ISSN 2398-2969      

Globoid cell leukodystrophy

icanis
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 para/tetraparesis, hypermetria, blindness, and dementia. 
  • Diagnosis: lysosomal enzyme analysis or molecular genetic testing. 
  • Treatment: none (see Bradbury et al, 2020 re successful experimental treatment). 
  • Prognosis: poor.

Pathogenesis

Etiology

  • Deficiency of beta-galactocerebrosidase due to an autosomal recessive mutation affecting the β-galactocerebrosidase gene (GALC). This leads to 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. Life span 15.7 +- 4.8 weeks.

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.
  • Bradbury A M, Bagel J H, Nguyen D et al (2020) Krabbe disease successfully treated via monotherapy of intrathecal gene therapy. J Clin Invest 130(9), 4906-4920 PubMed.
  • Corado C R, Pinkstaff J, Jiang X, Galban E M, Fisher S J, Scholler O, Russell C, Bagel J H, O'Donnell P A, Ory D S, Vite C H, Bradbury A M (2020) Cerebrospinal fluid and serum glycosphingolipid biomarkers in canine globoid cell leukodystrophy (Krabbe disease). Mol Cell Neurosci 102, 103451 PubMed.
  • Story B D, Miller M E, Bradbury A M, Million E D, Duan D, Taghian T, Faissler D, Fernau D, Beecy S J, Gray-Edwards H L (2020) Canine models of inherited musculoskeletal and neurodegenerative diseases. Front Vet Sci 7, 80 PubMed.
  • Bongarzone E R, Escolar M L, Gray S J, Kafri T, Vite C H, Sands M S (2016) Insights into the Pathogenesis and Treatment of Krabbe Disease. Pediatr Endocrinol Rev 13 Suppl 1, 689-96 PubMed.
  • Bradbury A M, Bagel J H, Jiang X, Swain G P, Prociuk M L, Fitzgerald C A, O'Donnell P A, Braund, K G, Ory D S, Vite C H (2016) Clinical, electrophysiological, and biochemical markers of peripheral and central nervous system disease in canine globoid cell leukodystrophy (Krabbe's disease). J Neurosci Res 94, 1007-1017 PubMed
  • Graziano A C, Cardile V (2015) History, genetic, and recent advances on Krabbe disease. Gene 555, 2-13 PubMed.
  • Fletcher J L, Williamson P, Horan D, Taylor R M (2010) Clinical signs and neuropathologic abnormalities in working Australian Kelpies with globoid cell leukodystrophy (Krabbe disease). J Am Vet Med Assoc 237, 682-688 PubMed
  • Monaldi A, Martínez Munera A M (2010) Globoid leukodystrophy in a West Highland terrier. / Leucodistrofia de células globoides en un westy. Argos—Informativo Veterinario 158, 38-41. 
  • Beltran E, Matiasek L A, De Risio L, Mellersh C, Platt S R (2008) Globoid cell leukodystrophy in a litter of kelpies with episodic cerebellar disease. Journal of Veterinary Internal Medicine 22, 723.
  • Capucchio M T, Prunotto M, Lotti D, Valazza A, Galloni M, Dore B, Pregel P, Amedeo S, Catalano, D, Cornaglia E, Schiffer D (2008) Krabbe's disease in two West Highland White terriers. Clin Neuropathol 27, 295-301 PubMed.
  • McGraw R A, Carmichael K P (2006) Molecular basis of globoid cell leukodystrophy in Irish setters. Vet J 171, 370-372 PubMed
  • McGowan J C, Haskins M, Wenger D A, Vite C (2000) Investigating demyelination in the brain in a canine model of globoid cell leukodystrophy (Krabbe disease) using magnetization transfer contrast: Preliminary results. Journal of Computer Assisted Tomography 24, 316-321, 2000 PubMed.
  • Wenger D A (2000) Murine, canine and non-human primate models of Krabbe disease. Molecular Medicine Today 6, 449-451, 2000 PubMed.
  • Wenger D A, Victoria T, Rafi M A, Luzi P, Vanier M T, Vite C, Patterson D F, Haskins M H (1999) Globoid cell leukodystrophy in cairn and West Highland white terriers. J Hered 90, 138-1429 PubMed.
  • Cozzi F, Vite C H, Wenger D A, Victoria T, Haskins M E (1998) MRI and electrophysiological abnormalities in a case of canine globoid cell leucodystrophy. J Small Anim Pract 39, 401-405, 1998 PubMed.
  • Victoria T, Rafi M A, Wenger D A (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, 457-462, 1996 PubMed.
  • Poncelet L, Heimann M, Coignoul F, Balligand M (1994) Globoid cell leucodystrophy in seven West Highland White Terrier pups. Annales de Medecine Veterinaire 138, 513-519.
  • Suzuki K, Suzuki K (1985) Genetic galactosylceramidase deficiency (globoid cell leukodystrophy, Krabbe disease) in different mammalian species. Neurochem Pathol 3, 53-68, 1985 PubMed.
  • Bjerkas I (1979) Hereditary leukodystrophy in Dalmatian dogs in Norway Norsk. Veterinaertidsskrift 91, 167-170.    
  • Yunis E J, Lee R E (1976) The morphologic similarities of human and canine globoid leukodystrophy. Am J Pathol 85, 99-114 PubMed.
  • Boysen B G, Tryphonas L, Harries N W (1974) Globoid cell leukodystrophy in the Bluetick Hound dog. I. Clinical manifestations. Can Vet J 15, 303-308.    
  • Fletcher T F, Lee D G, Hummer R F (1971) Ultrastructural features of globoid cell leukodystrophy in the dog. Am J Vet Res 32, 177-181 PubMed.
  • Howell J M, Palmer A C (1971) Globoid cell leukodystrophy in two dogs. J Small Anim Pract 12, 633-642 PubMed
  • Suzuki Y, Suzuki K (1971) Krabbe's globoid cell leukodystrophy: deficiency of galactocerebrosidase in serum, leukocytes, and fibroblasts. Science 171,73-75 PubMed.
  • Suzuki K (1970) Ultrastructural study of experimental globoid cells. Lab Invest 23, 612-619 PubMed.

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