Globoid cell leukodystrophy

From Dog
Generalized paresis in a Coonhound with Globoid cell leukodystrophy[1]

Globoid cell leucodystrophy (Galactocerebrosidase deficiency, Galactosylceramide lipidosis, Krabbe disease) is an autosomal-recessive genetic lysosomal storage disease that results in neurological disease of dogs characterized by peripheral nerve, spinal cord and cerebellar dysfunction.

This condition is caused by defective mutation in the gene encoding galactocerebrosidase which is responsible for lysosomal hydrolysis of specific galactolipids found primarily in myelin[2]. Mutations in this gene (GALC gene (14q31))[3] are the result of numerous nonsense, missense, small insertion and small deletion mutations spanning the entire length of the gene[4].

A breed predisposition for this lysosomal storage disease has been reported in the Cairn Terrier, West Highland White Terrier, Miniature Poodle[5], Irish Setter, Bluetick Coonhound[1] and Australian Kelpie[6].

Clinically affected dogs are often young (3 - 18 months of age) and present with poor weight gain, progressive peripheral neuropathy including ataxia, leg crossing, tremors and paresis which worsens with exercise[7].

Behavioral changes[8], blindness[9], dementia, anorexia, cachexia, urinary incontinence and quadriparesis are usually present in terminal stages of the disease with death occurring 2 - 6 months after onset of clinical signs[10], necessitating euthanasia.

A diagnosis is usually based on the clinical evaluation, neurological testing, histochemical and ultrastructural features. Additional testing includes brainstem auditory evoked response, peripheral nerve conduction velocity, repetitive stimulation, F wave analysis, electromyography and MRI imaging[11].

A definitive diagnosis requires DNA testing[12][13].

A differential diagnosis would include cerebellar hypoplasia, Coonhound paralysis and other causes of peripheral neuropathy.

Histological examination of the central nervous system usually reveals diffuse, bilateral and symmetrical white matter lesion consisting of varying degrees of demyelination and axonal degeneration[14]. extensive chromatolytic degeneration of neurons and moderate secondary Wallerian-type degeneration in the spinal cord and brain stem.

There is no known treatment for this condition, and use of corticosteroids and other drugs appears ineffective at halting disease progression.

References

  1. 1.0 1.1 Boysen BG et al (1974) Globoid cell leukodystrophy in the bluetick hound dog. I. Clinical manifestations. Can Vet J 15(11):303-308
  2. Wenger DA et al (1999) Globoid cell leukodystrophy in cairn and West Highland white terriers. J Hered 90(1):138-142
  3. Chen YQ et al (1993) Cloning and expression of cDNA encoding human galactocerebrosidase, the enzyme deficient in globoid cell leukodystrophy. Hum Mol Genet 2:1841–1845
  4. Wenger DA et al (1997) Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications. Hum Mutat 10:268–279
  5. Zaki, FA & Kay, WJ ((1973) Globoid cell leukodystrophy in a miniature poodle. J Am Vet Med Ass 163:248-250
  6. Fletcher JL et al (2010) Clinical signs and neuropathologic abnormalities in working Australian Kelpies with globoid cell leukodystrophy (Krabbe disease). J Am Vet Med Assoc 237(6):682-688
  7. Zaal MD et al (1997) Progressive neuronopathy in two Cairn terrier litter mates. Vet Q 19(1):34-36
  8. Fletcher, TF & Kurtz, HJ (1972) Animal model: Globoid cell leukodystrophy in the dog. Am J Path 66:375-378
  9. Fankhauser, R et al (1963) Leukodystrophie vom Typus Krabbe beim Hund. Scheiz Tierheilk 105:198-207
  10. LIDA
  11. Cozzi F et al (1998) MRI and electrophysiological abnormalities in a case of canine globoid cell leucodystrophy. J Small Anim Pract 39(8):401-405
  12. McGraw RA & Carmichael KP (2006) Molecular basis of globoid cell leukodystrophy in Irish setters. Vet J 171(2):370-372
  13. Victoria T et al (1996) Cloning of the canine GALC cDNA and identification of the mutation causing globoid cell leukodystrophy in West Highland White and Cairn terriers. Genomics 33(3):457-462
  14. Capucchio MT et al (2008) Krabbe's disease in two West Highland White terriers. Clin Neuropathol 27(5):295-301