Globoid cell leukodystrophy

Raphael Schiffmann MD (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Shire.)
Originally released December 28, 1993; last updated November 21, 2016; expires November 21, 2019

This article includes discussion of globoid cell leukodystrophy, galactosylceramide lipidosis, and Krabbe disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Globoid cell leukodystrophy, or Krabbe disease, is an autosomal recessive, rapidly progressive fatal disease when it occurs in infancy. The disease usually begins between the ages of 3 and 6 months with ambiguous symptoms, such as irritability or hypersensitivity to external stimuli, but soon progresses to severe mental and motor decline. Patients are initially hypertonic with hyperactive reflexes, but they later become flaccid and hypotonic. Blindness and deafness are common. Patients with late-onset forms, including adult onset, may present with blindness, spastic paraparesis, and dementia. Peripheral neuropathy is present in the infantile form and may be the only presenting abnormality in the later-onset forms (Adachi et al 2016). Brain MRI has characteristic features that depend on the age of onset of the disease (infantile, juvenile, or adult). Optic nerve and cauda equina enlargement and enhancement is common as well as midbrain atrophy. Newborn screening and presymptomatic hematopoietic stem cell transplantation have not yielded clear benefits.

Key points

 

• Globoid cell leukodystrophy may occur at any age, but the infantile type is the most common.

 

• Typical MRI changes that vary according to each phenotype suggest the diagnosis.

 

• The adult onset type is the most prevalent in certain populations such as Japan.

 

• Hematopoietic stem cell transplantation in presymptomatic infants only mitigates the disease and may not be the optimal therapy it was once hoped to be.

Historical note and terminology

Globoid cell leukodystrophy, or Krabbe disease, was described in 1916. Krabbe reported the clinical and neuropathologic description of 5 cases that appeared to represent a new disease entity (Krabbe 1916). Previous neuropathologic studies, however, had described the "diffuse gliosis" of brain that was later characterized as "diffuse brain-sclerosis" in Krabbe patients (Bullard and Southard 1906; Beneke 1908). Collier and Greenfield in 1924 used the term "globoid cells" to describe the phagocytic cells that appeared unique to this disorder (Collier and Greenfield 1924). Hallervorden suggested that these globoid cells may contain kerasin or cerebroside (Hallervorden 1948). Biochemical and histochemical studies confirmed the presence of cerebroside in globoid cells (Blackwood and Cumings 1954; Austin 1963), and galactocerebroside was the only glycolipid that could produce globoid cells when injected into the central nervous system of experimental animals (Anzil et al 1972). Analytical biochemical studies of total brain lipids did not show an increase in galactosylcerebroside in this disease, but rather a lowering of total cerebroside and sulfatide and a reduced sulfatide-to-cerebroside ratio (Svennerholm 1963). Only a fraction of brain lipids enriched in the specialized globoid cells showed an increase in galactosylceramide (Austin 1963). In 1970, Malone reported a deficiency of leukocyte galactosylceramide beta-galactosidase in a Krabbe disease patient (Malone 1970); this was confirmed by Suzuki and Suzuki, who demonstrated the enzyme deficiency in the brain, liver, and spleen of 3 Krabbe disease patients (Suzuki and Suzuki 1970). Psychosine, a related glycolipid, was suggested to be the toxic metabolite responsible for the pathogenesis of this disorder (Miyatake and Suzuki 1972; Suzuki 1998). The gene for the galactosylceramidase (GALC) enzyme has been mapped to chromosome 14 (Zlotogora et al 1990), and the cDNA has been cloned by Chen and associates (Chen et al 1993).

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