What Is Metachromatic Leukodystrophy (MLD)?

Metachromatic Leukodystrophy (MLD), a disease caused by mutations in the ARSA gene, is the most common disorder in a group of diseases known as leukodystrophies which primarily affect the nervous system. These diseases affect the myelin sheath, a fatty covering that insulates and protects nerve cells. MLD results from a deficiency in an enzyme called arylsulfatase A. The lack of this enzyme 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.

Individuals with MLD will progressively lose intellectual and motor functions. Symptoms may include stiffness and tightness of the muscles (spasticity), seizures, personality changes, and progressive dementia. As the disease progresses, the patient loses the ability to walk, talk, see, and hear, eventually leading to paralysis and unresponsiveness.

MLD can be divided into three forms: infantile (early-onset), juvenile (late-onset), and adult (late-onset). 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 affected family members.

Infantile Form

This is the most common form of MLD, accounting for 50 to 60% of all cases. Symptoms appear between the first and second years of life. Initially, affected children lose any language abilities they have developed and have trouble walking. Gradually their muscles waste away and become rigid. They will lose mental function and often experience seizures and loss of sensation in their limbs. By the final stages of the disease, children with infantile MLD become blind and deaf and require a feeding tube. They are unresponsive to their surroundings and eventually become paralyzed. Infantile MLD is usually fatal by the age of 10.

Juvenile Form

In the juvenile form of MLD, symptoms appear after the age of 3 but before adolescence. Approximately 20 to 30% of individuals with MLD have the juvenile form. Initial signs of the disease include difficulties in school and behavioral problems. Clumsiness, slurred speech, incontinence, and strange behavior often prompt parents to seek a diagnosis. As the disease continues, symptoms are similar to infantile MLD but the disease progresses more slowly in the juvenile form. The disease is usually fatal 10 to 20 years after the first symptoms appear.

Adult Form

In the adult form of MLD, symptoms appear after puberty and may not appear until an individual is in their forties or fifties. Roughly 15 to 20% of individuals with MLD have the adult form. Early signs of the disease often include personality changes, problems at school or work, numbness in the extremities of one's limbs, muscle weakness, loss of coordination, and psychiatric problems such as delusions, hallucinations, or drug and alcohol abuse. MLD can be initially misdiagnosed as schizophrenia, depression, or multiple sclerosis.

Over time, an affected individual's behavior will become inappropriate and he or she will have trouble making good decisions. Everyday skills become difficult, and movement will grow spastic and awkward. Eventually, an individual affected by the adult form will lose the ability to carry on a conversation. In the final stages of the disease, symptoms are similar to the infantile form: blindness, deafness, unresponsiveness, and paralysis.

This form of the disease progresses more slowly than the other forms. Affected individuals may experience periods of stability or periods of particularly rapid decline. Individuals with the adult form of MLD may live 20 to 30 years after their initial diagnosis.

How Common Is MLD?

Worldwide, the prevalence of MLD varies from 1 in 40,000 to 1 in 160,000 individuals. It is more common among Habbanite Jews in Israel, Israeli Arabs, Christian Israeli Arabs, and individuals in the western parts of the Navajo Nation.

How Is MLD Treated?

There is currently no cure for MLD. Bone-marrow transplantation may be an option for some individuals with MLD. It has shown the most promise in those who are not yet showing symptoms of MLD. At best it slows, but does not stop, the progression of the disease. This is a controversial treatment because of its substantial health risks.

Most treatments aim to manage symptoms of the disease as they arise. Seizures and muscle tightness may be treated with medication. Physical therapy may help preserve movement as long as possible. Walking aids, wheelchairs, feeding tubes, and other supportive devices may also be beneficial.

What Is the Prognosis for an Individual with MLD?

All individuals with MLD will experience mental and motor deterioration, eventually reaching a state of paralysis and unresponsiveness.

Most children with the infantile form of MLD 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 forties or fifties and can live 20 to 30 years after symptoms begin. Death most commonly occurs from pneumonia or other infections.

Other names for
metachromatic leukodystrophy

  • ARSA deficiency
  • Arylsulfatase A deficiency
  • Cerebroside sulfatase deficiency
  • Metachromatic leukoencephalopathy
  • Sulfatide lipidosis


  • Adang et al., 2017, Mol Genet Metab, 122(1-2):18-32, PMID: 28863857
  • Fluharty, 2014, https://www.ncbi.nlm.nih.gov/books/NBK1130/
  • OMIM: Online Mendelian Inheritance in Man, OMIM [250100], 2016, http://www.omim.org/entry/250100
  • Ługowska et al., 2011, PLoS One, 6(6):e20218, PMID: 21695197