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.