Metachromatic leukodystrophy (NORD)

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Metachromatic leukodystrophy (NORD)



Metachromatic leukodystrophy (NORD)


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Metachromatic leukodystrophy (NORD)

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A 4-year-old boy is brought to the emergency room with a single seizure-like episode. One parent states the patient started contracting his upper and lower extremities for 30 seconds. His parents state he has had several behavioral complaints at preschool over the past few months. He was able to walk without support until several weeks ago, when they noticed that he had an unsteady gait while walking. Temperature is 37.5°C (99.5°F), pulse is 124/min and blood pressure is 110/85 mmHg. The patient is awake but lethargic. Neurological examination reveals symmetric peripheral neuropathy with diminished sensation to pain and absent deep tendon reflexes. Fundoscopy reveals optic atrophy. Motor examination reveals hypotonia and extensor plantar responses bilaterally. Abdominal examination is unremarkable. He says one and two-word phrases but is unable to speak in complete sentences. MRI of the brain reveals hyperintensities in the periventricular regions of the brain matter. Which of the following is the most likely diagnosis? 

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Arylsulfatase A

metachromatic leukodystrophy p. 86


metachromatic leukodystrophy p. 86


metachromatic leukodystrophy p. 86


metachromatic leukodystrophy p. 86

Metachromatic leukodystrophy p. 86


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.


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