Authors David A. Wenger    Kunihiko Suzuki    Yoshiyuki Suzuki    Kinuko Suzuki   
Abstract

Infantile globoid cell leukodystrophy (GLD, or Krabbe disease) is a rapidly progressive, invariably fatal disease. It is transmitted as an autosomal recessive trait. The disease usually begins between ages 3 and 6 months with ambiguous symptoms, such as irritability or hypersensitivity to external stimuli, but soon progresses to severe mental and motor deterioration. Patients rarely survive the second year. Clinical manifestations are limited to the nervous system, with prominent long-tract signs. There is hypertonicity with hyperactive reflexes in the early stages, but patients later become flaccid and hypotonic. Blindness and deafness are common. Peripheral neuropathy is almost always detectable. Patients with later onset, including adult-onset, forms may present with blindness, spastic paraparesis, and dementia.

The presence of numerous multinucleated globoid cells, almost total loss of myelin and oligodendroglia, and astrocytic gliosis in the white matter are the morphologic basis for diagnosis. The globoid cells are hematogenous macrophages that contain undigested galactosylceramide. Segmental demyelination, axonal degeneration, fibrosis, and histiocytic infiltration are common in the peripheral nervous system.

Consistent with the myelin loss, the white matter is severely depleted of all lipids, particularly glycolipids. However, the ratio of galactosylceramide to sulfatide is abnormally high. Galactosylceramide, a sphingoglycolipid consisting of sphingosine, a fatty acid, and galactose, is normally present almost exclusively in the myelin sheath.

The cause of Krabbe disease is a genetic deficiency of galactosylceramidase (galactocerebroside β-galactosidase [GALC]) activity. This lysosomal enzyme normally degrades galactosylceramide to ceramide and galactose. One infant with a clinical picture similar to Krabbe disease was found to have a mutation in saposin A, an activator protein that assists in the action of GALC on galactosylceramide. It is postulated that accumulation of a toxic metabolite, psychosine (galactosylsphingosine), which is also a substrate for the missing enzyme, leads to early destruction of the oligodendroglia. The total brain content of galactosylceramide is not increased. However, the extensive globoid cell reaction indicates that impaired catabolism of galactosylceramide is also an important factor in the pathogenesis.

Assays of GALC activity in leukocytes or cultured fibroblasts with the use of appropriate natural glycolipid substrates can readily establish a definitive diagnosis. Intrauterine diagnosis of affected fetuses is available by measuring GALC activity in amniotic fluid cells or biopsied chorionic villi.

Treatment at this time is limited to hematopoietic stem cell transplantation in asymptomatic individuals and those with only minimal neurologic involvement. This seems to slow the expected course of the disease and result in improved magnetic resonance imaging findings and cerebrospinal fluid protein.

The human GALC gene has been mapped to chromosome 14q31. The human cDNA and gene have been cloned. The cDNA consists of 3795 nucleotides, including 2007 bp of coding region, 1741 bp of 3′ untranslated sequence, and 47 bp of 5′ untranslated sequence. The gene is about 56 kb, consisting of 17 exons. Analysis of the 5′ flanking region revealed GC-rich sequences, one potential SP1 binding site, and one YY1 element. Evidence for inhibitory elements were found in the 5′ flanking region and within intron 1. Over 60 disease-causing mutations have been found in patients with all types of GLD. However, a few specific mutations are found in a significant number of unrelated cases with European ancestry and within some inbred communities. In addition, a number of polymorphisms in this gene have been identified, and their role in the phenotype may be considerable.

GLD, also due to genetic GALC deficiency, occurs in other mammalian species, most notably in certain breeds of dogs, monkeys, and mice. Clinical and pathologic features are similar to those in the human disease. These animal models will be available for future therapy trials.