IEM

INBORN ERROR OF
URINE ODOR
METABOLISM
Glutaric acidemia Sweaty feet,
(type II)
acrid
Hawkinsinuria
Swimming pool
3-Hydroxy-3methylglutaric
Cat urine
aciduria
Sweaty feet,
Isovaleric acidemia
acrid
Maple syrup urine

Hypermethioninem
ia
Multiple
carboxylase
deficiency
Oasthouse urine
disease
Phenylketonuria
Trimethylaminuria
Tyrosinemia

Boiled cabbage
Tomcat urine
Hops-like
Mousey or musty
Rotting fish
Boiled cabbage,
rancid butter

Juvenile onset of DM
Protein deficiency DM
Fibrocalcific pancreaticopathy

Homocystinuria
cystathionine synthetase deficiency (AR) type 1
Here cystathionine is not synthesized from
homocysteine and serine homocsteine
accumulates oxidized to homocystine
excreted in urine
Methionine donates its CH3 group group to form
homocysteine. The reaction is catalyzed by an
enzyme methyltransferase ( derived from N5
methyl THF or betaine)

developmental delay, seizures

ectopia lentis-medial, downward
High myopia, diplopia
Mental retardation
Pectus excavatum
Skeletal manifestations resemble Marfan's syndrome.
Thromboembolic episodes

Homocystine in urine cyanide nitroprusside test

cherry red
Rx: coenzyme pyridoxine + folic acid

Types of homocystinurias
Homocystinuria Classical Cystathionine
synthase
Homocystinuria II def of N5-methyl-tetrahydrofolate methyl transferase dementia,
seizures and megaloblastic anemia
Homocystinuria III N5,10 methylene
tetrahydrofolate reductase mental
retardation. Improves on taking Folate.

Cystinuria
AR
Selective increase in the renal clearance and urinary
excretion of basic amino acids cystine, lysine, arginine
and ornithine.
As concentration of cystine in urine is high tends to
precipitate leading to formation of radio opaque
cystine renal calculi (transparent, hexagonal crystals
which are soluble in alkaline urine)
Rx: stone formation reduced by maintaining a good flow
of urine and urinary alkalinization.
D-penicillamine
Captopril

Phenylketonuria
AR
Def. of phenylalanine hdroxylase or
cofactor tetrahydrobiopterin (BH4)
Phenylalanine converted to phenyl
pyruvic acid, phenyl lactic acid, ohydroxy phenyl acetic acid
Phenylalanine
hydroxylase
L- Phenylalanine
Tyrosine
O2

L-

H2 O

Mental retardation,
microcephaly, CHD in children
if maternal PKU.
musty odour of urine or sweat
blond hair, fair skin (no
tyrosine formn and hence no
melanin)
aggressive or self-injurious
behavior
Reduced tendon reflexes
Enamel hypoplasia
vomiting

Screening testFerric chloride test

(Phenestix) in urine
- Dark green
colour
Confirmatory testGuthrie
microbiological
assay
in blood or
Rx: restrict
urine
phenylalanine

 Maternal phenylketonuria/
hyperphenylalaninemia MR,
microcephaly, congenital heart
disease

Tyrosinemia
Type 1 = def. of fumarylacetoacetate hydrolase
affects liver, peripheral nerves, renal (fanconis like
syndrome rickets, failure to thrive)

Type 2 =oculocutaneous tyrosinemia.

Def. of tyrosine aminotransferase

Type 3 = def of 4HPPO

 Tyrosinemics more susceptible to

develop hepatic carcinoma
Rx restrict phenylalanine, tyrosine,
methionine

Albinism
Tyrosinase deficiency
Oculocutaneous type and ocular type
Depigmented skin
Photophobia, nystagmus
Decreased visual acuity

Chediak higashi oculocutaneous albinism,

neutropenia, susceptibility to pyogenic infection

Alkaptonuria
Def of homogentisic
acid oxidase (in the liver
and kidney)
Inhib breakdown of
homogentisic acid
excreted unchanged in
urine
Blackening of urine
upon standing.
Homogentisic acid
oxidised to
benzoquinone acetate

 Arthritis and connective tissue pigmentation

( ochronosis usually cartilage of nose and ears)
pigment alkapton or benzoquinone acetate.
Deposition in sclera
Fusion of vertebral bodies, narrowing of joint
spaces
Ferric chloride test-transient blue colour
Rx: Vit C, Nitisinone inhib enzyme that produces
HGA

MSUD
Defect in branched chain alpha ketoacid
dehydrogenase (BCAKAD)
Valine, isoleucine, leucine
Neurotoxic affects (ataxia, seizures, decerebrate
rigidity), maple syrup smell, hypoglycemic attacks
(increased leucine)
Screening tests in urine1. Ferric chloride test -gray blue colour
2. 2, 4 dinitrophenyl hydrazine test yellow white
precipitate

Organic Aciduria
Presents with increased anion gap
metabolic acidosis
Clinical presentation of toxic
encephalopathy vomiting, poor
feeding, neuro symptoms like
seizures, aabnormal tone, lethargy
and coma.
Older children loss of intellectual
function, ataxia, other focal neuro

Clinical pointers to specific organic

acidurias
Perioral eruptions, kinky hair,
alopecia multiple carboxylase
deficiency
Dysmorphic features mevalonic
aciduria, 3 OH isobutyric aciduria

Urea cycle defects

5 steps in urea cycle deficiency of
enzymes accumulation of
ammonia encephalopathy
Defect in stage 1,2 - ammonia
Defect in stage 3 cutrullinemia
Defect in stage 4 arginino-succinic
acidemia
Last stage defect hyperargininemia

 c/f- patients intolerant to proteins vomiting,

irritability
lethargy, coma, ataxia, convulsions
mental retardation, muscular rigidity, opisthotonos
Argininosuccinic acidemia - dry, breakable and short
hair
Rx: sodium benzoate, sodium phenylacetate
conjugates with ammonia; carnitine supplementation
hemodialysis, peritoneal dialysis, hemofiltration if
ammonia exceeds 500 mmol/L

 Defect in transport of monoamino monocarboxylic

acid across renal tubular cells
Clinical features simulate Pellagra

Pellagra
Photosensitivity
Cerebellar ataxia
Psychological disturbance

Rx: oral intake of Nicotinamide; high protein intake

Lipid metabolism disorders

Wolmans disease acid lipase
Farbers disease acid ceramidase
Niemann Pick Sphingomyelinase
Gaucher Acid beta glucosidase

 Krabbe- Globoid cell leukodystrophy Galactocerebrosidase

Metachromatic leukodystrophy
Arylsulfatase A
Fabry Alpha galactosidase A

 GM 1 gangliosidosis beta galactosidase

Hsmegaly, cherry red spots, dysostosis,
die of respi infection before 2 years
GM2 Gangliosidosis
type 1 = Tay Sachs Hexosaminidase A
(devt delay, hyperacusis, cherry red
spots, hypotonia, apathy, no
organomegaly)

 type 2 - Sandhoffs
Hexosaminidase A and B features
of Tay Sachs + visceral involvement
Mannosidosis alpha and beta
mannosidosis

Carb metabolism
Galactosemia type 1 galactose 1 PO4
uridyl transferase
Benign fructosuria fructokinase deficiency
Hereditary fructose intolerance fructose 1
PO4 aldolase
Pentosuria L- Xylulose reductase

Galactosemia
Absence ofGalactose-1-Phosphate
Uridyltransferase(Uridyl Transferase)
orGalactokinase (milder- only cataract)to act
onGalactose.
Galactoseis acted on byAldose Reductaseand
turned into accumulation ofGalactitol(toxic -esp
in eye causing cataract oil drop cataract)
c/f liver dysfunction, MR, vomiting, diarrhea, FTT
Associated with E.coli sepsis

Glycogen storage disorders

Type 1 Von Gierke glucose 6 phosphatase
deficiency
Type 2 Pompes affects the Pump (Heart) lysosomal alpha 1,4 glucosidase deficiency/ acid
maltase
Type 3 limit dextrinosis or cori or forbes disease
debranching enzyme deficiency
Type 4 Anderson branching enzyme deficiency
(only one which is a defect in glycogen synthesis)
Type 5 McArdle muscle phosphorylase deficiency
Type 6 - Hers Hepatic phosphorylase enzyme
deficiency
Type 7 Tarui phosphofructokinase deficiency

Von gierke
Hypoglycemia (cannot synth
glycogen), Lactic acidosis, seizures
Doll like facies
Hepatomegaly
Glucose 6 phosphatase defect

Pompes
0-6m
Tall QRS, left axis deviation, short PR interval
Lysosomal acid alpha 1,4 glucosidase
deficiency
Dx: low levels of acid maltase
Floppy infant syndrome, feeding difficulties,
macroglossia, hepatomegaly, heart failure

 Liver affected in GSD type 1,3,4,6,7,9,10

2 cardiac
Skeletal muscle 2b, 3, 5, 7 hypotonia,
muscle weakness
Abnormal structure -3,4 abnormal
branching, debranching causes change in
structure.

Wilsons disease
AR
Chr 13 ATP7B
Lysosomal Cu excreted in insufficient
amount in bile
Binding of copper by metallothionine
is increased
Jaundice, hepatomegaly, basal
ganglia involvement, ataxiaparkinsonism, KF ring.

 Low serum ceruloplasmin (a

glycoprotein with 6 Cu atoms)
Low serum Cu
Liver Cu > 250 microgm of dry
weight
Rx: d- Penicillamine, decrease Cu
intake, Zinc, Triethline tetra-amine
dihydrochloride (trien)

Gauchers disease
AR
MC lysosoml storage disorder
Massive spleen, pathological
fractures, bone pain, hypersplenism
Deficiency of glucosylceramide beta
glucosidase / glucocerebrosidase

 Dx:
Gaucher cells cerebroside laden, eccentric
nuclei, cytoplasm like crumpled silk, PAS +
Types:
Type 1 chronic non neuropathic visceral
involvement
Type 2 acute neuronopathic death before 2
years, prominent neuro symptoms
Type 3 chronic neuronopathic

 Rx:
Treated with enzyme replacement therapy
with recombinant acid beta glucosidase
OGT 918 therapy Miglustat principle
of substrate redution therapty
First storage disorder with treatment
available.

Enzyme deficiencies
Fabry disease alpha galactosidase A
Niemann Pick disease sphingomyelinase
Tay sachs hexosaminidase
Krabbes galactosylceramidase
Metachromatic leukodystrophy Arylsulfatase
A

 Wolmans disease Acid lipase

Farber disease Acid ceramidase
Sialidosis Neuraminidase
Mucolipidoses UDP-N-Acetyl
glucosamine-1-phosphotransferase

Wolmans disease
Acid lipase deficiency
Calcification of adrenals

Fructose intolerance
Jaundice, hepatomegaly, vomiting,
hypoglycemia, hyperuricemia,
hypophosphatemia,
hypermagnesemia after ingestion of
fruits
Aldolase B deficiency
By detection of reducing substance
in patients urine

Multiple carboxylase
deficiency
Deficiency in holocarboxylase synthetase
3 biotin dependent enzymes:
propionyl coenzyme A carboxylase,
pyruvate carboxylase,
beta methylcrotomyl co A carboxylase

 skin manifestations, acidosis,

organic acids in urine, seizures and
ketosis
Rx: Biotin, a cofactor for all 4
enzymes

MELAS
Mitochondrial Encephalopathy
Lactic Acidosis
Stroke like episodes blindness,
paralysis, vomiting

 Hunters (hurler phenotype) and

Fabrys X linked
All other lysosomal diseases
Autosomal Recessive

Mucopolysaccharidoses

I-H, Hurler disease

I-S, Scheie disease
II Hunter disease
III Sanfilippo disease
IV Morquio disease
VI Maroteaux-Lamy disease
VII Sly disease

MANIFESTATIO
NS
I-H

MUCOPOLYSACCHARIDOSIS TYPE
I-S

II

III

IV

VI

VII

Mental
deficiency

Coarse facial
features

(+)

(+)

(+)

(+)

(+)

Dysostosis
multiplex

(+)

(+)

Leucocyte
inclusions

(+)

Mucopolysacch
ariduria

Corneal
clouding
Visceromegaly
Short stature
Joint
contractures

 Mental retardation severe in 3 and 7

sanfilippo and sly
Cloudy cornea not seen in 2 (hunter)
Bone changes most marked in type 4
(morquio) trunk is short with flattened
narrow vertebrae, barrel shaped chest
with sternum protruding forwards.

MPS
TYPE

I-H

EPONYM

MAIN CLINICAL FEATURES

Severe Hurler phenotype, mental

Pfaundlerdeficiency, corneal clouding, death
Hurler
usually before age 14yr

DEFECTIVE
ENZYME

-L-Iduronidase

I-S

Scheie

Stiff joints, corneal clouding, aortic valve

disease, normal intelligence, survive to -L-Iduronidase
adulthood

I-HS

HurlerScheie

Phenotype intermediate between I-H and

-L-Iduronidase
I-S

Hunter

Severe course similar to I-H but clear

corneas. Mild course: less pronounced
Iduronate
features, later manifestation, survival to sulfate
adulthood with mild or no mental
sulfatase
deficiency

II

III-A

Sanfilippo
A

Behavioral problems, sleeping

disorder, aggression, progressive
dementia, mild dysmorphism, coarse Heparan-S-sulfamidase
hair, clear corneas, survival to
adulthood possible

II-IB

Sanfilippo
B

N-Ac--glucosaminidase

III-C

Sanfilippo
C

Ac-CoA-glucosaminide-Nacetyltransferase

III-D

Sanfilippo
D

N-Ac-glucosaminine-6sulfate sulfatase

IV-A

Short-trunk dwarfism, fine corneal

Morquio A opacities, characteristic bone
dysplasia; final height <125cm

IV-B

Morquio B

N-Ac-galactosamine-6sulfate sulfatase

Same as IV-A, but milder; adult height

-Galactosidase
>120cm

VI

Marotea
ux-Lamy

VII Sly

IX

Hyaluro
nidase
deficien
cy

Hurler phenotype with

marked corneal clouding N-Ac-galactosbut normal intelligence; amine--4mild, moderate, and
sulfate sulfatase
severe expression in
(arylsulfatase B)
different families
Varying from fetal
hydrops to mild
-Glucuronidase
dysmorphism; dense
inclusions in granulocytes
Periarticular masses, no
Hyaluronidase 1
Hurler phenotype

Canavans disease

leukodystrophy
Autosomal recessive
N-Aspertoacylase deficiency
Accumulation of N-acetyl aspartic
acid

Clinical triad of hypotonia, head lag

and macrocephaly

Adrenoleukodystrophy
X linked recessive
Acyl Co A synthetase
Main symptoms are ataxia, motor
deficits, cortical blindness

Metachromatic
leukodystrophy
Autosomal recessive
Arylsulfatase A deficiency
Macrocephaly late, gait disturbance,
incoordination, mental deterioration
CT diffuse symmetric attenuation of the
cerebellar and cerebral white matter

 Sulfated glycosphingolipids accumulate

in the white matter.
Leukodystrophies affect the growth
and/or development ofmyelin throughout
thecentralandperipheralnervous
systems.
Usually death before 10 years.

Alexanders disease
Sporadic
Rosenthal fibres in the brain
histopath
Mutation in glial fibrillary acidic
protein (gfap)

Krabbes leukodystrophy
Def. of beta galactosidase
Optic atrophy, spasticity
CT- low density areas in white matter
and increased density in thalamus

Niemann Pick
Sphingomyelinase deficiency
Type A = MR, HSmegaly, macular
cherry red spots, Childhood
cholelithiasis
Type B = milder form with no neuro
involvement

Leigh disease
also known as Subacute Necrotizing
Encephalomyelopathy (SNEM), is a rare
neurometabolic disorder that affects the
central nervous system.
mutations in mitochondrial DNA (mtDNA) or
in nuclear DNA (gene SURF1 and some COX
assembly factors) cause degradation of
motor skills and eventually death.
Dystonia, rigidity, tremor, chorea,
myoclonus, hypokinesia, tics.

pseudotumor cerebri
Idiopathic intracranial hypertension (IIH),
sometimes called by the older names benign
intracranial hypertension (BIH) or pseudotumor
cerebri (PTC), is a neurological disorder that is
characterized by increased intracranial pressure
(pressure around the brain) in the absence of a tumor or
other diseases.
The main symptoms are headache, nausea, and
vomiting, as well as pulsatile tinnitus (buzzing in the
ears synchronous with the pulse), double vision and
other visual symptoms.
If untreated, it may lead to swelling of the optic disc in
the eye, which can progress to vision loss.

 The Monro-Kellie rule states that the

intracranial pressure (literally:
pressure inside the skull) is
determined by the amount of brain
tissue, cerebrospinal fluid (CSF) and
blood inside the bony cranial vault.

Fabrys

X linked
Acroparesthesia
Angiokeratoma
Corneal and lenticular opacities
Maltese crosses in urinary sediment

Enzyme deficiencies
Tyrosinemia type 1 fumaryl
acetoacetate
hydrolase
Tyrosinemia type 2 tyrosine amino
transferase
Transient neonatal tyrosinemia POH phenyl pyruvic acid oxidase

 Albinism tyrosinase
Alkaptonuria- homogentisic acid
oxidase
Homocystinuria cystathionine
synthetase
Cystathioninemia - cystathionase

 Cystinosis defective efflux of cystine from

lysosomes
Cystinuria defective cystine transport across
renal tubular cells and intestines
MSUD defective decarboxylation of keto acids
Hartnup disease defective transport of mono
amino mono carboxylic acids

IEM and their treatment

Alkaptonuria Vit C, nitisinone
Cystinuria alkalinization of urine + dpenicillamine, captopril
Hartnup disease Nicotinamide
Multiple carboxylase deficiency Biotin

 Homocystinuria Pyridoxine, folic acid

Methyl malonic aciduria vit b12
Hyperoxaluria - pyridoxine
Urea cycle defects sodium benzoate,
arginine, haemodialysis, sodium phenyl
acetate

 MSUD thiamine
Methylmalonic acidemia - B12, Lcarnitine, Metronidazole
Propionic acidemia, Isovaleric
acidemia, Glutaric aciduria Carnitine

Indicanuria
Blue diaper syndrome
Tryptophan malabsorption

Lesch Nyhan

X linked recessive
HGPRT deficiency
Gout
Renal problems

Abetalipoproteinemia
Absence of apo B containing lipoproteins
Genetic defect maybe: 1. deficient synthesis of
apoprotein of low density beta lipoproteins
2. increased utilization of apoproteins
3. difficulty in incorporation of apoproteins into
lipoprotein
Beta lipoproteins are necessary for formation of
chylomicrons which are absent in the plasma
Plasma cholesterol and triglyceride levels are low

 c/f: abnormally crenated thorny

erythrocytes (acanthocytes), malabsorption
of fats, retinitis pigmentosa, neurological
signs of ataxia, tremors, athetosis, loss of
vibration and position sense
Fats normally digested and assimilated
through intestinal mucosa these cannot
be transported to plasma from there
because of inability to form chylomicrons

 Abeta lipoproteinemia Vit E

Hereditary spherocytosis Folate/
folic acid

dinitrophenylhydrazinetest
Atesttodeterminethepresenceofketoac
ids;
usedinscreeningformaplesyrupurinedis
ease.
Gives yellow ppt

Peroxisomal disorders
Peroxisome Biogenesis Disorders - Zellweger
syndrome (ZS), neonatal adrenoleukodystrophy
(NALD), infantile Refsum disease (IRD)
PEX1 gene mutations
Refsum disease - impaired alpha-oxidation of branched
chain fatty acids resulting in buildup of phytanic acid and
its derivatives in the plasma and tissues. This may be
due to deficiencies of phytanoyl-CoA hydroxylase or
peroxin-7 activity. In general, Refsum disease is caused
by PHYH mutations. onion bulb formation.

 Zellweger syndrome - If the case indicates an infant

who shortly after birth develops jaundice,
hepatomegaly, intractable seizures, facial
abnormalities, hypotonia, developmental delay and
later mental retardation, vision and hearing
abnormalities, and deterioration of renal function then
we have to think of Zellweger syndrome.
Zellweger syndrome is an autosomal recessive
disorder in which there's abnormal development of
peroxisomes which are the cellular organelles
responsible for beta oxidation of very long chain fatty
acids.

Alpha 1 antitrypsin
deficiency
It is a protease inhibitor (Pi) synth in liver and
protects lung tissues from neutrophil elastase.
PiM type normal
PiZ mutation emphysema alpha 1 AT conc
below 0.6 g/L
Late hemorrhagic disease of childhood,
cholestasis or CLD
Lung affected in adults