GALACTOCEREBROSIDASE DEFICIENCY IN THE DOG - MODEL OF KRABBE DISEASE IN HUMANS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Globoid cell leukodystrophy (GLD) or Krabbe disease is an autosomal recessively inherited neurological disease caused by mutations in the gene coding for the lysosomal enzyme galacto-cerebrosidase (GALC). GALC is responsible for the degradation of specific galactolipids, including several that are important in the production of compact, stable myelin. A failure to adequately degrade galactosylceramide and psychosine (galactosylsphingosine) results in the characteristic pathological findings observed in tissue from humans and animals affected with GLD. These galactosphingolipids are normally synthesized during active myelination, and psychosine accumulates in individuals with very low GALC activity. Psychosine is highly toxic to the myelin-forming oligodendrocytes, causing their death and the paucity of myelin found on autopsy. While most human patients present with symptoms before six months of age and die before 18 months of age, older children and adults can also be diagnosed with GLD. The only treatment available at this time is heterologous bone marrow transplantation (BMT). This disease has three naturally occurring animal models, the twitcher mouse, the Cairn and West Highland White terriers, and the rhesus monkey. The human, mouse, and monkey GALC genes have been cloned and characterized in the laboratory of David Wenger, PhD, at the Jefferson University School of Medicine. Cloning of the gene in Cairn and West Highland White Terriers was reported in 1996. The colony of breeding carrier dogs was established by the Referral Center by working with breeders and was maintained RR02512. However, the colony was subsequently transferred to Dr. Wenger¿s grant and have been maintained within the Veterinary School¿s animal care facilities by a subcontract from Dr. Wenger¿s long-standing NIH grant on this disorder. Some support for breeding, diagnostic testing, and pediatric care is provided by the Referral Center personnel.