Generality
Metachromatic leukodystrophy is a rare neurodegenerative disease that occurs mainly in childhood.
It is a pathology caused by a genetic mutation transmitted in an autosomal recessive manner by parents (healthy carriers) to children. The severity of the clinical picture is usually related to the age at which the disease occurs. Generally, the sooner the disease occurs, the more serious the condition is. Unfortunately, in many cases, the disease begins just in childhood and hopes of survival are quite low, since there are no definitive cures that can completely counter the metachromatic leukodystrophy. Fortunately, research is progressing in this direction and the gene therapy that forces are focusing more on could be a valuable tool to ensure patient survival.
What is that
What is Metachromatic Leukodystrophy?
Metachromatic leukodystrophy is a progressive neurodegenerative disease, forming part of the large group of lysosomal diseases . The pathology is characterized by an accumulation of sulfatides (or sulfatides) in different tissues of the body and, in particular, at the level of the myelin sheath that covers the axons of nerve cells (ie, in the nervous system).
Metachromatic leukodystrophy is an autosomal recessive disease ; this means that parents (healthy carriers who are not affected by the disease) have a 25% chance of transmitting the disease to their children, a 25% chance of having healthy children and a 50% chance of having healthy carrier children.
Deepening: Lysosomal and Sulfatid diseases
- Lysosomal diseases - or, more correctly, lysosomal storage diseases - are pathologies characterized by an alteration of any of the functions performed by lysosomes, particular cellular organelles responsible for the degradation and recycling of substances produced by cellular metabolism. The group of lysosomal diseases includes about 50 different types of diseases.
- Sulfatids are sulfuric esters of galactocerebrosides (particular types of glycolipids) that are found mainly in the myelin sheath produced by oligodendrocytes in the central nervous system and by Schwann cells in the peripheral nervous system. In addition to being part of the composition of the myelin sheath, sulfatids perform numerous other functions and are implicated in the mechanisms of neural plasticity, in memory and in glial-axon cell interactions. Alterations in the metabolism of sulfatides are associated with various diseases, among which we also find metachromatic leukodystrophy.
Different Forms of Metachromatic Leukodystrophy
Depending on the severity of the disease and the age at which it appears, it is possible to distinguish four different forms of metachromatic leukodystrophy:
- Late-infantile form, it occurs between 6 months and 2 years of age;
- Early juvenile form, it occurs between 4 and 6 years of age;
- Late juvenile form, the onset is between 6 and 12 years;
- Adult form, it arises after 12 years of age.
The juvenile and infantile forms represent the most serious types of metachromatic leukodystrophy with tragic implications. Unfortunately, the late-infant form is the most common.
Causes
What are the Causes of Metachromatic Leukodystrophy?
The causes of metachromatic leukodystrophy reside in a genetic mutation located on chromosome 22 at the level of the gene that codes for the lysosomal enzyme arylsulfatase A ( ARSA gene ), implicated in the metabolism and degradation of sulfatides. To be fair, there is no single genetic mutation capable of triggering metachromatic leukodystrophy, but numerous mutations of the ARSA gene have been identified that can give rise to the disease.
Because of the aforementioned genetic mutations, patients present a more or less marked arylsulfatase A deficiency leading to an accumulation of sulfatides in the body; accumulation that is localized above all in the myelin sheath present on nerve cells, but also at the level of the kidneys and gall bladder.
Due to the accumulation of sulfatides in the central and peripheral nervous system, we witness the demyelination of nerve cells and the loss of motor and cognitive functions of patients.
Did you know that ...
In some rare cases of metachromatic leukodystrophy, the responsible genetic mutation was not localized on the ARSA gene, but on a different gene that codes for a fundamental activator of sulfatide metabolism. In these cases, we speak more properly of metachromatic leukodystrophy due to activator deficiency . Therefore, in patients experiencing this mutation, the activity of arylsulfatase A is normal, but the sulfatides are not degraded - therefore they accumulate - due to the lack of the aforementioned activator.
Symptoms
Symptoms and Clinical Manifestations of Metachromatic Leukodystrophy
The symptoms and clinical manifestations of metachromatic leukodystrophy can be more or less severe depending on the form (late-infant, early juvenile, late juvenile, adult) that affects the patient.
In any case, in all forms, patients report a gradual deterioration of the motor and neurocognitive functions acquired up to the moment in which the disease manifests itself. Unfortunately, the diagnosis is not always timely because the symptoms can manifest themselves in a subtle way, developing slowly. As reiterated several times, the late-infantile and juvenile forms are the most serious, both as regards the symptomatology and with regard to the course and outcome - unfortunately ominous - of the disease.
The following are the main symptoms, manifestations and clinical signs that characterize each form of metachromatic leukodystrophy.
Late infantile form
This form of metachromatic leukodystrophy is the most widespread and probably the most serious. It is characterized by a marked sulfatiduria (presence of sulfatides in the urine) and by a considerable reduction in nerve conduction ; the activity of arylsulfatase A is extremely reduced or even absent . This form of metachromatic leukodystrophy is generally manifested during the period during which the child begins to walk (between six months and two years) with symptoms such as difficulty walking, hypotonia and optic atrophy . The disease proceeds with a motor regression followed by the loss of cognitive functions . Patients suffering from the late-infantile form, therefore, progressively lose the ability to walk and talk, although they can still communicate through eye movement, crying or laughter. As the disease progresses, however, we are witnessing the loss of any capacity for communication and movement: children struggle to move their eyes and have difficulty swallowing and difficulty breathing. Unfortunately, within a few years of the first symptoms appearing, the patient dies.
Youth forms
There are two juvenile forms of metachromatic leukodystrophy: the early and late forms that occur, respectively, between four and six years and between six and twelve years. Also in this case there is sulfatiduria and a reduction in the activity of the enzyme arylsulfatase A which, however, appear to be less marked than in the late infantile form.
The juvenile forms manifest themselves with an arrest of the psychic development which follows the motor regression, often accompanied by symptoms like ataxia and convulsions .
The juvenile forms progress more slowly than the late-infantile form, but these are however very serious conditions with tragic implications. In this regard, it is estimated that most patients with juvenile forms of metachromatic leukodystrophy will die before the age of 20.
Adult form
The adult form of metachromatic leukodystrophy usually occurs after 12 years of age, sometimes even after 15-16 years. The onset is subtle, so much so that, very often, the diagnosis is made only in adulthood. The progression is slower than the infantile and juvenile forms, but still characterized by a gradual loss of motor and neurocognitive abilities .
Even the adult form is characterized by sulfatiduria, although it appears to be decidedly less marked than that present in the infantile form. As for the activity of arylsulfatase A in the adult form, there is usually a residual enzyme activity .
Diagnosis
How can you diagnose Metachromatic Leukodystrophy?
The diagnosis of metachromatic leukodystrophy is made on the basis of the symptoms that occur in the child and on the basis of both instrumental and laboratory tests, such as:
- The dosage of the enzymatic activity of arylsulfatase A;
- The dosage of sulfatides not metabolized in the urine;
- Genetic tests for the detection of mutations in the ARSA gene;
- Measurement of nerve conduction velocity (in fact, in patients with metachromatic leukodystrophy, the nerve conduction velocity is reduced);
- Tomography and magnetic resonance, thanks to which it is possible to highlight the presence of anomalies in the white matter of the brain typical of leukodystrophies.
Prenatal Diagnosis of Metachromatic Leukodystrophy
Prenatal diagnosis of the disease can be made in those cases where there is a pregnancy considered to be at risk, as happens, for example, in the presence of a family history of metachromatic leukodystrophy. Prenatal diagnosis of the disease can be made by amniocentesis or villocentesis .
Identification of Healthy Carriers of Metachromatic Leukodystrophy
Testing for the determination of the enzymatic activity of arylsulfatase A is not only useful for diagnosing disease in patients, but can also be useful for identifying healthy carriers in families at risk. For the same reason, it is also possible to perform specific genetic tests.
Understanding whether an individual is a healthy carrier or not is very important because, in this way, it is possible to know if you run the risk of passing on the genetic mutation to your children.
Possible cure
Is there a cure for metachromatic leukodystrophy?
Unfortunately, at the moment there is no definitive cure for metachromatic leukodystrophy and the therapies currently provided to patients are mostly supportive and symptomatic .
In some selected cases, in patients with late-childhood or juvenile forms, it is possible to consider the opportunity of performing a bone marrow or umbilical cord stem cell transplant, in order to try to restore neurocognitive functionality. However - besides being a very complex procedure - the efficacy of a bone marrow transplant in metachromatic leukodystrophy is not guaranteed.
Future hopes for Metachromatic Leukodystrophy: Gene Therapy
For the treatment of metachromatic leukodystrophy, the use of gene therapy is currently being studied. This particular type of therapy aims to treat genetic diseases such as metachromatic leukodystrophy by inserting "correct" and non-mutated genetic material into the patient's cells.
In this regard, an interesting approach based on gene therapy that has given encouraging results was conducted in Italy, starting in 2010, at the San Raffaele-Telethon Institute in Milan. The therapeutic protocol developed here provides for the collection of stem cells from the patient's bone marrow, the correction of genetic material in the laboratory by introducing the vector containing the non-mutated gene (defined as a " therapeutic gene ") and the reintroduction of cells in the patient. The study in question involved several patients, both in the pre-symptomatic phase and in the initial phases of the disease (manifestation of the first symptoms). Treatment of patients in the pre-symptomatic phase was possible because the disease was diagnosed early because it was present in the older siblings of the same patients.
The results obtained were very encouraging with regard to eight of the patients in the pre-symptomatic phase who have benefited significantly from the treatment with gene therapy (prevention of the onset of the disease or arrest of its progression). With regard to patients who already had the first symptoms of metachromatic leukodystrophy, the results obtained were more variable and more detailed research is therefore needed to determine whether gene therapy can be effective even after the onset of the disease.
However, gene therapy currently appears to be the only therapeutic approach capable of offering concrete hope to patients with metachromatic leukodystrophy.
