Metachromatic leukodystrophy is an autosomal recessive inherited demyelinating pathology of the central nervous system, the distinctive feature of which is metachromatic staining of demyelination zones. The clinic is dominated by developmental delay, paresis, convulsive seizures, extrapyramidal and cerebellar disorders, visual impairment. During the diagnosis, a study of the cerebrospinal fluid, the level of sulfatides, the activity of aryl sulfatase A, CT / MRI of the brain, genetic examinations are carried out. Prenatal diagnosis is possible. Treatment is symptomatic, in some cases umbilical cord blood or stem cells are transplanted.
General information
Metachromatic leukodystrophy is one of the main types of leukodystrophy, characterized, like its other types, by delayed psychomotor development, mental disorder, spastic paresis, cerebellar syndrome, extrapyramidal disorders, convulsive syndrome and optic nerve atrophy. It occurs in the population with a frequency of 1 case per 40 thousand . Inherited autosomal recessive. It was first isolated as a nosological form in 1910 by Alzheimer, described in detail in 1925 by Scholz. The time of manifestation of the disease varies significantly and determines its clinical course. In accordance with these features, several variants of pathology are distinguished: the congenital (early childhood) form, the late childhood form of Greenfield, the juvenile form of Scholz and the adult form. The most frequently observed is the post-child form. Due to the lack of effective treatment methods, metachromatic leukodystrophy is a problematic pathology for modern pediatrics, neurology and genetics.
Causes
The main substrate of the disease is a defect located on the 22nd chromosome of the gene responsible for the synthesis of aryl sulfatase A. The result of the deficiency of this enzyme is the blocking of the metabolism of sulfatide into galactocerebroside. Sulfatides are deposited in the white matter of the brain and spinal cord, skin, somatic organs (liver, lungs, heart, kidneys) and in bones. However, the function of internal organs does not suffer (the exception is the gallbladder), and progressive degenerative changes occur in the brain substance, leading to the death of the patient.
The deposition of sulfatides in the nervous tissue leads to the destruction of myelin and the accumulation of its decay products. Not only the structures of the central nervous system, but also peripheral nerve trunks are involved in the process of demyelination. Diffuse foci of demyelination are formed in the brain, giving metachromatic staining during their histochemical examination.
Symptoms
Congenital metachromatic leukodystrophy debuts before the age of 3 months with developmental delay and episyndrome. Spastic paresis and swallowing disorders quickly join. Children die at the 1st year of life.
Late childhood metachromatic leukodystrophy (late infantile form) usually manifests in the 2nd year of life with deterioration of motor skills and mental retardation. There is an unstable gait, a decrease in muscle tone. During the late childhood form, there are 4 periods. The first is characterized by muscle hypotension and weakness, extinction of tendon reflexes, difficulty walking. Lasts from 1-3 months to 1 year, sometimes longer. The second period is marked by a pronounced lag in the intellectual sphere, the change of hypotension to muscle hypertension. The child loses the ability to stand. There is dysarthria, atrophy of the optic nerves. The period takes several months. In the third period, tetraplegia, severe oligophrenia, bulbar and pseudobulbar paralysis are noted. The fourth period is accompanied by a loss of reactions to surrounding events. The child does not speak, cannot eat, develops complete blindness. With good care and feeding through a gastrostomy or gastric tube, this period can last 1-2 years.
Juvenile metachromatic leukodystrophy begins after 3 years of age in the period up to 10 years (more often at the age of about 6 years). Debuts with emotional lability, changes in behavior, a decrease in cognitive functions (students have a sharp deterioration in academic performance), ataxia, difficulty walking. Epiprimes are often noted. The disease is steadily progressing and, depending on the onset of symptoms, leads to death by 10-15 years of life.
Adult metachromatic leukodystrophy manifests after puberty, can occur up to the age of 60. As a rule, it begins with mental disorders of a schizophrenic or psychopathic nature, which is why the sick initially become patients of a psychiatrist. In some cases, the debut occurs with symptoms of polyneuropathy. The development of pathological changes is slower than in other age-related variants of the disease. In the late period, tetraparesis, bulbar disorders, and dementia develop. The fatal outcome is observed 10-20 years after the onset of symptoms.
Diagnostics
Diagnostic measures are complex in nature and allow to differentiate metachromatic leukodystrophy from other neurodegenerative diseases and other forms of leukodystrophy. Lumbar puncture is performed, increased protein concentration, aryl sulfatase deficiency, protein-cell dissociation are determined during the study of cerebrospinal fluid. Electromyography reveals an increase in the duration of nerve impulses. CT brain visualizes dilated ventricles and determines a reduced density of white cerebral matter. MRI of the brain reveals foci of demyelination.
Biochemical studies are of great diagnostic importance: determination of sulfatides in blood and urine, assessment of aryl sulfatase A activity in leukocytes taken for blood analysis. Patients are advised to consult a geneticist with a genealogical study; DNA diagnostics is possible. A method of prenatal diagnosis of pathology has also been developed — determination of aryl sulfatase A activity in cells of amniotic fluid obtained during amniocentesis. Studies have shown that carriers of the pathogenic gene also have a reduced level of aryl sulfatase A. In this regard, instead of prenatal diagnosis of the fetus, it is proposed to examine the parents of the unborn child in order to avoid medical abortion of the fetus, which is only the carrier of the defective gene.
Treatment
Therapy that can prevent the fatal outcome of the disease has not yet been found. Treatment is carried out aimed at relieving its individual symptoms: anticonvulsant therapy, the fight against joint contractures; in the later stages — prevention of bedsores, parenteral nutrition. There is a search for more effective methods of treatment, especially in the field of gene therapy.
Attempts are being made to treat by transplantation of bone marrow and umbilical cord blood. In a number of patients, stem cell transplantation makes it possible to achieve temporary stabilization of the condition and slow down the progression of pathological changes. The donor of stem cells is usually a relative of the patient who does not have leukodystrophy and has been thoroughly examined. However, it should be remembered that transplantation itself can entail a number of complications: rejection, intercurrent infections, a graft-versus-host reaction. In addition, with the rapid progression of symptoms, the fatal outcome outstrips the onset of the effect of transplantation.
Forecast
While no effective therapy for leukodystrophy has been found, it has an extremely unfavorable prognosis. With a congenital form, children do not live up to 1 year. In the late—childhood variant, the duration of the disease, as a rule, does not exceed 4 years, in the juvenile – 6 years. Among patients with an adult form, there are some cases when the life expectancy was about 50 years. So far, the only way to prevent leukodystrophy is to prevent the birth of a child with a corresponding gene mutation. In this regard, the main importance is genetic counseling of couples planning childbearing, as well as examination of future parents from the risk group for the degree of aryl sulfatase A activity.