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Metachromatic leukodystrophy, or MLD, is a rare disease that belongs to two large groups of genetic disorders called leukodystrophies and lysosomal diseases. MLD is caused by pathogenic variants, also called genetic mutations, in the ARSA or PSAP genes. This causes the destruction of the myelin sheath (the protective covering around nerve cells), which leads to permanent nerve damage.
The symptoms and progression of MLD vary depending on how old a person is when they start experiencing symptoms. Loss of motor skills, poor muscle tone and problems with balance and walking are more common when onset occurs at a younger age, whereas cognitive issues, intellectual impairment and behavioral problems are more common in adolescence and adulthood forms. Loss of feeling in the extremities and seizures may occur at any age. For children who are diagnosed before the age of four, the disease progresses more rapidly and can be fatal within six years. Children who are older when they start experiencing symptoms may live to early adulthood, and adult-onset MLD often progresses very slowly. Targeted treatment for MLD has been approved in Europe and is in the pre-review process in the U.S. There are a number of other novel treatments to slow or stop disease progression under investigation. In the case of later-onset MLD, bone marrow transplant might be an option to slow progression of the disease.
- Difficulty talking
- Difficulty walking
- Progressive loss of vision
- Behavior and personality changes
MLD is caused by pathogenic variants, also called genetic mutations, in the ARSA gene or, more rarely, the PSAP gene. MLD is inherited in an autosomal recessive manner, which means that each parent carries a single copy of the variant gene, but does not have symptoms themselves. MLD results when a child inherits both variant copies of the gene from each parent.
Individuals with MLD have low or undetectable levels of an enzyme involved in the breakdown of a type of fat called sulfatide. This leads to the accumulation of sulfatides in the nervous system, which destroys the cells that make up the protective myelin sheath surrounding nerves in the brain, spinal cord and all other body parts. The myelin sheath is required for nerve function, so destruction of these cells leads to permanent nerve damage.
How MLD is diagnosed
MLD is suspected when an individual demonstrates the condition's characteristic pattern of progressive impairment, which varies based on how old a person is when their symptoms start. In late-infantile MLD, the first sign is often slowing or regressions of motor skills — often difficulty walking and/or missed milestones. People with juvenile and adult MLD may display motor and/or cognitive symptoms such as challenges remembering, carrying out multiple-step activities and doing schoolwork or job tasks.
Several tests may be required to diagnose MLD. It often starts with an MRI to look for problems with the brain, followed by formal diagnostic confirmation via a genetic test to look for variants in the ARSA or PSAP genes and/or a test to measure enzyme activity in the blood. Urine may also be tested for elevated sulfatides.
There is no curative treatment for MLD. A stem cell transplant using bone marrow from a donor may help to slow the progression of the disease in some people, and is most effective when given before symptoms develop. Gene therapy has been approved in Europe since late 2020 and is showing excellent results for pre-symptomatic patients. In the absence of therapy or as a complement to therapy medications can be used to reduce the severity of symptoms, and physical, occupational and speech therapies can help with physical functioning. As the condition progresses, additional assistance may be needed to help with feeding, walking and breathing.
The worldwide estimate for prevalence of MLD is between 1 in 40,000 and 1 in 160,000, though this rate is higher in the Middle East. The Navajo community also has a higher prevalence rate, at 1 in 2,500 people. Over half of individuals with MLD have late-infantile MLD, and begin to show symptoms in the first three years of life. Juvenile MLD is less common, and occurs in 20-30% of patients with MLD. Adult-onset MLD occurs in 15-20% of all cases.
MLD is one of a large group of genetic disorders called leukodystrophies, which are characterized by destruction or impaired development of the myelin sheath, the fatty covering that protects the nerves in the central nervous system and the peripheral nervous system. Other leukodystrophies include adrenoleukodystrophy, Alexander disease and Krabbe disease.
MLD is also one of a large group of genetic disorders called lysosomal diseases, which are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is missing or can’t fully function as a result of a genetic mutation, the large molecules accumulate within the cell and can cause damage to the cell. Other lysosomal diseases include Tay–Sachs disease, Gaucher disease, Niemann–Pick disease, lysosomal acid lipase deficiency, Pompe disease and the mucopolysaccharidoses (including Hurler and Hunter syndromes, Sanfilippo).
This resource was created with input from MLD Foundation.