Metachromatic leukodystrophy is an inherited disease and neurodegenerative which affects the white matter of the nervous system and is caused by enzyme deficiency. This disorder causes serious effects on the neurocognitive level and on motor functions.
In this article we will tell you what this disease is and what are its main features, variants, causes that provoke it, symptoms and the indicated treatment.
Metachromatic leukodystrophy: definition and characteristics
Metachromatic leukodystrophy is a rare inherited disease, belonging to the group of diseases caused by lysosomal deposits, which is characterized by accumulation of sulfates in cells, especially in the nervous system. This build-up causes the gradual destruction of white matter in the brain, formed by nerve fibers coated 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 has devastating effects on the cognitive and motor functions of the patient.
The main feature of leukodystrophies belonging to the group of lysosomal diseases, as in the case of metachromatic leukodystrophy, is dysfunction of lysosomal enzymes, A cellular structure that contains many enzymes and whose function is to break down and recycle intracellular material (of external and internal origin), in a process called cell digestion.
This disease can have its onset in childhood, adolescence or adulthood and is inherited with an autosomal recessive pattern; that is, the person must inherit two copies of the genetic mutation (one from each parent) to suffer from 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, several mutations in the ARSA and PSAP genes seem to be responsible for an aryl sulfatase A (ARSA) deficiency, Which is responsible for breaking down sulfates and other fats.
Rarely, a deficiency in the activating protein of saposin B (Sap B), which helps the ARSA enzyme to break down these fats, could also be another possible cause of the disease. The accumulation of sulphates in cells is due to a dysfunction of the joint work carried out by ARSA and Sap B to degrade 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 this is the most common and represents about 50 to 60% of cases. It usually starts in the first two years of life and children, after a period of relative normality, lose their acquired skills and suffer from mobility problems (abnormal or erratic movements) and muscle weakness (problems with walking or dragging. ).
These children are often diagnosed with cerebral palsy due to reduced mobility. As the disease progresses, muscle tone decreases to a state of absolute rigidity, speech problems become more evident, and fine motor difficulties appear.
Eventually, the child loses the ability to think, understand and interact with other people. The death rate is high and children usually do not survive past childhood.
2. Juvenile form
This form of metachromatic leukodystrophy is the second most common (approximately 20 to 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 can also occur during the school 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 stiffness with possible loss of walking. The progression of the disease is slower than that which occurs in the late childhood variant, and affected children can survive for about 20 years after diagnosis.
3. Adult form
The adult form is the less common variant of metachromatic leukodystrophy (15-20% of cases). The first symptoms appear in adolescence or later and result in poor academic or professional performance, with a gradual decrease 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 awkwardness and may become incontinent. There is also paralysis of the arms and legs, which develops gradually. Sometimes seizures can also occur. In the later stages of the disease, sufferers can reach a vegetative state.
With all, if you have this variant, you can survive for 20 or 30 years after diagnosis. During this time, there may be periods of relative stability, compared to other periods of greater instability.
Although there is no definitive cure for metachromatic leukodystrophyThe usual treatments for this disease include:
1. Symptomatic and supportive treatment
It is based on antiepileptics, muscle relaxants, physiotherapy to improve muscle function and mobility, cognitive stimulation and support for loved ones to anticipate future decisions on the acquisition of technical aids (walkers, armchairs rollers, food tubes, etc.).
2. Hematopoietic stem cell or bone marrow transplant
Here is the use of healthy stem cells obtained from the blood or bone marrow of a donor and injected into the patient. This procedure is not recommended in the late childhood variant, 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 research and clinical trials are ongoing, animal studies suggest that it may reduce sulfate build-up and lead to functional improvement in the patient.
4. Gene therapy
It consists of replacing defective genes with healthy copies it may be a treatment in the future and work is in progress and sought for it.
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” cells and incorporate the gene into them. Thus, theoretically, the enzyme levels would be restored. In animal models, it has been successful and clinical trials are underway in several countries.
- Álvarez-Pabón, I., Lozano-Jiménez, JF, Lizio-Miele, D., Katyna, G., and Contreras-García, GA (2019). Late Childhood Metachromatic Leukodystrophy: A Case Presentation. Argentine Pediatric Archives, 117 (1), E52-E55.
- Gieselmann, V. and Krägeloh-Mann, I. (2010). Metachromatic leukodystrophy: an update. Neuropediatrics, 41 (01), 1-6.