Indian Journal of Pediatrics, Volume 72April, 2005 325

Symposium on Fest - Schrift for Late Dr. P.M. Udani

Correspondence and Reprint requests : Dr. N.B. Kumta, Department
of Pediatrics, KEM Hospital, Mumbai, Maharashtra, India.
Inborn Errors of Metabolism (IEM) An Indian
Perspective
N.B. Kumta
Department of Pediatrics, KEM Hospital, Mumbai, Maharashtra, I ndia.
There is an accelerating demographic switch from
communicable diseases to genetic disorders. The
expression of a genetic disease is the combined effect of
genes and the environment. There are 24 million births in
India annually; 780,000 are born with congenital
malformation, 340,000 with G6PD, 20,800 with metabolic
disorder, 21,000 with Down syndrome, 10,400 with
congenital hypothyroidism, 9000 with thalassemia and
5200 with sickle cell anemia. In a hospital based study in
India biochemical screening of 4400 cases of mental
retardation revealed that 5.75 % (256 cases ) were due to
a metabolic disorder.
1,2
Mechanism of Metabolic Disorders
commenced early and long term outcome maybe
improved
3
and correct early diagnosis helps in genetic
counseling. Use of blood gases, electrolytes, ammonia,
lactate, pyruvate, urine metabolic spot tests, gas
chromatography mass spectroscopy (GCMS) or tandem
mass spectrometry (TMS) for organic acids, amino acid
chromatography, enzyme estimations in white cells, skin
fibroblasts and other tissues have made diagnosis
possible.
In neonatal IEM pregnancy, delivery is uneventful. The
newborn baby with IEM is normal for the first three or
four days after which the disorder presents due to intake
of dietary protein etc. Neonates with IEM are
misdiagnosed to have sepsis or other disorders. Sepsis
often accompanies IEM and may confound diagnosis
further. Pediatricians often think that neonatal IEM is
rare. Though individual disorders may be uncommon
these disorders are fairly common when considered
together. Though IEM are usually recessive disorders they
are very often occur in only one sib. The neonate has a
limited response to illness and predominant symptoms &
signs are poor feeding, lethargy, coma, failure to thrive,
seizures, acidosis or ketosis. Emergency adequate
laboratory facilities to diagnose neonatal IEM are scarce
and lacking in India leading to delays in diagnosis,
treatment and hence a poor prognosis in most cases.
A high index of suspicion is necessary when the
following are present :
Parental consanguinity
Positive family history of a similar illness/death
Symptoms onset a few days after feeding (refusal to feed,
lethargy, vomiting, hypotonia, coma, seizures)
Ketosis, acidosis, hypoglycemia
Unusual odour to the urine
Jaundice, visceromegaly
Dysmorphic features or coarse facies
Abstract. The inborn errors of metabolism (IEM) constitute a diverse heterogeneous group of disorders with protean clinical
manifestations presenting mainly in the pediatric population. Though individually rare, together they constitute a significant
percentage of children seen in genetic and neurology clinics. This review focuses on selected IEMs and highlights those seen
in the neonatal period. Data from Indian centers are presented. It also emphasizes principles of management in these difficult
disorders in the context of a developing country. [Indian J Pediatr 2005; 72 (4) : 325-332] E-mail : nbkumta@hotmail.com
Key words : Inborn errors of metabolism; Neurometabolic; Childhood; India
Toxic metabolite D
Precursor A EA Substrate B EBC Product C
EAB is an enzyme converting A into B. EBC, the enzyme
converting B into C, is absent and is the cause of the IEM.
This leads to accumulation of substrate B to abnormal
levels which then gets diverted to an abnormal metabolic
pathway to yield a toxic metabolite D. B or D could be
toxic. B & D could be detected and EAB can be estimated
biochemically.
NEONATAL IEM
Organic aciduria or urea cycle disorders are not
uncommon and often present fulminantly. Early
diagnosis is crucial for three reasons,
1
the condition is
rapidly progressive and causes irreversible damage early
in the course,
2
the treatment can often be effective if
N.B. Kumta
326 Indian Journal of Pediatrics, Volume 72April, 2005
Specific Features in Certain Neonatal IEM.
(1) Abnormal urine or body odour is characteristic of some
IEM MSUD maple syrup or burnt sugar smell,
Isovaleric acidemia, Glutaric aciduria type II
sweaty feet smell, Phenylketonuria -mousy or
mushy, methyl crotonyl aciduria tom cat urine,
Methionine malabsorption cabbage, Trimethyl
aminuria rotting fish, Tyrosinemia rancid or
fishy odour.
(2) Diarrhoea: (a) Severe watery diarrhoea congenital
chloride diarrhoea, galactosemia, primary lactase,
sucrase, isomaltase deficiency. (b) Chronic
diarrhoea- bile acid disorder,infantile Refsum
disease, respiratory chain disorders associated with
steatorrhoea , vitamin deficiency osteopenia,
hypocholesterolemia (c) Diarrhoea, failure to thrive,
hypotonia hepatomegaly - GSD I, Wolmans disease
(3) Cardi omyopathy, Cardi ac Fai l ure - Pompes
disease GSD II,respiratory chain disorder, fatty acid
oxidation (FAO) defects
(4) Hepatomegal y - Tyrosinemia, galactosemia,
fructosemia and alpha 1 antitrypsin deficiency,
GSD. Hepatomegaly with splenomegaly consider
mucolipidosis, Gauchers disease Niemann-Pick
type A
(5) Seizures - Nonketotic hyperglycinemia, pyridoxine
dependency, and molybdenum co-factor
deficiency. In most others seizures are associated
with coma and hyperglycinemia
IEM has a Characteristic
1 Age of onset
2 Temporal profile i.e. evolution of the disease with
characteristic symptom & sign as the disease
advances; affected sibs usually show a similar
temporal profile
3 IEM has a characteristic inheritance pattern eg.
ornithine transcarbamylase deficiency (OTC), Fabrys
disease, Menkes disease and Hunters disease are X-
linked recessive and most others are autosomal
recessive.
4 Often there are characteristic triggers environ-
mental factors which precipitate the presentation of
the IEM e.g. diet, infection, fasting, drugs (see below)
5 Age of neurological manifestations and death
Triggering Factors Precipitating IEM
1 Diet: Introduction of cane sugar - hereditary fructose
intolerance, milk - galactosemia, proteins = urea cycle
disorders (UCD), MSUD and other aminoacid
disorders. carbohydrate - pyruvate dehydrogenase
& respiratory chain disorders.
2 I nfection, Fasting and Fever: FAO defects, certain
aminoacid disorder and organic aciduria.
3 Anaesthesia - Homocystinuria
4 Drugs - Porphyria and G6 PD deficiency
Group 1- Aminoacidopathies: Neurologic Distress
Intoxication Type With Ketosis
MSUD Maple syrup urine disease only amino acid
disorder that presents acutely in the neonatal period.
TABLE 1. Diagnostic Approach to IEM - Small Molecular Diseases
Metabolic Ketosis Lactic Hyper- Liver
Acidosis Acidosis ammonemia Dysfunction
Group 1 Aminoacidopathies _ + + +/- _ _ _
Group 2 Organic acidopathies + + + + + + + +/- _
Group 3 Primary lactic acidosis + + + + + + + +/- +/-
Group 4a Urea cycle disorders _ _ _ + + + +/-
Group 4b Perxisomopathies, NKH,
SO deficiency _ _ _ _ _
Group 5 Galactosemia, Fructosemia,
Fat oxidation defects, GSD,
tyrosinemia +/- +/- +/- _ + + +
TABLE 3. Organic Acidurias (Total: 58 KEM Hospital 1978 2004 )
Glutaric academia type 1 12 B ketothiolase deficiency 6
Methylmalonic academia 10 Biotinidase deficiency 2
Propionic academia 7 3 methylglutaconic aciduria 2
Fatty acid oxidation defects 7 Carnitine transport defect 1
Undiagnosed 11
TABLE 4. Mitochondrial & Ox-phos Disorders (Total: 44 KEM
Hospital, Mumbai 1978 2004 )
Respiratory chain disorders 11
Leigh disease 6
Alper poliodystrophy 5
MELAS 2
Undifferential lactic acidosis/Mitochondrial disorders 16
Citric acid cycle defects 3
Pyruvate dehydrogenase deficiency 1
TABLE 2. Analysis of Cases of IEM Investigated at KEM Bombay
(from 1978 - 2004 ) Total IEM : 1016 aminoacid disorder =
204 (20.1 % )
Albinism 100 MSUD 7
Alkaptonuria 27 Tyrosinemia 4
Urea cycle defects 19 Hartnup disease 1
Homocystinuria 16 Histidinemia 1
Phenylketonuria 16 Cystinosis 1
Cystinuria 12
Inborn Errors of Metabolism (IEM) An Indian Perspective
Indian Journal of Pediatrics, Volume 72April, 2005 327
It is a branch chain amino acid (BCAA) disorder i.e.
leucine, isoleucine and valine. Deficiency of ketoacid
dehydrogenase results in formation of ketoacids, which
give a strongly positive urinary dipstick test for ketones.
There is a strong smell of maple syrup to the urine. Initial
3 - 4 days after birth are normal; feeding difficulties start
and gradually the neonate becomes comatose with
episodic generalized hypertonia, dystonia, ophisthotonos
and boxing / pedaling movements. Urine DNPH test is
strongly positive and test for acetone is negative. Plasma
amino acid chromatography displays elevation of
branched chain aminoacids. Dialysis removes the
branched chain aminoacids and should be instituted
promptly. Treatment of cerebral oedema is mandatory
and special f ormula feeding with low BCAA is the most
important part of management. Liver transplant offers
promising results. Prognosis is guarded. Intercurrent
infections leads to severe ketoacidosis, cerebral oedema
and death.
Group 2 - ORGANIC ACIDOPATHIES: Methylmalonic
academia (MMA), Propionic academia (PA), Isovaleric
academia (IVA) : Neurologic distress intoxication type
with ketoacidosis and hyperammonemia
Infants present with recurrent vomiting, deep acidotic
breathing and failure to thrive. They are acutely ill,
dehydrated and hypothermic. There is truncal and
peripheral hypotonia and coarse limb tremors. The blood
bicarbonate is low with an increased anion gap
Neutropenia and thrombocytopenia are also common,
along with ketonuria. GCMS or tandem mass
spectroscopy gives confirms the correct diagnosis and
MMA, PA and IVA account for 90% of neonatal
presenting organic acidopathies. Propionic acid is a potent
inhibitor of mitochondrial function resulting in
accumulation of lactic acid and ketones leading to
metabolic acidosis. MMA sometimes responds to high
doses of vitamin B
12
while PA might respond to biotin.
Treatment: Dialysis is used to to remove the offending
organic acid and elevated ammonia. Dietary protein
restriction, avoidance of fasting and metronidazole
therapy ( to reduce organic acid production by gut flora)
are other measures.
Differential diagnosis includes the adrenogenital
syndrome with high potassium and low sodium, sepsis
with neutropenia and thrombocytopenia and the UCD.
Group 3 Primary Lactic Acidosis (PDH PC ETC def.)
With Neurologic Distress; Energy Deficiency type
Enzyme defects in Krebs cycle leads to respiratory chain
deficiencies. The most common of these disorders are
pyruvate dehydrogenase (PDH), pyruvate carboxylase
(PC) and electron transport chain (ETC) deficiencies. PDH
is an X-linked disorder. Boys present with severe
metabolic and lactic acidosis in the neonatal period.
Clinically the neonate is neurologically depressed and
serum lactate is markedly elevated. There is an elevated
anion gap because of the elevated lactate and ketosis. The
ketogenic diet & dichloracetate 25 to 100 mg/kg orally or
parentally may produce a response in 24 hours.Thiamine
supplements may be tried. PC deficiency is an AR
disorder with lactic acidosis and neurological dysfunction
in the newborn period and intermittent ataxia in later life.
PC deficiency in early life characteristically has an
elevated lactate to pyruvate ratio, moderate citrullinemia,
hyperammonemia and hyperlysinemia (type B) while in
the later onset variant moderate lactic acidosis &
developmental delay occur (type A). The other features
are spasticity, severe psychomotor retardation and
seizures. Holocarboxylase, synthase and biotinidase
deficiencies present with rash, alopecia, lactic acidosis and
will remain asymptomatic if biotin supplementation (5 to
20 mg/day) is started before brain damage occurs. This is
possible after newborn screening. A trial of biotin is
warranted in all patients with lactic acidosis
Though ETC deficiencies may respond to specific
vitamins like riboflavin, L-carnitine and co-enzyme Q the
response is usually less than satisfactory.
Group 4a Urea Cycle Disorders (UCD): Neurologic
Distress Due to Intoxication; Hyperammonemia
Without Ketoacidosis
Transamination reactions in most amino acid catabolic
pathways result in transfer of amino group to glutamine
and glycine either of which might release ammonia into
the urea cycle converting it to urea.
Proximal defects in this pathway result in severe
accumulation of ammonia vis--vis distal defects.
Ammonia is toxic and causes cerebral oedema leading
to drowsiness, lethargy, coma, seizures and early death.
Ornithine transcarbamylase (OTC) deficiency is X-linked.
All others are inherited as autosomal recessive.
Measurement of plasma ammonia, plasma aminoacids
and urinary amino and orotic acids are crucial to identify
the specific defects in the UCD. Citrullinemia,
argininosuccinic acidemia and argininemia are diagnosed
by aminoacid chromatography, whereas OTC deficiency
and carbamoylphosphate synthetase (CPS) deficiency
being more proximal defects give deficiencies of citrulline
or arginine. These latter two are differentiated on the
basis of an elevated orotic acid excretion in the urine. The
diagnosis is also confirmed by enzyme estimation in skin
fibroblast or in the liver cells. Treatment of UCD involves
dietary protein restriction, sodium benzoate and phenyl
butyrate therapy. The more distal defects are more
amenable to treatments with drugs. Prognosis depends
heavily on the degree of the cerebral damage sustained
prior to the diagnosis and treatment.
Group 4b Nonketotic hyperglycinemia (NKH) :
Neurologic distress due to energy deficiency; type
without ketoacidosis and without hyperammonemia
This is characterized by poor feeding, failure to suck,
lethargy hypotonia, coma, and myoclonic jerks appearing
N.B. Kumta
328 Indian Journal of Pediatrics, Volume 72April, 2005
TABLE 5. Urea Cycle Disorders
Inheritance Deficient enzyme Orotic acid in urine Plasma citrulline Plasma argininosuccinic
acid
AR CPS Low Low
X-linked OTC High Low
AR ASS High Very high
(> 1000 uM)
AR ASL High High
(100 300 uM) High
AR Arginase High Normal
CPS Carbamoylphosphate synthetase, OTC ornithine transcarbamylase, ASS argininosuccinate synthetase
ASL arginiosuccinate lyase.
TABLE 9. Disorders of Carbohydrate Metabolism (n=63) during
1978-2004 at KEM Hospital, Mumbai
GSD 35 Galactosemia 20
GIPUT DEF 11
Type 1 6 GK DEF 6
Type 2 2 Duarte Variant 1
Type 3 16
Type 4 1 Disorders of Fructose Metabolism 2
Type 6 2
Type 8 1 Fructosuria 1
Type 9 3 FDP Deficiency 1
Untyped 5 Pentosuria 3
TABLE 10. Miscellaneous Diseases at KEM Hospital, Mumbai
(19782004)
Lesch Nyhan syndrome 3 Adrenoleukodystrophy 2
Porphyria 7 Refsum Disease 2
Criggler Najjar syndrome 3 Peroxisomal Untyped 1
Cerebrotendinous Xanthomatosis 2 Uric Acid Urolithiasis 1
Hypobetalipoproteinemia 3 B6 Dependancy 1
Chanarin Dorfman 2 Pelizaeus Merzbacher 6
TABLE 6. Small-molecule Disease Vs Complex Molecular Disease -Organelle Diseases
Clinical Feature Organelle Disease Small-molecule Disease
Onset Gradual Often sudden, especially with stress
Course Slowly progressive Characterized by relapses and remissions
Physical findings Often typical and helpful Nonspecific
Histopathology Often reveals typical changes Generally nonspecific
Response to supportive therapy Poor, incomplete Often brisk
Some examples Most lysosomal storage diseases; most Many of the aminoacidopathies; most organic
peroxisomal disorders; many mitochondrial acidopathies, UCDs
ETC defects
TABLE 7. Distribution of Mucopolysaccharidoses (n=189) &
Mucolipidosis (n=7) in KEM Hospital, Mumbai (1978
2004)
Mucopolysaccharidoses 189 Mucolipidoses 7
Type I H*/S**/HS*** 14/2/1 Type II 3
Type II 33 Type III 4
Type III 44
Type IV 44
Type VI 33
Type VII 1
Untyped 17
*Hurler, **Schei's, ***Hurler - Schei's
TABLE 8. Distribution of Lysosomal Storage Disorders (n=249) at
KEM Hospital, Mumbai (1978 2004)
GM2 Gangliosidosis 70 Fucosidosis 4
Metachromatic LD 53 Mannosidosis 3
Niemann Pick disease 33 Canavan disease 2
Krabbe disease 27 Farber disease 1
Gaucher disease 24 Fabrys disease 1
GM1 Gangliosidosis 24 Wolman disease 1
Mucosulfatidosis 4 Neuronal ceroid lipofuscinosis 2
within few hours of birth in an infant with no history of
perinatal insults. A burst suppression EEG pattern,
elevated plasma glycine, elevated CSF to plasma glycine
ratio constitutes the diagnosis of neonatal NKH.
Molybdenum co-factor deficiency / sulfite oxidase
deficiency present similarly with hypotonia, seizures,
dysmorphic features and cataracts. Diagnosis is suggested
by a very low plasma uric acid and presence of sulfites in
fresh urine while aminoacid chromatography shows high
sulfite concentration in the form of sulfocystenine.
Group 4c - Lysosomal Storage Disorders Without
Metabolic Disturbances
Few lysosomal disorders present in the neonatal period.
These disorders are GM 1 ganglioidosis, Gauchers
disease, Niemann-Pick disease type C, MPS VII and
sialiodosis.
Other disorders are glycogenosis (GSD) and
gluconeogesis defects, fatty acid oxidation defects etc.
Inborn Errors of Metabolism (IEM) An Indian Perspective
Indian Journal of Pediatrics, Volume 72April, 2005 329
SELECTED IEMS PRESENTING AFTER THE
NEONATAL PERIOD
Neurometabolic/Neurodegenerative Disorders
These are genetically inherited disorders with progressive
neurologic deterioration, having a demonstrable
biochemical abnormality associated with enzyme defects.
Heterozygote detection and prenatal diagnosis is
possible. Most of them belong to the lysosomal storage
disorders leading to neural, neurovisceral and musculo-
skeletal manifestations. Simple molecular disease like
amino acid, sugar, organic acids and UCD have a
catastrophic presentation whereas complex molecular
diseases have an insidious onset and a chronic cour
Fig. 1. Approach to A Neonate With Hyperammonemia
Neonatal
Hyperammonemia
Symptoms in first
24 hr of life
Symptoms in first
24 hr of life
Premature
Full-term
THAN*
PC Deficiency
Acidosis
No acidosis
ORGANIC
ACIDEMIA
UREA
CYCLE
DEFECTS
Plasma Aminoacids
Citrulline
Citrulline
moderately
elevated; ASA
present
Citrulline
markedly
elevated;
no ASA
Absent
citrulline
ARGININOSUC
CINIC
ACIDURIA
CITRULLINE
MIA
Urine orotic
acid
Elevated Low
OTC
DEFICIENCY
CPS
DEFICIENCY
N.B. Kumta
330 Indian Journal of Pediatrics, Volume 72April, 2005
DISORDERS OF COPPER METABOLISM
A total of 146 children were seen at the KEM with 142
being Wilsons disease and 4 being Menkes disease.
Wilsons disease is an inborn error of copper
metabolism. It is an autosomal recessive disorder with an
incidence 1 in 35,000 1,00,000; the gene is located at 13q
14 21. It is characterized by increased copper deposition
in the liver, brain, kidneys and corneas. Classically, there
are specific progressive neurological findings, chronic
liver disease or cirrhosis, renal tubular dysfunction,
sunflower cataract and pigmented corneal rings (Kayser
Fleischer rings). However, the variability of the disease
is such that it should be suspected in any patient with
unexplained neurologic or psychiatric dysfunction,
hepatitis, hemolytic anemia, renal Fanconi syndrome or
hematuria. The onset ranges from 4 to 50 years. An earlier
age of onset is in general associated with liver disease
often without neurological manifestation and not
invariable K-F rings. Liver involvement may present with
asymptomatic hepatomegaly, jaundice with edema and
ascitis, hepatosplenomegaly with vague gastrointestinal
symptoms or subacute viral hepatitis, fulminant hepatitis,
chronic active hepatitis, juvenile cirrhosis, post-hepatic
cirrhosis and cryptogenic cirrhosis. Neurological
manifestations range from dystonia-parkinsonism,
dysarrthria, drooling, scholastic deterioration/dementia
and behavioural changes.
Clinical and laboratory investigations include
peripheral blood for hemolytic anemia, liver function
abnormalities, urinary abnormality suggestive of Fanconi
syndrome, slit-lamp examination for K-F ring, low serum
ceuroplasmin ( < 20 mg/dl), increased urinary copper
excretion ( > 100 mcg/day) especially after D-
penicillamine challenge ( > 1000 mcg/day), increased
liver copper ( > 250 mcg/gm dry weight liver) and
positive radioactive copper studies.
Untreated Wilsons disease is invariably fatal. The
objective of treatment is to prevent copper from
accumulating in the tissues. Intake should be decreased
by restricting foods high in copper content (liver, cocoa,
chocolate, mushroom, shellfish, nuts, dried fruits and
vegetables) to less than 0.6 mg/day of copper. The
mainstay of medical therapy is the use of copper binding
agents like D-penicillamine. The usual starting dose is 10
mg/kg/day increased gradually over two weeks to 20
mg/kg/day for children under 10 years and 1 gm/day
for those above 10 years. Children receiving this therapy
require B6 supplementation, and monitoring for
proteinuria and blood count abnormalities. If treatment is
begun early the neurological and hepatic functions can be
normalized and K-F rings can disappear. On the other
hand, advanced disease may not be reversible. Further,
there is a subgroup of patients who seem to worsen after
initial treatment with D-penicillamine. Though these
patients recover, they do not usually recover to
pretreatment baseline. Side effects of D-penicillamine
Fig. 2. Approach to A Child with A Chronic Neurometabolic Disorder
Chronic Encephalopathy
Developmental Regression
Seizures
Hard Neurologic Signs
Abnormalities Outside the CNS
No Yes
( Only Neural) (Neuro Visceral & Muscular Skeletal)
Signs of gray
matter disease
seizures
visual impairment
dementia
Signs of white matter
disease
motor difficulties
disorders of tone
Muscle
Mitochondrial
myopathies
HSM + bone skin
con tissue
Gaucher disease
NDP
MPS I, II, III, VII GM!
Sialidosis II
Zellweger
Homocystinuria
Menkes
Fucosidoses
MSD
Galactosialidosis
Prolidase
deficiency
B-6 dependency
Biotinidase def.
NCL
GM2 (early)
CRSM
Syndrome
Leigh disease
Alpers disease
MELAS
Central only
Canavan
Alexander
GM2 (late)
GM1 (late)
XLALD
AAurias
QAurias
Central +
peripheral
MLD
Krabbe GLD
Peroxisomal
disorders
Inborn Errors of Metabolism (IEM) An Indian Perspective
Indian Journal of Pediatrics, Volume 72April, 2005 331
include early and late reactions including rash,
leucopenia, immune-complex nephritis, Goodpasture
syndrome, etc.
Other options for treatment are Trientene, Ammonium
tetrathiomolybdate, and oral zinc sulfate or acetate at 75
150 mg of elemental zinc per day. Zinc is becoming the
mainstay of maintenance treatment after the other agents
achieve initial decoppering. Liver transplant is the only
measure for patients with fulminant hepatic failure or
with end stage hepatic disease.
Screening of all siblings is advised. Absence of
symptoms or abnormalities on clinical examination does
not exclude the possibility of Wilsons, which needs
investigation. Haplotype analysis helps to diagnose
carriers and asymptomatic patients where serum
ceruloplasmin levels are inconclusive. Availability of
molecular diagnosis aids prenatal diagnosis. At the
moment these sophisticated tests pose a limitation in
Indian conditions.
DISORDERS OF CARBOHYDRATE METABOLISM
The commonest types are GSD3 and GSD1. GSD3 is
debrancher enzyme deficiency. The symptoms of GSD3
are similar to GSD 1 but milder. Both of them have
hepatomegaly and hypoglycemia .In GSD 1 there is
hyperlipidemia ketoacidosis, hyperlactic acidemia and
hyperuricemia. There is platelet dysfunction and
prolonged bleeding time. Failure to thrive, doll-like facies,
huge abdomen and early morning fasting hypoglycemia
with or without seizures and xanthomas are clinical clues
to the diagnosis. Liver biopsy reveals PAS positive and
diastase sensitive material and liver enzyme analysis
reveals glucose 6 phosphates deficiency. In GSD 3
profound hypoglycemia and extreme hyperlipidemia is
rare. Prognosis is fair to good.
Galactosemia presents with milk-triggered symptoms
of vomiting, diarrhoea, hypoglycemia, jaundice and the
later development of cirrhosis, mental retardation and
cataract. Reducing substances are present in the urine on
Benedicts test while glucostix are negative suggesting that
the sugar is other than glucose. Sugar chromatography
confirms the diagnosis. Treatment is avoiding milk
containing lactose and giving soy milk.
MANAGEMENT OF INBORN ERRORS OF
METABOLISM (IEM)
Basic Principles of Therapy
(a) Prevention of the accumulation of toxic levels of the
precursor substance. Restrict offending substrate in
the diet.
(b) Stimulation of elimination of a toxic substrate /
precursor by an alternative pathway
(c) Supply the deficient product.
(d) Enhance the activity of the deficient enzyme by
providing co-factors e.g. vitamins (see below).
(e) Supply essential nutrients / disease specific diet after
the diagnosis is established, sometimes specific
synthetic medical formulae are ideal
In majority of aminoacid disorders human breast milk
provides least protein load e.g.1gm%. Breast milk is
relatively safe to give except in galactosemia Animal milk
is unsafe because of high lactose concentration.
Emergency Management General Principles
1. Minimize intake of substrates that produce toxic
metabolite viz. protein in aminoacidopathies lactose
in galactosemia, sugar in hereditary fructose
intolerance, fats in fatty acid oxidation disorders.
Administer high carbohydrate IV fluids (10%
dextrose), maintainence fluid requirement 1.5 times
to promote diuresis and to avoid overload. As the
child improves, increase protein intake gradually
from 0.5 gm/kg/day to 1gm/kg/day. Avoid trigger
factors mentioned above.
2. Treat hypoglycemia, metabolic acidosis, electrolyte
imbalance, infections and coagulopathies using
conventional treatments.
3. Dialysis for sever hyperammonemia and resistant
life-threatening metabolic acidosis; peritonial
dialysis is slower but less technologically/
hemodynamically demanding than haemodialysis
4. Pharmacological agents to detoxify and accelerate
the excretion of toxic metabolites.
5. Vitamin co-factor therapy to increase residual
enzyme activity (see below).
6. Secondary carnitine deficiency occurs in many IEMs
and oral carnitine should be supplemented (100 mg/
kg/day). In critical cases collect enough blood -
separate plasma and RBCS collect 50-100 ml urine
and freeze it at -20 C. This could come useful for
diagnosis and genetic counseling. The importance of
diagnosis is underestimated. Once the samples are
collected one can start the treatment.
VITAMINS & COFACTORS
Vitamins which act as cofactors give striking
improvement in many simple molecular diseases.
TABLEL 11. Vitamin Responsive IEM Disorders
Disorder Vitamin used in the treatment
Maple syrup urine disease Thiamine
Homocystinuria Pyridoxine, folic acid & vitamin
B
12
Propionic academia Biotin
Methylmalonic academia Hydroxycobalamin
Glutaric academia Riboflavin
Biotinidase deficiency Biotin
Hartnup disease Nicotinic acid
Pyruvate dehydrogenase Thiamine
deficiency/Leigh's disease
Respiratory chain disorders Riboflavin
N.B. Kumta
332 Indian Journal of Pediatrics, Volume 72April, 2005
REFERENCES
1. Verma IC. Burden of genetic disease in India. Indian J Pediatr
2000; 67 (12) : 893-898.
2. ICMR Collaborating centres & central coordinating unit.
Multicentric study on genetic causes of mental retardation in
India. Indian J Med Res (B) 1991; 94 : 161-169.
3. Muranjan M. Personal communication analysis of data on
Inborn Errors of Metabolism seen over a period from 1979 to
2004 at the Genetic clinic PRL, KEM Hospital Mumbai.
Recommended readings
1. The Metabolic and Molecular Basis of Inherited Disease. CR
Scriver, AL Beaudet, WS Sly, D Valle, eds. 7
th
edn (1995)
McGraw Hill, Newyork.
2. Clinical Biochemistry and The Sick Child. BE Clayton, JM. Round.
2
nd
edn (1994), Blackwell Scientific Publications, Oxford.
3. A Clinical Guide to Inherited Metabolic Diseases. JTR Clarke 1996
Cambridge University Press, Cambridge
4. Burton BK. Inborn errors of metabolism in infancy : a guide to
diagnosis. Pediatrics 1998; 102: 6.
5. Neurology of Hereditary Metabolic Diseases of Children; Gilles Lyon;
Raymond D Adams Edwin H Kolodny. McGraw-Hill; 2
nd
edn.
Guiding Principle for Feeding Infants
and
Young Children
During Emergencies
World Health Organization (WHO), Geneva. http://bookorders.who.int
This book reveals the guiding principles intended to serve as a starting point for organizing
sustained pragmatic interventions that will be ensure appropriate feeding and care for infants and
young children at all stages of an organized emergency response.
Book Published