Globoid Cell Leukodystrophy (Krabbe's Disease)
NeuroLearn NeuroHelp Metabolic @ Lysosomal storage disorders, classification
Background Gross Pathology Histopathology & Immunohistochemistry
BACKGROUND AND CLINICAL INFORMATION:
Summary: Globoid cell leukodystrophy (Krabbe’s disease,
galactosylceramide lipidosis) is an autosomal recessive due to reduced lysosomal
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.
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
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
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.
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.
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.
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
“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
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.
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.
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:
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
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
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.
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.
NeuroLearn NeuroHelp Metabolic For Comment: KarMing-Fung@ouhsc.edu
Background Gross Pathology Histopathology & Immunohistochemistry