,
IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, GNS, GALNS, ARSB, HYAL1, MAN2B1, FUCA1, NAGA,
GLB1, ARSB, GUSB, CTSA and GNPTAB CTSA, GNPTAB, GNPTAG, CTNS and NEU1

Genetic mutations that cause specific clinical manifestations

Genetic mutations that cause non-specific symptoms

Fig. 1 | Organs affected in disorders of lysosomes and LROs. Mutations in genes causing lysosomal storage diseases
(LSDs) can be associated with symptoms in specific organs. Despite profound neurological involvement in many LSDs,
involvement of multiple organ systems is frequent. Blue-​shaded boxes relate to specific organs as indicated, whereas
yellow-​shaded boxes reflect symptoms that are not specific to one organ system. The specific LSDs associated with each
genetic mutation can be found in Table 1; note this figure is not exhaustive. LRO, lysosome-​related organelle.

alive at 18 months14,15. ERT, although life-​saving, was not As treatments become available for more LSDs,
definitive, and secondary complications of the disease clinicians should be alert to ‘secondary phenotypes’ that
have occurred in most patients receiving this therapy might require additional therapeutic interventions.
alone16. In addition, even in the absence of approved
therapy, infants with Tay–​Sachs disease who historically Mechanisms/pathophysiology
died at 1.5 years of age now survive to an average of General mechanisms
5–6 years of age owing to better supportive therapy17. Lysosomes are responsible for the breakdown and
In general, LSDs affect multiple organ systems but recycling of macromolecules (including carbohy-
have one defining system predominating, such as hyper- drates, lipids, nucleic acids and proteins) and function
trophic cardiomyopathy in patients with infantile Pompe as metabolic hubs that control nutrient sensing, amino
disease, CNS deficits in children with CNL2 or hepato­ acid and ion homeostasis and calcium signalling22–24.
splenomegaly in children with Gaucher disease type I. These organelles are constantly in a dynamic state;
For Pompe disease and Gaucher disease, the major com- they fuse with autophagosomes, phagosomes and the
plications have been mitigated with approved therapy, plasma membrane and therefore have a pivotal role
and the CNS deficits can be slowed in CNL2 (ref.18). in cell–cell and cell–extracellular matrix communi-
However, additional complications have been reported cation, response to infection and maintenance of cell
owing to this increased survival, such as oro-motor defi- homeostasis22,23 (Fig. 2). In addition, late endosomes and
ciencies and diaphragm weakness in Pompe disease19–21. lysosomes tether with other intracellular organelles

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 Primer

without fusing with them, such as mitochondria and are spared in associated LSDs, whereas other neurons
the endoplasmic reticulum, forming functional mem- will store these macromolecules, leading to neuronal
brane contact sites. These membrane structures are damage and death. Circulating monocytes and tissue
signalling microdomains that allow the transfer of macrophages (forming the mononuclear phagocytic
lipids and the exchange of metabolites and calcium system) are the primary cells affected in most LSDs
ions between the organelles24–26. The lipid and protein owing to their role in the phagocytic clearance of cellular
composition of these contact sites drives their func- debris, apoptotic or necrotic cells and microorganisms,
tional characteristics and influences each of the teth- and the impaired catabolism of products they themselves
ered organelles. For instance, mitochondria–lysosome synthesize. These cells have a central role in immune
contact sites modulate mitochondrial fission and lyso- responses and inflammatory processes that can be elic-
somal dynamics through GTP hydro­lysis of Ras-​related ited by loss of cell integrity and homeostasis in LSDs28;
protein Rab7a (RAB7; also known as RAB7A)27. Thus, indeed, the storage of macromolecules by macrophages
it is understandable that in an LSD, the biochemical in LSDs triggers inflammation that actively contributes
properties and in turn the functions of these micro- to disease progression29.
domains might be altered by changes in composition Substrate accumulation inside lysosomes can initi-
of the endosomal and lysosomal membranes due to ate a cascade of secondary effects, ultimately leading to
impaired lysosomal activity25,26. irreversible cellular damage, cell death as well as organ
As previously mentioned, mutations in genes encod- dysfunction and degeneration. Given the complexity of
ing lysosomal proteins, including lysosomal hydrolases, the clinical presentations and the broad range of accu-
lysosomal membrane proteins, lipid and ion transport- mulated macromolecules in LSDs, many of which are
ers, enzyme modifiers or activators, are the cause of still unknown, defining pathogenetic pathways that
LSDs. Mutations in these genes lead to the aberrant pro- are potentially common to all disorders is challenging.
cessing and degradation of substrates, impaired trans- However, in general terms, several common pathways
port of lipids and metabolites and progressive primary are dysregulated, including deficits in cellular trans-
accumulation of non-​degraded or partially degraded port and degradation (such as autophagy, endocytosis,
macromolecules inside lysosomes. The secondary stor- phagocytosis and lysosomal exocytosis), calcium
age of substrates can also occur in LSDs resulting from homeostasis, oxidative stress, inflammatory and innate
defects in non-​enzymatic lysosomal proteins (for exam- immune responses and cell death pathways (includ-
ple, transporters); although the mechanisms leading to ing apoptosis and in some instances necroptosis)30,31.
secondary storage are not fully understood, it might be In addition, general mechanisms of disease progres-
the result of trafficking defects. The biochemical type sion include chronic inflammation, including neuro–
of the stored macromolecules differentially affects lyso­ inflammation, which is linked to cellular dysfunction
some function as different macromolecules have roles in and death, and autoimmune responses to specific self-​
specific cellular processes, which underlies the variable antigens or accumulated metabolites28. Several stud-
clinical pathology of LSDs. Cells can store substrates ies have shown that the activation of innate immune
and/or metabolites only if the cell in question synthe- cells, such as microglia in the brain and macrophages
sizes or ingests these molecules. For example, glyco- in the periphery, actively contributes to LSD progres-
sphingolipid expression is variable in the CNS; some sion32–34. For example, in response to stress signals (that
neuronal populations cannot store these molecules and is, damage-​associated molecular patterns) of dying or
damaged neurons via pattern recognition receptors,
activated microglia release cytokines and chemokines to
Table 2 | Increased incidence of LSDs in specific populations before carrier screening recruit immune cells at affected sites or to activate neigh-
Disorder Region or population Incidence bouring neural cells in a paracrine and/or autocrine
(per 100,000 manner, hence amplifying the inflammatory response35.
individuals) In line with these findings, anti-​inflammatory therapies
Gaucher disease type I Ashkenazi Jews 100 (ref.9) have demonstrated benefits in some animal models of
LSDs34,36 (such as Niemann–Pick disease type C (NPC)
Tay–Sachs disease (infantile) Ashkenazi Jews 25 (ref.114)
and Sandhoff disease), and trials of biological agents that
Niemann–Pick disease type A Ashkenazi Jews 2.5 (ref.9) target tumour necrosis factor (TNF) are in clinical tri-
GM1 gangliosidosis Rudari isolate 10 (ref.198) als in some forms of mucopolysaccharidosis (MPS; see
Metachromatic leukodystrophy Western Navajo Nation 40 (ref.199) Management). In addition, adaptive immune responses
(for example, autoantibody production) have been
Pompe disease The Netherlands 2.5 (ref.200)
described in some LSDs37, and the precise pathophys-
Cystinosis Brittany 3.8 (ref.201) iological role of a dysregulated immune system mer-
Salla disease Finland or Sweden 2.5 (ref.202) its greater investigation as it is a potentially tractable
Aspartylglucosaminuria Finland 54 (ref.12) therapeutic target.
Notably, the common secondary pathways of LSDs
Niemann–Pick disease type C Nova Scotia 100 (ref.203)
(French Acadian) have also been implicated in other, more common adult
conditions that are mostly associated with ageing, includ-
Fabry disease Nova Scotia 9.3a ing cancer and neurodegenerative diseases. Moreover,
Hermansky–Pudlak (types 1 and 3) Puerto Rico 56 (refs13,14) unexpected roles of lysosomal enzymes and their sub-
a
M. West, personal communication. GM1, GM1-ganglioside; LSD, lysosomal storage disease. strates have been demonstrated in cellular pathways and

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Primer

Exocytosis
LYNUS machinery
Mature LRO
Lysosomal membrane SLC38A9
proteins
V-type Transporters
H+ ATPase
Lysosome LAMP2

Cytosol NPC1
Late endosome
Pre-LRO MVB
Early Lysosome membrane
LAMP1 ?
endosome Glycocalyx Lumen
Golgi
LIMP1

Recycling Microtubules
endosome
Traffic and
MCOLN1
fusion proteins

Hydrolases
Proteases: cathepsins Ion channels
Glycosidases
Biogenesis
Lipases Nucleases
Cargo transport

Fig. 2 | Complexity of lysosomal proteins and their functions. Lysosomes are involved in the breakdown and recycling of
several cellular macromolecules, including nucleic acids, lipids, proteins and carbohydrates, through the action of lysosomal
hydrolases. Substances are delivered to the lysosome for degradation via fusion with late endosomes (extracellular
material) or autophagosomes (intracellular material); a process that is mediated by SNARE (soluble N-​ethylmaleimide-
sensitive factor activating protein receptor) and Rab proteins (traffic and fusion proteins). Lysosomes can be transported to
required cellular compartments via microtubules such as dynein and kinesins and actin-​based motor myosins193.
Transporters such as NPC1, sodium-​coupled neutral amino acid transporter 9 (SLC38A9) and lysosome-​associated
membrane protein 2 (L AMP2) are responsible for the transport of substrates between the lysosome and the cytoplasm.
NPC1 facilitates the transport of lipid substrates and amines, SLC38A9 transports arginine and L AMP2 transports cytosolic
substrates. Ion channels, including mucolipin 1 (MCOLN1), act to regulate the ionic environment of lysosomes and
contribute to cell signalling. The lysosomal nutrient-​sensing (LYNUS) machinery is composed of protein complexes that
sense lysosomal nutrient composition and transfer signals to the nucleus. Lysosomal membrane proteins are involved in
lysosome–plasma membrane docking (L AMP1) and the sorting of lysosomal enzymes (such as lysosome membrane protein 1
(LIMP1)). L AMP1 binds to motor myosin, which is, in turn, speculated to bind to microtubules (denoted by ?). Illustrative
examples of lysosomal proteins are provided. Solid arrows reflect organelle maturation and/or biogenesis and dashed
arrows represent the movement of macromolecular cargo. LRO, lysosome-related organelle; MVB, multivesicular body.
Adapted with permission from ref.103, Annual Reviews.

regulatory networks that go beyond canonical lysosomal and glucosylsphingosine (GlcSph). GlcCer and GlcSph
degradation or recycling38,39. Importantly, this research accumulate in mononuclear phagocytes (due to the phago-
led to the discovery of parallel mechanisms between rare, cytic activity of these cells), primarily macrophages, which
paediatric LSDs and common, adult diseases, includ- have a foamy appearance and are referred to as Gaucher
ing age-​related neurodegenerative diseases (such as, cells51,52. Investigations into the chronic inflammation and
Parkinson disease (PD) and Alzheimer disease (AD)), in haematologic abnormalities in patient-​derived primary
addition to fibrosis and cancer40–45. These findings have macrophages53 have identified defects in macroautophagy
fostered the development of improved model systems and degradation, but not the initial uptake, of apoptotic
used to evaluate pathogenesis and new treatments for or necrotic cells (efferocytosis)49, likely as a result of gly-
LSDs, including models using patient-​derived induced cosphingolipid storage54,55. In acute and chronic Gaucher
pluripotent stem cells46–48 differentiated into specific cel- disease types II and III, which are neuropathic, microglial
lular lineages49,50. Overall, research into LSDs has sparked activation and neuroinflammation have been associated
the development of therapies that might benefit both with neuronal dysfunction and neuronal loss in the brain
patients with LSDs and those with other disorders. Below, and spinal cord56,57. The mechanism of neuronal loss and
we give some illustrative examples of LSDs in which fairly inflammation in murine models of Gaucher disease is
detailed pathogenetic pathways have been elucidated. deregulated processing and release of pro-​inflammatory
cytokines (that is, IL-1α, IL-1β, TNF, IL-6, CXC-​chemokine
Gaucher disease ligand 10 (CXCL10) and type I interferon58,59), altered
Gaucher disease, a prototypical LSD, is caused by the defi- chemotaxis of inflammatory and immune cells and pro-
ciency of the lysosomal hydrolase β-​glucocerebrosidase duction of reactive oxygen species60–65. This pathogenetic
(GCase), encoded by GBA51 (Fig. 3), leading to the accumu- cascade has been studied in a conditional knockout model
lation of the glycosphingolipids glucosylceramide (GlcCer) of Gaucher disease (Gbaflox/flox Nestin–Cre mouse), which

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 Primer

Gaucher disease Sialidosis

• Parkinson disease • Alzheimer disease
• Dementia with Lewy bodies • Fibrosis
• Cancer
Mitochondrion Danon disease
• Pauci-immune FNGN
MPS IIIB • Frontotemporal dementia
• Tauopathies • Proteases
• Alzheimer disease • Glycosidases
α-Synuclein • Amyloid-β
Ca2+ LAMP2 CMA • Exosomes
GCase GlcCer
P-tau Lyosomal
GlcCer APP exocytosis
NEU1
MPS IIIA, IIIB and IIIC HS-GAG PPCA GLB1 LAMP1
• Batten disease NaGlu
Cholesterol GM1 gangliosidosis
GM1 • Parkinsonian features
SCMAS NPC1 • Alzheimer disease
Ca2+
Cholesterol–sphingolipid
homeostasis
Ca2+
ER
NPC
Nucleus • Alzheimer disease

Fig. 3 | Selected examples of cellular pathogenesis in LSDs. The molecular pathways involved in lysosomal storage
diseases (LSDs) might become applicable to other adult diseases of ageing. Thus, deficiency of lysosomal ß-glucocerebro-
sidase (GCase) and accumulation of glucosylceramide (GlcCer), leading to Gaucher disease, are also associated with
accumulation and/or deposition of α-​synuclein, a characteristic of Parkinson disease and dementia with Lewy bodies. The
deficiency of α-​N-acetylglucosaminidase (NaGlu) and resulting accumulation of heparan sulfate (HS-​GAG) in mucopoly-
saccharidosis (MPS) IIIB leads to deposition of hyperphosphorylated tau (P-​tau), which is a cause of neurodegenerative
diseases, including Alzheimer disease. In addition, in Niemann–Pick disease type C (NPC) deficiency of NPC1 leads to
cholesterol and sphingolipid accumulation, and the cell biology of NPC parallels aspects of Alzheimer disease. In sialidosis,
excessive lysosomal exocytosis downstream of neuraminidase-1 (NEU1) deficiency and accumulation of the lysosome-​
associated membrane glycoprotein 1 (L AMP1) have a key pathogenetic role and might contribute to Alzheimer disease,
fibrosis and cancer. Interestingly , aberrant chaperone-​mediated autophagy (CMA), associated with protective protein
cathepsin A (PPCA , also known as CTSA) deficiency in patients with galactosialidosis and impaired L AMP2 degradation,
might have a role in frontotemporal dementia. In addition, the accumulation of GM1-ganglioside (GM1) in intracellular
membranes and the disturbance of calcium homeostasis are pathogenetic in GM1 gangliosidosis but might also occur in
Alzheimer disease. The occurrence of a lysosomal form of subunit c of mitochondrial ATP synthase (SCMAS) in MPS IIIA ,
IIIB and IIIC as well as in the neuronal ceroid lipofuscinosis diseases suggests a common pathology between these
conditions, but whether it reflects a pathogenetic sign is still unclear. Lastly , the fact that Lassa and Ebola viruses use
lysosomal integral membrane proteins L AMP1 and NPC1, respectively , as their intracellular receptors to potentiate their
infectivity has added to the multiplicity of functions and complexity of the eclectic lysosomal organelle (not shown)194,195.
Furthermore, Mycobacterium tuberculosis actively inhibits NPC1 in order to persist in host cells196, adding another twist to
the complex relationship between pathogens and lysosomal proteins (not shown). APP, amyloid precursor protein; ER ,
endoplasmic reticulum; FNGN, focal necrotizing glomerulonephritis; GLB1, β-​galactosidase.

suggests that neuroinflammation is elicited by damage- Natural history and population genetic studies have
associated molecular patterns released from dying neu- revealed that patients with Gaucher disease type I or
rons, astrocytes and oligodendrocytes58,66,67. These effectors carriers of GBA mutations have an increased risk of PD
promote pro-​inflammatory activity in microglia, which or Lewy body disorders45,68,69. These neurodegenerative
amplifies their neurotoxic process, ultimately leading to conditions are characterized by the presence of insolu-
neurodegeneration35. In the same Gaucher mouse model, ble, oligomeric or fibrillar α-​synuclein inclusions in neu-
the upregulation of receptor-​interacting serine/threonine-​ rons of the substantia nigra, the hippocampus and the
protein kinases 1 and 3 (RIPK1 and RIPK3, respectively), cerebral cortex55,70. Interestingly, an inverse relationship
coupled with necrotic cell death and inflammasome acti- between the levels of GCase and α-​synuclein aggregates
vation, have also been implicated in neurodegeneration31. has been demonstrated experimentally in cellular mod-
In addition, the chronic inflammation in experimental and els and mice, but the mode of interaction between these
clinical Gaucher disease could be due to the production molecules and their contribution to the development of
of complement-​activating GlcCer-​specific immunoglob- synucleinopathies have not been fully elucidated55,71,72. In
ulin G (IgG) autoantibodies, which have been proposed addition, GlcCer directly controls a reversible change
to drive a cycle of GlcCer and GlcSph accumulation and in α-synuclein that promotes its aggregation and toxi­city,
complement activation62. opening the possibility of therapeutic intervention by

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Primer

glycosphingolipid-​reducing agents73. Additional work is sialyl-​oligosaccharides or glycopeptides, which are typ-

needed to fully understand the connection between GBA ically excreted in body fluids but accumulate in lyso-
mutations, particularly in heterozygous individuals, and somes in NEU1-deficient cells87. In addition, NEU1 can
predisposition to PD. Notably, lysosomal dysfunction also cleave sialic acids on membrane glycoproteins and,
has been implicated as the link between LSDs and PD in doing so, alters their biochemical properties, which
(not specifically GBA mutations) as heterozygous then negatively affects cell–cell adhesion, cell migration,
mutations in 54 of the 70 LSDs are over-​represented in receptor–ligand recognition and signalling and antigen
patients with sporadic PD74. presentation87,88. Neu1−/− mice have pheno­types that
resemble those of sialidosis type II and manifest with
GM1 gangliosidosis neurodegeneration, muscle atrophy and splenomegaly,
GM1 gangliosidosis is a generalized CNS disease (that among other features89. Searching for the molecular
is, a disease affecting several brain regions) caused by cause or causes of these phenotypes identified NEU1 as
deficiency of lysosomal β-​galactosidase (GLB1), which a negative regulator of calcium-​driven lysosomal exo-
cleaves the sialyl-​glycosphingolipid GM1-ganglioside cytosis41–43,90,91. NEU1 regulates lysosomal exocytosis by
(GM1)75. GM1 is abundant in neuronal membranes cleaving the sialic acids from the lysosome-​associated
and is the only ganglioside that has been shown to membrane glycoprotein 1 (LAMP1), a mediator of
bind calcium and modulate calcium flux across mem- endolysosome docking at the plasma membrane90,92.
branes76–78. GM1 accumulation in the brain and spinal Different cell types, including neurons, with absent or
cord of patients with GM1 gangliosidosis promotes reduced NEU1 activity have increased LAMP1-positive
generalized neurodegeneration, and similarly, Glb1−/− endosome and lysosome docking and, in turn, excessive
mice undergo progressive neuronal cell death followed exocytosis of hydrolytic enzymes and other endosomal
by widespread neuroinflammation33,79. Mechanistically, and lysosomal contents, including exosomes90 (Fig. 3).
the neuronopathic phenotype is caused directly by GM1 Increased lysosomal exocytosis is at the basis of sial-
accumulation in neurons, as this molecule abnormally idosis pathogenesis in the mouse model and likely in
accumulates in the endoplasmic reticulum membranes patients, but the molecular effectors downstream of
in Glb1−/− neurons, causing endoplasmic reticulum cal- excessive lysosomal exo­cytosis vary between cells with
cium depletion, and activation of the unfolded protein different physiological functions and likely with a dif-
response, which induces apoptosis80. In addition, GM1 ferent composition of lysosomal contents. For instance,
accumulates at membrane contact sites between the in the bone marrow, excessive exocytosis of lysosomal
endoplasmic reticulum and mitochondria, known as proteases into the extracellular fluid causes the loss of
mitochondria-​associated endoplasmic reticulum mem- retention of haemato­poietic progenitor cells within the
branes (Fig. 3), and specifically in glycosphingolipid-​ bone marrow niche, their mobilization to peripheral
enriched or raft-​like microdomains (GEMs), which affect blood and their increased numbers in the spleen and,
mitochondrial function26,81. At GEMs, the interaction of consequently, time-​dependent splenic extramedullary
GM1 with the endoplasmic reticulum calcium channel haematopoiesis and spleen enlargement90. In muscle,
inositol 1,4,5-trisphosphate receptor type 1 promotes increased exocytosis of matrix metalloproteinases
abnormal calcium flux from the endoplasmic reticulum and cathepsins from connective tissue fibroblasts, and
to the mitochondria, leading to endoplasmic reticulum increased synthesis and deposition of collagens and other
calcium depletion, mitochondrial calcium overload and extracellular matrix components, triggers progres-
activation of mitochondria-​mediated apoptosis81. This sive expansion of the connective tissue that gradually
combined pathogenetic cascade, directly downstream invades the muscle bed, leading to myofibre fragmen-
of increased GM1 levels, explains, at least in part, the tation and muscle degeneration42. These findings have
complex CNS phenotype of GM1 gangliosidosis. shifted the focus of sialidosis research to the effect of
Whether GLB1 mutations, polymorphisms or haplo­ NEU1-regulated exocytosis of hydrolytic enzymes
insufficiency could be risk factors for AD is currently and exosomes on the extracellular microenvironment,
unknown. However, several studies have demonstrated which has important ramifications for the biology of
the occurrence of amyloid-β (Aβ)-generating secretases other conditions, including cancer43 (Fig. 3).
in GM1-containing lipid rafts, and GM1-bound Aβ pep- Interestingly, Neu1−/− mice have progressive Aβ dep-
tides with an altered conformation have been observed osition in the brain, particularly in the CA3 region of
in a post-​mortem brain of a patient with early-stage AD. the hippocampus, which resembles plaque formation in
Aβ bound to GM1 has been hypothesized to function patients with AD and in animal models for their location
as an endogenous seed for amyloid fibril deposition in and composition41. Amyloid precursor protein-​positive
AD brains82–84. Interestingly, GM1 is differentially dis- aggregate deposition occurs through two concomitant
tributed in the hippocampal grey matter of patients with events: lysosomal accumulation and aberrant processing
AD compared with healthy individuals85,86. of an oversialylated amyloid precursor protein (which is
a substrate of NEU1) and increased lysosomal exocytosis
Sialidosis of toxic Aβ42 polymers into the brain cerebrospinal fluid
Sialidosis is a rare neurodegenerative LSD that is (CSF) and interstitial fluid41. Thus, Neu1−/− mice might
caused by deficiency in neuraminidase 1 (NEU1, also be a spontaneously occurring model of AD, raising the
known as sialidase-1), which cleaves sialic acid resi- intriguing possibility that NEU1 loss of function con-
dues. Although the full range of NEU1 substrates is not tributes to the development of sporadic AD via altered
yet known, the enzyme preferentially cleaves soluble lysosomal exocytosis in the CNS.

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 Primer

NPC1 is a cholesterol-regulated transporter or a ded-

Cells containing LROs LROs Clinical features
when defective icated cholesterol transporter, as many view it to be.
Melanocyte Melanosomes
On the basis of homology to bacterial orthologues,
Ocular and cutaneous
hypopigmentation it is likely that NPC1 is involved in multisubstrate
Mast cell transport99–101.
Basophilic granules Immune deficiency Dementia is a common symptom in patients with
and allergies NPC, with post-​mortem brains sharing many histo-
Basophil
pathological features classically associated with late-​
α and β granules Bleeding disorders
onset AD. The links between these two diseases suggest
Platelet
that the cell biology of NPC accelerates amyloid pre-
Neutropenia, cursor protein processing and the tau phosphorylation
Neutrophil Azurophilic granules immune deficiency defects typically associated with ageing in the general
and bacterial infections
population102.
T cell Lytic granules Immune deficiency
and viral infections
LROs
Osteoclast Ruffled border Osteoporosis LROs are cell-​specific intracellular vesicles that are
found in specialized cell types (for example, melano-
Endothelial cell Weibel–Palade bodies Bleeding diathesis cytes, lymphocytes and platelets, among others) (Fig. 4).
Neuron Neuromelanin granules Neurodegeneration LROs share features with endosomes and lysosomes,
such as low pH, the presence of specific membrane
proteins and a similar pathway of formation (Fig. 4), but
Fig. 4 | LROs. Lysosome-​related organelles (LROs) are specialized organelles formed from
are distinct in function, morphology and their cargoes
early endosomes (see Fig. 2). LROs have similar characteristics to lysosomes and are found
in specific cell types; defects in these organelles can arise owing to genetic mutations that impart their physiological properties103,104. Genetic
(leading to LRO-​related disorders) and result in specific clinical features. Adapted with defects that affect the formation, maturation and secre-
permission from ref.103, Annual Reviews. tion of LROs can affect the function of these vesicles
in either one LRO-​containing cell type or multiple cell
types, resulting in a variety of clinical features referred
NPC to as LRO disorders (Table 1). Cells from patients with
Defects in non-​enzymatic lysosomal proteins can also LRO disorders or from mouse, fly or zebrafish models
cause LSDs, such as NPC. NPC is unusual as two appar- are important tools for the investigation of LRO biogen-
ently unrelated genes cause the same disease, suggest- esis, vesicular trafficking, membrane remodelling and
ing that the proteins they encode function in a common mechanisms of secretion.
cellular pathway. NPC type 1 is caused by mutations in
NPC1, which encodes a multipass membrane protein Diagnosis, screening and prevention
(NPC1) that resides in the limiting lysosomal membrane, As previously mentioned, LSDs are monogenic dis-
whereas NPC type 2 is caused by mutations in NPC2, orders, and the vast majority are inherited in an auto­
which encodes a soluble cholesterol-binding protein somal recessive manner. Exceptions to this inheritance
(NPC2)93. 95% of clinical cases of NPC have mutations pattern include MPS II (X-​linked recessive), CLN4
in NPC1 and present in infancy or childhood with disease (dominant and recessive forms), Fabry disease
a progressive neurodegenerative disorder, although (X-linked, although some females might have a later-​
adult-​onset cases occur and are likely underdiagnosed93. onset disease that does not usually involve the kidney)
NPC1 might have a role in the transport of sphingosine and Danon disease (X-​linked, in which females have later
out of lysosomes and accordingly, the pathogenetic onset than males and might have a milder phenotype
cascade in NPC is initiated by increased sphingosine that does not include skeletal myopathy or intellectual
storage that, via an unknown mechanism, reduces cal- disability) (Table 1).
cium levels in the lysosome94. Reduced calcium levels
in lysosomes means that insufficient calcium is released Clinical features
from the lysosome94–97, therefore calcium is unavaila- Enzyme deficiency disorders. The classical LSDs (that
ble for use by calcium-dependent proteins involved in is, the enzyme deficiency disorders) can be grouped
lysosome fusion and trafficking, leading to substan- according to the stored material and include sphingo­
tially impaired late endosome and lysosome fusion98. lipidoses, mucopolysaccharidoses, glycogen storage
Consequently, lipids, including low-​density lipoprotein disease and glycoproteinoses (Table  1) . The age of
(LDL)-derived cholesterol and sphingolipids (such as symptom onset is usually determined by the amount
glycosphingolipids and sphingomyelin), are stored in of residual enzyme activity, which is governed by the
many cell types, which can further contribute to the specific genetic mutations. These disorders are most
pathogenetic cascade but remain incompletely under- often multisystem disorders that have multiple sub-
stood (Figs 2,3). The consequences of lipid storage in types and can have symptomatic onset from the prenatal
NPC include, for example, mitochondrial dysfunction period to adulthood.
and activation of the innate immune system, lead- Most enzyme deficiency disorders involve CNS dys-
ing to inflammation. The major issues to be resolved function and patients often present with neurological
in the NPC field are how and why NPC1 and NPC2 symptoms. In adults, the onset of disease can be subtle,
cooperate in a common cellular pathway and whether and dysarthria (difficulty with speech), ataxia, weakness

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Primer

or abnormal movements are common presenting fea- affect the CNS, is characterized by proximal tubular dys-
tures and are easily confused with symptoms of more function owing to cystine accumulation, which leads to
common adult-​onset neurodegenerative disorders. renal Fanconi syndrome and renal failure in >90% of
Psychosis or depression can also be a presenting feature patients106. The prompt diagnosis and treatment with
in adult-​onset disorders, such as late-​onset Tay–​Sachs cysteamine prevents renal failure. However, cystinosis
disease, and can delay diagnosis by years to decades105. is a systemic disorder, with other symptoms including
Substrate storage in specific organ systems is characteris- photophobia and visual impairment owing to corneal
tic of some enzyme deficiency disorders, such as storage deposition of cystine crystals (which can be treated
in the kidney in Fabry disease, the heart in Pompe dis- effectively with cysteamine eye drops), endocrine abnor-
ease or the mononuclear phagocyte system in Gaucher malities (such as hypothyroidism and growth hormone
disease. Similarly, common constellations of findings deficiency) and skeletal deformities (including scoliosis,
such as hepatosplenomegaly, coarsening facial features stress fractures and joint pain). Even with cysteamine
and joint contractures (with or without corneal cloud- therapy, patients with cystinosis can also develop a sec-
ing) should suggest a MPS disorder. However, more-​ ondary phenotype of progressive myopathy and muscle
subtle presentations such as mild muscle weakness in weakness, dysarthria and swallowing difficulties. NPC
adults (which can occur in Pompe disease) or a clinical type 1 or 2 should be suspected in a child with isolated
sign with more common aetiologies such as proteinu- splenomegaly or neonatal liver disease, as patients can
ria, diminished renal function or cardiac hypertrophy have no other clinical findings for years before develop-
(which can occur in Fabry disease) can make diagnosis ing the characteristic supranuclear gaze palsy followed
more challenging. by intellectual decline. Neuropsychiatric symptoms and
cognitive decline can predominate in NPC with onset in
Disorders of post-​translational modification. Disorders adolescence and adulthood, resulting in long delays
of post-​translational modification include multiple sul- in diagnosis107,108.
fatase deficiency and mucolipidoses II and III and result
from mutations in genes that have a role in biochemi­ NCLs. The NCLs involve the CNS and were initially
cally modifying lysosomal hydrolases. Therefore, the classified on the basis of age at onset109 (Table 1). More
clinical manifestations of these disorders are more recently, the classification was updated to include the
gene­ralized than other forms of LSDs and have over- genetic mutation as well as the age of onset (for exam-
lapping features with disorders caused by defects in ple, CLN3 disease, juvenile onset). Symptom progres-
single lysosomal hydrolases (Table  1). For example, sion is variable10; some disorders present initially with
multiple sulfatase deficiency is caused by mutations progressive visual loss (for example, CLN3 disease,
in SUMF1, which encodes formylglycine-​generating juvenile onset)110, followed by mental decline and sei-
enzyme (FGE). FGE modifies sulfatases (a class of zures10. Indeed, most patients with CLN3 disease are
lysosomal enzymes), which include the enzymes that diagnosed by ophthalmologists owing to the early visual
degrade mucopolysaccharides that are affected in loss with characteristic retinal pathologies110. Other
MPS II, IIIA, IIID, IVA and VI. As a result, the clinical NCLs present with developmental delay (for example,
manifestations of multiple sulfatase deficiency over- CLN2 disease, late-​infantile onset), with visual loss
lap with the MPS disorders, making diagnosis chal- occurring at later stages111. In general, the NCLs involve
lenging. Similarly, mucolipidoses II and III are caused progressive movement disorders, epilepsy, dementia
by mutations in GNPTAB and GNPTG, respectively, and early death.
encoding the subunits of N-​ a cetylglucosamine-1-
phosphotransferase, which tags lysosomal hydrolases Disorders of LROs. The most notable LRO disor-
with mannose 6-phosphate for targeting to the lysosome. ders include the Hermansky–Pudlak, Griscelli and
As a result, hydrolases that require mannose 6-phos- Chédiak–​Higashi syndromes, which are all character-
phate tagging (which include degradative enzymes for ized by hypopigmentation (owing to a melanosome
most sphingolipids, mucopolysaccharides and glycopro- defect) and prolonged bleeding (owing to a platelet δ
teins) are not trafficked to the lysosome and are secreted granule defect)103. The classic form of Chédiak–​Higashi
into the extracellular space. This process leads to the syndrome also includes recurrent life-​threatening infec-
accumulation of multiple complex substrates in lyso- tions due to immunodeficiency, and 85% of patients
somes, which leads to disorders with severe phenotypes develop a life-​threatening hyperinflammatory condi-
that share clinical features with the sphingolipidoses, tion (haemophagocytic lymphohistiocytosis). Untreated
glyco­proteinoses and mucopolysaccharidoses, but, most patients die, usually of overwhelming bacterial infec-
notably the MPS disorders. tion, in infancy or early childhood103. Most LRO dis-
orders manifest during infancy, with the exception of
Disorders of integral membrane proteins. Similar to the Chédiak–​Higashi disease, which has juvenile and adult-​
enzyme deficiency disorders, most disorders of integral onset forms. Haematopoietic stem cell transplantation
membrane proteins can present during infancy, child- (HSCT) facilitates improved survival of patients with
hood and adulthood and can affect the CNS. Common classic Chédiak–Higashi syndrome into adulthood,
symptoms include intellectual disability, ataxia, seizures although a secondary phenotype similar to the adult-​
and spasticity. With the exception of NPC and cystinosis, onset form subsequently emerges, including tremor,
most integral membrane protein disorders are rare in the ataxia, peripheral neuropathy and cognitive decline that
general population. Cystinosis, which does not primarily is life-limiting112.

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 Primer

Diagnosis changes — all of which are general symptoms with a

The diagnosis of most LSDs is straightforward if they broad differential diagnosis.
are suspected on the basis of clinical presentation; Diagnosis of LSDs must be commenced early for
however, a diagnosis of LSDs is often not clinically sus- effective treatment, a target that is often not met. In one
pected owing to the general symptoms of these disorders study of children with late-​infantile and juvenile GM1
and their rarity. Any infant or child between 6 months and gangliosidosis type II, the average time to diagnosis from
10 years of age who initially has a period of typical the time of symptom onset was 24 months and 9.8 years,
development but plateaus and loses previously attained respectively115. In infants and toddlers, development is
skills should be considered to have an LSD until proved somewhat variable; accordingly, paediatricians will often
otherwise, irrespective of whether the LSD is confirmed monitor late-​infantile patients for several months until
as an enzyme deficiency or is found to be caused by a skills are clearly outside the range of normal develop-
different LSD-​causing mechanism. Diagnostic work-​up ment, or a child is actually losing skills, before referring
can be initiated with screening for a class of disorders the child to a neurologist. Similarly, a neurologist might
that have similar clinical presentations; one example of also take several months to complete diagnostic testing
such a screen is the detection of glycosaminoglycans in before arriving at a diagnosis. For juveniles who show
the urine of patients with MPS. Definitive diagnostic typical development up to 4–5 years of age, the process
testing for specific enzyme deficiency disorders includes of observation through the plateau phase and consider-
the evaluation of lysosomal enzyme levels in peripheral ation of more common conditions, including attention-
blood leukocytes using artificially synthesized fluoro- deficit/hyperactivity disorder and autism spectrum
genic substrates specific for each enzyme113. Enzyme disorders, might take even longer. GM1 gangliosidosis
levels are expressed as the amount of substrate cleaved type II includes progressive brain atrophy, implying that
per milligram of total protein per unit time and are delays in diagnosis would result in less effective or inef-
compared with a normal range113. When enzyme levels fective therapy. Most paediatricians and many neurol-
fall below the normal range, a diagnosis of a specific ogists are not aware that LSDs can present in juveniles,
LSD can be confirmed using genetic testing to identify and cranial imaging could initially show only non­
mutations in the gene encoding the deficient enzyme. specific findings. The increasing use of next-​generation
However, enzyme assays are performed in vitro on sequencing is expected to aid in more timely diagnosis
artificial substrates and might not accurately represent because practitioners would not need to have a specific
enzyme activity against natural substrates in vivo. For neurological diagnosis in mind to initiate diagnostic
some enzymes, such as hexosaminidase A, the testing testing. Next-​generation sequencing will also lead to
can also be performed on patient serum or plasma. identification of new genetic variants of uncertain
Indeed, such testing formed the basis of carrier detec- significance and might also expand the clinical pheno­
tion of infantile Tay–Sachs disease in the Ashkenazi type of individual LSDs as new genetic variants are
Jewish population (see Carrier screening, below)114. described116.
Unfortunately, carrier testing in serum or plasma is not
reliable for many lysosomal disorders. Screening and prevention
Genetic testing to identify specific mutations can Carrier screening. Tay–​Sachs disease is the prototypi-
be performed using DNA sequencing and can comple- cal LSD for population-​based carrier screening, as this
ment the enzyme studies and suggest prognosis if those disorder has a carrier frequency of 1 in 27 in Ashkenazi
mutations have been demonstrated in other patients. Jewish individuals117. Community screening was com-
However, if patients do not have parental consanguin- menced in the early 1970s in the United States and
ity or are members of a high-​r isk population, they consisted of a plasma-​based enzyme assay to identify
are generally compound heterozygotes, which makes couples who were both Tay–​Sachs disease carriers and,
phenotype–genotype correlation difficult. Some LSDs, therefore, have a 25% risk of having a child with this
such as disorders of integral membrane proteins, most of disorder. With this information, couples could undergo
the NCLs and the LRO disorders, can be diagnosed only amniocentesis or chorionic villus sampling to identify
by direct gene sequencing. If identified mutations have affected fetuses and consider pregnancy termination or
been previously reported as pathogenetic or disease-​ could choose to adopt a child. Couples can now undergo
causing, a diagnosis of LSDs can be confirmed. However, in vitro fertilization (IVF) followed by pre­implantation
if new variants of undetermined significance are found, diagnosis to identify unaffected embryos for uterine
then the results are tentative and must be correlated with implantation. Screening within the Ashkenazi Jewish
the clinical phenotype. community decreased the number of children born
Despite available diagnostic testing for LSDs, the key with Tay–Sachs disease in the United States from
to diagnosis, particularly in patients after infancy, is con- 60 per year before 1970 to 3–5 per year by 1983 (a 90%
sidering an initial LSD diagnosis. In adults, several more reduction in the incidence within this population)114
common disorders can present with symptoms similar and resulted in the birth of ~2,000 healthy infants
to LSDs, including ataxia, myoclonus, dementia or psy- from at-risk couples who would otherwise not have
chiatric symptoms, and many clinicians are unaware attempted a pregnancy. The success of carrier screen-
that LSDs can present in adulthood. Juveniles might ing in this community has also prompted screening in
present with plateauing of academic skills with subse- other high-​risk groups, including French-Canadian,
quent regression as well as falling, increased difficulty Irish and Cajun individuals118. More recently, the use
walking and talking, visual difficulties or behavioural of next-​generation sequencing to screen for the three

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Box 1 | Newborn screening for LSDs enzyme activity is currently being used rather than
DNA sequencing owing to poor phenotype–genotype
Universal screening for lysosomal storage diseases (LSDs) correlations in many disorders119. However, some con-
is mandated in the following regions and is under troversy surrounds screening for LSDs, as screening
development or in pilot phases in several other regions:
assays identify newborn babies with enzyme defi-
• Pompe disease: Taiwan and, in the United States, ciencies who might have adult-​onset disease and who
Illinois, Kentucky, Minnesota, Missouri, New York, might not require treatment for decades, or at all, such
Pennsylvania and Tennessee
as Fabry disease and Gaucher disease. Ultimately,
• Mucopolysaccharidosis I: Illinois, Kentucky, Minnesota, newborn screening using next-​generation sequencing
Missouri, New York, Pennsylvania and Tennessee
(whole-​exome or whole-​genome sequencing) will mag-
• Krabbe disease: Illinois, Kentucky, New Mexico, New nify this dilemma, as practitioners try to interpret vari-
York and Pennsylvania
ants of uncertain significance in disease-​causing genes.
• Fabry disease: Illinois and Missouri The unmet needs for newborn screening in LSDs are
• Gaucher disease: Illinois and Missouri robust, cost-​effective assays, more pilot programmes
• Niemann–Pick disease types A and B: Illinois demonstrating utility and increased understanding of
the benefits of early treatment.
common mutations that cause Tay–Sachs disease in
Ashkenazi Jewish individuals has been proved superior Prenatal screening and prevention. In families who
to traditional enzyme testing, although the detection already have a child with a diagnosed LSD and the spe-
of variants of unknown significance has restricted the cific disease-​causing mutations are ascertained, using
sole use of next-​generation sequencing for carrier detec- IVF with preimplantation genetic diagnosis (PGD) to
tion117. Despite the success of carrier screening, owing to identify unaffected embryos for implantation offers
the dispersion of high-​risk individuals across the world at-​risk couples the chance to have additional children
due to increased migration, some individuals might not who do not have the disorder. For families with chil-
realize they are at increased risk of Tay–​Sachs disease, dren with a juvenile-​onset disease or when a child with
which emphasizes the need for cost-effective universal early-​onset disease has a protracted diagnostic odyssey,
screening. using IVF with PGD is not an option and often results
in multiple children in a sibship with the LSD. PGD is
Newborn screening. The rationale for mandatory new- expensive, but is approved in the United Kingdom by
born screening has historically included disorders with the Human Fertilization and Embryology Authority
an effective therapy, a cost-​effective and relatively high-​ for several LSDs. PGD is available in the United States,
throughput detection method and disorders for which Canada and Western Europe but might not be covered
early detection (therefore allowing timely treatment) is by health insurance, and PGD is typically not available
essential; phenylketonuria is the prototype. Newborn in low-​resource countries. As an alternative to PGD, at-​
screening can identify patients rapidly using testing risk couples can utilize prenatal diagnosis during the first
for increased levels of metabolites, such as phenyl­ trimester of pregnancy, with termination of fetuses with
alanine in the case of phenylketonuria, or identifying LSDs. Using donor sperm or eggs to produce an embryo
common disease-​causing mutations, such as ΔF508 in without LSD-​causing mutations and the use of adoption
cystic fibrosis. Newborn screening is correctly viewed are additional choices for at-risk couples.
from the perspective of the affected child but can also
affect subsequent reproductive choices for the parents. Management
The goal of newborn screening is better public health Some LSDs are treatable; for example, the missing or
outcomes and requires not only a reliable detection defective enzyme can be provided exogenously through
assay but also parental education, clinical follow-up ERT, the amount of stored material within lysosomes
and available treatments for all positive newborn babies. can be reduced by substrate reduction therapy (SRT) or
Although universal newborn screening is mandated for compounds can improve the function of the defective
some disorders in most developed countries, the num- enzyme using chaperone therapy and proteostasis mod-
ber of specific disorders varies by country and, within ulators. Alternatively, genetic therapies might be a pos-
the United States, varies by state. In addition, manda- sibility, such as gene therapy or stop codon readthrough
tory screening for LSDs is limited, although the tech- drugs (see Outlook). Although treatments are currently
nology and availability for such screening is expanding available for a number of LSDs, most disorders cannot
rapidly (Box 1). be treated and are managed symptomatically (Table 3).
Until 2006 when alglucosidase alfa was approved by Additional therapeutic strategies might be developed
the US FDA for the treatment of Pompe disease, none for specific LSDs, although this will require a thorough
of the LSDs met the criteria for newborn screening as no understanding of their pathophysiology120. Treatment
effective therapies were available; however, this has now outcomes vary between LSDs and range from very effec-
changed with the development of treatments for some tive to minimally effective. As new therapies are devel-
disorders. Owing to the development of these treat- oped, there might be a choice between different therapies;
ments, parents and advocacy groups continue to lobby unless a medical or scientific reason exists for proceeding
to include LSDs on newborn screening panels. Newborn with one drug, the choice might be based on cost and/or
screening for LSDs using fluorometric enzymatic assays the expertise of the attending physicians. Combination
and more recently tandem mass spectro­metry to measure therapy is also likely given that a combination of

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 Primer

Table 3 | Approved therapies

Disease Type of therapy Drug name Comments
Gaucher disease Recombinant enzyme a
• Imiglucerase ERT is effective only for type I Gaucher disease (the non-​
• Velaglucerase alfa neuronopathic phenotype) and is not effective for types II
• Taliglucerase alfa and III (neuronopathic phenotypes)
Substrate reduction therapy • Miglustat Effective only for non-​neuronopathic Gaucher disease
• Eliglustat
Fabry disease Recombinant enzyme • Agalsidase beta • Agalsidase alfa and beta have the same amino acid
• Agalsidase alfa composition but different glycosylation
• Agalsidase beta was approved by the US FDA , although
both drugs are approved by the EMA
Chaperone therapy Migalastat Active site inhibitor and/or chaperone
Pompe disease Recombinant enzyme Alglucosidase alfa Reverses cardiac but not skeletal muscle abnormalities in
Pompe disease and is approved by the EMA
MPS I (Hurler–​Scheie and Recombinant enzyme Laronidase Effective for attenuated forms of MPS I (Hurler–Scheie and
Scheie syndromes) Scheie syndromes) but is not effective for severe form of
MPS I (Hurler syndrome)
MPS II (Hunter syndrome) Recombinant enzyme • Idursulfase • Not effective for CNS or skeletal disease
• Idursulfase beta • Idursulfase beta approval by Korean Ministry of Food and
Drug Safety
MPS VI (Maroteaux–​Lamy Recombinant enzyme Galsulfase Efficacy variable and depends on the severity of the disease
syndrome) and the age at which ERT was started
MPS IV (Morquio Recombinant enzyme Elosulfase Not effective on bone disease, which might need surgical
syndrome A) intervention
MPS VII (Sly syndrome) Recombinant enzyme Vestronidase alfa Approved for use in paediatric and adult patients
Lysosomal acid lipase Recombinant enzyme Sebelipase alfa Multiple disease-​related lipid abnormalities reduced
deficiency
Late infantile neuronal Recombinant enzyme Cerliponase alfa First treatment available for any form of Batten disease;
ceroid lipofuscinosis type 2 requires intracerebroventricular administration
(CLN2 disease)
Niemann–Pick disease type C Substrate reduction therapy Miglustat First small-​molecule modifier of CNS disease in an LSD
CNS, central nervous system; EMA , European Medicines Agency ; ERT, enzyme replacement therapy ; LSD, lysosomal storage disease; MPS, mucopolysaccharidosis.
a
The names of the recombinant enzymes represent the generic name. The use of α and β in the name of the natural enzyme is to distinguish between different
preparations of the recombinant enzymes.

drugs is more likely to mitigate the many symptoms development, whereas transplantation of older patients
of these complex diseases. (26 months of age) allowed peripheral improvement
but did not prevent cognitive decline124. HSCT has also
Available therapies been used for other LSDs for which no other treatment
HSCT. Bone marrow transplantation was initially per- was available, the most prominent being metachromatic
formed on a 1-year-​old patient with Hurler syndrome leukodystrophy and Krabbe disease; however, the results
(the severe form of MPS I) in 1981 (ref.121). The ration- have been less promising than with Hurler syndrome.
ale for using bone marrow transplantation was that
this therapy would provide a lasting source of bone-​ ERT. ERT is based on the ability of cells to take up macro­
marrow-derived cells with normal enzyme levels that molecules (such as enzymes) by endocytosis, which
would donate enzyme to the patient’s deficient cells. This can be packaged into lysosomes through endosome
therapy was the first treatment of an LSD to show any and lysosome fusion. Receptor-​mediated endocytosis
success and was continued to be used despite its high underlies the cellular uptake and lysosomal targeting of
morbidity and mortality. Over time, the use of umbili- several lysosomal enzymes; for example, GCase (which
cal cord blood instead of bone marrow, as well as better is deficient in Gaucher disease) contains mannose resi-
conditioning regimens and donor selection, reduced dues, which bind to mannose receptors on the surface of
the adverse effects of transplantation122 and improved macrophages, whereas other soluble lysosomal enzymes
efficacy. HSCT is currently the standard of care for contain mannose 6-phosphate groups, which bind to
infants with Hurler syndrome, owing to the benefit of mannose 6-phosphate receptors on the surface of most
this therapy for preventing the development of neuro- cells125. Thus, a lysosomal enzyme, made in recombi-
logical symptoms, which do not respond to intravenous nant form and containing an appropriate carbohydrate
ERT123. Younger patients have better results from HSCT modification, will be taken up by cells, incorporated
than older patients; the transplantation of umbilical cord into lysosomes and, accordingly, can be used to treat a
blood in patients with Hurler syndrome <9 months of lysosomal enzyme deficiency. Non-​carbohydrate mod-
age prevented the onset of both neurological and ifications are also being tested, such as insulin growth
peripheral symptoms and allowed normal cognitive factor 2, which also binds to the mannose 6-phosphate

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Primer

receptor and can be used when there is inadequate man- type I136–139, and miglustat is approved for NPC140,141.
nose 6-phosphate on the enzyme126. ERT is feasible only Both drugs block GlcCer synthase, which inhibits the
with enzymes that are soluble or easily solubilized and first step in glycosphingolipid biosynthesis142,143.
does not work for membrane-​bound enzymes. SRT drugs are orally administered and are stable at
ERT has been developed and approved by the FDA ambient temperatures. Thus, in contrast to ERT, SRT
or the European Medicines Agency (EMA) for the treat- does not involve a labile product and invasive delivery,
ment of several enzyme deficiency disorders (Table 3), and owing to their low molecular mass, SRT drugs are
including Gaucher disease, Fabry disease, Pompe dis- non-​immunogenic. Miglustat can cross the blood–brain
ease, lysosomal acid lipase deficiency and MPS I, II, IV, barrier and, accordingly, can slow the progression of
VI and VII, and therapies are under development for neurological symptoms of NPC, including improving
other LSDs (Table 4). Most clinical manifestations of swallowing, which reduces the number of deaths result-
type I Gaucher disease can be treated or prevented with ing from aspiration pneumonia144,145. However, some
ERT (which can be started in childhood or adulthood), SRT drugs such as eliglustat do not cross the blood–
allowing the patients to live essentially normal lives127,128. brain barrier and are restricted to non-​neuronopathic
However, the use of ERT for other LSDs has more limited glycosphingolipidoses, in which, for example, they
results. A major limitation of ERT is that not all organs reduce visceral disease and improve haematological
are accessible to the exogenously administered enzyme; parameters in Gaucher disease type I146,147.
orthopaedic, cardiovascular, neurological and ocular SRT drugs have a slower onset of efficacy than ERT,
symptoms are especially difficult to treat. In addition, as substrate turnover (a particularly slow process in
the blood–brain barrier prevents entry of the exogenous the brain but which is more rapid in organs with cell
enzyme into brain parenchyma; as a result, the enzyme turnover, such as the liver) must occur before clinical
requires modification to take advantage of existing trans- benefit. As with all small-​molecule drugs, SRT drugs
port systems (such as the insulin or transferrin recep- have adverse effects or complications relating to drug
tors) or requires direct administration into the brain or metabolism. For example, miglustat causes osmotic diar-
spinal canal. Accordingly, intracerebroventricular and rhoea148, whereas eliglustat requires cytochrome P450
intrathecal methods of administration through which 2D6 (CYP2D6) status to be determined to avoid the
recombinant enzymes are infused into the CSF through use of this drug in CYP2D6 ultra-​rapid metabolizers149.
catheters inserted into the lateral ventricle or the intrath- This requirement is because eliglustat is a CYP2D6 and
ecal space, respectively, are used126,129. ERT directed to CYP3A substrate. If eliglustat is used to treat patients
the cerebral ventricles has been recently approved for with ultra-​rapid CYP2D6 metabolism status, they will
CLN2 (ref.130) (Table 3). For peripheral symptoms, ERT not achieve an effective dose. Also, if eliglustat is com-
is administered intravenously. Depending on the com- bined with drugs that inhibit these cytochrome P450
plexity of the required approach, ERT infusions can be system enzymes (CYP2D6 and CYP3A), it increases
carried out at the patient’s home. eliglustat exposure and can potentially cause cardiac
Another limitation of ERT is that the therapeu- arrhythmias. SRT drugs are expensive, and, as with
tic enzyme often elicits the production of antibodies, ERT, access globally is restricted to relatively affluent
which can reduce the efficacy of the treatment and lead health-care systems.
to adverse events, including anaphylaxis. The likelihood In principle, SRT could be developed for all LSDs but
of antibody production and adverse immune responses currently is restricted to glycosphingolipidoses because,
can be a major issue associated with ERT in patients with to date, only biosynthetic inhibitors specific to this path-
Pompe disease and varies depending on the nature of the way have been identified. Trials in other sphingolipi-
mutation; it occurs in nearly all patients who have a null doses are in progress (Table 4). Several other SRT drugs
mutation and no residual protein131. In addition, the high are currently being evaluated in clinical trials, including
cost of ERT might discourage the use of this therapy, genistein (an isoflavone that indirectly reduces proteo-
particularly in developing countries with limited health glycan biosynthesis) for MPS III, ibiglustat for Gaucher
budgets. As the dose of the therapeutic enzyme is deter- disease and Fabry disease and lucerastat for Fabry dis-
mined by the patient’s body mass, the cost of treatment ease (Table 4). In addition to small molecules, another
increases as the patient grows and can reach costs of technique for achieving SRT is ASO-​mediated suppres-
several hundred thousand US dollars annually132. sion of biosynthetic enzymes, which is in preclinical
The therapeutic benefit of ERT is transient and, accord- evaluation150. Also, in principle, SRT drugs can be com-
ingly, this therapy must be repeated throughout life. bined with other therapies that target different steps in
However, lysosomal enzymes and recombinant enzymes the pathogenetic cascade.
for ERT generally have a long half-​life in vivo, and adminis-
tration of therapeutic enzymes can therefore be performed Chaperone therapy. Many mutations in the genes encod-
weekly, biweekly or monthly. As LSDs are progressive, ERT ing lysosomal enzymes result in an unstable protein
appears to be most effective if started early124,133. that is prone to rapid turnover and/or reduced cata-
lytic activity151. Subinhibitory concentrations of active
SRT. SRT uses small molecules to inhibit the build-​up site inhibitors (known as chaperone therapy) can sta-
of macromolecules in the lysosome to reduce stor- bilize the mutant enzyme, which extends half-​life and
age134,135 and includes drugs that inhibit the biosynthesis improves catalysis, thereby reducing storage. The only
of storage metabolites. SRT using miglustat and eliglus- approved chaperone drug is migalastat for the treat-
tat is approved for the treatment of Gaucher disease ment of Fabry disease152,153, which improves ventricular

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 Primer

Table 4 | Summary of current trials for LSDs

Disease Type of therapy Drug name or procedure Clinical trial
number examples
α-​Mannosidosis Recombinant enzyme rhL AMAN Velmanase alfa EudraCT Number:
2016-001988-36
Niemann–​Pick disease type B Recombinant enzyme rhASM Olipudase alfa NCT02004691
Niemann–​Pick disease type C Proteostasis modifier Arimoclomol NCT02612129
Disease-​specific Hydroxypropyl-​beta-cyclodextrin (VTS 720) NCT02534844
Metachromatic leukodystrophy Recombinant enzyme rhASA NCT01887938
Gene therapy LV/ARSA-​transduced HSC transplantation NCT01560182
Gene therapy LV/ARSA/ABCD1 transduced autologous HSC transplantation NCT02559830
Gene therapy Intracerebral AAVrh.10cuARSA NCT01801709
MPS I Gene therapy Intravenous AAV/ SB-318-IDUA NCT02702115
Anti-​inflammatory Adalimumab NCT03153319
MPS II Anti-​inflammatory Adalimumab NCT03153319
Gene therapy AAV/SB-913-IDS NCT03041324
MPS IIIA Recombinant enzyme rhHNS NCT01299727
(Sanfilippo syndrome A)
Gene therapy Intravenous scAAV9.U1a.hSGSH NCT02716246
MPS IIIB Recombinant enzyme BMN250 NCT02754076
(Sanfilippo syndrome B)
Substrate reduction therapy Genistein EudraCT:
2013-001479-18
Gene therapy Intracerebral rAAV2/5-hNAGLU NCT03300453
Gene therapy Intravenous rAAV9.CMV.hNAGLU NCT03315182
MPS VI Gene therapy AAV2/8.TBG.hARSB NCT03173521
Fabry disease Substrate reduction therapy Lucerastat NCT02930655
Substrate reduction therapy Ibiglustat NCT02228460
Gene therapy LV galactosidase-​α-transduced stem cells NCT02228460
Gaucher disease Substrate reduction therapy Ibiglustat NCT02843035
Chaperone therapy Ambroxol NCT01463215
Pompe disease Gene therapy Intramuscular AAV9-DES-​hGAA NCT02240407
Tay–Sachs and Sandhoff Chaperone therapy Pyrimethamine NCT01102686
disease
Trials are listed on publicly available databases and are available at ClinicalTrials.gov. AAV, adeno-​associated virus; ARSA , arylsulfatase A ; HSC, haematopoietic
stem cell; LSD, lysosomal storage disease; LV, lentivirus; MPS, mucopolysaccharidosis.

hypertrophy and reduces the severity of diarrhoea, reflux progressive neurodegenerative disease. Together with
and indigestion154,155 (Table 3). physical, occupational and speech therapists, physiatrists
The inhibitory nature of chaperone therapies requires can provide patients with assistive devices for ambula-
dosing every other day to allow maximal enzyme tion, such as walkers or canes and a well-fitted wheel-
enhancement. Allosteric enhancers are in development chair for children and adults with progressive disease.
to avoid the use of active site inhibitors and will allow Providing patients with appropriate seating with trunk
conventional daily dosing156. Some of these chaperone support will prevent scoliosis and restrictive lung disease
drugs (including migalastat) can enter the CNS and, and requires periodic adjustments as the child grows. An
therefore, could potentially treat neurological symptoms occupational therapist can provide or recommend adap-
in neuronopathic LSDs. Similar to drugs for other LSDs, tive equipment that facilitates independence in feeding,
these chaperone therapies are expensive. Chaperone dressing and other activities of daily living. Physical
therapies for Tay–Sachs disease and Gaucher disease therapists can design a regimen of active and passive
are currently in clinical trials (Table 4). stretching for patients that maintains range of motion
and prevents joint contractures. Speech and language
Supportive care therapists can help patients with dysarthria maintain
Many LSDs that do not have an approved therapy can intelligible speech for as long as possible and can evalu-
be managed symptomatically, particularly in patients ate functional swallowing with various food textures to
who were diagnosed at an early stage. Regular follow-​up facilitate safe feeding. In addition, speech and language
with a physiatrist or rehabilitative medicine specialist, in therapists can provide adaptive communication devices
addition to a neurologist, is important for patients with when speech is no longer intelligible. For patients with

NATUre RevIewS | DISeASe PRImeRS | Article citation ID: (2018) 4:27 19
Primer

Direct gene transfer Indirect gene transfer similar to the QOL of patients with more common dis-
orders, such as AD, PD and Huntington diseases. Some
Therapeutic Brain Stem cells
gene
late-​onset LSDs, such as the GM2 gangliosidoses, can
include or even present with psychosis, which affects the
Liver
QOL of caregivers. For adult-​onset LSDs without cog-
nitive dysfunction, depression might be a comorbid fea-
Delivery
vehicle ture, particularly for Fabry disease, in which the rate of
Delivery to
target tissues depression varies from 15% to 62% with the most com-
Cell mon associated factor being neuropathic pain162. Patients
expansion
Delivery to with Fabry disease also have a lower overall QOL than
target tissues healthy individuals163.
Seeking out health-​care providers with specific exper-
Fig. 5 | Gene therapy methods in use for the treatment of LSDs. In general, there are tise in LSDs, usually within the context of an academic
two main methods for introducing a normal copy of the faulty transcript into patients. medical centre, is important for optimal management of
In direct gene transfer, a normal cDNA sequence, usually expressed from a ubiquitous therapies including supportive care. Clinical experience
promoter and containing a non-​native poly(A) signal, is inserted into a vector (common
matters, particularly for patients who require anaesthe-
vectors include adeno-​associated virus and lentivirus), tested for potency in animal
sia for surgery or other procedures164. Patient advocacy
models and/or cells and then manufactured for human application. In direct gene
transfer, the vector is infused into the bloodstream, the cerebrospinal fluid or target groups can aid in providing up-​to-date information on
organs (for example, the brain). In indirect gene transfer, the vectors manufactured for clinical trials and research, as well as durable medical
human use are applied ex vivo to stem cells in culture. Cells expressing the gene product equipment and supportive therapies, and can instruct
are harvested and re-​implanted back into the donor (autologous stem cell therapy). families how to navigate the health-​care system to obtain
In indirect gene therapy , methods of bone marrow ablation (for example, partial or them. Knowing what to expect in the next phase of disease
complete) can affect the extent of grafting. LSD, lysosomal storage disease. progression and how to mitigate its effects on the QOL
can be empowering and transformational for patients and
visual impairment, vision specialists can recommend caregivers. Advocacy groups along with knowledgeable
large-​print books or audio books as well as low-​vision health-​care providers can prepare families for the difficult
strategies for performing activities of daily living. discussions of gastrostomy or tracheostomy tube place-
ment and end-​of-life care. As the parent of a child with
Quality of life infantile Tay–Sachs disease once shared, “Every life has
Diagnosing patients and providing them with a patient a beginning, a middle, and an end. Some are just shorter
advocacy community that has experience in caring for than others. We must plan for a full life for our children”.165
patients and family members with their LSD is impor-
tant and substantially improves the quality of life (QOL) Outlook
of patients and caregivers. Studies addressing QOL for Enormous progress has been made in LSD research
patients with LSDs or their caregivers are uncommon and therapy development over the past two decades,
and, accordingly, are still required. For QOL studies, and many successful clinical trials have resulted in
LSDs can be divided into disorders of childhood or FDA-​approved and/or EMA-​approved therapies that
adult onset and those with progressive neurodegener- have improved patient QOL and survival. However,
ation or those with preserved cognitive functioning. the majority of LSDs remain without an effective ther-
Of 266 parents with children with life-​limiting conditions apy, particularly those with CNS involvement. As such,
(including LSDs), 95% identified receiving information major research efforts are in progress to develop new
from their physician on their children’s QOL as the most generations of therapies that effectively target the brain.
important factor in establishing trust in their child’s Progress has also been made in developing new cellu-
physician157. Parents with children with MPS disorders lar and animal models that better mirror the aberrant
feel the isolation and stigma of living with a rare disor- physiology and pathological processes of patients with
der, the disruption of typical family life, anxiety about LSDs than older models and that can be used to yield
their children’s well-​being (both children with LSDs and new insights into disease mechanisms. These models are
healthy children) and an effect on their own physical also useful for understanding how the pathophy­siology
and psychological health158. Among parents and children of LSDs converges with other human diseases and will
diagnosed with rare disorders, anxiety, social isolation, improve our ability to develop new therapies for rare
fear and uncertainty have been reported in addition to LSDs and more common neurodegenerative diseases.
symptoms of depression159,160. In addition, parents of
chronically ill children who have not been diagnosed New mechanisms of disease
identified increased anxiety and depression161. This The study of LSDs has led to a much greater under-
finding is relevant to the parents of children with LSDs standing of fundamental lysosome biology and has
because the time from onset of symptoms to diagnosis revealed the lysosome to be a highly complex signalling
is lengthy for many families. hub in addition to its role as the catabolic and recycling
Many adult-​onset LSDs involve neurodegeneration, centre of the cell. The integration of lysosomal func-
including loss of the ability to ambulate or perform activ- tion with other aspects of cell metabolism explains why
ities of daily living, with some characterized by progres- lysosomal dysfunction causes damage to many aspects
sive dementia or disordered movement. Accordingly, of cellular homeostasis and damage to other organelles.
the QOL for these patients and their families might be Studying other functions of lysosomes is currently

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 Primer

a very active area of research and will likely hold the key to heat shock proteins such as heat shock protein 70, which
identification of novel clinical interventions in the future. is a protein that is synthesized in response to stress and is
part of the cellular network of molecular chaperones that
Therapeutics assist in protein folding166. To this end, one trial of ari-
ERTs remain the major class of approved therapies for moclomol, which stabilizes the transcription factor that
LSDs. The original ERT drugs were developed for dis- induces heat shock protein 70 expression, is ongoing in
orders that did not include CNS pathology and, there- patients with NPC, and could, in the future, be a general
fore, did not need to access the CNS to show efficacy. LSD therapy as this mechanism could be applicable to
However, the majority of LSDs involve the CNS and the multiple LSDs167 (Table 4).
peripheral nervous system, and drug development must
now include drugs that cross the blood–brain barrier. Stop codon readthrough therapy. In-​frame premature
To accomplish this task, several drugs are being deliv- termination codons can be 'over-​ridden' using small
ered directly to the CNS, and some small molecules that molecules such as gentamycin168, with many more com-
cross the blood–brain barrier are either approved or in pounds now under evaluation or development169. None
clinical trials for LSDs, including SRT, chaperones or are yet approved for an LSD and are not easily tested in
proteostasis modifiers (Table 4). Other major advances most knockout animal models as this would require the
are nucleic-​acid-based or targeted approaches such as model to recapitulate the human stop codon mutation.
gene therapy that have now advanced to clinical trials One example in which this has been achieved in animal
for several LSDs. studies is in the Iduatm1Kmke mouse (a model of Hurler
syndrome), which carries a mutation homologous to the
Proteostasis modifiers. One potential therapeutic human W402X nonsense mutation170.
approach for LSDs is based on rescuing the function
of misfolded mutant proteins by harnessing the cell’s Disease-​specific and anti-​inflammatory therapies. For
endogenous proteostasis machinery via enhancement of some LSDs, such as NPC, disease-​specific modifiers
are being evaluated in clinical trials (Table 4). For exam-
ple, intrathecal hydroxypropyl-​β-cyclodextrin is being
a Genomic DNA evaluated in phase II/III clinical trials on the basis of
3' 5'
promising phase I/II clinical data from an observational
5' 3'
Target gene study171. The precise mechanism of action of this drug
has not been completely defined172,173, but the drug mobi-
Double-stranded break lizes storage of cholesterol and sphingolipids from the
brain in animal models of NPC173,174. Anti-​inflammatory
therapies, such as adalimumab, an anti-​TNF monoclonal
antibody, are also being evaluated in trials for several
Homology-directed repair Non-homologous end joining LSDs, including MPS I and MPS II (Table 4).

Gene therapy. Gene therapy for the LSDs has a similar

Insertions or deletions (indels)
premise to ERT, with the important benefit that frequent
dosing would be unnecessary or at the very least infre-
quent. For gene therapy in general, an expression cas-
Single base-pair change sette containing the gene encoding the deficient enzyme
is delivered to cells via a vector175, usually an adeno-​
b Zinc fingers TALENs CRISPR–Cas9 associated virus (AAV), a lentivirus or a non-​viral-based
system176 (Fig. 5). These cells can secrete the recombinant
enzyme into the blood, the CSF or surrounding tissues.
The tropism of lentiviruses and AAVs can vary depend-
ing on the characteristics of the viral envelope (with
lentiviruses) or the viral capsid (with AAVs)177–179. One
Fig. 6 | Gene editing. a | Gene editing for correcting lysosomal enzyme deficiencies could positive feature of the AAV9 serotype is that it can trans-
involve inactivating an enzyme that has a role in substrate production, therefore, less duce cells of the CNS after intravenous infusion180,181,
substrate is available for storage (through non-​homologous end joining) or by editing and and AAV variants based on this serotype can be engi-
correcting the mutant gene through homology-​directed repair. Non-​homologous end neered to enhance gene delivery. Accordingly, several
joining after DNA editing often leads to a deletion or insertion that reduces target gene AAV9 vectors are in clinical trials for LSDs182. Studies
expression, providing for lasting substrate reduction therapy. For homology-directed using AAV9 in patients with spinal muscular atrophy
repair of a mutant lysosomal disease gene, a DNA template containing a sequence-​ (a neurodegenerative disease) have resulted in profound
corrected portion of the gene is provided along with the editing machinery ; with cutting clinical improvement in neurological symptoms follow-
and homology-​directed repair, the mutation is corrected. Gene editing approaches
ing intravenous infusion183. Affected children that would
could also be used to insert functional cDNA expression cassettes into a safe harbour
locus using a similar homology-​directed repair mechanism. b | The most common
normally succumb to disease without gaining the abil-
methods to achieve gene editing include zinc-​finger nucleases, TALENs (transcription ity to crawl or roll over are meeting major milestones,
activator-​like effector nucleases) and the more easily adaptable CRISPR–Cas9 systems. including walking and talking.
Each system can be adapted to induce targeted non-​homologous end joining or The most clinically advanced gene therapy for LSDs
homology-​directed repair. is a dual approach for metachromatic leukodystrophy,

NATUre RevIewS | DISeASe PRImeRS | Article citation ID: (2018) 4:27 21
Primer

in which bone marrow stem cells isolated from patients Challenges of designing clinical trials
are transduced in vitro using lentiviral vectors encoding LSDs are individually rare and for many the natural
ARSA to overexpress the missing arylsulfatase A enzyme history is not well characterized. A major hurdle in
and are subsequently re-infused into the patient (Table 4). the approval of disease-​modifying therapies is patient
After transplantation, the cells migrate to the brain and recruitment and a clinical trial design that can defin-
other organs, where they secrete arylsulfatase A. Patients itively determine whether a treatment is efficacious.
with metachromatic leukodystrophy who receive this In addition, the time from onset of symptoms to diag-
treatment have improved function and lifespan relative nosis is excessive, disease progression is variable even
to their untreated siblings184. Direct infusions of AAV within a given subtype and good natural history data
expressing the corrected gene into blood, CSF or tissues are lacking for many LSDs. Recruiting fairly homo­
have also been tested in early clinical studies (Table 4). In geneous patient populations is therefore difficult, and
these studies, although only some cells would be geneti- robust outcome measures are often lacking. Trials for
cally corrected, the supposition is that a sufficient num- rare diseases are by definition small and tend to be
ber of cells will overexpress the gene product for cross underpowered, and for LSDs this is compounded by
correction of non-gene-corrected cells. clinical heterogeneity. What clinical parameters might
ASOs are often considered a tool for reducing the be responsive to a given therapy and in what time
expression of a mutated gene and act by binding to target frame clinical change will manifest is also unclear and
mRNAs to block the translation of the abnormal pro- can affect trial design. Efforts to improve the situation
tein or induce its degradation. ASOs could be useful for include creating patient registries, increasing awareness
inhibiting the proteins necessary for the production of to reduce the diagnostic delay and improving clinical
stored substrates (nucleic-​acid-based SRT)185. However, trial design where possible.
ASOs can also promote splicing around mutations186,187.
Although ASO therapies for LSDs are only in early pre- Era of treatment leading to new symptoms
clinical testing using cellular and animal models, this LSDs are multisystem disorders. Therapies understand-
therapy has been approved for clinical use for other indi- ably target the most clinically meaningful (often life-​
cations188,189, which might warrant further investigation altering) finding (for example, cardiovascular symptoms
for broader utility in LSDs. in infantile Pompe disease). With the primary symp-
Genome editing for treating an LSD can refer to cor- tom improved or ameliorated with effective therapies,
recting the mutated gene directly or editing the genome ‘secondary phenotypes’ are now emerging and require
to insert a new functional copy of the deficient gene190,191 treatment. Combination therapies to address the diverse
(Fig. 6a). For the correction of LSD-​causing genes, the symptoms of LSDs will undoubtedly be required and are
target locus needs to be edited and a functional copy of now being employed.
the gene or a corrected copy of a portion of the mutant In summary, the LSD field is a vibrant basic research
locus inserted. These types of editing require homology-​ and translational arena with major advances in under-
directed repair and, regardless of the delivery method standing disease mechanisms and the development of
used (viral and non-​viral approaches), can be done novel therapeutics to complement approved ERTs and
with zinc-​finger nucleases, transcription activator-​like small molecules. The convergence in pathogenetic
effector nucleases (TALENs) or CRISPR–Cas9-based pathways between LSDs and other diseases will shed
systems192 (Fig. 6b). The first gene therapy trials using much-​needed light on fundamental disease mechanisms
editing for correcting an LSD are underway for MPS II and lead to some innovative cross-​disease therapeutic
and involve the AAV-​mediated correction of a mutant platforms in the future.
IDS sequence using zinc-​finger nucleases (Table 4) based
on earlier preclinical work191. Published online xx xx xxxx

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