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Metachromatic leukodystrophy
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Metachromatic leukodystrophy

Reviewed September 2007

What is metachromatic leukodystrophy?

Metachromatic leukodystrophy is an inherited disorder characterized by accumulation of fats called sulfatides in cells, especially cells of the nervous system. This accumulation results in progressive destruction of white matter, which consists of nerve fibers covered by myelin. Myelin is a substance that insulates and protects nerves.

Metachromatic leukodystrophy affects myelin-producing cells, the major components of white matter in the brain and spinal cord (the central nervous system) as well as the nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound (the peripheral nervous system). As a result, individuals with this disorder exhibit progressive deterioration of intellectual functions and motor skills, such as the ability to walk. They also develop loss of sensation in the extremities (peripheral neuropathy), incontinence, seizures, paralysis, inability to speak, blindness, and hearing loss. Eventually they lose awareness of their surroundings and become unresponsive.

The most common form of metachromatic leukodystrophy, affecting about 50 to 60 percent of all individuals with this disorder, is called the late infantile form. This form of the disorder usually appears in the second year of life. Affected children lose any speech they have developed, become weak, and develop problems with walking (gait disturbance). As the disorder progresses, muscle tone generally first decreases, and then increases to the point of rigidity. The late infantile form of metachromatic leukodystrophy progresses over approximately 5 to 10 years.

In 20 to 30 percent of individuals with metachromatic leukodystrophy, onset occurs between the age of 4 and adolescence. In this juvenile form, the first signs of the disorder may be increasing difficulties with schoolwork and behavioral problems. Progression of the disorder is slower than in the late infantile form, and symptoms may develop over 10 to 20 years.

The adult form of metachromatic leukodystrophy affects approximately 15 to 20 percent of individuals with the disorder. In this form, the first symptoms appear during the teenage years or later. Often behavioral problems such as alcoholism, drug abuse, or difficulties at school or work are the first symptoms to appear. The affected individual may experience psychiatric symptoms such as delusions or hallucinations. The adult form of metachromatic leukodystrophy may progress over 20 to 30 years. During this time there may be some periods of relative stability and other periods of more rapid decline.

Metachromatic leukodystrophy gets its name from the microscopic appearance of cells with the sulfatide accumulation that occurs in this disorder. The sulfatides form granules which are metachromatic, which means they pick up color differently than surrounding cellular material when stained for microscopic examination.

How common is metachromatic leukodystrophy?

Metachromatic leukodystrophy is reported to occur in 1 in 40,000 to 160,000 individuals worldwide. Much higher incidence has been reported in certain genetically isolated populations, such as 1 in 75 in a small group of Jews who immigrated to Israel from southern Arabia (Habbanites), 1 in 2,500 in the western portion of the Navajo Nation, and 1 in 8,000 among Arab groups in Israel.

What genes are related to metachromatic leukodystrophy?

Mutations in the ARSA and PSAP genes cause metachromatic leukodystrophy.

Most individuals with metachromatic leukodystrophy have mutations in the ARSA gene, which provides instructions for making the enzyme arylsulfatase A. This enzyme is located in cellular structures called lysosomes, which are the cell's recycling centers. Within lysosomes, arylsulfatase A helps process sulfatides, one subtype of a group of fats called sphingolipids.

Mutations in the ARSA gene decrease arylsulfatase A activity. Extremely low arylsulfatase A enzyme activity interferes with the breakdown (metabolism) of sulfatide, resulting in the accumulation of sulfatides characteristic of metachromatic leukodystrophy.

In some cases, individuals with arylsulfatase A activity as low as 3 to 5 percent of normal show no symptoms of metachromatic leukodystrophy. This condition is called pseudoarylsulfatase deficiency.

A few individuals with metachromatic leukodystrophy have mutations in the PSAP gene. This gene provides instructions for making a protein called prosaposin. Prosaposin is broken up (cleaved) into four smaller proteins called saposin A, B, C, and D, which are activator proteins that assist enzymes in breaking up various sphingolipids. The saposin B protein is the activator that works with the enzyme arylsulfatase A to break down sulfatides. Mutations in the PSAP gene that result in a shortage (deficiency) of the saposin B protein interfere with its role in sulfatide metabolism, resulting in the accumulation of sulfatides characteristic of metachromatic leukodystrophy.

Excess sulfatides are toxic to the nervous system. The accumulation gradually destroys the cells forming the myelin sheath, the covering that protects nerves and promotes the efficient transmission of nerve impulses. Destruction of the myelin (demyelination) leads to loss of white matter (leukodystrophy) and impairment of nervous system function, resulting in the signs and symptoms of metachromatic leukodystrophy.

Read more about the ARSA and PSAP genes.

How do people inherit metachromatic leukodystrophy?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about treatment for metachromatic leukodystrophy?

These resources address the management of metachromatic leukodystrophy and may include treatment providers.

You might also find information on treatment of metachromatic leukodystrophy in Educational resources and Patient support.

Where can I find additional information about metachromatic leukodystrophy?

You may find the following resources about metachromatic leukodystrophy helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for metachromatic leukodystrophy?

  • ARSA deficiency
  • Arylsulfatase A Deficiency Disease
  • cerebral sclerosis, diffuse, metachromatic form
  • Cerebroside Sulphatase Deficiency Disease
  • Greenfield Disease
  • metachromatic leukoencephalopathy
  • MLD
  • Sulfatide Lipidosis
  • Sulfatidosis

What if I still have specific questions about metachromatic leukodystrophy?

Where can I find general information about genetic conditions?

What glossary definitions help with understanding metachromatic leukodystrophy?

References (11 links)


The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? in the Handbook.

Reviewed: September 2007
Published: January 23, 2009