Metachromatic leukodystrophy

February 8, 2017

Metachromatic leukodystrophy (MLD) is a rare inherited disorder affecting mainly the ‘white matter’ of the brain, causing a progressive loss of physical and, later, mental skills. MLD is the most common in a group of diseases known as leukodystrophies. These diseases affect the myelin sheath, a fatty covering that insulates and protects nerve cells.

Symptoms may include spasticity, seizures, personality changes, and progressive dementia. As the disease progresses, the person loses the ability to walk, talk, see, and hear. Eventually he or she become paralyzed and unresponsive.

MLD results from a deficiency in an enzyme called arylsulfatase A. The lack of arylsulfatase A causes a fatty substance called sulfatide to build up to toxic levels in the body. This gradually destroys the myelin sheath, without which brain cells die and nerves in the body cannot function properly.

Metachromatic leukodystrophy can be divided into early-onset and late-onset forms. The early-onset form is also called the infantile form, and the late-onset form can be further divided into juvenile or adult forms. The course of the disease is similar, but the age at which symptoms appear varies, as does the rate at which symptoms progress. The age at which symptoms begin is usually similar among family members.

Most children with the infantile form die by the age of 10. Those with the juvenile form typically develop symptoms between the ages of 3 and 14 and can live 10 to 20 years after the onset of symptoms. The adult form of the disease is more variable, but affected adults may not develop symptoms until their 40s or 50s and can live 20 to 30 years after symptoms begin. Death most commonly occurs from pneumonia or other infections


Generally, there are considered to be three main types of MLD that have different ages of onset

  • 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


MLD is inherited in an autosomal recessive manner, and is most commonly caused by a mutation in a gene called arylsulfatase A (ASA), also called sulfatide sulfatase. The protein produced by ASA is present in the lysosome, a compartment of the cell that specializes in general “cleanup” of the cell. You may hear MLD referred to as a lysosomal storage disorder, since ASA is a lysosomal enzyme.  MLD can also be caused by a defect in Saposin B (also referred to as the cerebroside sulfate activator), which is a protein required for ASA to work properly.

ASA is required for the breakdown of sulfatides, also called glycolipid- cerebroside sulfates, which are fats present in myelin. When ASA is deficient, the sulfatides build up in the myelin to high levels, disrupting the myelin structure and causing demyelination to occur in both the central nervous system and in the peripheral nervous system. The sulfatides will also build up in the visceral organs (such as the kidneys), and will be excreted at high levels in the urine.

Previously, a disorder known as multiple sulfatase deficiency (MSD) was sometimes considered a subset of MLD. While many symptoms of MSD are similar to those of MLD, we have chosen to classify it as a separate disorder. To learn more about MSD, please see our MSD fact sheet.

Risk Factors

Metachromatic leukodystrophy is a rare disorder that affects males and females in equal numbers. People of all ethnic backgrounds may be affected by this disease. More than 160 cases have been reported in the medical literature. The prevalence of the late infantile form is 1 in 40,000. The prevalence of the juvenile form is 1 in 150,000.

Metachromatic leukodystrophy is reported to occur in 1 in 40,000 to 160,000 individuals worldwide. The condition is more common in certain genetically isolated populations: 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.


The symptoms for MLD are –

  • Abnormally high muscle tone, abnormal muscle movements
  • Behavior problems
  • Decreased mental function
  • Decreased muscle tone
  • Difficulty walking
  • Feeding difficulties
  • Frequent falls
  • Inability to perform normal tasks
  • Incontinence
  • Irritability
  • Loss of muscle control
  • Nerve function problems
  • Personality changes
  • Poor school performance
  • Seizures
  • Speech difficulties, slurring
  • Swallowing difficulty


Umbilical Cord, blood or stem cell or Bone marrow transplantation – This means that cells that produce normal ASA are introduced into the patient, and the normal ASA protein is then taken up into the deficient cells, allowing sulfatides in those cells to be broken down. However, this is only useful for those who are pre-symptomatic or those with very mild neurological manifestations.

Drugs can be given to relieve muscle spasms, treat infections and try to control seizures (should they occur). Pain relief and sedative drugs can be given if required, and feeding can be assisted.

Physiotherapists and others can advise parents on positioning, seating and exercising the limbs to maintain comfort.

Specialist schooling will be required and it is important for the child to have this stimulating environment and social contact and, indeed, for the parents to have some time for themselves and other family members and friends.

Alternative Treatment

Enzyme Replacement Therapy – A therapeutic strategy useful in other metabolic storage diseases is direct enzyme replacement. The difficulty with this strategy has always been getting adequate enzyme activity into the Central Nervous System (CNS). Intravenous injections of a recombinant human Arylsulfatase-A in a mouse model of metachromatic leukodystrophy initially demonstrated no evidence of impact on CNS stores of sulfatide. However, with a significant increase in the injection frequency, researchers were able to demonstrate a reduction in CNS stores.


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