In other species: Rhesus monkey , domestic cat , sheep

Categories: Lysosomal storage disease

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 245200 (trait) , 606890 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0009499: Krabbe disease

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1996

Cross-species summary: Also known as globoid cell leukodystrophy (GLD), galactosylceramide lipidosis, galactocerebrosidase deficiency, GALC deficiency, globoid cell leukoencephalopathy, galactosylceramide beta-galactosidase deficiency. A lysosomal storage disease in which there is a buildup (storage) of myelin, due to the lack of the enzyme galactosylceramidase (galactocerebrosidase), whose task is to break down myelin into its constituent molecules. Characterised by weakness progressing to paralysis.

Species-specific name: globoid cell leukodystrophy

Species-specific symbol: GLD

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Victoria et al. (1996) identified the cause of this disorder, in both West Highland White terriers and Cairn terriers, as a base substitution (A to C transversion) at position 473 of the cDNA for galactocerebriosidase (GALC), resulting in an amino acid substitution (tyrosine to serine) at position 158 in the peptide. They have developed a PCR genotyping test which is being used within both breeds, to identify carriers. In an Irish Setter family, McGraw and Carmichael (2006) identified a 78 bp insertion in the same gene as the causative mutation. Hammack et al. (2023) identified a "novel missense variant in GALC (NC_006590.4:g.58893972G>A)" as the putatively causative variant for globoid cell leukodystrophy in a family of mixed-breed dogs with 4 affected puppies. "Among the related dogs (n = 33), 3 dogs were homozygous and 7 heterozygous. The variant allele was not detected in screening 278 dogs from 5 breeds. The novel variant is either unique to this family or has an extremely low allele frequency in the general population."

Clinical features: Clinical signs are usually apparent in affected dogs by 4-6 weeks of age (Corado et al., 2020). Affected dogs initially present with tremors and pelvic limb weakness which then progresses to pelvic limb ataxia as well as thoracic limb dysmetria, followed by tetraparesis and then eventually hind limb paralysis (Corado et al., 2020). Other clinical signs may include a wide-based stance, hypermetria, generalised incoordination and muscle atrophy (Bradbury et al., 2018). [IT thanks DVM student Sharna Allison, who provided the basis of this contribution in April 2022]

Pathology: This disease results in extensive characteristic white matter demyelination, globoid cell infiltration and low leukocyte galactosylceramidase activity (Fletcher et al., 2010). Demyelination usually begins in the spinal cord, peripheral nerves and hindbrain before progressing to the cerebellum (Fletcher et al., 2010). Histopathological changes in GLD-affected dogs include reactive astrocytosis and microglial activation (Fletcher et al., 2010). Psychosine, a GALC substrate, is believed to be responsible for cell death in GLD (Corado et al., 2020). [IT thanks DVM student Sharna Allison, who provided the basis of this contribution in April 2022]

Breeds: Australian Kelpie (Dog) (VBO_0200090), Basset Hound (Dog) (VBO_0200126), Beagle (Dog) (VBO_0200131), Bluetick Coonhound (Dog) (VBO_0200183), Cairn Terrier (Dog) (VBO_0200267), Dalmatian (Dog) (VBO_0200427), Irish Setter (Dog) (VBO_0200702), Mixed Breed (Dog) (VBO_0200902), Poodle, Miniature (Dog) (VBO_0201051), Rottweiler (Dog) (VBO_0201143), West Highland White Terrier (Dog) (VBO_0201415).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: