Metachromatic leukodystrophy is a hereditary and neurodegenerative disease that affects the white substance of the nervous system and is caused by an enzyme deficiency. This disorder causes severe effects on neurocognition and motor functions.

In this article we explain what this disease consists of and what its main characteristics are, its variants, the causes that provoke it, its symptoms and the indicated treatment.

Metachromatic leukodystrophy: definition and characteristics

Metachromatic leukodystrophy is a rare hereditary disorder, belonging to the group of lysosomal deposition diseases, which is characterized by the accumulation of sulfatides in cells, especially in the nervous system . This accumulation causes the progressive destruction of the white substance of the brain, formed by myelin-coated nerve fibres.

Myelin is a substance that coats the axons of nerve cells and its function is to increase the speed of transmission of nerve impulses. Its deterioration or destruction causes devastating effects on the patient’s cognitive functions and motor skills.

The main characteristic of leukodystrophies that belong to the group of lysosomal diseases, such as metachromatic leukodystrophy, is the incorrect functioning of the enzymes of the lysosome , a cellular structure that contains numerous enzymes and whose function is to degrade and recycle intracellular material (of external and internal origin), in a process known as cellular digestion.

This disease may begin in childhood, adolescence, or adulthood and is inherited in an autosomal recessive pattern. That is, a person must inherit two copies of the gene mutation (one from each parent) to have the disease. The incidence of metachromatic leukodystrophy at birth is estimated at 1 case per 45,000 children, and represents about 20% of all leukodystrophies.


The causes of metachromatic leukodystrophy are genetic; in particular, various mutations in the ARSA and PSAP genes appear to be responsible for a deficiency in the enzyme arylsulfatase A (ARSA) , which is responsible for breaking down sulfatides and other fats.

Rarely, a deficiency of the activating protein saposin B (Sap B), which helps the enzyme ARSA break down these fats, may also be another possible cause of the disease. The accumulation of sulfatides in the cells is due to a malfunction of the work performed jointly by ARSA and Sap B in degrading these fatty compounds.

Types (and symptoms of each)

There are three types of metachromatic leukodystrophy, which are classified according to the age of onset of the disease, each with its distinctive symptoms. Let’s see what they are:

1. Late infantile form

This form of metachromatic leukodystrophy is the most common and accounts for about 50-60% of cases . It tends to originate in the first two years of life and children, after a period of relative normality, gradually lose their acquired skills and suffer from mobility problems (abnormal or erratic movements) and muscle weakness (problems with walking or crawling).

These children are often diagnosed with cerebral palsy due to alterations in mobility . As the disease progresses, muscle tone decreases to a state of absolute rigidity, speech problems are increasingly evident and difficulties in fine motor skills appear.

Eventually, the child loses his or her ability to think, understand and interact with other people. The mortality rate is high and children often do not survive beyond childhood.

2. Youthful form

This form of metachromatic leukodystrophy is the second most common (about 20-30% of cases). It usually begins between the ages of 2 or 3 and adolescence. The first symptoms of the disease are related to problems with fine motor skills and concentration . Behavioural alterations may also occur during the academic year.

These children may also have difficulty interacting with their peers, and a possible diagnosis of schizophrenia or depression is sometimes suspected. In the early stages, they are barely able to move, coordinate, walk, or develop speech properly.

As the symptoms progress, other neurological signs appear such as involuntary flexion, tremors, muscle stiffness with eventual loss of gait . The progression of the disease is slower than in the late infantile variant and affected children can survive for about 20 years after diagnosis.

3. Adult form

The adult form is the least common variant of metachromatic leukodystrophy (15-20% of cases). The first symptoms appear during adolescence or later and are reflected in poor school or work performance, with a progressive decrease in cognitive faculties and behavioural problems . The affected person may also suffer psychiatric symptoms such as delusions or hallucinations.

In addition, patients have motor clumsiness and may become incontinent. There is also paralysis of the arms and legs, which develops progressively. Occasionally, seizures may also occur. In the final stages of
disease, affected individuals can reach a vegetative state.

However, if you have this variant you can survive for 20 or 30 years after diagnosis . During this time there may be some periods of relative stability, compared to other periods of greater instability.


Although there is still no definitive cure for metachromatic leukodystrophy , common treatments for this disease include

1. Symptomatic and supportive treatment

It is based on antiepileptic drugs, muscle relaxants, physical therapy to improve muscle function and mobility, cognitive stimulation and support for family members to anticipate future decisions on the acquisition of technical aids (walkers, wheelchairs, feeding tubes, etc.).

2. Hematopoietic stem cell or bone marrow transplant

This makes use of healthy stem cells that are obtained from the blood or bone marrow of a donor and injected into the patient . This procedure is not recommended in the late childhood form, but may be potentially beneficial in patients with the juvenile and adult form, especially in the early stages of the disease.

3. Enzyme replacement therapy

Although this therapy is still under investigation and clinical trials are underway, animal studies suggest that it may reduce sulfate accumulation and lead to functional improvement in the patient.

4. Gene therapy

Replacing the defective genes with healthy copies may be a treatment in the future and work and research is underway to this end .

5. Injection of adeno-associated viral vectors

This method involves injecting a genetically modified virus containing a normal copy of the ARSA gene into the brain so that it can “infect” the cells and incorporate the gene into them. This would theoretically restore enzyme levels. It has been successful in animal models and clinical trials are underway in several countries.

Bibliographic references:

  • Alvarez-Pabón, Y., Lozano-Jiménez, J. F., Lizio-Miele, D., Katyna, G., & Contreras-García, G. A. (2019). Late infantile metachromatic leukodystrophy: A case report. Argentinean archives of pediatrics, 117(1), e52-e55.
  • Gieselmann, V., & Krägeloh-Mann, I. (2010). Metachromatic leukodystrophy-an update. Neuropediatrics, 41(01), 1-6.
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