- Thomas J Langan, MD
Thomas J Langan, MD
- Associate Professor of Neurology, Pediatrics, and Physiology & Biophysics
- University at Buffalo
- Section Editors
- Marc C Patterson, MD, FRACP
Marc C Patterson, MD, FRACP
- Section Editor — Pediatric Neurology
- Professor of Neurology, Pediatrics, and Medical Genetics
- Chair, Division of Child and Adolescent Neurology
- Mayo Clinic College of Medicine
- Helen V Firth, DM, FRCP, DCH
Helen V Firth, DM, FRCP, DCH
- Section Editor — Genetics
- Consultant Clinical Geneticist
- Addenbrooke's Hospital, Cambridge, UK
Krabbe disease (globoid cell leukodystrophy) is a rare autosomal recessive lysosomal storage disorder (table 1) caused by the deficiency of galactocerebrosidase. This topic will review the clinical aspects of Krabbe disease. Other lysosomal storage disorders are discussed separately. (See "Neurologic manifestations of Fabry disease" and "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis" and "Metachromatic leukodystrophy" and "Mucopolysaccharidoses: Clinical features and diagnosis" and "Mucopolysaccharidoses: Complications and management" and "Overview of Niemann-Pick disease".)
Krabbe disease (globoid cell leukodystrophy) is a rare autosomal recessive disorder caused by the deficiency of the enzyme galactocerebrosidase (GALC), also known as galactosylceramidase. Galactocerebrosidase is responsible for the liposomal hydrolysis of galactolipids formed during white matter myelination. The pathologic changes in the peripheral and central nervous system (globoid cell formation and decreased myelin) are hypothesized to result from the toxic nature of accumulated psychosine (galactosylsphingosine), which cannot be degraded because of the galactocerebrosidase deficiency [1,2]. Many aspects of the pathophysiology of Krabbe disease are unknown.
The galactosylceramidase gene (GALC), also known as the galactocerebrosidase gene, is located on chromosome 14q31 . More than 70 GALC mutations, including numerous small deletions and insertions, have been identified in patients with all clinical types of Krabbe disease . Some mutations result in the infantile type if found homozygous or with another severe mutation, and one mutation predicts a less severe phenotype. However, genotype-phenotype correlations are not well established for Krabbe disease, with the exception of patients who are homozygotes for the most common deletion, or those who have other truncation, frameshift, or nonsense mutations .
●A 30 kb deletion is particularly common [1,5]. This mutation makes up approximately 40 to 45 percent of the mutant alleles in infantile patients in northern Europe and is present in approximately 35 percent of the mutant alleles in infantile Mexican patients.
●Approximately one-half of patients with the juvenile or adult phenotype are heterozygous for the large 30 kb gene deletion . Other mutations in these patients may occur in a low-activity GALC allele . As an example, a few reported patients with at least one copy of the 809G mutation have had a juvenile or adult phenotype, regardless of the mutation in the second allele .
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- CLINICAL MANIFESTATIONS
- Infantile onset
- Juvenile onset
- Adult onset
- Electrodiagnostic studies
- Cerebrospinal fluid
- Newborn screening
- Other biomarkers
- DIFFERENTIAL DIAGNOSIS
- Hematopoietic stem cell transplantation
- SUMMARY AND RECOMMENDATIONS