Biochemical studies may disclose a biotinidase deficiency, methylmalonic aciduria, glutaric acidemia, methylglutaconic acidemia, or any number of other organic acid abnormalities. Each can be identified by a now established genetic cause. As remarked above, some of these enzymes act in conjunction with a specific vitamin cofactor, so that exact diagnosis is imperative. The biotinidase deficiency may respond to 10 mg of biotin per day; the methylmalonic acidemia to 1 to 2 mg of vitamin B12 per day; maple syrup urine disease to 10 to 20 mg of thiamine per day; and glutaric acidemia types I and II to 300 mg of riboflavin per day. The administration of carnitine may increase the elimination of toxic metabolites.
These are extremely rare autosomal recessive disorders of sulfur metabolism due to a mutation in SUOX, manifest clinically during the neonatal period by seizures, axial hypotonia, reduced level of responsivity, and spasms with opisthotonos. There may be added dislocation of lenses, blindness, coloboma, and enophthalmos in combination with severe mental retardation and dysmorphic facial features (widely spaced eyes, long face and philtrum, puffy cheeks). There are no differences in clinical manifestations between pure sulfite oxidase deficiency and that associated with molybdenum cofactor deficiency. With survival into infancy, episodic confusion and stupor give way to seizures, mental retardation, and ataxia. In one of our cases, described by Shih and colleagues (1977), a stroke-like syndrome of hemiplegia and aphasia appeared during a relapse at the age of 4.5 years, and in one case, subluxation of the lenses and choreoathetosis appeared at 8 months of age.
The biochemical abnormality is the accumulation of sulfite and possibly sulfatase as a result of the enzyme deficiency. Cerebral atrophy with loss and destruction of white matter and gray matter (cerebral cortex, basal ganglia, and cerebellar nuclei) was observed in one postmortem examination. Increasing the intake of molybdenum or lowering the dietary intake of sulfur amino acids is a therapeutic possibility not yet fully evaluated.
Diagnosis of Neonatal Metabolic Diseases
An important clue, of course, is provided by the history of a neonatal disease or unexplained death earlier in the same sibship or in a male maternal relative. A history that protein foods are rejected by the infant, or even a history among relatives of a dislike of protein or feeding difficulties in infancy, should raise the suspicion of an inherited hyperammonemic disorder or an organic acidemia. Measurements of blood ammonia and lactate and of the urine for ketones and reducing substances (that react with cupric sulfate) are the key laboratory tests. A wide-spectrum screening program may disclose a biochemical abnormality; this is the optimal state of affairs, especially when this type of screening provides the information before symptoms appear.