Metachromatic leukodystrophy is an inherited disorder characterized by the accumulation of fats called sulfatides in cells. This accumulation especially affects cells in the nervous system that produce myelin, the substance that insulates and protects nerves. Nerve cells covered by myelin make up a tissue called white matter. Sulfatide accumulation in myelin-producing cells causes progressive destruction of white matter (leukodystrophy) throughout the nervous system, including in the brain and spinal cord (the central nervous system) and 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).
The types, which may overlap, include:
- Infantile form, occurring between ages 6 months and 2 years
- Juvenile form, occurring between ages 3 and 6 (early juvenile) or between ages 6 and 16 (late juvenile)
- Adult form, occurring at age 17 or older
In people with metachromatic leukodystrophy, white matter damage causes progressive deterioration of intellectual functions and motor skills, such as the ability to walk. Affected individuals also develop loss of sensation in the extremities (peripheral neuropathy), incontinence, seizures, paralysis, an inability to speak, blindness, and hearing loss. Eventually they lose awareness of their surroundings and become unresponsive. While neurological problems are the primary feature of metachromatic leukodystrophy, effects of sulfatide accumulation on other organs and tissues have been reported, most often involving the gallbladder.
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 worsens, muscle tone generally first decreases, and then increases to the point of rigidity. Individuals with the late infantile form of metachromatic leukodystrophy typically do not survive past childhood.
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 behavioral problems and increasing difficulty with schoolwork. Progression of the disorder is slower than in the late infantile form, and affected individuals may survive for about 20 years after diagnosis.
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. People with the adult form of metachromatic leukodystrophy may survive for 20 to 30 years after diagnosis. 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 way cells with an accumulation of sulfatides appear when viewed under a microscope. The sulfatides form granules that are described as metachromatic, which means they pick up color differently than surrounding cellular material when stained for examination.
Like many other genetic disorders that affect lipid metabolism, there are several forms of MLD, which are late infantile, juvenile, and adult.
- In the late infantile form, which is the most common form of MLD (50-60%), affected children begin having difficulty walking after the first year of life, usually at 15–24 months. Symptoms include muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Children may become comatose. Untreated, most children with this form of MLD die by age 5, often much sooner.
- Children with the juvenile form of MLD (onset between 3 and 10 years of age) usually begin with impaired school performance, mental deterioration, and dementia and then develop symptoms similar to the late infantile form but with slower progression. Age of death is variable, but normally within 10 to 15 years of symptom onset although some juveniles can live for several decades or longer after onset.
- The adult form commonly begins after age 16 often with an onset in the 4th or 5th decade of life and presents as a psychiatric disorder or progressive dementia. Adult-onset MLD usually progresses more slowly than the late infantile and juvenile forms, with a protracted course of a decade or more.
Palliative care can help with many of the symptoms and usually improves quality of life and longevity.
Carriers have low enzyme levels compared to their family population ("normal" levels vary from family to family) but even low enzyme levels are adequate to process the body's sulfatide.
- Behavioral abnormality
- Cognitive impairment
- Decreased nerve conduction velocity
- Developmental regression
- Gait disturbance
- Genu recurvatum
- Muscle weakness
- Neurological speech impairment
- Peripheral neuropathy
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 break down sulfatides. A few individuals with metachromatic leukodystrophy have mutations in the PSAP gene. This gene provides instructions for making a protein that is broken up (cleaved) into smaller proteins that assist enzymes in breaking down various fats. One of these smaller proteins is called saposin B; this protein works with arylsulfatase A to break down sulfatides.
Mutations in the ARSA or PSAP genes result in a decreased ability to break down sulfatides, resulting in the accumulation of these substances in cells. Excess sulfatides are toxic to the nervous system. The accumulation gradually destroys myelin-producing cells, leading to the impairment of nervous system function that occurs in metachromatic leukodystrophy.
In some cases, individuals with very low arylsulfatase A activity show no symptoms of metachromatic leukodystrophy. This condition is called pseudoarylsulfatase deficiency.
Metachromatic leukodystrophy is inherited in an autosomal recessive manner. This means that both copies of the disease-causing gene in each cell must have a mutation for an individual to be affected. Individuals inherit two copies of each gene - one copy from each parent. Typically, an individual is affected because they inherited a mutated copy of the gene from each parent. Individuals with one mutated copy of the gene (such as an unaffected parent of an affected individual) are referred to as carriers; carriers typically do not have any signs or symptoms of the condition.
When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) chance to have the condition, a 50% (1 in 2) chance to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.
If someone has a family history of metachromatic leukodystrophy (MLD) or someone is known to be a carrier for MLD, individuals who are biologically related to the affected individual or carrier are at risk to be a carrier. Generally speaking, the more closely related an individual is to the affected individual or carrier, the greater the chance for that person to be a carrier. Prior to genetic testing, the chance to be a carrier for some biological relatives of an affected individual are as follows:
- Parent of affected individual: assumed to be 100% (called an obligate carrier)
- Unaffected sibling of affected individual: 2 in 3 (~66.6%)
- Aunt or uncle of affected individual: 1 in 2 (50%)
- First cousin of affected individual: 1 in 4 (25%)
If someone has carrier testing and is found to be negative (not a carrier), that person's children are typically assumed to be negative also.
More information about the use of genetic carrier testing is available on GeneTests' Web site and can be viewed by clicking here.
Individuals who are interested in learning about genetic testing and about their specific risk to be a carrier should speak with a genetics professional.
The prognosis for metachromatic leukodystrophy (MLD) is poor. The late infantile form of the disorder, the most common type, usually appears in the second year of life. This form typically progresses over approximately 5 to 10 years. Most children with the infantile form die by age 5. The juvenile form, with onset between the age of 4 and adolescence, has a slower progression than the late infantile form and symptoms may develop over 10 to 20 years; death typically occurs 10 to 20 years following onset. In the adult form, the first symptoms typically appear during the teenage years or later. This form may possibly progress over 20 to 30 years, although many individuals with the adult form die within 6 to 14 years following the onset of symptoms. During the progression of this form there may be some periods of relative stability and other periods of more rapid decline.
Metachromatic leukodystrophy can't be cured, and few treatment options are available.
- Medications. Medications may reduce your signs and symptoms and relieve your pain.
- Bone marrow transplant. Bone marrow transplant sometimes has slowed the progression of metachromatic leukodystrophy.
- Physical, occupational and speech therapy. You may have physical therapy to move your muscles and joints, to keep joints flexible and maintain your range of motion as much as possible. You may need a wheelchair, walker or other assistive devices as your condition progresses. You may have occupational and speech therapy to improve your quality of life.
- Nutritional assistance. You and your family may work with a nutrition specialist (dietitian) to determine how to provide your diet, as it may become difficult to swallow food or liquid. You may need assistive feeding devices as your condition progresses.
- Follow-up care. Doctors will coordinate your follow-up care with your primary doctor. In follow-up care, doctors will monitor you for changes in movement, swallowing, communication, behavior and other functions. Doctors will also provide comprehensive care and treat any other medical conditions.
- Mayo Clinic
- Genetics Home Reference