Metachromatic leukodystrophy – causes, symptoms, diagnosis, treatment, pathology


Metachromatic leukodystrophy, or MLD, is a
rare lysosomal storage disorder that results from mutations in the ARSA gene, which codes
for arylsulfatase A – an enzyme that normally breaks down a fat called sulfatide. Without
this enzyme, sulfatide accumulates in neurons and myelin-producing cells like Schwann cells
and oligodendrocytes, resulting in their degeneration. MLD is an autosomal recessive disorder, which
means that two mutated copies of the gene, one from each parent, are needed to develop
the disease. In rare cases, MLD can also be caused by mutations in the PSAP gene, which
codes for saposin B, which is a protein that activates arylsulfatase A. Without arylsulfatase A, cells cannot recycle
sulfatides. The sulfatide accumulates within cells of the nervous system like Schwann cells
and oligodendrocytes, and aggregates to forms intracellular granules. These sulfatide aggregates
are called metachromatic since they appear differently colored than the cellular material
when stained and seen under the microscope. Sulfatide granules interferes with the cells’
ability to produce myelin, resulting in demyelination, or loss of myelin sheath, of the neurons.
The end result is impaired nerve impulse transmission. Demyelination in MLD occurs both in the central
as well as peripheral nervous system, resulting in a variety of symptoms. Common symptoms
include peripheral neuropathy, which is the loss of sensation in the extremities, diminished
deep tendon reflexes, visual disturbances, difficulty in speaking, difficulty in walking,
ataxia, behavior and personality changes, and seizures. Now, there are three forms of
MLD based on the age at onset of symptoms – late-infantile form, juvenile form, and
adult form. In the late-infantile form, symptoms develop within the first three years of life,
and include irritability and developmental delay. In the juvenile form, symptoms usually
develop between the age of 4 and adolescence, which is around 12- 14 years of age, and include
behavioral changes and decreased ability in school. In the adult form, symptoms usually
develop after the age of 16, and include memory loss and psychosis. As the symptoms progress,
all forms of MLD result in blindness, paralysis, unresponsiveness, dementia, and psychosis. Diagnosis includes blood tests to measure
arylsulfatase A enzyme activity in white blood cells, measurement of the urine sulfatide
levels and genetic testing to evaluate the ASA and PSAP genes. A brain MRI in a person
with MLD shows areas of hyperintensities in the white matter regions, which indicate the
loss of myelin. Currently, there’s no cure for MLD and treatment
involves supportive care to manage symptoms. Usually, this involves an array of specialists
including neurologists to manage seizures, gastroenterologists to manage feeding, as
well as occupational and physical therapists to assist with the tasks of daily living and
mobility. In asymptomatic and mildly symptomatic MLD, hematopoietic stem cell transplantation
can be used to slow down disease progression. All right, as a quick recap… Metachromatic
leukodystrophy, or MLD, is a lysosomal storage disorder characterized by accumulation of
sulfatide due to decreased activity of the enzyme arylsulfatase A. It is an autosomal
recessive disorder caused by mutation in the ARSA gene or the PSAP gene. There are three
forms of MLD based on the age at onset of symptoms – late-infantile form, juvenile form,
and adult form. Common symptoms include peripheral neuropathy, which is the loss of sensation
in the extremities, diminished deep tendon reflexes, visual disturbances, difficulty
in speaking, difficulty in walking, ataxia, behavior and personality changes, and seizures.
MLD is diagnosed by measuring arylsulfatase A activity, urine sulfatide levels and genetic
testing. Treatment involves supportive care to manage symptoms and stem cell transplantation.

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