Globoid Cell Leukodystrophy (Krabbe's Disease)

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Background   Gross Pathology    Histopathology & Immunohistochemistry  

BACKGROUND AND CLINICAL INFORMATION: Head  

Summary: Globoid cell leukodystrophy (Krabbe’s disease, galactosylceramide lipidosis) is an autosomal recessive due to reduced lysosomal galactocerebroside b-galactosidase. The structural gene is on chromosome 14q24-q32. Both peripheral and central nervous systems are involved. Infantile onset is most common but later or adult onset cases have also been described. Clinically features vary with the age of onset. The infantile form is associated with death at 1-2 years of age. Pathologically, the brain is markedly atrophic and shows extensive demyelination associated with large, multinucleated cells (globoid cells). The white matter but not grey matter is predominantly affected. Crystalline needle-like inclusions that correspond to the globoid material are seen under electron microscope.

Biochemistry:

Diagnostic test: Antemortem and prenatal test of galactocerebroside b-galactosidase with natural glycolipid substrate and synthetic substrate can be used for diagnosis. This differentiates Krabbe’s disease from GM1 gangliosidosis which show normal b-galactosidase activity but deficient enzymatic activity when assayed with synthetic substrates. Intermediate levels of enzymatic activity are found in heterozygotes.

Genetics: Transmitted through an autosomal recessive trait. The b-galactocerebrosidase gene has been mapped to chromosome 14q24-q32. Over 60 mutations have been found and most of them are associated with reduced enzymatic activity. Patients with same mutation may have different clinical presentations.

Clinical forms: Children with Krabbe’s disease have a more predictable course than with other leukodystrophy.

Infantile form: This is the most common type and onset is almost always before 6 months of age and even during the first week of life.

Infantile or early childhood form: Onset is between 1 and 3 years of age with motor symptoms, failing vision, and progressive mental deterioration as major clinical features.

Juvenile form has a more variable clinical picture. Onset is usually between 2 to 6 years of age but later onset has also been reported. Visual failure and gait difficulties are the most common presenting symptoms. Visual problems may be resulted from both optic nerve atrophy and cortical blindness. Gait difficulties may be caused by hemiparesis, paraparesis, progressive cerebellar ataxia. Peripheral neuropathy may or may not be present and, if present, may contribute to the ataxia. 

CSF: At the initial stage of Krabbe’s disease, the protein level is often elevated in the infantile form. Electrophoresis may reval elevated albumin and a2-globulin levels while b1- and g-globulin levels are reduced. This pattern may be diagnostic helpful. In the juvenile form, protein level is often normal.

GROSS PATHOLOGY: Head  

The brain is small and weighs about 600-800 grams. There is atrophy of both cerebral hemispheres and cerebellum. The white matter is rubbery and covered by a cortex of normal consistency that gives the feel of an “iron fist in a velvet glove”. The subcortical arcuate fibers are typically spared. The ventricles are dilated.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head  

White matter: There is a maturation of lesions leading to a gliotic stage that contain only a few globoid or epithelilid cells.

Gray matter: The cortex is only minimally affected. Neurons are largely preserved and contain no storage material. Dendritic processes are preserved. However, there is almost total loss of neurons in the dentate nucleius and the inferior olivary nuclei. Neurons of other nuclei and the cerebellum are largely unaffected.

Electron microscope: Inclusions are seen only in globoid and epithelioid cells. Two types of inclusions are seen:

PNS: There is a moderate reduction in the myelinated fibers and segmental demyelination and remyelination. Non-oriented straight or curved prismatic or tubular inclusions in a clear matrix are seen in Schwann cells and macrophages.

Other organs: No changes are seen in blood cells or bone marrow.

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Background   Gross Pathology    Histopathology & Immunohistochemistry