About a dozen variants of globoid cell leukodystrophy have been reported, many of them allowing survival for years. In these, neurologic regression begins in the 2to 6-year-old period. Visual failure with optic atrophy and a normal electroretinogram is an early finding. Later there is ataxia, as well as spastic weakness of the legs, mental regression, and finally decerebration. In three patients observed by R.D. Adams, a progressive quadriparesis with mild pseudobulbar signs, slowly progressive impairment of memory and other mental functions, dystonic posturing of the arms, and preserved sphincteric control constituted the clinical picture. The patients were alive at ages 9, 12, and 16 years. We have observed another rare variant, beginning in adult years, with spastic quadriparesis (asymmetrical) and optic atrophy. Mentation was essentially normal and, on imaging, the cerebral lesion was restricted. Unlike typical Krabbe disease, these CNS abnormalities are unaccompanied by any change in the spinal fluid. The nerve conduction velocities in the late-onset form may be either normal or abnormal.
Kolodny and colleagues reported 15 cases of even later onset (ages 4 to 73 years); pes cavus, optic pallor, progressive spastic quadriparesis, a demyelinating sensorimotor neuropathy, and symmetrical parietooccipital white matter changes (on imaging studies) were the main features. Galactocerebrosidase levels were not as reduced as in the infantile form; possibly these late-onset variants represent a structural mutation of the enzyme (see Farrell and Swedberg).
In this disease, as well as others described in this chapter, it has become clear that different mutations involving the same enzyme or metabolic pathway can produce strikingly different phenotypes and that there is a wide range in the age of onset in what had been considered, until relatively recently, a disease confined to infancy and early childhood.
In what may be considered a breakthrough in the treatment of childhood metabolic disease, Escolar and colleagues reported the successful use of transplanted umbilical cord hematopoietic cells in asymptomatic babies with Krabbe disease. Patients who were treated after becoming symptomatic did not benefit, but 14 patients who had been diagnosed prenatally or very soon after birth demonstrated progressive myelination of the nervous system, normalization of blood galactocerebroside activity, and attained visual, developmental, and cognitive function. The donors were partially human leukocyte antigen (HLA)-matched and substantial antirejection medication was required.
This more recently described and peculiarly named disease with variable age of onset is most typically manifest in this age group. After a period of normal development, and sometimes precipitated by infection or fever, there is a progressive encephalopathy punctuated by episodes of more rapid deterioration. The core syndrome is of irritability, loss of vision, seizures, ataxia, and coma, sometimes with recovery to a disabled state. The denominative feature is a symmetrical leukodystrophy with progressive disappearance of white matter and replacement by CSF or gliosis. The nature of this disease appears to be predominantly genetic with most cases caused by one of five mutations in eIF2B. We include it in this section because exacerbation with fever, similar to the case in some mitochondrial diseases, is suggestive of a metabolic disorder (see Leegwater et al).
Lipogranulomatosis (Farber Disease, Ceramidase Deficiency, ASAH1 Mutation)