Inheritance of this disorder is autosomal recessive. The biochemical abnormality consists of a defect in galactose-1-phosphate uridyl transferase as a result of a mutation in GALT. This enzyme catalyzes the conversion of galactose-1-phosphate to uridine diphosphate galactose, and three forms of the enzyme are included in newborn screening. Several forms of galactosemia have been described, based on the degree of completeness of the metabolic block and some of these are due to mutations in other galactose pathway genes. In the typical (severe) form, the onset of symptoms is in the first days of life, after the ingestion of milk; vomiting and diarrhea are followed by a failure to thrive. Drowsiness, inattention, hypotonia, and diminution in the vigor of neonatal automatisms then become evident. The fontanels may bulge, the liver and spleen enlarge, the skin becomes yellow (in excess of the common neonatal jaundice), and anemia develops. In a small number, there is thrombocytopenia with cerebral bleeding. Cataracts form as a result of the accumulation of galactitol in the lens. Studies of the outcome of surviving infants have shown delayed psychomotor development (IQ about 85), visual impairment, osteoporosis, ovarian failure, and residual cirrhosis, sometimes with splenomegaly and ascites. This seems to happen even with treatment. However, it is not known whether, in such patients, the treatment is always maintained through a critical developmental period. In one such patient, who died at age 8 years, the main change in the brain was slight microcephaly with fibrous gliosis of the white matter and some loss of Purkinje and granule cells in the cerebellum, and also gliosis (Crome). The diagnostic laboratory findings are an elevated blood galactose level, low glucose, galactosuria, and deficiency of the applicable enzyme in red and white blood cells and in liver cells. The treatment is essentially dietary, using milk substitutes; if this is instituted early, the brain should be protected from injury.
A late-onset neurologic syndrome has also been observed by Friedman and colleagues in galactosemic patients who had survived the infantile disease. By late adolescence, they were cognitively delayed; some showed cerebellar ataxia, dystonia, and apraxia. One of these patients was middle-aged.
Organic Acidurias of Infancy
These have been divided into ketotic and nonketotic types. Most of these disorders are included in newborn screening. Among the ketotic types, the main one is propionic acidemia. This is an autosomal recessive disease caused by a primary defect in organic acid metabolism that is expressed clinically by episodes of vomiting, lethargy, coma, convulsions, hypertonia, and respiratory difficulty. The onset is in the neonatal or early infantile period; in time, psychomotor retardation becomes evident. Death usually occurs within a few months despite dietary treatment. Propionic acid, glycine, various forms of fatty acids, and butanone are elevated in the serum. As with other ketotic organic acidurias, high protein intake induces ketotic attacks. Marked restriction of dietary protein (specifically leucine) may prevent attacks of ketoacidosis and permit relatively good psychomotor development.