Leukodystrophy is a neurodegenerative disease caused by a hereditary metabolic disorder with the accumulation of metabolites in the brain and spinal cord that provoke the destruction of myelin. Manifests mainly in childhood with delayed psychomotor development, motor disorders, damage to the visual and auditory nerves, hydrocephalus, epileptic seizures. Leukodystrophy is diagnosed according to the neurological status, anamnesis, genetic studies, MRI or CT pictures of the brain, biochemical analyses. Treatment is symptomatic. With early detection and slow progression, cord blood or bone marrow transplantation is possible.
ICD 10
E75.2 Other sphingolipidoses
General information
Leukodystrophy got its name in connection with the lesion of the white matter of the brain (from the Greek leukos — white). There are about 60 varieties of leukodystrophy, determined by the type of gene anomaly and the age of manifestation of clinical manifestations. Along with individual inflammatory lesions of the central nervous system (for example, Schilder’s leukoencephalitis), leukodystrophy refers to the syndrome of diffuse sclerosis of the brain. At the same time, the dominant lesion of myelin brings it closer to demyelinating diseases (multiple sclerosis, REM, etc.), and some forms can be attributed to lipidoses.
The main forms of leukodystrophy include metachromatic, sudanophilic, globoid-cellular, Van Bogart-Bertrand degeneration, Alexander’s disease, Gallervorden-Spatz variant. The first 3 types of leukodystrophy are the most common. Their occurrence ranges from 0.4 to 1 case per 100 thousand newborns. A number of forms of leukodystrophy are so rare that only a few hundred of their clinical observations are described in the world literature on neurology. Depending on the age period in which leukodystrophy debuts, each of its forms can be divided into infantile, late infantile, juvenile and adult variants.
Causes
Basically, each leukodystrophy has a genetic anomaly of a certain enzyme. The type of anomaly and localization of the gene mutation have so far been established only for the most common forms of pathology. In most cases, leukodystrophy has an autosomal recessive pathway of hereditary transmission, but some of its forms can be inherited linked to gender. In addition, cases of spontaneous mutations are not alone. A genetically determined enzyme defect leads to metabolic disorders (more often in lipid metabolism) with the deposition of a certain metabolite in nerve structures and individual somatic organs, primarily in the liver and kidneys.
The consequence of the metabolic anomaly is the destruction of the myelin sheaths of nerve trunks and pathways, the death of neurons with their replacement by expanding glial tissue. Morphologically, leukodystrophy is characterized by diffuse and symmetrically located in the hemispheres of the brain areas of myelin death, accumulation of myelin decay products, increased proliferation of glia. In some nosological variants, leukodystrophy has a specific morphological picture — metachromatic or sudanophilic staining of myelin decay products, accumulation of globoid cells in demyelination zones, etc.
Symptoms
In most cases, leukodystrophy debuts in early childhood. Newborns, as a rule, look healthy. For a certain period, they develop normally, and then gradually various neurological symptoms arise, characterized by steady progression. The rate of increase of symptoms is higher the earlier the leukodystrophy manifested. The leading manifestations are progressive oligophrenia, visual impairment, hearing loss, episyndrome, spastic paresis. The first symptoms of leukodystrophy may be ataxia, musculotonic disorders (hypo- or hypertonus, muscle twitching), extrapyramidal manifestations, behavior changes. Then there are epiprimes, bulbar manifestations, hearing and vision decrease, there is an intellectual decline with a gradual loss of previously acquired skills. Sensory disorders are not typical. At the later stages of the disease development, paralysis, pronounced oligophrenia, gross swallowing disorder, amaurosis, deafness are observed. In the terminal phase, decerebration rigidity is usually noted.
Types
Metachromatic leukodystrophy, depending on the manifestation, has 4 variants. The congenital variant debuts in the first 1-3 months of life with developmental delay and convulsive syndrome; children do not reach the age of 1 year. The late-childhood variant of metachromatic leukodystrophy begins in the period from 1 to 3 years with muscular hypotension and weakness, ataxia, mental retardation (MR). Then spastic tetraplegia, aphasia, pseudobulbar syndrome is formed. In rare cases, patients live to the age of 10. The juvenile variant manifests in 4-6 years and lasts an average of 7 years. The adult version debuts in the third decade of life, sometimes later, the life expectancy of patients from the beginning of the clinic varies between 10-20 years.
Sudanophilic leukodystrophy is inherited linked to the X chromosome and has several varieties. Peliceus-Merzbacher leukodystrophy can start at the 1st year of life or at 3-4 years. The first sign is large-scale nystagmus, later there is MR, cerebellar ataxia, hyperkinesis, paresis. The greatest progression occurs at the age of 10 years, then the disease takes a slow course with long remissions. Patients can live to adulthood. Adrenoleukodystrophy is a variant in which leukodystrophy is combined with adrenal insufficiency. It is characterized by a progressive course with a fatal outcome after 6-8 years from the beginning of the clinic.
Globoid-cell leukodystrophy (Krabbe disease) is a lipoidosis with accumulation of galactocerebroside in the foci of demyelination and the formation of large rounded globoid cells. The early childhood variant develops in the first half of life with hyperexcitability and periodic hyperthermia, psychomotor development is delayed, muscle tone increases, then spastic tetraparesis, oligophrenia, episyndrome develops, opisthotonus is possible. At the age of one year, a fatal outcome occurs. The late-childhood variant is more rare, manifests a deterioration in vision.
Spongiose degeneration of Van Bogart-Bertrand is characterized by episindrome, hypersomnia, severe hydrocephalus with an increase in the size of the head, causing amaurosis atrophy of the optic nerves. Sharp intracranial hypertension leads to a divergence of cranial sutures, recorded during radiography of the skull. Patients with this form of leukodystrophy die before the age of 3.
Alexander’s disease (leukodystrophy with fibrous formation) is caused by a mutation of the gene responsible for the synthesis of GFAP protein. As a result, abnormal GFAP protein containing Rosenthal fibers accumulates in glial cells. The neonatal variant has a severe course with a fatal outcome by the end of the 1st year. The infantile variant occurs in about half of the cases, manifests itself in the first 1-2 years of life of the MR, then spastic paresis, ataxia, hydrocephalus join. Children die after a few years. Alexander’s juvenile leukodystrophy debuts in the period from 4 to 10 years of age, proceeds with mainly stem symptoms. Life expectancy ranges from 10-30 years. The adult variant is characterized by late manifestation and a relatively slow course within 10 years or more.
Gallervorden-Spatz leukodystrophy most often starts at the age of 10. It is manifested by the dysfunction of the striopallidar system, then tetraparesis progresses against the background of hyperkinesis, hemeralopia and retinitis pigmentosa develop, there is a decrease in intelligence, epiprimes occur.
Diagnostics
Diagnostic search requires the involvement of a number of specialists: a neurologist, a pediatrician, a medical geneticist, an otolaryngologist and an ophthalmologist for the diagnosis of visual and hearing disorders. It is important to study the history of the disease (age and symptoms of the debut, the sequence of development of the clinic) and family history (the presence of leukodystrophy in relatives). Neurosonography through the fontanel and echo-encephalography in older patients, as a rule, reveals an increase in intracranial pressure. Leukodystrophy is accompanied by a significant increase in protein concentration due to the destruction of cerebral cells, which is determined by the study of cerebrospinal fluid.
In order to diagnose the type of metabolic anomaly, a number of biochemical tests are carried out to determine the level of enzymes and accumulating metabolites. Foci of demyelination are well visualized using MRI, and can be detected on CT scans of the brain. Usually demyelination is visible on the MRI of the brain even before the clinical manifestation of leukodystrophy. Due to the development of genetics, leukodystrophy has developed DNA diagnostics, and its individual forms (metachromatic, adrenoleukodystrophy, globoid cell) – the possibility of prenatal diagnosis.
Treatment
To date, leukodystrophy has no effective methods of therapy that can stop the progression of symptoms. Symptomatic treatment is carried out — mainly dehydration and anticonvulsant therapy. The only method that can increase the life expectancy of patients with leukodystrophy and improve their quality of life is cord blood transplantation or bone marrow transplantation. Transplantation leads to normalization of metabolism. However, this process takes a long time (from 12 to 24 months), during which the progression of leukodystrophy continues. Therefore, severe disability or death of the patient often occurs even after successful transplantation.
It should be emphasized that transplantation does not affect the already developed neurological deficit in any way, it only allows to suspend its further progression. Due to the fact that the effect of such treatment occurs after 1-2 years, it is advisable in the case of early preclinical diagnosis of leukodystrophy (with appropriate alertness of the parents of the born child due to the presence of such pathology in the family) or with a slowly progressing course. In addition, it should be taken into account that transplantation is associated with the risk of a number of serious complications, such as rejection, graft-versus-host reaction, and the development of infections.
