Metabolic and Neurodegenerative Disorders
What to know
Categorize by pattern: leukodystrophy (white matter), gray matter degeneration, mitochondrial disease, lysosomal storage, peroxisomal disorders, and small-molecule disorders such as amino and organic acidopathies and urea cycle defects. Age at onset and associated features narrow the differential.
Metachromatic leukodystrophy (arylsulfatase A) causes regression, peripheral neuropathy, and gallbladder involvement. Krabbe disease (galactocerebrosidase) causes irritability, hypertonia, and optic atrophy in infancy. X-linked adrenoleukodystrophy (ABCD1) causes posterior white matter change, behavioral decline, and adrenal insufficiency. Canavan disease (aspartoacylase) causes macrocephaly with a markedly elevated N-acetylaspartate peak on spectroscopy; Alexander disease (GFAP) causes macrocephaly with frontal-predominant white matter change. Pelizaeus-Merzbacher disease (PLP1) presents with nystagmus and spasticity.
Mitochondrial disease: Leigh syndrome (basal ganglia lesions, lactic acidosis), MELAS (stroke-like episodes, m.3243A>G), MERRF (myoclonus, epilepsy, ragged red fibers), and Alpers disease (POLG, liver failure precipitated by valproate). Lysosomal: Tay-Sachs (cherry-red spot, hyperacusis), Gaucher (hepatosplenomegaly, bone crises), Pompe (cardiomegaly, hypotonia). Urea cycle defects cause hyperammonemia and encephalopathy; OTC deficiency raises orotic acid.
Newborn screening has transformed phenylketonuria management; maternal PKU causes microcephaly and intellectual disability.
Traps
Macrocephaly plus leukodystrophy suggests Canavan or Alexander. Stroke-like episodes in a child suggest MELAS. Valproate is contraindicated in POLG disease and urea cycle disorders.
Rule of thumb
Acute encephalopathy with respiratory alkalosis and hyperammonemia equals a urea cycle defect until proven otherwise; stop protein and give calories plus nitrogen scavengers.