Sunday 4 June 2006
Definition: Krabbe disease (also known as globoid cell leukodystrophy or galactosylceramide lipidosis) is a rare, often fatal neurodegenerative disease that affects the myelin sheath of the nervous system.
This disease is an autosomal-recessive leukodystrophy resulting from a deficiency of galactocerebroside β-galactosidase (galactosylceramidase), the enzyme required for the catabolism of galactocerebroside to ceramide and galactose.
Over 40 different mutations have been found in the gene encoding this enzyme, which is located on chromosome 14q31.
While some accumulation of galactocerebroside may occur, this is not the direct toxic agent in this disease. Instead, it appears that an alternative catabolic pathway removes a fatty acid from this molecule, generating galactosylsphingosine, which is a cytotoxic compound that could cause oligodendrocyte injury.
The clinical course is rapidly progressive, with onset of symptoms often between the ages of 3 and 6 months. Survival beyond 2 years of age is uncommon. The clinical symptoms are dominated by motor signs, including stiffness and weakness, with gradually worsening difficulties in feeding.
The brain shows loss of myelin and oligodendrocytes in the CNS and a similar process in peripheral nerves. Neurons and axons are relatively spared. A unique feature of Krabbe disease is the aggregation of macrophages filled with cerebroside, forming multinucleated cells (globoid cells), around blood vessels.
Krabbe disease is a disease involving the white matter of the central and peripheral nervous systems. While most patients present within the first 6 months of life (’infantile’ or ’classic’ disease), others present later in life, including in adulthood. Krabbe disease is caused by mutation in the galactosylceramidase gene (GALC) (MIM.606890).
The classic globoid cell leukodystrophy (Krabbe disease) is caused by genetic defects in a lysosomal enzyme, galactosylceramidase. It is one of the two classic genetic leukodystrophies, together with metachromatic leukodystrophies.
The mode of inheritance is autosomal recessive. Typically, the disease occurs among infants and takes a rapidly fatal course, but rarer late-onset forms also exist. Clinical manifestations are exclusively neurologic with prominent white-matter signs.
The pathology is unique, consisting of a rapid and nearly complete disappearance of myelin and myelin-forming cells—the oligodendrocytes in the central nervous system and the Schwann cells in the peripheral nervous system, reactive astroytic gliosis, and infiltration of the unique and often multinucleated macrophages ("globoid cells") that contain strongly periodic acid-Schiff (PAS)-positive materials.
A normally insignificant but highly cytotoxic metabolite, galactosylsphingosine (psychosine), is also a substrate of galactosylceramidase and is considered to play a critical role in the pathogenesis.
The galactosylceramidase gene has been cloned, and a large number of disease-causing mutations have been identified.
Equivalent genetic galactosylceramidase deficiency occurs in several mammalian species, such as mouse, dog, and monkey.
Recently, deficiency of one of the sphingolipid activator proteins, saposin-A, was demonstrated to cause a late-onset, slowly progressive globoid cell leukodystrophy at least in the mouse, with all of the phenotypic consequences of impaired degradation of galactosylceramidase substrates.
Human globoid cell leukodystrophy owing to saposin A deficiency might be anticipated and should be suspected in human patients with a late-onset leukodystrophy with normal galactosylceramidase activity when other possibilities are also excluded.
The only serious attempt at treating human patients is bone marrow transplantation, which can provide significant alleviation of symptoms, particularly in those patients with later-onset, more slowly progressive globoid cell leukodystrophy. (#14572137#)
genetic metabolic diseases
Suzuki K.Globoid cell leukodystrophy (Krabbe’s disease): update. J Child Neurol. 2003 Sep;18(9):595-603. PMID: #14572137#