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Metachromatic leukodystrophy. This type of leukodystrophy is the most common type of white matter degeneration in children. It is inherited in an autosomal recessive manner. In this disease, a deficiency of the enzyme arylsulfatase A in the brain and other tissues is determined. Normally, when exposed to this enzyme, a sulfate group is cleaved from ceramide galactose sulfate, or sulfatide, a normal component of myelin lipids. Large amounts of sulfatide accumulate in the white matter of the brain, which is easily identified by light microscopy by its metachromatic (reddish-brown) staining with toluidine blue. Similar accumulations of sulfatide are found in peripheral nerves. Diffuse demyelination, spreading to all parts of the nervous system, is especially pronounced in areas where myelination occurs later.
Clinical signs usually appear around one year of age, but may appear at older ages. Initially, the child's gait is disturbed, and he cannot learn to run or walk up the stairs. In the early stage of the disease, spasticity of the limbs, hyperreflexia and the extensor plantar reflex are noted. All tendon reflexes are alive, with the exception of the knee reflex, which is reduced or absent due to damage to the peripheral nerves. In case of severe damage, paresis and atrophy of the distal muscles, especially the legs, occur. Ultimately, the child ends up bedridden and his mental development is retarded. Death usually occurs before the child reaches the age of 10 years. With late onset, the main symptoms are extrapyramidal motor disorders and mental retardation.
The final diagnosis depends on the absence or significant decrease in sulfatase A activity in one or more body tissues. To determine the activity of the enzyme, renal tubular cells obtained from urine sediment, leukocytes or a culture of fibroblasts are most suitable. Fast, but not sufficiently accurate methods include the determination of metachromatic material in urine sediment stained with toluidine blue. Dysfunction of the gallbladder due to the accumulation of sulfatides on its walls can be determined by a filling defect detected by oral cholecystography. Conduction in peripheral motor and sensory nerves is disrupted. The protein level in the CSF is usually elevated, which serves as a valuable diagnostic feature in differentiating leukodystrophy from the large group of non-progressive movement disorders related to cerebral palsy. Differentiation is of great importance in terms of genetic counseling and prognosis. Metachromatic leukodystrophy in the fetus is diagnosed based on the activity of arylsulfatase in amniotic fluid cell culture; The study is offered to future parents if they have pathologically altered genes.
Krabbe disease(cerebroside lipidosis or spherical leukodystrophy). The disease is inherited in an autosomal recessive manner. Its pathological signs include a diffuse absence of myelin in the white matter of the brain and an accumulation of specific giant multinucleated cells (spherical cells). It contains an increased ratio of cerebroside (ceramide galactose) to sulfatide (ceramide galactose sulfate) against the background of an unchanged absolute amount of cerebroside. These changes are considered secondary to insufficient galactocerebrosidase activity.
The disease is detected at an early age, when the child develops progressive rigidity, hyperreflexia, the swallowing process is disrupted, and his physical and mental development lags behind. Involvement of peripheral nerves in the process leads to muscle hypotension; the child dies in the first 2 years of life. The diagnosis is established by determining the activity of galactocerebrosidase in peripheral blood leukocytes. CSF protein levels are elevated and peripheral nerve conduction is decreased. Prenatal diagnosis is possible by determining enzyme activity in amniotic fluid cell culture.
Adrenoleukodystrophy. The disease is inherited in a recessive manner, linked to the X chromosome. Pathological signs are reduced to degeneration of white matter with the accumulation of myelin breakdown products, mainly neutral fats. Typical zigzag inclusions are detected in macrophages of affected tissues. In the atrophied adrenal cortex, cells contain similar inclusions.
The disease is based on a violation of the metabolism of hexacosanoate, a C26 long-chain fatty acid, which accumulates in the brain, adrenal glands, muscles, plasma and fibroblast culture. Plasma testing helps clarify the diagnosis and identify gene carriers.
The disease usually begins by the end of the first 10 years of life and is manifested by progressive spasticity, dementia, and at a later date - skin pigmentation and other signs of Addison's disease. In some cases, the process primarily involves the spinal cord and peripheral nerves (adrenomyeloneuropathy). A variant of the disease with onset in early childhood has been described.
Some forms of leukodystrophies are still not fully defined and are usually diagnosed only by sectional examination of the brain.
Canavan disease(spongy degeneration of the white matter of the brain). The disease is inherited in an autosomal recessive manner. Histological examination of the brain reveals characteristic diffuse vacuolation of cells in the deep layers of the cortex and subcortical white matter, apparently as a result of excessive accumulation of water in glial cells and myelin matter. Symptoms in young children include poor control of head movements, blindness, optic atrophy, rigidity, hyperreflexia, and progressive macrocephaly. Based on the latter, hydrocephalus or fluid accumulation in the subdural space is assumed. However, the size of the ventricles does not change or they are slightly dilated: Death occurs within 5 years.

Peliceus-Merzbacher disease. The disease is inherited in a recessive manner, linked to the X chromosome. In children, it begins with nystagmus and head shaking, followed by ataxia, spasticity and choreoathetosis. The disease progresses slowly and patients survive into adulthood. It is quite difficult to differentiate from cerebral palsy.

Main symptoms:

• Big head
• Muscle hypertonicity
• Delay in psychomotor development
• Behavior change
• Swallowing disorder
• Mental development disorder
• Involuntary muscle twitching
• Mental retardation
• Increased nervous excitability
• Increased intracranial pressure
• Decreased vision
• Decrease in intelligence
• Decreased muscle tone
• Partial paralysis

Leukodystrophy is a pathology of neurodegenerative origin, of which there are more than sixty varieties. The disease is characterized by a metabolic disorder, which leads to the accumulation of specific components in the brain or spinal cord that destroy a substance such as myelin.

The causes of the disease lie in gene mutations, but some forms can be inherited from one of the parents. In addition, cases of spontaneous mutations have been recorded.

The symptoms of the disease will differ depending on the form in which the disease occurs. The most frequently expressed signs are decreased hearing or visual acuity, as well as decreased or increased muscle tone.

The correct diagnosis can be made based on genetic studies and instrumental examinations of the patient. Treatment is symptomatic, but if the disease is detected early, specific surgical interventions may be required to save the child’s life.

Etiology

Leukodystrophy, or progressive sclerosis of the brain, got its name because the white matter of this organ is involved in the pathological process. Today, a large number of forms of the disease are known, differing in the type of genetic mutation and the age category in which symptoms manifest.

The most common types of the disease, for example, metachromatic leukodystrophy, are diagnosed in one infant per hundred thousand newborns. However, there are types of pathology, of which no more than several hundred are registered.

The main cause of any type of disease is a genetic abnormality of a particular enzyme. The types and localization of mutated genes have been established only for the most common forms of pathology.

Leukodystrophy is often characterized by an autosomal recessive mode of inheritance, but some types can be transmitted purely by gender, that is, from mother to daughter or from father to son.

A genetically determined defect most often leads to disruption of metabolic processes, which is fraught with the accumulation of a particular substance in the body. The following organs are mainly affected:

• brain;
• kidneys;
• spinal cord;
• liver.

The consequence of metabolic disorder is:

• destruction of myelin in the sheaths of nerve trunks;
• death or atrophy of neurons;
• replacement of dead neurons with glial tissue, which constantly grows.

According to morphological characteristics, leukodystrophy is characterized by:

• diffuse or symmetrical arrangement of areas of myelin loss in both hemispheres of the brain;
• accumulation of a large number of products released after the breakdown of myelin;
• increased proliferation of glia.

All groups of the disease are characterized by development in early childhood, even before the child goes to school.

Classification

Depending on the age category in which such a pathology manifests itself, it has the following forms:

• infantile– symptoms begin to be expressed in the interval from the first three to six months of life;
• late infantile– is such if the diagnosis is made in a period that begins at six months and ends at one and a half years.
• juvenile or typical children's– the disease manifests itself between the ages of three and ten years;
• adult– differs in that the first symptoms can appear from the age of sixteen.

Symptoms

Often forms of leukodystrophy are expressed in childhood, while newborns in the vast majority of cases look completely healthy. For a certain period of time, the child experiences normal development, which corresponds to his age category. However, various neurological signs will gradually appear, prone to constant progression.

Depending on the earlier the manifestation occurred, the faster the pathology will progress. Despite the fact that clinical manifestations often depend on the type of leukodystrophy, the initial symptoms will be approximately the same.

Thus, the group of first symptoms includes:

• oligophrenia;
• deterioration of visual function;
• symptomatic epilepsy;
• persistent hearing loss;
• spastic paresis;
• hypotonicity or hypertonicity of muscles;
• impaired coordination of movements;
• involuntary muscle twitching;
• sudden changes in behavior;
• mental retardation - moreover, children lose acquired skills over time;
• violation of the swallowing process;
• paralysis.

Metachromatic dystrophy is characterized by the following symptoms:

• decreased muscle tone, which leads to constant weakness of the child;
• ataxia;
• mental development disorder;
• formation of spastic tetraplegia;
• partial or complete loss of the ability to use one’s own speech;
• development of pseudobulbar syndrome.

The severe clinical picture leads to the fact that patients with this form of pathology rarely survive beyond the age of ten. If the manifestation occurs in an adult, then the period from the onset of the first symptoms to death is approximately twenty years.

The sudanophilic variety of pathology is divided into several types. The first is Pelizaeus-Merzbacher leukodystrophy. In the vast majority of cases, it develops either in the first year of life or at three years of age. Among the symptoms it is worth highlighting:

• nystagmus;
• mental retardation;
• cerebellar ataxia;
• paresis of the limbs.

It is noteworthy that after the patient reaches ten years of age, the progression of the disease slows down, which allows the person to live into adulthood.

The second type is adrenoleukodystrophy; in addition to the above symptoms, there will be manifestations characteristic of a disease such as. It differs from the first form in that it progresses rapidly and leads to the death of the patient eight years after the onset of manifestation.

Krabbe leukodystrophy or globoid cell disease develops in the first six months of a baby’s life and is expressed in:

• increased excitability;
• delayed psychomotor development;
• increasing muscle tone;
• development of spastic tetraparesis;
• oligophrenia;
• convulsive seizures.

Such symptoms lead to the baby dying before reaching one year of age.

Spongy leukodystrophy or Canavan-Bertrand disease in its symptom complex has:

• episyndrome;
• pronounced;
• increased size of the head in relation to the entire body;
• atrophy of the optic nerves.

Children with this form of the disease often die at the age of three.

Alexander disease is another type of pathology, which is characterized by:

• hydrocephalus;
• spastic paresis;
• delayed psychomotor development;
• ataxia.

It is noteworthy that the later the disease manifests itself, the longer a person will live. The maximum life expectancy can reach thirty years.

Schilder's disease has the following symptoms:

• decreased intelligence;
• seizures;
• disruption of the functioning of the striopallidal system;
• tetraparesis arising as a result of hyperkinesis;
• signs of pigmentation and hemeralopia.

Diagnostics

To determine the type of brain leukodystrophy, an integrated approach will be required, which is based on instrumental and laboratory studies.

However, primary diagnostics, which includes:

• studying the medical history of both the little patient and his parents - to find out the path of inheritance of the pathology;
• a thorough physical examination to assess muscle tone, reflexes, gait and coordination. This should also include consultations with an ENT doctor and an ophthalmologist to determine the presence of visual or hearing impairments;
• a detailed survey of the patient’s parents - to find out the first time of appearance of specific symptoms, since in some cases very important information regarding whether the symptoms arose in infancy or in the juvenile period.

Laboratory testing is limited to:

• cerebrospinal fluid analysis;
• biochemical blood tests - to identify which pathological substances accumulate during a particular variant of the disease.

Instrumental diagnostics clarifies the type of disease using the following procedures:

• neurosonography;
• echo-encephalography;
• CT and MRI.

Specific DNA diagnostic methods have also been developed that detect such a disease even at the stage of intrauterine development of the fetus. In such cases, consultation with a genetic specialist is necessary.

Treatment

Currently, there is no effective treatment for leukodystrophy that can completely eliminate the disease. Patients are prescribed symptomatic therapy, which in the vast majority of cases involves dehydration and anticonvulsant therapy.

The only treatment that helps prolong the life of patients is umbilical cord blood transplantation or donor bone marrow transplantation. However, this may take one to two years, during which the disease continues to develop and progress. It is for this reason that either the patient’s disability or death occurs.

It should be noted that even a hastily performed transplantation will not change the already formed neurological disorders. This will only slow down the process of further progression of the disease.

Given that the effect of such treatment occurs over a long period of time, it is most appropriate only with early preclinical diagnosis or with the slow progression of such a disorder.

It is also worth considering that transplantation can lead to bone marrow rejection, secondary infections, or the development of graft-versus-host syndrome.

Prevention and prognosis

Since leukodystrophy is a genetically determined disease, there are no preventive measures to prevent its development.

Krabbe disease (galactosylceramide lipidosis or globoid cell leukodystrophy) is a rare hereditary disease that belongs to the group of lysosomal storage diseases (caused by dysfunction of lysosomes). It manifests itself in damage to the myelin sheath of nerve fibers, progressive brain degeneration, increased muscle tone, very high body temperature (hyperpyrexia) and mental retardation.

General information

The first description of the disease dates back to 1916 and belongs to the Danish Knud Garaldensen Krabbe, so the disease is named after him.

The prevalence of the disease is 1 case per 100,000 people. Krabbe disease is more common in the Scandinavian Peninsula - 1 in 50,000, as well as in Arabs living in Israeli territory - 1 in 6,000.

The disease occurs in both sexes equally.

This disease can also occur in cats and dogs (mostly small terrier breeds).

Forms

Depending on the age at which the disease manifested itself, the following clinical forms of galactosylceramide lipidosis are distinguished:

• infantile or classic (the development of the disease begins at 3-6 months);
• late infantile (from 6-18 months);
• juvenile;
• an adult.

The classic form accounts for 85-90% of all cases.

Reasons for development

Krabbe disease is caused by mutations in the GALC gene, which is located on chromosome 14 in the q31 region.

The GALC gene provides the synthesis of the enzyme galactoceramidase (galactosylceramide-b-galactosidase). This enzyme breaks down the simplest glycolipid galactocerebroside into galactose and ceramide.

Galactocerebroside is an important component of myelin, which forms a protective coating around nerve fibers that allow rapid transmission of nerve impulses.

When a mutation in the GALC gene causes enzyme deficiency in the brain and other organs, an abnormally large amount of unsplit galactocerebroside derivative psychosine (galactosylsphingosine) is deposited. Significant accumulation of psychosine is toxic to the cells that form the myelin sheath, so it is gradually destroyed. As a result, the degeneration process affects not only the central nervous system, but also peripheral nerves.

The disease is inherited in an autosomal recessive manner.

Pathogenesis

In case of deficiency of the enzyme galactocerebrosidase or the protein saposin A, which is necessary for the enzyme to “recognize” the substrate, undigested glycolipids and their derivative psychosine accumulate in the brain, kidneys, spleen, liver, leukocytes and connective tissue cells (fibroblasts). As a result, the amount of psychosine exceeds the norm by 10-100 times.

Psychosine is toxic to the nervous system because it causes the death of neuroglial cells (oligodendrocytes), which provide myelination of axons. In areas of disintegration of the myelin sheath in the nervous tissue around blood vessels, characteristic inclusions are formed - globoid histiocytes (are macrophages that are able to capture and digest bacteria, etc.).

The death of oligodendrocytes is accompanied by damage to neurons, which are the main structural and functional unit of the brain. The place of dead neurons is filled with neuroglial cells and gliosis develops.

Axonal degeneration also affects peripheral nerves, in which foamy histiocytes accumulate.

The disease progresses rapidly.

Symptoms

Symptoms of Krabbe disease depend on the form of the disease.

There are three stages of the infantile form of the disease (develops up to 6 months).

Stage I is characterized by the presence of nonspecific symptoms, which manifest themselves in:

• increased muscle tone (spastic type);
• hyperexcitability;
• unmotivated rises in temperature;
• difficulties with feeding.

At the 6th – 8th month of life, disturbances in psychomotor development appear, and convulsions are possible.

Stage II of the disease is accompanied by:

• rapid loss of previously acquired skills;
• sudden chaotic contractions of individual muscles (myoclonus);
• an increase in muscle tone to a convulsive pose, in which the back is sharply arched and the support is only on the heels and the back of the head ();
• decreased intelligence;
• atrophy of the optic nerves, in which the reaction of the pupils to light decreases;
• decreased or absent tendon reflexes;
• malnutrition up to extreme exhaustion (cachexia).

Stage III is characterized by:

• convulsions;
• development of bulbar-pseudobulbar syndrome, in which the process of swallowing and pronunciation of sounds is disrupted, and loss of voice sonority is observed;
• loss of brain function.

Symptoms of the late infantile form are:

• early developing damage to the optic or retinal nerve, which, in the absence of defects in the visual organs, leads to blindness (can be partial or complete);
• gradual decline in intelligence;
• motor skills disorders.

Symptoms of the juvenile and adult forms include:

• Visual agnosia (inability to recognize and classify incoming visual information) or, in which half of the visual field falls out.
• Spastic paresis and paralysis that occur due to progressive neuropathy. They are detected primarily in cases of gait disturbances.

Diagnostics

Diagnosis of Crabe disease includes:

• The study of complaints and anamnesis, which clarifies at what age the first symptoms appeared, how quickly the disease develops, etc.
• A study of family history, which clarifies whether similar symptoms of the disease were observed in relatives.
• General inspection. During the examination, muscle tone, the severity of tendon reflexes, coordination of movements, gait, etc. are assessed.
• Analysis of cerebrospinal fluid (CSF), which evaluates the transparency and color of the fluid, its pressure, the amount of glucose, protein (increases during the destruction of neurons), and chlorine salts.
• Biochemical tests, which measure levels of the enzyme galactoceramidase or detect elevated levels of psychosine. Blood or skin cells are taken for analysis.
• CT, MRI and ENMG (electroneuromyography). At the initial stage of the disease, MRI reveals damage to the subcortical structures, white matter of the cerebellum and pyramidal tracts. Late stages are characterized by atrophy of the cerebrum, damage to the posterior parts of the brain stem or splenium, and damage to the white matter of the brain in the parieto-occipital regions. ENMG can detect a reduced speed of impulse transmission along peripheral nerves, as well as their demyelination.
• Molecular genetic examination.

Krabbe disease allows for prenatal diagnosis, during which the amniotic fluid is examined. Galactoceramidase activity is determined in the studied amniotic cells.

Treatment

An effective treatment for Krabbe disease is currently under development - scientists are studying the possibility of delivering the Galc gene into the patient's cells using viruses (gene therapy), but this method has not been fully studied.

In the early stages of the disease or in slowly progressing forms, transplantation is a fairly effective treatment method:

• bone marrow, which allows you to stabilize the patient’s condition and reduce symptoms;
• umbilical cord blood, which stops the further development of the disease.

In addition, symptomatic treatment is carried out, including taking anticonvulsants, etc.

The prognosis is unfavorable - in the infantile form of the disease, death occurs within 2 years. With late forms of the disease and slow progression of the disease, life expectancy increases.

Prevention

Krabbe disease is a hereditary disease, so the only possible prevention is genetic analysis if Krabbe disease is present in close relatives.
The disease manifests itself when both parents have a defective gene (probability 1 in 4).

If one of the parents has a mutation in the GALC gene, the person is simply a carrier of the defective gene.

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Pelyceus-Merzbacher is a disease that is the fourth form of leukodystrophy and can be transmitted in several ways.

The first is autosomal recessive. In this case, both parents must be carriers of the mutant gene. There is a 50% chance that their children will also be carriers of the damaged gene, and only a 25% chance that a healthy child will be born. The probability of having a child with this type of leukodystrophy is also the same.

The second is inheritance, which is linked to gender. For example, in a family, the disease is transmitted only to boys or only to girls.

What is the essence of the disease

Leukodystrophy of this type is considered one of the most severe. The basis of the disease is a violation of melanin metabolism, which results from the complete breakdown of the membranes of the brain. Melanin is a substance that ensures the transmission of signals throughout the central nervous system.

The disintegration of the membrane that covers all nerve endings, nerve cells, and the brain is a process that is constantly progressing and is irreversible. It is currently not possible to cure the pathology. The condition can be alleviated only with symptomatic treatment.

The disease primarily affects the white matter of the brain. Gray is affected to a lesser extent.

Causes and risk factors

According to statistics, pathology is diagnosed more often in boys than in girls. In 85% of all cases, marriages with close relatives occur.

What causes such a genetic failure, and why the disease in some cases appears spontaneously, that is, without any heredity, is not yet exactly clear. As for risk factors, parents who are carriers of this pathology need to be especially careful.

Symptoms

The first symptoms begin to appear between 5 and 10 months of age. Moreover, at birth the child looks absolutely healthy, and even doctors cannot suspect anything is wrong. The development is slow, there may be a clear period during which there are no symptoms of the disease, and the duration of this period ranges from several months to a couple of years.

As mentioned above, in the first few months the child is no different from his peers. It all starts with a movement disorder, a coordination disorder. All this is accompanied by severe muscle weakness, muscle tone, which can be increased or greatly decreased, and convulsions are also observed.

As the disease progresses, the child loses all the motor skills that he had previously, that is, he stops sitting, rolling over, holding his head up, and walking. Since myelin is destroyed in the brain, problems begin with the intellect, and memory deteriorates. Moreover, it should be noted that the earlier the first symptoms appear, the worse the disease will progress.

Diagnostics

An MRI of the head will help to understand how severely the brain is affected in Pelizaeus-Merzbacher leukodystrophy. Sometimes genetic testing is required to determine whether parents are carriers of the defective gene.

Also, when talking with parents, the doctor will definitely collect the most detailed medical history in order to understand exactly when exactly the first signs of the disease appeared, how quickly the progression occurs, how much memory and intelligence suffers, and also how much physical activity has changed.

Treatment and prognosis

There is no cure for leukodystrophy. In some cases, a bone marrow transplant may help, but it will not be able to restore all the destroyed melanin and damaged nerve cells. And for the bone marrow to start working, it takes a lot of time, and people with this diagnosis do not have it.

The second method of treatment is symptomatic. In this case, the child can only be saved from seizures, but other symptoms will continue to progress.

The prognosis for Pelizaeus-Merzbacher leukodystrophy is always unfavorable. The total life expectancy is no more than three years, and at the very end the child remains completely blind, deaf, and unable to swallow or move.

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, movement disorders, damage to the visual and auditory nerves, hydrocephalus, and epileptic seizures. Leukodystrophy is diagnosed based on neurological status, medical history, genetic studies, MRI or CT scan of the brain, and biochemical tests. Treatment is symptomatic. If detected early and progressing slowly, cord blood or bone marrow transplantation is possible.

General information

Leukodystrophy got its name due to damage to the white matter of the brain (from the Greek leukos - white). There are about 60 types of leukodystrophy, determined by the type of gene abnormality and the age of manifestation of clinical manifestations. Along with certain 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 damage to myelin brings it closer to demyelinating diseases (multiple sclerosis, REM, etc.), and some forms can be classified as lipidoses.

The main forms of leukodystrophy include metachromatic, sudanophilic, globoid cell, Van Bogart-Bertrand degeneration, Alexander disease, and Hallervorden-Spatz variant. The most common are the first 3 types of leukodystrophy. 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 of leukodystrophy

At its core, each leukodystrophy has a genetic abnormality of a certain enzyme. The type of anomaly and the location 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 path of hereditary transmission, but some of its forms can be inherited in a sex-linked manner. In addition, cases of spontaneous mutations are not alone. A genetically determined enzyme defect leads to metabolic disorders (usually in lipid metabolism) with the deposition of a certain metabolite in the nervous structures and individual somatic organs, primarily in the liver and kidneys.

The consequence of the metabolic abnormality is the destruction of the myelin sheaths of nerve trunks and pathways, the death of neurons with their replacement by growing glial tissue. Morphologically, leukodystrophy is characterized by diffuse and symmetrically located zones of myelin death in the cerebral hemispheres, accumulation of myelin breakdown products, and increased glial proliferation. In certain nosological variants, leukodystrophy has a specific morphological picture - metachromatic or sudanophilic staining of myelin breakdown products, accumulation of globoid cells in areas of demyelination, etc.

Symptoms of leukodystrophy

In most cases, leukodystrophy debuts in early childhood. Newborns generally appear healthy. They develop normally for a certain period, and then gradually various neurological symptoms appear, characterized by steady progression. The rate of increase in symptoms is higher, the earlier leukodystrophy manifests itself. The leading manifestations are progressive mental retardation, blurred vision, hearing loss, episyndrome, and spastic paresis. The first symptoms of leukodystrophy may be ataxia, muscular-tonic disorders (hypo- or hypertonicity, muscle twitching), extrapyramidal manifestations, and behavioral changes. Then epileptic seizures and bulbar manifestations occur, hearing and vision decrease, and intellectual decline is noted with a gradual loss of previously acquired skills. Sensory disturbances are not typical. In the later stages of the disease, paralysis, severe mental retardation, severe swallowing disorder, amaurosis, and deafness are observed. In the terminal phase, decerebrate rigidity is usually noted.

Types of leukodystrophy

Metachromatic leukodystrophy Depending on the manifestation, it has 4 options. The congenital variant debuts in the first 1-3 months. life developmental delay and seizure 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 muscle hypotonia and weakness, ataxia, and mental retardation (MRD). Then spastic tetraplegia, aphasia, and pseudobulbar syndrome are formed. In rare cases, patients live beyond 10 years of age. The juvenile variant manifests itself at 4-6 years of age and lasts an average of 7 years. The adult variant 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. Pelizaeus-Merzbacher leukodystrophy can start in the 1st year of life or at 3-4 years. The first sign is large-scale nystagmus, later there is ZPR, cerebellar ataxia, hyperkinesis, paresis. The greatest progression occurs before the age of 10 years, then the disease takes a slow course with long-term remissions. Patients can live into adulthood. Adrenoleukodystrophy is a variant in which leukodystrophy is combined with adrenal insufficiency. It is characterized by a progressive course with a fatal outcome 6-8 years after the onset of the clinic.

Globoid cell leukodystrophy(Krabbe disease) - lipoidosis with accumulation of galactocerebroside in the foci of demyelination and the formation of large round 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, mental retardation, episyndrome develops, and opisthotonus is possible. Death occurs at one year of age. The late childhood variant is more rare and manifests as visual impairment.

Van Bogart-Bertrand spongy degeneration characterized by episyndrome, hypersomnia, severe hydrocephalus with an increase in the size of the head, causing amaurosis and atrophy of the optic nerves. Severe intracranial hypertension leads to dehiscence of the cranial sutures, which is recorded by skull radiography. Patients with this form of leukodystrophy die before the age of 3.

Alexander disease(leukodystrophy with fibrous formation) is caused by a mutation in the gene responsible for the synthesis of the 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 approximately half of the cases, manifests itself in the first 1-2 years of life, followed by spastic paresis, ataxia, and hydrocephalus. Children die after a few years. Juvenile Alexander leukodystrophy debuts between 4 and 10 years of age and occurs with predominantly brainstem symptoms. Life expectancy ranges from 10-30 years. The adult version is characterized by late manifestation and a relatively slow course over 10 years or more.

Hallervorden-Spatz leukodystrophy most often starts at 10 years of age. It manifests itself as dysfunction of the striopallidal system, then, against the background of hyperkinesis, tetraparesis progresses, hemeralopia and retinitis pigmentosa develop, a decrease in intelligence is observed, and epileptic seizures occur.

Diagnosis of leukodystrophy

A diagnostic search requires the involvement of a number of specialists: a neurologist, a pediatrician, a medical geneticist, and for diagnosing vision and hearing disorders - an otolaryngologist and an ophthalmologist. It is important to study the medical history (age and symptoms of onset, sequence of clinical development) and family history (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 examining the cerebrospinal fluid.

In order to diagnose the type of metabolic abnormality, a number of biochemical tests are performed to determine the level of enzymes and accumulated metabolites. Foci of demyelination are well visualized using MRI and can also be detected on brain CT. Typically, demyelination is visible on MRI of the brain even before the clinical manifestation of leukodystrophy. Thanks to the development of genetics, leukodystrophy has developed DNA diagnostics, and its individual forms (metachromatic, adrenoleukodystrophy, globoid cell) have the possibility of prenatal diagnosis.

Treatment of leukodystrophy

To date, leukodystrophy does not have effective treatments to 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 umbilical 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 has no effect on an already developed neurological deficit; it only makes it possible to stop 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 a similar pathology in the family) or with a slowly progressive variant of the course. In addition, it must be taken into account that transplantation is associated with the risk of a number of serious complications, such as rejection, graft-versus-host disease, and the development of infections.