The hallmark of the hereditary metabolic diseases that affect the nervous system in infancy is failure to achieve psychosensorimotor milestones, or regression of previously attained behaviors. However, those that have their onset in the first year of life pose extraordinary problems in neurologic diagnosis. If the onset is in the first postnatal months, before the infant has had time to develop the normal complex repertoire of behavior, the first signs of disease may take the form of subtle delays in maturation rather than of psychomotor regression. Departures from normalcy include a lack of interest in the surroundings, a lack of visual engagement, poor head control, inability to sit up at the usual time, poor hand–eye coordination, and persistence of infantile automatisms. Of course, embryologic maldevelopment of the brain may have similar effects (Chap. 37), and systemic diseases and other visceral malformations—such as cystic fibrosis, renal disease, biliary atresia and congenital heart disease, chronic infection, malnutrition, and seizures (with drug therapy)—may impede psychomotor development. Diagnosis becomes somewhat easier in the second half of the first year, especially if development in the first half had proceeded normally. Then an observant parent, usually one with older children, can perceive a loss of certain early acquisitions, attesting to the progressive nature of a disease.
The most distinctive members of this category of neurologic disease are the leukodystrophies and the lysosomal storage diseases. The leukodystrophies are a group of inherited metabolic diseases of the nervous system characterized by progressive, symmetrical, and usually massive destruction of the white matter of the brain and sometimes of the spinal cord; each type of leukodystrophy is distinguished by a specific genetic defect in myelin metabolism. In the lysosomal storage diseases, there is a genetic deficiency of the enzymes (usually one or more of the acid hydrolases) necessary for the degradation of specific glycosidic or of peptide linkages in the intracytoplasmic lysosomes, causing nerve cells to become engorged with material that they would ordinarily degrade. These metabolites eventually damage the nerve cell or its myelin sheath.
Most of these diseases are classed as sphingolipidoses. Brady in 1966 made the observation that in each of these disorders an increased quantity of sphingolipid accumulated in the brain and other tissues. The sphingolipids are a class of intracellular lipids that all have ceramide as their basic structure, but each has a different attached oligosaccharide or phosphorylcholine. The rate of synthesis of the sphingolipids is normal and their accumulation results from a defect of a specific lysosomal enzyme that normally degrades each of the glycoproteins, glycolipids, and mucopolysaccharides by removing a monosaccharide or sulfate moiety. It is the type of enzyme deficiency and accumulated metabolite, as well as the tissue distribution of the nondegradable substrate, that impart a distinctive biochemical and clinical character to each of the diseases in this category.
The concept of lysosomal storage diseases, introduced by Hers in 1965, excited great interest at the time because it provided the potential for prenatal diagnosis and the detection of carriers. The diagnosis of this group of diseases has also been facilitated by the use of CT, MRI, and evoked response techniques, which confirm the existence of leukodystrophies and by the electron microscopic examination of skin, rectal, or conjunctival biopsies, circulating lymphocytes, and cultured amniotic fluid cells, which discloses the lysosomal storage material in nonneural cells.