Metabolic Diseases | The Massachusetts General Hospital Handbook of Neurology

Authors: Flaherty, Alice W.; Rost, Natalia S.

Title: Massachusetts General Hospital Handbook of Neurology, The, 2nd Edition

> Table of Contents > Child Neurology > Metabolic Diseases

Metabolic Diseases

A. See also

Progressive developmental delay, p. 132.

B. H&P

Progressive neurological deterioration with recurrent unexplained ataxia, spasticity, altered consciousness, vomiting, acidosis; or mental retardation in the absence of major congenital brain abnormalities.

C. Tests

Electrolytes, glucose, ABG, ammonia, lactate, urine ketones, urine colorimetric tests (ferric chloride, DNPH, reducing substances, nitroprusside, CTAB Berry spot). Consider carnitine, serum and urine amino acids, urine organic acids, ferritin glycosylation, full ophthalmologic exam, CT or MRI, skeletal films for bone age and defects, lysosomal enzyme studies, tissue biopsy.

P.143

Isolated ketosis: Suggests maple syrup urine dz.
Ketosis and acidosis: Organic acidopathy, lactate/pyruvate disorders.
Lactic acidosis: Lactate/pyruvate or mitochondrial disorders; hypoxia, sepsis, liver or renal failure, DM.
Hyperammonemia: Urea cycle disorders (without ketosis), organic acidopathies, Reye's syndrome, liver failure.
No ketosis, acidosis, or hyperammonemia: Nonketotic hyperglycinemia, sulfite oxidase deficiency; peroxisomal, lysosomal, or fatty acid disorders.

D. Causes

The entries below focus on disorders for which prompt rx is essential.

E. Abetalipoproteinemia

(Bassen-Kornzweig dz): Infants have steatorrhea, ataxia, retardation, retinitis pigmentosa, low cholesterol, acanthocytes. Responds to vitamin E and special diet.

F. Aminoacidurias

Homocystinuria: Autosomal recessive defect in cystathionine synthase causes accumulation of sulfur metabolites.
- H&P: Normal at birth. The neurological sx are from strokes. Frequently mentally retarded, with psychiatric disorders. Also see skin and eye problems. Adult heterozygotes are also at risk for strokes.
- Rx: Pyridoxine (B₆) 250-1,000 mg qd, and a methionine-restricted diet supplemented with cystine and betaine.
Maple syrup urine dz: Autosomal recessive defect in branched-chain amino acid metabolism (valine, leucine, isoleucine).
- H&P: Normal at birth; sweet-smelling urine. Within a week, get opisthotonos, intermittent increased muscle tone, irregular breathing. If untreated, severe retardation and spasticity; may die in infancy.
- Tests: Ferric chloride test on urine; serum amino acids.
- Rx: Diet restricted in branched-chain amino acids. If started in first 2 wk of life, most children develop normally. However, they are vulnerable to sepsis.
Phenylketonuria: Autosomal recessive defect of phenylalanine hydroxylase (converts phenylalanine to tyrosine)
- H&P: Normal at birth, vomiting and irritability by 2 mo, mental retardation by 4-9 mo; later seizures and imperfect hair pigmentation.
- Rx: Phenylalanine-restricted diet. If started early, children develop normally.
Nonketotic hyperglycinemia: Autosomal recessive defect in glycine processing.
- H&P: Severe early seizures sometimes associated with gyral abnormalities, agenesis of corpus callosum, cerebellar hypoplasia.
- Tests: CSF to plasma glycine ratios.
- Rx: Benzoate and dextromethorphan.

G. Hyperammonemias

Major causes include neonatal asphyxia, severe liver dz, drugs (e.g., valproic acid), urea cycle disorders, organic acidurias, lactic acidoses, and dibasic aminoacidurias.

Rx: Arginine, sodium benzoate, phenylacetate, dialysis, and low-protein diet.

P.144

H. Leukodystrophies

Defects in myelin metabolism, usually lysosomal or peroxisomal, causing white matter dz and peripheral neuropathy. See below.

I. Lysosomal enzyme disorders

Glycoprotein degradation disorders, mucolipidoses, mucopolysaccharidoses, sphingolipidoses.

Krabbe's leukodystrophy (globoid cell): Galactocerebrosidase deficiency. Onset in infancy, with irritability, hypertonia and opisthotonos, vision and hearing loss, seizures, peripheral neuropathy. Death in 2-3 yr.
Metachromatic leukodystrophy: Arylsulfatase A deficiency. Infant to adult onset. May be spastic or flaccid. Severe peripheral neuropathy and CSF protein elevation. Also dementia, ataxia, optic atrophy.
Others: Niemann-Pick's, Gaucher's, Tay-Sachs, GM1 gangliosidosis, Fabry's, Hurler's .

J. Peroxisomal disorders

Zellweger's syndrome (cerebrohepatorenal syndrome): Reduced or absent peroxisomes. Severe hypotonia, seizures, developmental delay, liver failure, and early death.
Adrenoleukodystrophy (ALD):
- Neonatal ALD and infantile Refsum's dz are milder variants of Zellweger's syndrome, above. N-ALD pts benefit from docosahexaenoic acid.
- X-linked ALD: Buildup of very long chain fatty acids. Childhood onset form starts with ADHD, progresses to seizures, dementia, ataxia, death. Adult onset form (adrenomyeloneuropathy) causes progressive spastic paraparesis, sphincter trouble, and adrenal insufficiency.

K. Others

E.g., metabolism of carbohydrate, glycoprotein, lipid, or purine; mucopolysaccharidoses, mucolipidoses; mitochondrial defects; endocrine defects.

Galactosemia: Autosomal recessive defect in galactose- 1-uridyltransferase.
- H&P: Usually normal at birth. First week: listlessness, jaundice, vomiting, diarrhea, no weight gain. Second week: hypotonia, cataracts, hepatosplenomegaly. Untreated infants get mental retardation and die of cirrhosis.
- Tests: Reducing substances in the urine; erythrocyte transferase activity.
- Rx: Lactose-free diet. Most treated infants have a normal IQ but visual-perceptual defects.
Hypothyroidism:
- H&P: Postterm, macrosomy, jaundiced, large fontanelles, skin mottling, listless, big belly, umbilical hernia. By age 2 mo: hypotonic, grunting cry, wide-open sutures. Later: mental retardation, deafness, and spasticity.
- Rx: Thyroid replacement. Even with early rx, pts usually have learning and cerebellar disorders.
Mitochondrial disorders: see p. 72.
Neuronal ceroid lipofuscinosis:
- Sx: Myoclonic seizures, ataxia/extrapyramidal abnormalities, visual loss (except in adult onset).
- Cause: Encoded by different gene with variable ages of onset.
- Dx: Skin biopsy and/or genetics.
Congenital disorders of glycosylation.
Pyridoxine (B₆) dependency: Can cause neonatal seizures that respond only to pyridoxine.