ISSN 2398-2950      

Globoid cell leukodystrophy

ffelis
Contributor(s):

Mark Lowrie

Simon Platt

Synonym(s): Krabbe's disease, Galactocerebrosidase deficiency, GLD


Introduction

  • Globoid cell leukodystrophy is a condition belonging to a group of genetic disorders known as storage diseases. 
  • Lysosomal storage disorders (LSDs) are a heterogeneous group of genetic diseases characterized by defective function in one of the lysosomal enzymes 
  • Failure of the metabolic pathway → accumulation of complex substrates → impaired cellular function. 
  • Cause: specific enzyme deficiency due to genetic defect, may occur as breed-specific inherited disease. Usually autosomal recessive mode of inheritance. 
  • Signs: chronic, progressive neurological signs - ataxia, intention tremor, progressive vestibular signs, paraparesis to paraplegia. 
  • Diagnosis: lysosomal enzyme analysis or molecular genetic testing. 
  • Treatment: none. 
  • Prognosis: poor.

Pathogenesis

Etiology

  • Autosomal recessive mutation due to a spontaneous missense mutation in the β-galactocerebrosidase (GALC) gene. This results in enzymatic deficiency of galactosylceramidase and an accumulation of galactosylsphingosine (psychosine) and galactosylceramide.

Predisposing factors

Specific

  • Most of these breed-specific diseases resulting in Globoid cell leukodystrophy are thought to be hereditary (usually as an autosomal recessive inheritance). 

Pathophysiology

  • Defect in gene coding for beta-galactocerebrosidase → accumulation and storage of galactocerebrosides throughout the nervous system. 
  • Galactocerebroside is found in oligodendrocytes, Schwann cells, and myelin sheaths and is related to the metabolism of myelin; as a consequence of the enzyme defect or impaired activity, the galactocerebroside metabolites accumulate in the peripheral and central nervous system. 
  • Accumulation of psychosine, a toxic upstream metabolite product of the alternative pathway of galactocerebroside metabolism, into phagocytic cells is responsible for the transformation of these cells into the specific globoid cells. Psychosine is a cytotoxic substance resulting in cell death and demyelination when present in oligodendrocytes. 

Timecourse

  • Slowly progressive over months.

Diagnosis

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Treatment

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Prevention

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Outcomes

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Further Reading

Publications

Refereed Papers

  • Recent references from PubMed and VetMedResource.
  • Graziano A C, Cardile V (2015) History, genetic, and recent advances on Krabbe disease. Gene 555, 2-13 PubMed.
  • Ogawa M, Uchida K, Isobe K, Saito M, Harada T, Chambers J K, Nakayama H (2014) Globoid cell leukodystrophy (Krabbe’s disease) in a Japanese domestic cat. Neuropathol 34(2), 190-196 PubMed
  • Salvadori C, Modenato M, Corlazzoli D S, Arispici M, Cantile C (2005) Clinicopathological features of globoid cell leucodystrophy in cats. J Comp Pathol 132, 350-356 PubMed
  • Sigurdson C J, Basaraba R J, Mazzaferro, E M, Gould D H (2002) Globoid cell-like Leukodystrophy in a domestic longhaired cat. Vet Pathol 39, 494-496 PubMed
  • Suzuki K, Suzuki K (1985) Genetic galactosylceramidase deficiency (globoid cell leukodystrophy, Krabbe disease) in different mammalian species. Neurochem Pathol 3, 53-68, 1985 PubMed

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