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Globoid cell leukodystrophy

ISSN 2398-2950

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Synonym(s): storage disease, demyelination, GALC, myelin

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.

Presenting signs

  • Most commonly associated with onset of clinical signs in immature animals - range of ages from 2- 6 months. 
  • 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 Brain: cerebellar disease, ataxia Ataxia, intention tremor, progressive vestibular signs, paraplegia.

Age predisposition

  • 4-8.5 weeks (not reported in older cats). 

Breed/Species predisposition

  • Only reported in 5 cats to date, 4 were domestic short-haired and one was a domestic long-haired cat. 

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

  • 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

Presenting problems

  • History. 
  • Age and breed. 
  • Signs.

Client history

  • Often death of litter mates. 
  • Abnormal gait. 
  • Tremors (fine muscle tremors and intentional). 

Clinical signs

  • Intention tremor (cerebellar). 
  • Abnormal gait/wide-based stance. 
  • Blindness. 
  • Hypermetria. 
  • Vestibular signs. 
  • Paraparesis progressing to paraplegia. 

Diagnostic investigation

Cytopathology 

Biochemistry 

Histopathology 

  • On pathology, the hallmark of the disease is the globoid cells which are multinucleated giant phagocytic cells and widespread myelin loss throughout the white matter.  
  • May have white matter pathology (globoid leukodystrophy). 
  • Peripheral nerve pathology has not been seen in cats. 
  • Biopsy: 

Other 

  • MRI scan: not reported in cats. 
  • Demonstrate deficiency of enzyme in the peripheral blood leukocytes or cultured (skin) fibroblasts. 
  • DNA based PCR analysis unavailable in cats. 

Confirmation of diagnosis

Discriminatory diagnostic features

  • Breed. 
  • Age. 
  • Signs. 
  • CSF analysis. 
  • Brain biopsy.

Definitive diagnostic features

  • Demonstration of specific enzyme deficiency, eg using leukocytes or cultured skin fibroblasts ante-mortem or by enzyme assay of brain/liver, etc post-mortem), and biochemical identification of neuronal storage products. 

Gross autopsy findings

  • Gross abnormalities are rarely seen. 
  • Lesions may consist of symmetric gray-yellow discolorations of white matter.

Histopathology findings

  • Destruction of white matter (brain/spinal cord) and replacement by aggregates of PAS +ve macrophages (globoid cells). Severe peripheral nerve degeneration (axonal/myelin). Severe myelin loss and gliosis were observed, especially in the internal capsule and cerebellum.

Differential diagnosis

Treatment

Initial symptomatic treatment

  • High-quality nursing care.

Standard treatment

  • None (preliminary trials are in progress in attempting enzyme replacement therapies, but to date are experimental not clinical). Some treatments have been successful in other species, eg bone marrow transplantation, enzyme replacement, gene therapy, which may become available for the cat.

Monitoring

  • Relentlessly progressive to death.

Prevention

Control

  • Do not breed from affected animals and their relatives.

Outcomes

Prognosis

  • Poor. Usually die by 6 months of age. 

Expected response to treatment

  • Look for stabilization of clinical signs. 
  • Globoid cell leukodystrophy shows no improvement with any medical therapy.

Reasons for treatment failure

  • Treatment is ineffective at this time but work is moving towards gene therapy but this remains experimental. 
  • Incorrect diagnosis. 
  • Owner non-compliance. 
  • Inadequate nursing care.

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