Metachromatic Leukodystrophy (Sulfatidosis)
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Background Gross Pathology Histopathology & Immunohistochemistry
BACKGROUND AND CLINICAL INFORMATION:
Head
Summary: Sulfatidosis (metachromatic leukodystrophy) is a
systemic disease that affects the CNS, PNS, and other organs. There are two
common clinical subtypes and two rare clinical subtypes. Biochemically, it is
characterized by abnormal catabolism of cerebroside sulfate resulted from
deficiency of cerebrosulphatase and lead to accumulation ofcerebroside sulfate.
The clinical test tests for arysulfatase A activity and pseudodeficiency can
occur. Histologically characterized by demyelination and dysmyelination with
accumulation of metachromatic inclusion bodies, presumably derivatives of
cerebroside sulfate. Rare cases due to deficiency of saponin B, a co-factor
necessary for cerebrosulphatase activity, can occur.
Biochemistry: Cerebroside sulfate requires both
cerebrosulphatase and saposin B, a co-factor, for its catabolism. The catabolism
of sulfatide, a sphingolipid that is normal consistuent of myelin and cellular
membranes, is defective in this disease. Metachromatic leukodystrophy is due to
deficiency of cerebroside sulfatase. Sulfatide is stored in the lysosomes of
oligodendrocytes and Schwann cells and also in many somatic tissues. No clinical
manifestation is apparent when arylsulfatase is 10% or higher of normal level.
Diagnostic test: In addition to the arylsulfatase, A deficiency,
there is a loss of activity of arylsulfatases B and C, and other sulfatases
involved in mucopolysaccharide degradation. Prenatal diagnosis can be made
by enzymatic assay in aminocytes or chorionic villi. Pseudodeficiency may
raise a difficult problem for prenatal diagnosis.
Pseudodeficiency: For practical reasons, the laboratory test involves
artificial substrates that test for arylsulfatase A activity but not
cerebrosulphatase. Pseudodeficiency is present in 7-15% of the general
population and results in absence or very low levels of arylsulfatase A
activity without causing disease. Thes patients have only 10-20% of normal
aryl sulfatase A activity. It is caused by two different mutations in the
cerebroside-sulfatase gene and can be detected directly by PCR. [Barth
ML et al., 1994]
Metachromatic lipids: The lipids accumulating in the white matter is
mainly cerebroside sulfate, and that in the kidney are mainly cerebroside
sulfate plus cerebtroside dihexose sulfate (lactosylceramide sulfate). Other
myelin lipids are decreased. The sulfatide in the white matter can be up to
10 times the normal level in the late infantile type, and lesser increases
are present in the adult type.
Genetics: Autosomal recessive. At least three genes are
involved. The genotype/phenotype correlation is not perfect. Complex
arylsulfatase A alleles (on chromosome 22q13) can cause various types of
metachromatic leukodystrophy. Compound heterozygosity seems to be responsible
for junvenile forms. Transmission is autosomal recessive in most cases although
autosomal dominant cases have been reported.
Cerebroside sulfatase gene on chromosome 22q13-22qter: A mutation on exon 2
(459.1G)is responsible for most cases of the late infantile form, whereas a
mutation on exon 8 (P426L) is commonly found in later onset form. Deletions
and mutation at splicing sites do not produce any functional enzyme and is
related with more serve symptoms. Point mutations can lead to production of
functional protein with markedly reduced half life.
Saposin B (or sphingolipid activator protein-1, SAP-1) gene
on chromosome 10q21-q22: This gene is involved in the post-translational
processing of sulfatase. Rare cases are due to mutation of this gene.
A gene that is involved in the post-translational
processing of sulfatase may also be involved.
Clinical features: there are two major phenotypes (late infantile
form and juvenile form) and two less common phenotypes (adult onset and
mucosulfatidosis). Only one variant is seen within an affected family.:
Late
infantile form (Scholz-Greenfield disease):
The late infantile form is most common and
comprises about 80% of all cases. The prevalence is about 1 in 40,000. Onset
is between 10 and 25 months of age. Arylsulfatase A level is almost always
totally absent.
Development is normal during the first year.
Clinical manifestations usually begins with irritability and floppiness and
porgress to gait disturbance. There is also stiffness, loss of ambulation,
spasticity of the lower limbs. Mental deterioration is relatively late and
seizures are uncommon and late. Strabismus frequently appears and optic
atrophy may develop. Death occrus one to four years after onset. In most
cases, there is a marked slowing of motor and sensory nerve conduction
velocities.
Juvenile
form:
The prevalence is about 1 in 150,000. Arylsulfatase
A level is about 0-10% of normal. Onset is between 4 and 10 years of age and
is often marked by mental regression and behavior disturbances.
In some cases, motor disturbances are the first
symptom although nerve conduction velocitiy may be normal in some children.
Convulsion and movement disorders can ocur. Adult forms may present as
psychiatric disease.
Adult
form:
Onset after puberty. Initial symptoms consist of
personality and mental changes, often misdiagnosed as schizophrenia, or
manic-depressive disorder. Movement disorders, ataxia, and paralysis appear
later. Usually no clinical sign of peripheral neuropathy.
The brain can appear normal externally or atrophic. The white matter is firm to touch and appears unusually white and chalky. Demarcation between grey and white matter is enhanced. The white matter is initially involved in a patchy fashion, but with time the entire white matter is affected, often in a symmetric fashion, resulting in a butterfly configuration. The subcortical U-fibers are typically spared. In severe and longstanding cases, the white matter is reduced to a narrow strip 1 to 2 cm in diameter with compensatory enlargement of the ventricles.
HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY:
Head
CNS changes:
White
matter changes with metachromatic granules: The salient feature is loss
of myelin and replacement by numerous PAS positive macrophages. The white
matter is much more severely involved than the gray matter. The macrophages
contain numerous metachromatic granules that are characteristic of the
disease. Dysmyelination and
demyelination are severe with the arcuate fibers relatively spared. Reactive
gliosis, loss of neurons and oligodendrogliocytes, and axonal degeneration
are found. There is no perivascular inflammatory cell infiltration.
Demyelination in the brain stem and spinal cord is prominent in
late-infantile cases, much less striking in juvenile cases, and absent in
cases of adult onset.
Metachromatic granules are 20-30 mm intra-
and extracellular deposits, metachromatic for Cresyl violet and Toulidine
blue, PAS and Sudan black positive. The material gives a brown metachromasia
when stained with toulidine blue. The metrachromasia is due to the accumated
cerebroside sulphate. Metachromatic granules are bound by a single membrane
and associated with acid phosphatase suggestive of a lysomal origin. They
also give a green birefringence in polarized light. Damaged areas contain
far more metachromatic granules than intact white matter.
Involvement of other organs: Metachromatic granules are also found in the Kuffer
cells of liver, gallbladder, pancreas (islets of Langerhans), adrenal glands,
lymph nodes, and ovaries. Tubular epithelium of the kidney is always involved,
and metachromatic granules are excreted, permitting the detection of the
disease. Storage cells are not present in bone marrow or in peripheral blood.
Sudanophilic
lipids are scanty and restricted to perivascular areas.
Peripheral nerve: Always involved. There is a reduction in
myelinated fibers and segmental demyelination. Hypertrophic changes (onion
bulbs) may be seen in prolonged cases. Fiber loss is less obvious in juvenile
and adult onset forms. Metachromatic granules (0.5-1 micron) can be seen in the
perinuclear region of the Schwann cell cytoplasm and in macrophages.
Electron
microscope: There are three major types of inclusions.
Prismatic inclusion: Consists of stacked discs with a herringbone
appearance in one plane and a hexagonal honeycomb in another.
Tuffstone inclusions: Consists of concentric and radial lamellae in a
granular matrix resembling volcanic limestone.
Zebra bodies: Under electron microscope, they are bound by a
single membrane, concentric or lamellated with a periodicity of 5.6-5.8 nm.
Zebra bodies are not unique to metachromatic leukodystrophy and can also be
seen in Tay-Sachs disease, Farber’s disease, mucolipidoses and
mucopolysaccharidoses.
NeuroLearn NeuroHelp Metabolic For Comment: KarMing-Fung@ouhsc.edu
Background Gross Pathology Histopathology & Immunohistochemistry