This is an autosomal recessive disease without ethnic predilection, first described by Krabbe, a Danish neurologist, in 1916. The onset is usually before the sixth month and often before the third month (10 percent after 1 year). Early manifestations are generalized rigidity, loss of head control, diminished alertness, frequent vomiting, irritability and bouts of inexplicable crying, and spasms induced by stimulation. With increasing muscular tone, opisthotonic recurvation of the neck and trunk develops. Later signs are adduction and extension of the legs, flexion of the arms, clenching of the fists, hyperactive tendon reflexes, and Babinski signs. Later still, the tendon reflexes are depressed or lost but Babinski signs remain, an indication that neuropathy is added to corticospinal damage. This finding, shared with some of the other leukodystrophies, is of diagnostic value. Blindness and optic atrophy supervene. Convulsions occur but are rare and difficult to distinguish from tonic spasms. Myoclonus in response to auditory stimuli is present in some cases. The head size is normal or, rarely, slightly increased. In the last stage of the disease, which may occur from one to several months after the onset, the child is blind and usually deaf, opisthotonic, irritable, and cachectic. Most patients die by the end of the first year and survival beyond 2 years is unusual, although a considerable number of cases of later onset have been reported (see below).
The EEG shows nonspecific slowing without spikes, and the CSF protein is usually elevated (70 to 450 mg/dL).
Imaging shows symmetrical nonenhancing areas of increased signal in the internal capsules and basal ganglia. As the disease advances, more of the cerebral white matter and brainstem become involved (Fig. 36-2). An additional feature in many cases is enlargement of the prechiasmatic optic nerves, also shown in the figure. Neuropathy is a feature in most cases, but clinical signs may be difficult to detect except for a decrease or loss of tendon reflexes; however, there is evidence of denervation and slowed motor and sensory nerve conduction velocities, reflecting a demyelinating polyneuropathy (see later comments on late-onset cases).
The deficient lysosomal enzyme in Krabbe disease is galactocerebrosidase (GALC; also called galactosylceramide beta-galactosidase); it normally degrades galactocerebroside to ceramide and galactose. The deficiency results in the accumulation of galactocerebroside; a toxic metabolite, psychosine, leads to the early destruction of oligodendrocytes and depletion of lipids in the cerebral white matter. The globoid cell reaction, however, indicates that impaired catabolism of galactosylceramide is also important. Gross examination of the brain discloses a marked reduction in the cerebral white matter, which feels firm and rubbery. Microscopically, there is widespread myelin degeneration, absence of oligodendrocytes, and astrocytic gliosis in the cerebrum, brainstem, spinal cord, and nerves. The characteristic globoid cells are large histiocytes containing the accumulated metabolite. Schwann cells have tubular or crystalloid inclusions under electron microscopy.