Globoid cell leukodystrophy in Cairn and West Highland white terriers

Abstract

Krabbe disease or globoid cell leukodystrophy (GLD) is an autosomal recessive disorder resulting from the defective lysosomal hydrolysis of specific galactolipids found primarily in myelin. This leads to severe neurological symptoms including seizures, hypotonia, blindness, and death, usually before 2 years of age in human patients. In addition to human patients, several animals, including dog, mouse, and monkey, have the same disease caused by a deficiency of galactocerebrosidase (GALC) activity. In this article we describe studies in cairn and West Highland white terriers (WHWT) affected with GLD. Through a screening test based on the molecular defect found in these breeds, over 50 cairn terrier carriers have been identified and a colony of five carrier dogs has been established. Affected dogs from this colony plus an affected WHWT were available for study. An affected WHWT was evaluated by magnetic resonance imaging at 6 and 11 months of age and pronounced changes in the T-2 weighted fast spin-echo images were found. Biochemical and pathological evaluation of the same dog after euthanasia at 12 months of age showed a large accumulation of psychosine in the brain and white matter filled with globoid cells. Some comparisons were made to younger affected and carrier dogs. Studies have shown successful transduction of cultured skin fibroblasts from an affected dog and normal canine bone marrow using a retroviral vector containing the human GALC cDNA. Successful treatment of this canine model will lead to studies in some humans with GLD.

In utero Hematopoietic Stem Cell Transplantation in Canines: Exploring the Gestational Age Window of Opportunity to Maximize Engraftment

“…(5) The canine experiences few obstetrical complications and their uterus is tolerant to surgical manipulation. (6) Future treatment trials and modeling for human applications are possible because canines have many analogous medical conditions [17,18]. …”

In vitro growth and differentiation of canine olfactory bulb-derived neural progenitor cells under variable culture conditions

“…Similarly, neural stem cells isolated from adult human olfactory bulb biopsies contained self-renewing, multipotential neural stem cells as evidenced by clonal analysis (Pagano et al, 2000). Many neurologic diseases that may potentially benefit from NPC transplantation occur in the dog (Griffiths et al, 1981;Haskins et al, 1984;Alroy et al, 1985;Koppang, 1988;Fischer et al, 1998;Wenger et al, 1999). We recently found that defects in canine NPCs occur in a model of a lysosomal storage disease (Walton and Wolfe, 2007).…”

Recognition and Diagnosis of Lysosomal Storage Diseases in the Cat and Dog

“…Frequently, however, many of the neuronal storage diseases begin with cerebellar or cerebellovestibular signs such as tremor, ataxia, dysmetria, and nystagmus with progression to paresis and paralysis. These signs are prevalent early in the clinical course for gangliosidoses in dogs and cats, [7][8][9][10][11][12][13] Niemann-Pick disease types A 23,24 and C 25,26,45 and globoid cell leukodystrophy, [19][20][21][22] canine Gaucher disease, 18 and feline ␣-mannosidosis. [2][3][4] Later, behavioral abnormalities and seizures may be seen, although these changes may also be found earlier in diseases such as globoid cell leukodystrophy in the Poodle, 21 fucosidosis, 1 and ceroid lipofuscinosis.…”