Globoid cell leukodystrophy
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.
Presenting signs
- Most commonly associated with onset of clinical signs in immature animals (4-6 weeks).
- Adult dogs can present with this condition on occasion (a 4 year old Bassett hound and 2 Pomeranians; 4.5 and 14 years respectively)
- It is thought that the early clinical signs in dogs with apparent adult onset may be very subtle or absent, resulting in adult animals that present with clinical signs of disease.
- Vary according to underlying defect and reflect the abundance of the enzyme substrate within a particular tissue of the body, since substrate accumulation leads, directly or indirectly, to cellular dysfunction.
- All diseases have progressive clinical signs and are ultimately fatal.
- Progressive blindness.
- Possible neurological signs: cerebellar dysfunction, hyporeflexia due to peripheral nerve involvement, dementia/loss of learned behavior, and para/tetraparesis (typically present with ataxia or paresis of the pelvic limbs, conscious proprioceptive deficits, and dysmetria which then progresses).
Age predisposition
- 4-6 weeks (can rarely present in adult animals - up to 14 years).
Breed/Species predisposition
- Basset Hound Basset Hound.
- Beagle Beagle.
- Cairn Terrier Cairn Terrier.
- Irish Setter Irish Setter.
- Dalmatian Dalmatian.
- Pomeranian Pomeranian.
- Miniature Poodle Poodle: Miniature.
- Standard Poodle Poodle: Standard.
- Toy Poodle Poodle Poodle: Toy.
- West Highland White Terrier West Highland White Terrier.
- Australian Kelpie Australian Kelpie.
- Mixed breed.
Cost considerations
- Moderate to high costs can be incurred in diagnostic work-up.
Special risks
- General anesthesia - must monitor oxygen supply carefully because hypoxia due to seizure activity and airway compromise → cytotoxic brain edema → possibly increased intracranial pressure.
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.
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