Dr.Manjeet Kaur*
Head, Division of Genetics, Dr. Lal Path Lab, New Delhi Email : *
The disorders caused by inherited metabolic errors (IME) are often overlooked due to their clinical symptoms mimicking simple illness such as fever, vomiting, sepsis, seizures, coma. Many a times, clinical symptoms are episodic. The initial index of suspicion of IME should occur in acutely ill infant presenting neurological symptoms, cardiac abnormalities, liver dysfunction, dysmorphism. The level of suspicion should be raised if the common laboratory evaluation shows
  1. Neutropenia
  2. Acidosis
  3. Raised anion gap
  4. Hypoglycemia
  5. Hyperammonemia
  6. Elevated lactate

Diagnosis of IME depends on laboratory findings as most disorders share same clinical symptoms.

Child with Metabolic Acidosis:
Major cause of metabolic acidosis falls in two categories: normal anion gap and elevated anion gap. Inborn errors should be suspected when acidosis is accompanied with elevated anion gap. If the anion gap is elevated, the serum glucose concentration should be determined to rule out diabetes mellitus. If the serum glucose level is normal or low, an inborn error of metabolism should be suspected. Most likely caused inborn errors can be branched chain amino acid disorders (MSUD, Hypervalinemia), organic acid disorders, Type 1a (Glucose-6-phosphate deficiency) and Type 3 glycogen storage disorders.

Child with Hyperammonemia:
Excessive concentration of circulating ammonia occurs in a various inherited metabolic errors. Raised ammonia usually is found in an initial well infant after several days of protein feeding. The main causes of hyperammonemia are urea cycle disorder, organic academia and in either case respiratory alkalosis may be the initial acid-base disturbance. Specific specialized tests are required for diagnosing correct inborn error. Laboratory parameters required are amino acids in blood and urine, urine orotic acid, urine organic acids, acylcarnitines in dried blood spots. As these tests take some time, for immediate clinical management, first line investigation based on urea, blood gases, liver function tests, sodium and potassium, calcium, lactate and glucose levels can give clues. In urea cycle disorders, urea may be inappropriately low compared to other parameters of dehydration/renal function. Metabolic acidosis is more a feature of organic acid disorders. Liver function tests, sodium feature of organic acid disorders. Liver function tests, sodium and potassium are usually normal in urea cycle disorders. Hypoglycemia is not a feature of urea cycle disorders. Although raised ammonia concentration can guide to search for IME, it must be emphasized that hyperammonemia can occur in many situations in newborns including prematurity, sepsis and other non specific liver dysfunction, viral infections and intoxications.

Child with Hypoglycemia:
Low blood glucose level usually indicates inborn errors of
  1. Fatty acid metabolism
  2. Defect in gluconeogenesis
  3. Glycogen storage disorders
  4. Galactosemia
  5. Hereditary Fructose Intolerance
  6. Certain amino acid and organic acid disorders such as MSUD, Methylmalonic academia, Glutaric academia type II, hypoglycemia can also occur due to endocrine abnormalities.

Child with Elevated Lactate:
Persistent or recurrent lactic academia can occur in inborn errors of metabolism. Chronic lactic academia results in increased blood alanine levels. Alanine levels are normal in transient lactic academia. Increased alanine levels are sensitive marker in patients with mitochondrial dysfunction.
Raised lactate with normal glycemia and ketosis indicates congenital lactic acidosis and organic acidurias. Raised lactate alongwith ketosis and hypoglycemia indicates Gluconeogenesis defects and respiratory chain defects. Raised lactate accompanied with ketosis and low glucose level indicates fatty acid oxidation disorders, HMG-CoA lyase, Fructose diphosphate defect.

Test Profile in Selected Inborn Metabolic Disorders:
Aminoacid Disorders:
  1. Phenylketonuria:
    Diagnostic Metabolites on MS/MS : Increased Phenylalanine, decreased Tyrosine. Elevated Organic Acid: Phenyl lactic acid, Phenyl pyruvic acid, 2-Hydroxyphenylacetis acid.
  2. Maple Syrup Urine Disease:
    Diagnostic Metabolites on Ms/MS: Increased Leucine/Isoleucine, increased Valine, Increased Leucine/Alanine molar ratio, Increased Leucine/Tyrosine molar ratio.
    Transient elevations of branched chain amino acids may develop in patients with ketotic hypoglycemia.
    Alloisoleucine not detected on screen by MS/MS.
    Alloisoleucine can be detected by HPLC. Alloisoleucine may not appear until the 6th day of life, even when leucine level elevated.
    Elevated Organic Acids in Urine: 2-Oxoisocaproic acid, 2-hydroxyisocaproic acid, 2-hydroxyisovaleric acid, 2-Oxoisovaleric acid, 2-hydroxy-3-methylvaleric acid, 2-oxo-3-methylvaleric acid.
  3. Homocystinuria:
    Diagnostic Metabolite on MS/MS: Methionine Amino acids by HPLC Total Homocysteine elevated in Blood and urine.
    Positive cyanide nitroprusside test on urine
  4. Tyrosinemia
    Diagnostic metabolite on MS/MS: Elevated Tyrosine. In Hepatorenal Tyrosinemia both Methionine and Tyrosine elevated.
    Elevated Organic acids in Urine: 4-Hydroxyphenyllactic acid, 4-hydroxyphenylacetic acid, 4-Hydroxyphenylpyruvic acid, N-acetyl tyrosine, Succinylacetone (type 1 only)
  5. Non-Ketotic Hyperglycinemia:
    Diagnostic Metabolite: Elevation of Glycine in blood, urine and CSF: A value of CSF/Serum glycine concentration ratio is diagnostic. Serum and CSF sample should be collected at the same time. Values of sample collected on different days should be used for calculating ratio. Glycine elevation can be transient. Patients of transient NKH are clinically indistinguishable from patients with neonatal NKH. By 2-8 weeks blood and CSF glycine levels return to normal. The most common cause of hyperglycinemia is administration of anticonvulsant valproate. The diagnosis of NKH cannot be established in the presence of Valporate therapy. Urine Organic acids should be tested by GC/MS to rule out hyperglycinemia secondary to Organic academia. Ketotic hyperglycinemia can be due to Methylmalonic academia, Propionic acidemia, Isovaleric acidemia, ketothiolase deficiency. Carnitine deficiency and transient hyperammonemia may be seen. Diagnosis of NKH should be confirmed by demonstrating deficient GCS activity. This necessitates a liver biopsy as NKH activity is not expressed in fibroblasts nor untransformed lymphocytes. Liver GCS activity is indicated to determine the severity of the disease and for prenatal diagnosis.

Urea Cycle Defects:
  • Aminoacid citrulline and Arginine levels
  • Ammonia
  • Orotic Acid in Urine

Organic Acid Disorders
  • Methylmalonic Acidaemia
    Diagnostic Metabolite on MS/MS: Elevated C3 acylcarnitine.
    Elevated Organic acid in Urine; Methylmalonic acid, methyl citric acid, 3-hydroxypropionic acid, propionyl glycine, 3-hydroxyvaleric acid.

  • Propionic Acidemia:
    Diagnostic Metabolite on MS/MS: Increased C3 acylcarnitine elevated Organic acids in Urine: Propionyl glycine, methyl citric acid, 3-hydroxypropionic acid, 3-hydroxyvaleric acid.

  • Glutaric Acidemia Type 1
    Diagnostic Metabolite on MS/MS: Increased C5DC acylcarnitine. Elevated Organic acids in Urine: Glutaric acid, glutaconic acid, 3-hydroxyglutaric acid.

  • Isovaleric Acidemia
    Diagnostic Metabolite on MS/MS; Increased C5 acylcarnitine.
    Elevated Organic acids in Urine; Isovaleryl glycine, 3-hydroxyisovaleric acid.

  • Multiple Carboxylase Deficiency:

    Diagnostic Metabolite on MS/MS: Increased C3 and C5OH.

    Elevated Organic acid in urine by CG/MS; 3-Methylcrotonylglycine, methyl citric acid, lactic acid, 3-hydroxyisovaleric acid, triglycine, 3-hydroxypropionic acid.

Fatty Acid Oxidation Disorders
  • Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD)

    Diagnostic Metabolite on MS/MS: Increased C8-C10 acylcarnitines.
    Elevated Organic acids in Urine by GC/MS: Adipic acid, Suberic acid, Octanoic acid, Suberylglycine, hexanoylglycine, Octenoic acid, phenyl propionyl glycine, 5-hydroxyhexanoic acid.

  • Multiple Acyl-CoA Dehydrogenase Deficiency (Glutaric Acidemia Type II)
    Diagnostic Metabolite on MS/MS: Multiple elevations from C4-C18.
    Elevated Organic acids by GC/MS: Glutaric acid, adipic acid, Suberic acid, 2-hydroxyglutaric acid, methylmalonic acid, isovalerylglycine.

  • Short Chain Acyl CoA Dehydrogenase Deficiency (SCAD)
    Diagnostic Metabolite on MS/MS: Increased C4 acylcarnitine

Peroxisomal Disorders

There are two types of Peroxisomal disorders: single peroxisomal enzyme deficiencies and peroxisomal biogenesis disorders (PBDs). Laboratory diagnoses are elevation of VLCFAs and decreased RBC plasmalogens

Lysosomal Storage Disorders

Enzyme activity level in white cells (Leucocytes) is the gold standard test.
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