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

Treatment

Prevention

Outcomes