- 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 "Fabry disease: Neurologic manifestations" and "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis" and "Metachromatic leukodystrophy" and "Mucopolysaccharidoses: Clinical features and diagnosis" and "Mucopolysaccharidoses: Complications" 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 .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Wenger DA. Krabbe disease. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1238/ (Accessed on December 14, 2011).
- Turgeon CT, Orsini JJ, Sanders KA, et al. Measurement of psychosine in dried blood spots--a possible improvement to newborn screening programs for Krabbe disease. J Inherit Metab Dis 2015; 38:923.
- Luzi P, Rafi MA, Wenger DA. Structure and organization of the human galactocerebrosidase (GALC) gene. Genomics 1995; 26:407.
- Orsini JJ, Kay DM, Saavedra-Matiz CA, et al. Newborn screening for Krabbe disease in New York State: the first eight years' experience. Genet Med 2016; 18:239.
- Rafi MA, Luzi P, Chen YQ, Wenger DA. A large deletion together with a point mutation in the GALC gene is a common mutant allele in patients with infantile Krabbe disease. Hum Mol Genet 1995; 4:1285.
- De Gasperi R, Gama Sosa MA, Sartorato EL, et al. Molecular heterogeneity of late-onset forms of globoid-cell leukodystrophy. Am J Hum Genet 1996; 59:1233.
- Wenger DA, Rafi MA, Luzi P. Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications. Hum Mutat 1997; 10:268.
- Wasserstein MP, Andriola M, Arnold G, et al. Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State. Genet Med 2016; 18:1235.
- Barczykowski AL, Foss AH, Duffner PK, et al. Death rates in the U.S. due to Krabbe disease and related leukodystrophy and lysosomal storage diseases. Am J Med Genet A 2012; 158A:2835.
- Duffner PK, Barczykowski A, Jalal K, et al. Early infantile Krabbe disease: results of the World-Wide Krabbe Registry. Pediatr Neurol 2011; 45:141.
- Dunn HG, Lake BD, Dolman CL, Wilson J. The neuropathy of Krabbe's infantile cerebral sclerosis (globoid cell leucodystrophy). Brain 1969; 92:329.
- Duffner PK, Jalal K, Carter RL. The Hunter's Hope Krabbe family database. Pediatr Neurol 2009; 40:13.
- Marks HG, Scavina MT, Kolodny EH, et al. Krabbe's disease presenting as a peripheral neuropathy. Muscle Nerve 1997; 20:1024.
- Kolodny EH, Raghavan S, Krivit W. Late-onset Krabbe disease (globoid cell leukodystrophy): clinical and biochemical features of 15 cases. Dev Neurosci 1991; 13:232.
- Abdelhalim AN, Alberico RA, Barczykowski AL, Duffner PK. Patterns of magnetic resonance imaging abnormalities in symptomatic patients with Krabbe disease correspond to phenotype. Pediatr Neurol 2014; 50:127.
- Loes DJ, Peters C, Krivit W. Globoid cell leukodystrophy: distinguishing early-onset from late-onset disease using a brain MR imaging scoring method. AJNR Am J Neuroradiol 1999; 20:316.
- Sehgal R, Sharma S, Sankhyan N, et al. Selective corticospinal tract involvement in late-onset Krabbe disease. Neurology 2011; 77:e20.
- Miller RG, Gutmann L, Lewis RA, Sumner AJ. Acquired versus familial demyelinative neuropathies in children. Muscle Nerve 1985; 8:205.
- Husain AM, Altuwaijri M, Aldosari M. Krabbe disease: neurophysiologic studies and MRI correlations. Neurology 2004; 63:617.
- Siddiqi ZA, Sanders DB, Massey JM. Peripheral neuropathy in Krabbe disease: electrodiagnostic findings. Neurology 2006; 67:263.
- Wenger DA, Rafi MA, Luzi P, et al. Krabbe disease: genetic aspects and progress toward therapy. Mol Genet Metab 2000; 70:1.
- Kleijer WJ, Keulemans JL, van der Kraan M, et al. Prevalent mutations in the GALC gene of patients with Krabbe disease of Dutch and other European origin. J Inherit Metab Dis 1997; 20:587.
- Li Y, Brockmann K, Turecek F, et al. Tandem mass spectrometry for the direct assay of enzymes in dried blood spots: application to newborn screening for Krabbe disease. Clin Chem 2004; 50:638.
- Duffner PK, Caggana M, Orsini JJ, et al. Newborn screening for Krabbe disease: the New York State model. Pediatr Neurol 2009; 40:245.
- Steiner RD. Commentary on: "Newborn screening for Krabbe Disease: the New York state model" and "the long-term outcomes of presymptomatic infants transplanted for Krabbe disease. A report of the workshop held on July 11 and 12, 2008, Holiday Valley, New York". Genet Med 2009; 11:411.
- Dimmock DP. Should states adopt newborn screening for early infantile Krabbe disease? Genet Med 2016; 18:217.
- Carter RL, Wrabetz L, Jalal K, et al. Can psychosine and galactocerebrosidase activity predict early-infantile Krabbe's disease presymptomatically? J Neurosci Res 2016; 94:1084.
- Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 2009; 72:750.
- Gelinas J, Liao P, Lehman A, et al. Child Neurology: Krabbe disease: a potentially treatable white matter disorder. Neurology 2012; 79:e170.
- Krivit W, Shapiro EG, Peters C, et al. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy. N Engl J Med 1998; 338:1119.
- Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med 2005; 352:2069.
- Langan TJ, Barcykowski AL, Dare J, et al. Evidence for improved survival in postsymptomatic stem cell-transplanted patients with Krabbe's disease. J Neurosci Res 2016; 94:1189.
- Siddiqi ZA, Sanders DB, Massey JM. Peripheral neuropathy in Krabbe disease: effect of hematopoietic stem cell transplantation. Neurology 2006; 67:268.
- Berardi AS, Pannuzzo G, Graziano A, et al. Pharmacological chaperones increase residual β-galactocerebrosidase activity in fibroblasts from Krabbe patients. Mol Genet Metab 2014; 112:294.
- Helman G, Van Haren K, Bonkowsky JL, et al. Disease specific therapies in leukodystrophies and leukoencephalopathies. Mol Genet Metab 2015; 114:527.
- 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