Metachromatic leukodystrophy: symptoms, causes and treatment

Metachromatic leukodystrophy is an inherited disease and neurodegenerative that affects the white matter of the nervous system and is produced by an enzyme deficiency. This disorder causes serious effects at the neurocognitive level and on motor functions.

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

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Metachromatic leukodystrophy: definition and characteristics

Metachromatic leukodystrophy is a rare hereditary disorder, belonging to the group of lysosomal storage diseases, characterized by the accumulation of sulfatides in cells, especially in the nervous system. This accumulation causes the progressive destruction of the white matter of the brain, formed by nerve fibers covered with myelin.

Myelin is a substance that covers 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 the leukodystrophies that belong to the group of lysosomal diseases, such as metachromatic leukodystrophy, is malfunction of lysosome enzymes, 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 can begin in childhood, adolescence, or adulthood, and is transmitted hereditarily in an autosomal recessive pattern; that is, the person has to inherit two copies of the genetic 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.

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Causes

The causes that cause metachromatic leukodystrophy are genetic; specific, various mutations in the ARSA and PSAP genes seem to be responsible for the production of a deficiency of 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 ARSA enzyme break down these fats, could also be another possible cause of the disease. The accumulation of sulfatides in the cells is due to a malfunction of the joint work carried out by ARSA and Sap B when it comes to degrading these fatty compounds.

Types (and symptoms of each of them)

There are three types of metachromatic leukodystrophy, which are classified based on 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 It is the most common and represents around 50-60% of cases.. It usually originates in the first two years of life and children, after a period of relative normality, gradually lose their abilities. acquired and have mobility problems (abnormal or erratic movements) and muscle weakness (trouble walking or creep).

These children are often diagnosed with cerebral palsy due to impaired mobility.. As the disease progresses, muscle tone decreases until it reaches a state of absolute rigidity, speech problems are becoming more evident and fine motor skill difficulties appear.

Eventually, the child loses his ability to think, understand, and interact with other people. The mortality rate is high and children do not usually survive past infancy.

2. juvenile form

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

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

As the symptoms progress, other neurological signs appear such as involuntary flexion, tremors, muscle rigidity with eventual loss of gait. Disease progression is slower than that of 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 decline in cognitive faculties and behavioral problems. The affected person may also suffer from psychiatric symptoms such as delusions or hallucinations.

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

With everything, 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.

Treatment

Although still there is no definitive cure for metachromatic leukodystrophy, the usual treatments for this disease include:

1. Symptomatic and supportive treatment

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

2. Hematopoietic stem cell or bone marrow transplant

Here use is made 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 infantile variant, but can be potentially beneficial in patients with the juvenile and adult forms, especially in the early stages of disease.

3. enzyme replacement therapy

Although this therapy is still under investigation and clinical trials are underway, studies in animals suggest that it could reduce the accumulation of sulfatides and lead to a functional improvement of the patient.

4. gene therapy

It consists of replacing defective genes with healthy copies. It may be a treatment in the future and work and research is being done for it..

5. Injection of adeno-associated viral vectors

This method consists of injecting into the brain a genetically modified virus that contains a normal copy of the ARSA gene, so that it can "infect" cells and incorporate the gene into they. Thus, theoretically, enzyme levels would be restored. 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. TO. (2019). Late infantile metachromatic leukodystrophy: Presentation of a case. Argentine archives of pediatrics, 117(1), e52-e55.
• Gieselmann, V., & Krägeloh-Mann, I. (2010). Metachromatic leukodystrophy–an update. Neuropediatrics, 41(01), 1-6.