What is Krabbe Disease?
Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive neurodegenerative disorder that affects both the central and peripheral nervous systems due to an enzymatic defect of the galactocerebrosidase. It is caused by mutations in the GALC gene that encodes the lysosomal enzyme galactosylceramidsase (galactocerebroside β-galactosidase). As a result of these mutations the activity of galactosylceramidase is lowered and the degradation of galactosylceramide during myelin turnover is impaired. Galactocerebrosidase is coded by exons 1-17 of the GALC gene on chromosome 14q31.
Type Bdisease results from deficiencies in the gene encoding α-N-acetylglucosaminidase (genesymbol NAGLU). The NAGLU gene is located on chromosome17q21.
Type Cdisease results from deficiencies in acetyl-CoA:α-glucosaminide acetyltransferase, also called heparan-α-glucosaminide N-acetyltransferase (gene symbol HGSNAT). This enzyme has also been called transmembrane protein 76 (TMEM76). The enzyme is active on heparan sulfates. The HGSNAT gene is located on chromosome 8p11.1.
Type Ddisease results from deficiencies in N-acetylglucosamine 6-sulfatase (gene symbol GNS). The GNS gene is located on chromosome 12q14 comprising 14 exons encoding a 375 amino acid glycoprotein. The enzyme is active on heparan and keratan sulfates. At least 4 isoforms of the enzyme have been identified that are the result of processing the precursor protein.
Inciedence-Krabbe disease occurs in about one in 100,000 births. A higher incidence, about six in 1,000, has been reported in certain communities in Israel. Scandinavian countries have comparatively high rates of the disease, reported to be one in 50,000 births.
Sign and symptom?
Infants with Krabbe disease are normal at birth. Symptoms begin between the ages of 3 and 6 months with irritability, fevers, limb stiffness, seizures, feeding difficulties, vomiting, and slowing of mental and motor development. In the first stages of the disease, doctors often mistake the symptoms for those of cerebral palsy. Other symptoms include muscle weakness, spasticity, deafness, optic atrophy, optic nerve enlargement, blindness, paralysis, and difficulty when swallowing. Prolonged weight loss may also occur. Juvenile- and adult-onset cases of Krabbe disease also occur, which have similar symptoms but slower progression.
What genes are related to krabbe disease?
Krabbe disease is caused by mutations in the GALC gene located on chromosome 14 (14q31), which causes a deficiency of an enzyme called galactosylceramidase. In rare cases it may be caused by a lack of active saposin A. The build-up of unmetabolized lipids affects the growth of the nerve's protective myelin sheath (the covering that insulates many nerves) and causes severe degeneration of motor skills. As part of a group of disorders known as leukodystrophies, Krabbe disease results from the imperfect growth and development of myelin. GALC deficiency also results in a build-up of a glycosphingolipid called psychosine. Psychosine has been suggested to cause axonal degeneration in both the central and peripheral nervous systems by disrupting lipid rafts and may play a role in Krabbe disease
How do people inherit Krabbe disease?
This condition is inherited in an autosomal recessive pattern.
The disease may be diagnosed by its characteristic grouping of certain cells (multinucleated globoid cells), nerve demyelination and degeneration, and destruction of brain cells. Special stains for myelin (e.g.; luxol fast blue) may be used to aid diagnosis
Although no cure for Krabbe disease is known, bone marrow transplantation has been shown to benefit cases early in the course of the disease. Generally, treatment for the disorder is symptomatic and supportive. Physical therapy may help maintain or increase muscle tone and circulation. Cord blood transplants have been successful in stopping the disease as long as they are given before overt symptoms appear
When to contact a Medical Professional?
When a diagnosis of Krabbe disease is made.When pregnancy is planned in a family with history of Krabbe disease.
Who to contact for more information?
The Department of Health Research and Indian Council of Medical Research have constituted a National Task Force to perform a multicentric collaborative study at different research institutes across the country. Further information can be found at http://www.icmrmetbionetindia.org/taskforce- disoredrs.php Lysosomal Storage Society of India - LSDSS http://www.lsdss.org
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Dr Parag Tamhankar
Genetic Research Centre, Mumbai