arginine: glycine amidinotransferase (AGAT) deficiency; OMIM 602360; and guanidinoacetate methyltransferase (GAMT) deficiency (OMIM 601240)) and one disorder of creatine transport (X-linked recessive SLC6A8 creatine transporter deficiency (OMIM 300036)).
Severe hypotonia is a common symptom of sick neonates..few iem present as predominant hypotonia in newborn period
when there is ingestion of fructose or sucrose, in the neonate usually a soy formula
Electrolytes and blood gases are required to determine whether an acidosis or alkalosis is present and, if so, whether the abnormality is associated with an increased anion gap. The organic acidemias and the primary lactic acidosis cause metabolic acidosis with a raised anion gap in early stages. Most metabolic conditions result in acidosis in late stages as encephalopathy and circulatory disturbances progress. A persistent metabolic acidosis with normal tissue perfusion may suggest an organic acidemia or a congenital lactic acidosis. A mild respiratory alkalosis in nonventilated babies suggests hyperammonemia. However, in late stages of hyperammonemia, vasomotor instability and collapse can cause metabolic acidosis.
4. Plasma uric acid test is a convenient screen for the few IEM that are associated with either hyperuricemia (type I glycogen storage disease) or hypouricemia (xanthine dehydrogenase deficiency).
, as may be falsely normal if the child is off feeds.
by measurement of abnormal metabolites in the amniotic fluid or by enzyme assay or DNA analysis of amniocytes by amniocentesis
.(CSF glucose level is equal to or less than 1/3rd of the blood glucose level.. responds to the ketogenic diet.)
, as IEM may present in different age groups in members of the same family.
The catalytic properties of many enzymes depend on the participation of non protein prosthetic groups, such as vitamins and minerals, as obligatory cofactors. The following co-factors may be beneficial in certain IEM Electron transport flavoprotein
Therefore when the diagnosis is known and confirmed in the index case, prenatal diagnosis can be offered, wherever available for the subsequent pregnancies.
DR.GOKULDAS P K
Junior resident in Pediatrics
Govt.medical college, Kozhikkode
Introduction to IEM
Differential diagnosis of any sick neonate
IEM are individually rare
Overall incidence upto 1 in 2000
High index of suspicion for diagnosis
Deterioration after a period of apparent normalcy
Family history of neonatal deaths
Rapidly progressive encephalopathy and seizures
of unexplained cause
Severe metabolic acidosis
Low Normal High
Urine orotic acid
Plasma ASAPlasma arginine
Normal Normal NormalElevated Elevated
Liver function tests
mitochondrial respiratory chain disorders
Niemann-Pick disease type C.
Urine-reducing substances, ketones &
Clinitest reaction :galactose and glucose, but not
Clinistix reaction (glucose oxidase) specific for
pH <5 indicate IEM
Ketonuria is abnormal in neonates
Dinitrophenylhydrazine :α-ketoacids in MSUD.
Plasma carnitine and acylcarnitine
Elevation of carnitine esters
Fatty acid oxidation defects
low carnitine levels
Disorders of carnitine biosynthesis
Preterm infants and neonates receiving total
parenteral nutrition without adequate carnitine
Secondary carnitine deficiency.
Second line investigations
• To be performed in a targeted manner
Gas chromatography mass spectrometry of urine
Plasma amino acids and acyl carnitine profile: by
tandem mass spectrometry
Urea cycle defects
Fatty acid oxidation defects.
High performance liquid chromatography :
Quantitative analysis of amino acids in blood
Organic acidemias and aminoacidopathies
Lactate/pyruvate ratio- in cases with elevated
Urinary orotic acid- in cases with
hyperammonemia for classification of urea cycle
Enzyme assay: This is required for definitive
diagnosis, but not available for most IEM
biotinidase assay- biotinidase deficiency
(intractable seizures, seborrheic rash, alopecia)
GALT (galactose 1-phosphate uridyl transferase )
assay- galactosemia (hypoglycemia, cataracts,
reducing sugars in urine).
IEM may be associated with structural malformations
e.g. Zellweger syndrome has diffuse cortical migration
and sulcation abnormalities.
Agenesis of corpus callosum :
Pyruvate decarboxylase deficiency
MSUD: brainstem and cerebellar edema
Propionic & methylmalonic acidemia: basal
ganglia signal change
Magnetic resonance spectroscopy :
lactate peak elevated in mitochondrial disorders
leucine peak elevated in MSUD.
Comb-like rhythm suggests MSUD
Burst suppression in NKH and holocarboxylase
Plasma very long chain fatty acid (VLCFA)
levels: elevated in peroxisomaldisorders.
Mutation analysis when available.
CSF aminoacid analysis: CSF Glycine levels
elevated in NKH.
Should be collected before specific treatment
is started or feeds are stopped
Samples for blood ammonia and lactate
should be transported in ice and immediately
Lactate sample should be arterial or central
line and should be collected after 2 hrs fasting
in a preheparinized syringe.
Ammonia sample is to be collected
approximately after 2 hours of fasting in EDTA
vacutainer. Avoid air mixing.
Sample should be free flowing.
Detailed history including drug details should
be provided to the lab. (sodium valproate
therapy may increase ammonia levels).
Samples to be obtained in infant with suspected
IEM when diagnosis is uncertain and death
Blood: 5-10 ml; frozen at -200C; both heparinized
(for chromosomal studies) and EDTA (for DNA
Urine: frozen at –20oC
CSF: store at –20oC
Skin biopsy: including dermis in culture
medium or saline with glucose. Store at 4-80C.
Do not freeze.
Liver, muscle, kidney and heart biopsy: as
Clinical photograph (in cases with
Infantogram (in cases with skeletal
MANAGEMENT OF INFANT AT RISK
FOR A METABOLIC DISORDER
When a sibling has had symptoms consistent
with a metabolic disorder, or has died of a
Before or during subsequent pregnancy
Prenatal discussion of possible diagnoses, and the
parents and relatives should be screened for
Old hospital charts and postmortem material
should be reviewed.
When a diagnosis is known, intrauterine
diagnosis to be tried.
The new baby should be delivered in a facility
equipped to handle potential metabolic or
Initial evaluation includes a careful physical
examination for the signs of IEM
All nonmetabolic causes of symptoms should
The newborn screening program should be
contacted for the results of the screening and
for a list of the disorders screened.
Blood and urine tests before starting
treatment for metabolic disease.
The specimens can be frozen (plasma, urine)
and analysis performed later.
Enzyme assay of red blood cells, or enzyme
and DNA analysis of white blood cells,
fibroblasts, or liver tissue may be done for
confirmation of diagnosis.
DNA analysis can sometimes be performed on
a dried blood specimen (Guthrie blood spot).
In most cases, treatment needs to be
instituted empirically without a specific
The metabolic screen helps to broadly
categorize the patient’s IEM (e.g. urea cycle
defect, organic academia, congenital lactic
Aims of treatment
Decreasing substrate availability (by stopping
feeds and preventing endogenous catabolism)
To provide adequate calories
To enhance the excretion of toxic metabolites.
To institute co-factor therapy for specific
disease and also empirically if diagnosis not
Supportive care- treatment of seizures (avoid
sodium valproate – may increase ammonia
maintain euglycemia and normothermia
fluid, electrolyte & acid-base balance
treatment of infection
mechanical ventilation if required.
Management of hyperammonemia
Discontinue all feeds.
Provide adequate calories by intravenous
glucose and lipids.
Maintain glucose infusion rate 6- 8mg/kg/min.
Start intravenous lipid 0.5g/kg/day (up to
After stabilization gradually add protein 0.25
g/kg till 1.5 g/kg/day.
Dialysis is the only means for rapid removal of
ammonia, and hemodialysis is more effective
and faster than peritoneal dialysis. Exchange
transfusion is not useful.
Sodium benzoate (IV or oral)- loading dose
250 mg/kg then 250-400 mg/kg/day in 4
divided doses. (not available in India).
L-carnitine (oral or IV)- 200 mg/kg/day
Sodium phenylbutyrate (not available in
India)-loading dose 250 mg/kg followed by
L-arginine (oral or IV)- 300 mg/kg/day
(Intravenous preparation not available in
Suspected organic acidemia
• Acute management
The patient is kept nil per orally and
intravenous glucose is provided.
Supportive care: hydration, treatment of
sepsis, seizures, ventilation.
Carnitine: 100 mg/kg/day IV or oral.
Treat acidosis: Sodium bicarbonate 0.35-
0.5mEq/kg/hr (max 1-2mEq/kg/hr)
Biotin 10 mg/day orally.
Vitamin B12 1-2 mg/day I/M (useful in B12
responsive forms of methylmalonic acidemias)
Thiamine 300 mg/day (useful in Thiamine-
responsive variants of MSUD).
If hyperammonemia is present, treat as
Refractory seizures with suspected
Seizures despite 2 or 3 antiepileptic drugs
Pyridoxine 100 mg intravenously. oral 15
Despite pyridoxine.. give trial of biotin 10
mg/day and folinic acid 15 mg/day (folinic acid
Rule out glucose transporter defect: measure
CSF and blood glucose
Asymptomatic newborn with a
History of sibling death with
After baseline metabolic screen, start oral
dextrose feeds (10% dextrose).
After 24 hours, repeat screen. If normal, start
breast feeds. Monitor sugar, blood gases and
urine ketones, blood ammonia 6 hourly.
Medium chain triglycerides (MCT oil) before
starting breast feeds
After 48 hours, repeat metabolic screen.
Obtain samples for TMS and urine organic acid
Follow-up for the first few months
Long term treatment of IEM
Dietary treatment: phenylketonuria, maple
syrup urine disease, homocystinuria,
galactosemia, and glycogen storage disease
Type I & III.
Special diets for PKU and MSUD are
commercially available in the west can be
Based on the amino acid content of some
common food products available in India, a
low phenylalanine diet for PKU and diet low in
branched chain amino acids for MSUDcanbe
urea cycle disorders and organic acidurias
require dietary modification (protein
Enzyme replacement therapy
ERT is now commercially available for some
lysosomal storage disorders.
Pompe’s disease (Glycogen storage disorder
Cofactor replacement therapy
thiamine responsive variants of MSUD
PDH deficiency & complex I deficiency
Glutaric aciduria Type I, Type II
mild variants of ETF
ETFDH complex I deficiency
50% of cases of homocystinuria due to
cystathionine β-synthetase deficiency
pyridoxine dependency with seizures
primary hyperoxaluria type I
Hyperornithemia with gyrate atrophy
Holocarboxylase synthetase deficiency
• Genetic counselling and prenatal diagnosis:
• Most of the IEM are single gene defects,
inherited in an autosomal recessive manner,
with a 25% recurrence risk.
• The samples required are chorionic villus
tissue or amniotic fluid.
Substrate or metabolite detection:
lysosomal storage disorders like Niemann-Pick
disease , Gaucher disease.
DNA based (molecular) diagnosis:
Detection of mutation in proband/carrier parents
Tandem mass spectrometry is used in some
countries for neonatal screening for IEM
Aminoacidopathies ( phenylketonuria, MSUD,
Homocystinuria, Citrullinemia, Argininosuccinic
aciduria, hepatorenal tyrosinemia) fatty acid
Organic acidemias (glutaric aciduria, propionic
acidemia, methylmalonic acidemia, isovaleric
The cost of this procedure is high
Test is highly sensitive, the specificity is
relatively low; and there are difficulties in
interpretation of abnormal test results in
apparently healthy infants.