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:

Mutation of the galactocerebrosidase gene result in reduced enzymatic activity and decreased ability to degrade galactocerebroside that is found almost exclusively in myelin.
Psychosine: The pathologic changes probably result from the highly toxic nature of psychosine which has a 100 times increase in Krabbe’s leukodystrophy.
Galactocerebroside:sulfatide content: Lipid analysis of the affected areas show an increase in ratio of galactocerebroside content to sulfatides a (normal myelin is about 3:1, Krabbe’s disease is about 5:1 to 10:1). The galactocerebroside content in these areas is not increased but rather decreased overall.
Globoid cell content: The enriched globoid cell fraction, however, contains a high concentration of galactocerebroside. This is a unique feature of Krabbe’s disease among the spingolipidoses.

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.

Initial symptoms include restlessness, intermittent fever, irritability and progressive stiffness (irratible-hypertonic presentation). Symptoms may develop acutely. Fever without infection is common. Convulsion may be part of the symptoms. There are also increased muscle tone and pyramidal signs. Deep tendon reflexes are often absent or weak due to peripheral neuropathy.
The second phase is characterized by rapid deterioration in motor function, with chronic opisthotonos and myoclonic jerking, accompanied by hyperpyrexia, hypersalivation, and hypersecretion from the lungs. Rapid and severe motor and metal deterioration follows. In all cases, a high CSF protein is found and nerve conduction velocities are considerably reduced.
A final “burnt out” stage occurs eventually. The infant become decerebrate and has no contact with the surroundings. The baby usually die within the first one or two years of life, most commonly due to infection and/or bulbar palsy.

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.

Early stage: There is accumulation of PAS (+) material in oligodendrocytes. Characteristic PAS (+) epithelioid cells of 10-20 mm in diameter with abundant cytoplasm cytoplasm and eccentric pale nuclei are present. These cells are also weakly sudanophilic. Unlike most other demyelinating conditions, lipid-laden macrophages are usually absent. There is minimal myelin and axonal loss.
Advanced stage: There is lost of oligodendrocytes, axonal degeneration and reactive gliosis. Epithelioid cells are found in clusters around small blood vessels. They may also be larger (up to 50 mm) and contain multiple peripherally located nuclei (globoid cells). Globoid cells: They are PAS(+), faintly sudanophilic, and non-metachromatic. They have strong activity of acid phosphatase, other lysosomal enzymes and dehydrogenes.
Final stage: Myelin and axons are largely destroyed. There is a dense astrocytosis and diffuse proliferation of microglial cells. Globoid cells become uncommon but an abundant amount of epithelioid cells is still present.

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:

Type 1: They are characteristic for Krabbe’s disease, are straight or curved hollow tubular structures of moderate electron density. They have an irregular polygonal or crystalloid cross section.
Type 2: They are reminiscent of those found in Gaucher’s disease. They are right-handed twisted tubules in longitudinal section and irregularly round in cross section.

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