Inborn Errors of Metabolism

Namrata Singh M.D

Introduction to IEM
 Usually a single gene defect that
causes a block in metabolic
pathways.

 Problems are because of

accumulation of enzyme substrate
behind the metabolic block or
deficiency of the reaction product.
Intro. Contd…

 In some instances the substrate is

diffusible & affects distant organs &
in some there is just a local effect
( lysosomal storage disease ).
Intro. Contd…
 Clinical presentation is varied 
mild to severe forms ( mutations
even in the same gene may be
different in different people ).

 Can present at any time.

 Can affect any organ system.
IEM ~~ General approach
 DIAGNOSIS : Some clinical
presentations:-
 Consider in DDx . when dealing with :-
 Critically ill infant
 Seizures
 Encephalopathy (Reyes like syndrome )
 Liver disease
 MR or developmental delay or regression
 Recurrent vomiting
 Unusual odor
 Unexplained acidosis
 Hyperammonemia
 hypoglycemia
IEM~~ General approach
 Some clues to look for :-
 *Symptoms accompany changes in
diet.
 *Developmental regression.
 *History of food preferences or
aversions.
 *History of consanguinity in parents.
 *Family history of MR , unexplained
deaths in cousins or siblings etc.
IEM ~~ General approach
 Physical exam:- common findings—
 Alopecia or abnormal hair
 Retinal cherry red spot
 Cataracts or corneal opacities
 Hepatosplenomegaly
 Coarse features
 Skeletal changes ( gibbus)
 Ataxia
 FTT
 Micro or macrocephaly
 Rash / jaundice /hypo or hypertonia
 IEM ~~ General approach
 Lab tests:- almost always needed—
 Serum electrolytes
 Ph ( anion gap & acidosis )
 Se lactate
 Se pyruvate
 Ammonia
IEM ~~ General approach
 Labs:- more specific labs—
 Serum & urine amino acids
 Urine organic acids
 DNA probes
 Glycine in CSF (glycine encephalopathy)
 Urine ketones
 If + in neonates  IEM
 If – in older child  IEM ( defect in f.a.

oxidation )
IEM – Clinical situations
 MR or dev delay 
 Can occur alone.
 Seen in urea cycle ,a.a disorders.
 Also in organic acidemias ,peroxisomal
& lysosomal storage disorders.
 Serum & urine a.a .
 Urine for mucopolysacchiduria.
IEM – Clinical situations
 Ill neonate :-
 Clinically indistinguishable from sepsis.
 Usually disorders of protein & CHO
metabolism.
 Acidosis or altered mental status out of
proportion to systemic symptoms.
 Labs:
 Lytes , NH3, gluc , ketones , urine ph ,glycine

in CSF.
 Se & urine for a.a & o.a (* before oral intake

is stopped or pt is transfused)
IEM – Clinical situations
 Vomiting & encephalopathy :-
 Same studies !!
IEM – Clinical situations
 Hypoglycemia :-
 Seen in fatty acid oxid
defects ,glycogen storage
diseases ,hereditary fructose
intolerance & organic acidemias.
 Other labs:-
Urine ketones ~(+) in GSD & organic
acidemias. ~(-) in HFI & f.a. oxidation
disorders
IEM Clinical situations
 Hypoglycemia contd…
 Other labs:-
 NH3 elevated in organic acidemias &
fatty acid oxidation defects.
 Urine reducing subst.– (+) in

galactosemia ,HFI.
 Urine organic acids
IEM Clinical situations
 Hyperammonemia :-
 initially – poor appetite , irritability . Then ,
vomiting , lethargy , seizures & coma.
 Tachypnea – direct effect on resp. drive.
 Seen in (1)- urea cycle disorders (2)- organic
acidemias (3)- transient hyperammonemia of
the newborn.
 Resp alkalosis : urea cycle disorders &
transient hyperammonemia of newborn.
 Acidosis : organic acidemias
 HYPERAMMONEMIA

RESP ALKALOSIS ACIDOSIS

UREA CYCLE DEFECTS ORGANIC ACIDEMIAS

TRANSIENT HYPERAMMONEMIA OF NEWBORN

SE CITRULLINE—LOW– EARLY UREA CYCLE DEFECT

SLIGHTLY ELEV– TRANSIENT HYPERAMMONEMIA OF NB

MARKEDLY ELEV– CITRULLINEMIA & ARGINOSUCCINIC ACIDEMIA

IEM Contd…
 Early urea cycle defects :
 OTC Defect 
 incr. Urine orotic acid levels
 Fam hx of male newborn deaths
 X- linked trait
IEM Contd…
 Acidosis :-
 With recurrent vomiting.
 With elevated NH3.
 Out of proportion to clinical picture.
 Difficult to correct.
 Seen in organic acidemias , MSUD ,GSD ,
disorders of gluconeogenesis.
 Increased anion gap (ketoacids ,lactic acid ,
methylmalonic acid.)
IEM Contd…
 Acidosis :- additional tests—
 Se glucose
 NH3
 Urine pH
 Ketones
 Amino & organic acids
 Blood lactate & pyruvate
IEM Contd…
 Lactate & pyruvate—
 Measure in arterial blood.
 Normal Ratio is 10:1 to 20:1.
 High ratio
 Mitochondrial disorders.
 Pyruvate carboxylase deficiency.

 Normal or low ratio

 Glycogen storage disease.
 Pyruvate dehydrogenase deficiency
IEM~~ Management
 Broad management :-
 Problems severe acidosis , hypoglycemia ,
hyperammonemia . Can lead to coma & death!
 Stop all oral intake.
 Give I/V glucose to stop catabolism.( most
respond favorably to glucose – some do not
eg. Primary lactic acidosis in pyruvate
dehydrogenase deficiency .)
 Bicarb.
 Hyperammonemia – may need dialysis .
IEM ~~ Management
 Specific interventions :-
 Urea cycle disorders-
 * preventing protein catabolism ( high
calorie diet , arginine supplementation )
 * decreasing NH3 load (protein

restriction )
 * utilizing NH3 scavengers

( benzoate ,phenylbutyrate)
IEM~~ Management
 PKU-
 *Avoid enzyme substrate in diet.
 *Diet low in phenylalanine ( Lofenelac ,

Phenylfree, Analog XP , Maxamaid XP )

 *Protein restriction.

 Galactosemia-
 *galactose free diet ( soy formulas
contain sucrose rather than lactose )
IEM~~Management
 Isovaleric acidemia-
 Pharmacotherapy to remove accumulated
substrate –( glycine treatment).
 Methylmalonic acidemia-
 Provide co-enzyme ( vit B12)
 Gauchers disease-
 Provide normal enzyme (enzyme
infusions)
IEM~~Management
 Wilsons disease-
 Liver transplantation.
 HFI-
 Restriction of fruits & fruit juices .
IEM Some associations

 Sweaty feet odor  only 2 disorders !!

 Isovaleric acidemia
 Glutaric acidemia type 2
 Glutaric acidemia type 1
 Extra pyramidal movement disorders
 Retinal hemorrhages /IC bleeding (like shaken
baby syndrome)
IEM Associations
 Fatty acid oxidation defects –
 LC Acyl CoA dehydrogenase deficiency
cardiomyopathy!!
 MC Acyl CoA dehydrogenase deficiency no
cardiomyopathy!!
 Both have hypoketotic hypoglycemia.
 Carnitine deficiency cardiomyopathy
( carnitine is essential for transportation
of LCFA into mitochondria for
metabolism )
IEM  Associations
 All are AR inherited other than
 Lesch Nyhan syndrome – XLR.
 OTC deficiency – XLR.
 Fabry’s disease – XLR.
 Hunter’s syndrome – XLR ( vs Hurler’s
syndrome – AR)
IEM Associations
 Odors :-
 Glutaric acidemia type 2– sweaty feet
 Isovaleric acidemia – sweaty feet
 Hawkinsuria – swimming pool
 MSUD – maple syrup
 Methionine malabsorption – cabbage
 Multiple carboxylase deficiency – tomcat urine
 Oasthouse urine disease– hops like
 PKU – mousy or musty
 Trimethlyaminuria – rotting fish
 Tyrosinemia – rancid fishy or cabbage like
IEM  Associations
 Cherry red spot 
 Sialidosis
 Nieman –Pick’s disease
 Gaucher’s disease (flank shaped
osteolytic lesions)
 GM1 gangliosidosis
 Tay- Sach’s disease ( eastern european
Jews)
 Sandoff’s disease ( pan ethnic)
IEM  Associations
 Wolman’s syndrome  adrenals enlarged
& calcified.
 Farber’s disease  arthropathy , painful
joints .subcutaneous nodules.
 Metachromatic leukodystrophy ataxia ,
dementia.
 Lesch-Nyhan’s self mutilation ,
hyperuricemia , hyperuricosuria , gouty
arthritis , urate ureterolithiasis)
IEMAssociations
 Corneal clouding
 Seen in mucopolysaccharidosis.
 Seen in Hurler’s, Scheie’s & Morquio’s.
 Hurler’s – AR, HSM, umbilical hernia ,
coarse facies , corneal clouding , gibbus
, heart disease).
 Hunter’s – X –linked ( all the above but
no corneal clouding & no gibbus.)
 INITIAL FINDINGS ( POOR FEEDING , VOMITING , LETHARGY, CONVULSIONS ,COMA )

METABOLIC DISORDER INFECTION

OBTAIN PL. NH3

HIGH NORMAL

OBTAIN BLOOD Ph & CO2 OBTAIN BLOOD Ph & CO2

NORMAL ACIDOSIS NORMAL

UREA CYCLE DEFECTS ORGANIC ACIDEMIAS AMINOACIDOPATHIES

GALACTOSEMIA
Disorders Of CHO Metabolism
 Glycogen storage diseases:-
 Glycogen is stored in liver & muscle.
 Can see growth failure , hepatomegaly,
hypoglycemia.
 LIVER:- ( 1,3,6,9)
 TYPE 1– Von Gierkes ( gluc-6-
phosphatase def)
 TYPE 3– Def of debrancher enzyme

 TYPE 6– Hepatic phosphorylase def

 TYPE 9– Phosphoryl kinase def

CHO Metabolism
 GSD :--
 MUSCLE :- ( 2,5,7)
 TYPE 2– Pompes --acid maltase def. 
cardiomegaly & macroglossia.
 TYPE 5– Muscle phosphorylase def
 TYPE 7– Phosphofructokinase def.
( easy fatigability ,muscle weakness,
stiffness)
CHO Metabolism
 Diagnosis response of blood glucose to
fasting & glucagon.
 Enzyme assays on leucocytes , liver , muscle.
 Pompes – fibroblasts or WBC’s (peripheral ).
 Treatment 
 Prevent hypoglycemia while avoiding storage
of even more glycogen in liver.
 Specific diets ( restrict free sugars ; continuous
night time CHO feedings )
CHO Metabolism
 GALACTOSEMIA :-
 AR
 Classic  def of galactose-1-PO4-uridyl
transferase.
 Accumulation of galactose -1-PO4 in
liver (liver parenchymal disease) ,
brain( MR) , renal tubules (renal
fanconi syndrome).
 Galactilol accumulation in lens causes
cataracts.
CHO Metabolism
 Galactosemia contd:-
 Severe form vomiting ,jaundice ,
hepatomegaly
 E.Coli sepsis
 Cataracts develop in 1st 2 mos of life

 Hepatic cirrhosis is progressive

 Less severe cases  survival is possible

but MR is inevitable
 Ovarian failure is also commomly seen
CHO Metabolism
 Galactosemia contd:
 Diagnosis:-
 Enzyme def in RBC’s – Beutler test
 False neg with blood transfusions

 False pos with blood sample deterioration

 Increased serum galactose

 Galactosuria
 Proteinuria & aminoaciduria
 Tx :- galactose free diet.
CHO Metabolism
 HEREDITARY FRUCTOSE INTOL:-
 AR
 Def. of Fructose -1-PO4- aldolase.
 Signs /symptoms:-
 Hypoglycemia (tissue accumulation of fructose
-1-PO4 after fructose ingestion).
 FTT.

 Jaundice

 Hepatomegaly.

 Proteinuria & aminoaciduria.

 Liver failure & death.

CHO Metabolism
 HFI – contd:
 Diagnosis-
 Fructosuria after fructose load
( inpatient).
 Hypoglycemia.

 Hypophosphatemia .

 Tx:--
 Eliminate fructose. ( problem lots of
things have sucrose in it ).
Disorders of A.a. Metabolism
 Urea cycle disorders:
 In infancydefects in early urea cycle
enzymes seen.
 Carbamoyl PO4 synthetase def (AR).
 Ornithine transcarboxylase def(X-linked)
 S/S 
 severe & rapidly fatal hyperammonemia.

 Vomiting & encephalopathy.

 Always check NH3 in an acutely ill

newborn ,without an identifiable cause!!
A.A metabolism
 Urea cycle defects contd:
 Childhood:-
 Citrullenemia – arginosuccinic acid
synthetase deficiency.
 Arginosuccinicacedemia –
arginnsuccinic acid lyase deficiency.
 More chronic course with MR.
A.A Metabolism
 Diagnosis :--
 Incr. NH3 with resp. alkalosis.
 Se. citrulline is low in CPS & OTC deficiency.
 Se. citrulline is high in arginosuccinicacidemia.
 Se. citrulline isVERY high in citrullinemia.
 Urine orotic acid is high in OTC deficiency &
also h/o deaths in male newborn infants.
 s/s sometimes vary with age , protein intake ,
growth & stressful situations like infections.
A.A Metabolism
 Many female carriers of OTC def
show protein intolerance – migraine
like symptoms with protein
intake ,vomiting & encephalopathy
with infections and L&D.
 Trichorrehxis nodosa is common in
chronic forms of
arginosuccinicacidemia.
A.A Metabolism
 Treatment :--
 Decrease NH3 by hemo or peritoneal dialysis
or double volume exchange transfusion.
 d/c protein intake.
 Give glucose to reduce endogenous protein
breakdown.
 Give arginine I/V ( essential a.a for pts. With
UC defects ; increases the excretion of
nitrogen in pts. With citrullenemia &
arginisuccinicacidemia .)
 I/V Na benzoate ,Na phenylbutyrate ,Na
phenylacetate – for coma due to increased
NH3.
A.A Metabolism
 Long term treatment :-
 Oral administration of arginine or
citrulline.
 Low protein diet.
 Na benzoate to incr. Excretion of
nitrogen as hippuric acid or
phenylacetylglutamine.
A.A Metabolism
 PKU & Hyperphenylalanemia:
 PKU  decreased activity of
phenylalanine hydroxylase ; ( converts
phenylalanine to tyrosinen)
 1 in 10,000
 AR.

 With normal phenylalanine intake pts

develop hyperphenylalanemia, make &

secrete phenylpyruvic , phenylactic &
phenylacetic acid.
A.A Metabolism
 PKU :-
 Clinical features:
 MR
 Hyperactivity

 Seizures

 Light complexion

 Eczema

 Mouse like odour

A.A Metabolism
 In classic PKU little or no
phenylalanine hydroxylase activity
but in less severe forms there is
significant residual activity.
 Some have dihydropterin reductase
deficiency or other defects in
biopterin synthesis.
 All are inherited as AR.
A.A Metabolism
 PKU Dx :
 In newborn- persistent incr in levels of
phenylalanine.( > 20 mg/dl.)
 Nl or low levels of tyrosine.
 Phenylpyruvic acid in urine.

 Normal pterins.

 Transient hyperphenylalanemia in NB if
mother has PKU.
A.A Metabolism
 Note :- if PA levels are persistently high in
the mother  MR ,microcephaly, FTT &
CHD.
 Restrict PA intake before conception &
maintain through pregnancy.
 Treatment:-
 Limit dietary intake of PA to levels that
promote normal G&D.
 Monitor levels of PA.
 monitor growth.
A.A Metabolism
 Pku tx contd:-
 PA restriction should continue all thru
life decrease in IQ & behavior
changes take place in pts who go off
the diet early  can happen anytime.
 Potential for normal G&D if treatment
started early.
A.A Metabolism
 HEREDITARY TYROSINEMIA :-
 Def of fumaryl acetoacetase.
 AR.
 Progressive liver parenchymal disease.
 Renal tubular dystrophy.
 Hypophosphatemic rickets.
 Hypermethionemia.
 Tyrosine metabolites in urine.
 Rapidly fatal.
 Common in Scandinavia & Quebec.
A.A Metabolism
 Hereditary tyrosinemia contd :
 Diagnosis :-
 Incr succinyl acetone in urine. ( similar
clinical & biochemical findings as in
Galactosemia & fructose intolerance.)
 Treatment :-
 Diet low in PA & tyrosine.( 50mg/kg/day
each)
 Not usually sucessful.

 Liver transplantation is the only effective

treatment.
A.A Metabolism
 MSUD :- (branched chain
ketoaciduria)
 AR.
 Def of enzyme that catalyses oxidative
decarboxylation of branched chain
ketoacid derivatives of leucine ,
isoleucine & valine.
 Accumulated ketoacids of leucine &
isoleucine cause characteristic odor.
 Only ketoacid of leucine is implicated in
CNS dysfunction.
A.A Metabolism
 MSUD:-
 Diagnosis :-
 Often normal @ birth but soon develop
characteristic odor.
 Vomiting ,lethargy ,feeding problems , coma ,
death.
 If not diagnosed early & dietary restrictions of
branched chain a.a not started, most die in 1st
month of life.
 Prognosis is good if tx is begun before 10 days of
life.
 Labs :- Br. Chain a.a esp. alloisoleucine
(transamination product of isoleucine ) is almost
pathognomic.
A.A Metabolism
 MSUD:-
 Treatment:-
 Dietary restriction of br. Chain a.a in
amounta sufficient for growth.
 Check levels of br. Ch. A.a at frequent

intervals( 1-2 months ) {protein

requirements change in 1st few months of
life }
A.A Metabolism
 HOMOCYSTINURIA:-
 Def of cystathione synthase.
 AR
 MR.
 Arachynodactyly.
 Dislocated lenses.
 Thromboembolic phenomenon (assoc with
arteriosclerotic heart problems & mild
hyperhomocystinemia )
A.A Metabolism
 Diagnosis :-
 Homocystinuria.
 Se methionine levels are high.
 Megaloblastic anemia when def of methyl B12.
 Treatment:-
 50% respond to large doses of pyridoxine.
 Cobalamin.
 Betaine.
 Methionine restriction.
Others
 NONKETOTIC HYPERGLYCENEMIA:
 AR.
 Glycine encephalopathy:-
 Unremitting seizures.

 Hiccups.

 Hypotonia.

 Burst suppression pattern on EEG.

 Death in infancy.

 Dx: incr glycine in CSF.

 Tx: generally unsucessful , Na benzoate may
help seizures.
Others
 ORGANIC ACIDEMIAS:
 Isovaleric acidemia &glutaric acidemia 2 only
two assoc with sweaty feet odor.
 Ketotic hyperglycinemia is an organic
acidemia.(Propionic & Methylmalonic
acidemia.)
 Glutaric acidemia 1:
 Extrapyramidal movt disorders (dystonia &
athetosis )
 Retinal hges & IC bleeding ( like shaken baby
synd)
 Macrocephaly.
Others
 FATTY ACID OXIDATION DEFECTS:
 LC Acyl CoA def - cardiomyopathy.
 MC Acyl CoA def  NO
cardiomyopathy!
 Both have hypoketotic hypoglycemia.
 Carnitine def :- cardiomyopathy
( carnitine is essential for transport of
LCFA into mitochondria for
metabolism.)
Others
 PURINE METABOLISM :-
 Lesch Nyhan Syndrome:
 X – Linked recessive.
 Hypoxanthine Guanine Phosphoribosyl
Transferase deficiency.
 CNS dysfunction with hyperuricemia &
hyperuricosuria.
 MR, chorea , spasticity , mutilating fingers
& toes.
 Gouty arthritis.

 Urate ureterolithiasis.
Others
 LYSOSOMAL DISEASES:-
1. Mucopolysaccharidoses .
2. Lipidoses .
3. Mucolipidosis .
Deficiency of lysosomal enyzymes
causing the substrate to
accumulate in specific tissues .
Others
 Mucopolysaccharidosis :-
 Hurler :-
 AR
 MR.

 HSM.

 Umblical hernia

 Corneal clouding.

 Gibbus.

 Heart disease.
Others
 Mucopolys:-
 Hunter :-
 X – linked.
 All of Hurlers BUT :-

 NO CORNEAL CLOUDING .

 NO GIBBUS.

 Scheie & Morquio synd also have

corneal clouding.
Others
 Mucolipidosis :-
 Sialidosis  cherry red macular spot.
 Lipidosis :-
 Nieman Pick 
 Eastern Jews.
 Sphingomyelinase def.

 Accumulation of sphingomyelin in
lysosomes of RE system & CNS.
 HSM , cherry red spot in macula.
Others
 Lipidosis :-
 Metachromatic leukodystrophy:-
 Accumulation of sulfatide in white matter.
 Gait problems.

 Ataxia ,inco-ordination , dementia .

 Fabry’s  X – Linked recessive.

 Farber’s  arthropathy , painful joints ,
subcutaneous nodules.
Others
 Lipidosis :-
 Gauchers –
 Macular cherry red spot.
 Flask shaped osteolytic lesions.
 GM 1 gangliosidosis  cherry red spot.
 GM 2 gangliosidosis:
 Tay – Sach’s :
 Eastern european jews , hyperacusis , MR ,
hypotonia , cherry red spot.
 Sandoff’s:
 Similar but PANETHNIC.
 Wolman’s adrenals big & calcified.