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Signs of leukodystrophy. Leukodystrophy as a hereditary disease

Leukodystrophy- these are hereditary diseases of the nervous system, characterized by impaired myelin metabolism due to a genetically determined enzyme defect. The main type of inheritance is autosomal recessive, but it can also be sex-linked recessive. With a number of inflammatory diseases (Schilder’s periaxial encephalitis, etc.) they form the syndrome of so-called diffuse cerebral sclerosis. At the same time, some forms of leukodystrophy are classified as lipidoses (see). Finally, the dominance of myelin lesions in the morphological picture of leukodystrophy brings them closer to the group of demyelinating diseases.

The entire group of leukodystrophy is characterized by an onset in childhood, less often in adolescence, a progressive course with the presence in the clinical picture of mental degradation, decreased vision and spastic paresis as the leading symptoms; in the terminal stage, decerebrate rigidity syndrome usually develops.

Morphological examination reveals symmetrical, diffuse, poorly demarcated areas of myelin decay in the cerebral and cerebellar hemispheres. The breakdown products of myelin lipids accumulate in brain tissue and internal organs. Axons in areas of myelin death and ganglion cells contain products of impaired myelin metabolism. Features of the morphological picture make it possible to distinguish a number of separate nosological forms among leukodystrophy.

Pelizaeus-Merzbacher disease (early infantile form of leukodystrophy) characterized by the formation of islands of intact myelin in areas of severe demyelination (“leopard skin”). The disease begins in the first months of life and is characterized by horizontal nystagmus, head tremors, pyramidal, extrapyramidal and cerebellar symptoms. Mental disorders are moderate. The maximum development of all symptoms occurs in the first years of life, and then remains constant. Patients can live up to the third decade, dying from intercurrent diseases.

Greenfield metachromatic leukodystrophy (late infantile form of leukodystrophy). The breakdown of myelin is accompanied by a massive accumulation of metachromatically colored products due to disrupted metabolism of cerebrosides (sulfatides).

The development of infectious-toxic shock requires, first of all, intravenous administration of corticosteroid hormones, strophanthin, and fluid transfusion. In case of coma - resuscitation measures.

Sulfatides are found in nerve cells, the retina of the eye, the Schwann sheath of nerve fibers, and in the kidney tubules. It begins at the age of 1-3 years, when muscle hypotonia appears with decreased reflexes, valgus position of the feet, unstable gait, ataxic syndrome, nystagmus. Children stop talking. There is moderate protein cell dissociation in the cerebrospinal fluid. Then convulsions, atrophy of the optic nerves appear, muscle hypotension gives way to hypertension. Nerve conduction velocity studies and cutaneous nerve biopsies indicate that metachromatic leukodystrophy involves the peripheral nervous system. In the final phase of the disease, hyperthermia, bulbar disorders, tetraplegia, and decerebrate rigidity are noted. Death occurs at the age of 3-7 years from intercurrent diseases. The most important diagnostic criterion is the decrease or absence of sulfatase activity in the urine (staining urine with blue toluidine gives a golden brown color).

Spongy degeneration of white matter. In the white matter of the brain, demyelination is observed in the absence or sharp decrease of phospholipids, cerebrosides, and sphingomyelins. This form of leukodystrophy occurs in the prenatal period. At birth, adynamia, anorexia, and convulsions are observed. Characterized by optic nerve atrophy, hydrocephalus, hypotonia of the neck muscles, increased tone in the limbs, dementia, and hearing loss. In the terminal phase, decerebrate rigidity and tabloid symptoms are noted. The duration of the disease is up to 2 years.

Krabbe leukodystrophy (globoid type). Characterized by diffuse demyelination and sclerosis. The deep sections of the cortex, U-shaped fibers are in a pongy state. Large globoid naked nuclei appear in the cortex and white matter, resembling the second type of Alzheimer's glia. The disease develops in infancy (from the 4th-5th month), affects almost exclusively boys and is manifested by increased excitability, tearfulness, and convulsions. The neurological status includes muscle hypertension, atrophy of the optic nerves, hearing loss, and bulbar symptoms. Increased protein content in the cerebrospinal fluid. A study of nerve conduction velocity shows that in the Krabbe form, the peripheral nervous system is also involved in the process. The disease progresses rapidly. By the end of the first year, children die from cachexia and aspiration pneumonia.

Leukodystrophy is a group of diseases affecting the cerebellum, white matter, and cerebral hemispheres with preservation of cortical structures.

Neurodegeneration of brain tissue is accompanied by the accumulation of metabolic compounds inside the spinal cord and brain that destroy myelin. Damage to the membrane of neurons leads to irreversible diseases, accompanied by movement disorders, impaired psychomotor function, damage to hearing and vision, epilepsy, seizures, neurological disorders, and epileptic seizures.

Leukostrophy MRI

Classification according to ICD 10

The International Classification of Diseases, 10th revision, classifies leukodystrophies as sphingolipidoses - diseases accompanied by excessive deposition of pathological fats (lipids). Nosology code – “E 75”.

Disorders of ganglioside metabolism are coded “GM 2”:

Juvenile form;
Adult leukodystrophy;
Sandhoff's disease;
Tay-Sachs syndrome.

Other gangliosidoses (“E 75.1”):

Mucolipidosis IV;
Ganliosidoses GM3, GM1.

Other sphingolipidoses (“E 75.2”):

Sulfatase deficiency;
Metachromatic leukodystrophy;
Niemann-Pick disease;
Krabbe syndrome;
Faber syndrome;
Fabry-Anderson disease.

Unspecified sphingolipidosis - “E 75.3”. The category includes all forms of etiological factors that could not be established. Neuronal lipofuscinosis – “E 75.4”. Excessive formation of atypical fatty parts leads to disruption of nerve signal transmission. Unclassified conditions (“E 75.5”):

Wolman's disease;
Van Bogaert-Scherer cholesterosis.

An imbalance of metabolic connections within the brain provides an atypical clinical picture.

Unspecified lipid storage disease - “E 75.6”.

The international classification ICD 10 has been adopted throughout the world to unify pepper nosological forms. Standardization of treatment tactics.

Types of leukodystrophy

The list of biochemical changes leading to leukodystrophy of the cerebellum, stem structures of the brain and spinal cord has not been identified. Scientists consider the pathology to be a variant of lysosome damage. Scientific studies have not identified the enzymes responsible for the clinical manifestations of the nosology.

Lysosomal types of leukodystrophies:

Hallerwoden-Spatz;
Krabbe;
Pelicius-Merzbacher.

Most forms of leukodystrophy occur at an early age, but pathology is also found in adults. With all varieties, neurological and pyramidal disorders, extrapyramidal rigidity, and demyelination of nerve fibers occur. The list of laboratory changes in leukodystrophies is an increase in protein, increased pleocytosis.

Metachromatic leukodystrophy

Appears in adults after 21 years of age. The nosology occurs predominantly in men. Inherited by an autosomal recessive mechanism. Metachromatic leukodystrophy of the brain develops gradually. More than twenty years may pass before pronounced clinical symptoms occur. Features of manifestations of psychosis:

Forgetfulness;
Declining academic opportunities;
Unreasonable actions;
Oddities of behavior;
Excessive suspicion.

Similar clinical symptoms occur in schizophrenia. The addition of neurological symptoms of cerebellar ataxia, pyramidal disorders, and awkwardness of the patient’s movements provokes mental degradation of the individual. Helplessness, lack of contact with other people, bedridden conditions ensure rapid clinical progression due to a number of metabolic changes:

Decrease in the activity of leukocyte enzymes (arylsulfatase A);
Increased excretion of sulfatides in urine;
An imbalance in the conduction of nerve impulses along damaged fibers;
Redistribution of pigment substance.

Metachromatic leukodystrophy in children (Greenfield) is accompanied by convulsions, ataxia, and nystagmus. Signs of end-stage leukodystrophy in children:

Decerebrate rigidity;
Bulbar disorders;
Tetraplegia.

The cause of the metachromic appearance is excessive accumulation of lipids. The pathogenetic mechanism for the formation of pathology is the deficiency of the enzyme cerebroside sulfatase. The nosology develops later than the Krabbe or Tay-Sachs forms. At about 5 years of age, a child’s gait becomes impaired due to increased muscle tone. Reflex activity and tendon innervation are gradually lost.

Clinical symptoms of leukodystrophy

Most types occur in childhood. Immediately after birth, no pathological changes are observed in the child. After several months or years, neurological or mental symptoms are observed, which gradually worsen.

Signs of the early stages of leukodystrophy:

Pathology of vision;
Oligophrenia;
Muscle spasm;
Jerking of limbs;
Hypertonicity;
Tonic convulsions;
Signs of extrapyramidal pathology (shaky gait);
Decline in intelligence.

Multiple sensory disorders, swallowing pathology, and deafness are diagnosed in preschool children.

Symptoms of brain leukodystrophy in infants of the second year of life:

Slow psychomotor development (oligophrenia);
Gait pathology.

Clinical manifestations starting from the third year of life:

Hearing and vision loss;
Hyperthermic syndrome;
Tetraplegia;
Hyperthermia (increased temperature).

Severe symptoms appear 10 years after the onset of primary brain changes.

Primary brain changes are accompanied by spasticity, myoclonus, developmental delay, and muscle tremors. In adults, the progressive form is accompanied by a rapid loss of personality traits, speech disorders, and pathological thinking. Gradual progression is accompanied by various changes in the mucous membrane with the development of spasticity, muscle cramps, and hypertonicity.

A variant of metachromatic leukodystrophy is accompanied by psychosis, dementia, emotional instability, speech disorder, and thinking disorder.

Tomograms of metachromatic leukodystrophy

The first signs of leukodystrophy in a child

With most leukodystrophies, the first symptoms appear in the fourth year of life. Nosology can be diagnosed based on the following characteristics:

Increased muscle tone;
Severe nervous excitability;
Psychomotor development does not correspond to age;
The child's fists are clenched.

Late manifestations:

Atrophy of the optic nerves up to blindness;
Strengthening tendon reflexes;
Muscular spastic tetraparesis;
Myoclonic spasms;
General motor reaction.

Peripheral neuropathy occurs only in selected children. Deaths in children can be observed between the ages of seven months and three years.

Alexander fibrous leukodystrophy

The pathogenetic mechanism for the development of Alexander disease is a defect in the gene responsible for the production of the GFAP protein. The defect causes excess protein accumulation within the glial tissue of the brain. The unique structure of the protein makes it possible to diagnose nosology by detecting special Rosenthal fibers.

The neonatal form is fatal 1 year after onset.

The infantile form is less dangerous, in which developmental defects, hydrocephalus, ataxia, paresis, and spastic muscle contraction occur. In most cases, death occurs within a couple of years.

Juvenile Alexander dystrophy appears in schoolchildren aged 4-10 years. Stem symptoms last a long time. Symptoms progress over 10-20 years. Manifestation in adulthood has a slow course. The total duration of the disease is over 10 years.

Hallervorden-Spatz leukodystrophy

The disease begins in children aged 10 years.

Clinical symptoms of the pathology:

Epileptic seizures;
Tetraparesis;
Dysfunction of the striopallidal sphere;
Retinitis pigmentosa;
Hymeralopia.

A late form that occurs in children during school years. The duration of the nosology until the full appearance of clinical manifestations is about ten years.

Main features:

Epileptic seizures;
Convulsive twitching;
Muscular rigidity;
Hyperkinetic states.

The pathology is transmitted in an autosomal recessive manner. Occurs in females and males. Accompanied by severe dementia and complete immobility of patients. Pathomorphological changes:

Excessive accumulation of iron inside tissues;
Infiltrative accumulations in the glial layer;
Degenerative axonal lesions;
Increased pigmentation of the thalamus, cerebellum, cerebral cortex, subthalamic structures;
Disorder of pigment-lipid metabolism;
Imbalance of catecholamines.

Pathological examination reveals morphological signs.

Inherited by an autosomal recessive mechanism.

Niemann-Pick disease

Sphingomyelin disorders types A and B occur due to deficiency of the enzyme sphingomyelinase. The compound is necessary for the destruction of sphingomyelin.

Symptoms of Niemann-Pick disease:

Enlargement of the spleen, pancreas, liver;
Redness of the intraocular retina;
Neurological disorders;
Obesity of internal organs.

Sphingomyelin fatty lipidosis leads to gradual damage to parenchymal structures (kidneys, liver, spleen).

Gaucher disease

The nosology is characterized by lipidosis, accompanied by deficiency of the enzyme glucosylceramidase. Early stages are accompanied by hepatosplenomegaly. Pain and other symptoms do not increase until the size of the organs becomes enormous.

Progressive neurological disorders cause early death.

A type of pathology in adults is due to an autosomal recessive transmission mechanism. Transmission from generation to generation has not been proven, but practice shows the likelihood of information.

Gaucher disease belongs to the category of adult diseases, but the first changes appear in children at the age of 10 years. At an earlier or later age, symptoms occur much less frequently. Hypersplenia, pathological fractures, aseptic necrosis of the femoral head, pseudoosteomyelitis are common secondary conditions against the background of primary Gaucher leukodystrophy.

For all types of nosology, special “loaded cells” are identified in bone marrow puncture.

Fabry disease

The pathology occurs due to a defect in the enzyme alpha-galactosidase. A substance called trihexoside accumulates excessively in tissues. The nosology is inherited on the X chromosome, therefore it is often found in men.

Pathology usually develops in old age. The clinical manifestation of the nosology is painful neuropathy. Magnetic resonance imaging of the brain does not reveal pathological changes until progressive kidney damage occurs. The average age of patients is 20-40 years.

Arterial thrombosis during the disease occurs in childhood. Death occurs due to severe renal failure.

Wolman's disease

Develops in young children. Initially, hepatosplenomegaly is observed, then secondary manifestations are added:

Gag reflex;
Anemic syndrome;
Adrenal calcification;
Increased cholesterol levels;
Liver fibrosis.

Wolman's disease is transmitted in an autosomal recessive manner.

Krabbe-Benecke disease

Hereditary disease - Krabbe leukodystrophy is transmitted in an autosomal recessive manner. Nosology is formed in childhood and is characterized by a number of clinical signs:

Decreased hearing and vision up to complete blindness;
Dementia;
Spastic paralysis;
Muscle cramps;
Decerebrate rigidity.

Morphological manifestations of the nosology are accompanied by demyelination of the nerve sheaths and impaired production of cerebrolysides. Krabbe leukodystrophy is genetically determined. Clinical symptoms:

Blindness;
Hearing loss;
Muscle spasms;
Convulsive seizures.

The carriage of the abnormal gene cannot be detected. There is no effective treatment.

Synonyms: diffuse infantile sclerosis, Krabbe-Benecke disease, globoid cell leukodystrophy.

Pelizaeus-Merzbacher Sudanophilic Leukodystrophy

The nosology occurs mainly in boys, since the pathological gene is localized on the X chromosome. Scientists have not studied the pathogenetic mechanisms of pathology. Diffuse demyelination causes clinical manifestations in the first year of life. Damage occurs to the stem structures of the brain, spinal cord, and cerebellum. Damage to the myelin sheath leads to the destruction of central and peripheral nerve fibers. In the first year of life, a person develops specific signs:

Intraocular nystagmus;
Nodding twitching of the head;
Muscular hypo- and hyperclonia;
Parkinsonian syndrome;
Degeneration of optic nerve fibers;
Decreased intellectual function.

Diffuse Pelizaeus-Merzbacher demyelination is inherited through an autosomal recessive mechanism. Changes in gray matter are accompanied by damage to the axial cylinders.

Diagnosis of pathology at an early stage is based on primary signs:

Nystagmus;
Loss of coordination;
Trembling of the head.

Later, optic nerve atrophy, decreased intelligence, muscle hypertonicity, and speech impairment occur. The severe stage of the pathology is accompanied by increasing dementia, parkinsonian syndrome, and hyperkinesis.

Periventricular leukomalacia

The disease is accompanied by damage to the white matter of the brain. It is characterized by the appearance of necrotic foci localized in the periventricular segments. Accompanied by the appearance of foci of necrosis in the hemispheres and periventricular areas. The cause of morphological disorders is hypoxic-ischemic encephalopathy. Clinical manifestations of nosology:

Holding your breath immediately after birth;
Reduced blood pressure;
Damage to white matter.

Ischemic changes contribute to the emergence of nosology in children. Hypoxia, hypocapnia, and acidosis occur in newborns due to intrauterine infection and prolonged labor. Lack of oxygen leads to the formation of foci of necrosis localized between the ventriculopetal and ventriclophagal arterial branches.

Canavan-van-Bogart-Bertrand disease

Progressive damage to nerve cells in the brain leads to neurodegenerative diseases. The disease refers to a series of genetic changes that lead to the destruction of the membrane of neurons. Demyelination is triggered by a gene located on chromosome seventeen.

The complex of morphological changes in Canavan disease is provoked by the accumulation of defective ASPA protein due to a deficiency of the enzyme aspartoacylase.

Symptoms of leukodystrophy:

Mental retardation;
Loss of motor activity;
Defects in muscle tone;
Visual blindness;
Difficulty holding the head in a physiological position.

Diagnosis of leukodystrophy

The initial signs of the disease are identified by clinical specialists - pediatricians, therapists, neurologists, ophthalmologists, otolaryngologists.

Genetic counseling identifies abnormal genes that cause brain sphingolipidoses.

Clinical methods of echo-encephalography and neurosonography reveal an increase in intracranial pressure. Cerebrospinal fluid examination is performed to detect increased protein concentrations.

Metabolic disorders are detected by biochemical blood tests.

An MRI of the child’s brain is done to identify areas of demyelination in the brain. The study makes it possible to verify pathological changes at an early stage.

The most accurate diagnostic method is innovative DNA diagnostics of globoid cell, metachromatic leukodystrophy.

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 version 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 visual 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.

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Symptoms and course of the disease

At birth, children with leukodystrophy usually appear healthy and take some time to develop according to their age. However, then symptoms of damage to the central nervous system gradually appear. These symptoms vary somewhat depending on the specific disease and its form, but still have common features.

Characteristic are:

increasing pyramidal, cerebellar, extrapyramidal disorders, boulevard and pseudobulbar symptoms;
decreased vision and hearing;
epileptiform seizures;
progressive dementia;
changes in behavior occur;
memory and intelligence gradually decline;
Sensory disturbances are rare;
the disease most often begins in preschool age;
the earliest symptoms include motor disorders in the form of central paralysis and paresis, as well as hyperkinesis;
in children, coordination of movements worsens, problems with balance are noted, it becomes difficult to walk and run;
possible muscle weakness, abnormally increased or decreased muscle tone, muscle twitching;
later, convulsive attacks and atrophy of the optic nerves may occur;
the child gradually “rolls back” in his development, losing previously acquired motor and intellectual skills;
in the later stages of the disease, blindness, deafness, paralysis, and the inability to swallow food normally occur.

As a rule, the earlier in age signs of the disease appear, the faster it progresses. The entire group of leukodystrophy is characterized by an onset in childhood, less often in adolescence, a progressive course with the presence in the clinical picture of mental degradation, decreased vision and spastic paresis as the leading symptoms; in the terminal stage, decerebrate rigidity syndrome usually develops.

Morphological examination reveals symmetrical, diffuse, poorly demarcated areas of myelin decay in the cerebral and cerebellar hemispheres. The breakdown products of myelin lipids accumulate in brain tissue and internal organs. Axons in areas of myelin death and ganglion cells contain products of impaired myelin metabolism.
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Leukodystrophies are a group of rare diseases that vary in nature and frequency of occurrence. Here are some of them:

Pelizaeus-Merzbacher disease (an early infantile form of leukodystrophy) is characterized by the formation of islands of intact myelin in areas of severe demyelination (“leopard skin”). The disease begins in the first months of life and is characterized by horizontal nystagmus, head tremors, pyramidal, extrapyramidal and cerebellar symptoms. Mental disorders are moderate. The maximum development of all symptoms occurs in the first years of life, and then remains constant. Patients can live up to the third decade, dying from intercurrent diseases.
Greenfield metachromatic leukodystrophy (late infantile form of leukodystrophy). The breakdown of myelin is accompanied by a massive accumulation of metachromatically colored products due to disrupted metabolism of cerebrosides (sulfatides). The development of infectious-toxic shock requires, first of all, intravenous administration of corticosteroid hormones, strophanthin, and fluid transfusion. In case of coma - resuscitation measures. Sulfatides are found in nerve cells, the retina of the eye, the Schwann sheath of nerve fibers, and in the kidney tubules. It begins at the age of 1-3 years, when muscle hypotonia appears with decreased reflexes, valgus position of the feet, unstable gait, ataxic syndrome, nystagmus. Children stop talking. There is moderate protein cell dissociation in the cerebrospinal fluid. Then convulsions, atrophy of the optic nerves appear, muscle hypotension gives way to hypertension. Nerve conduction velocity studies and cutaneous nerve biopsies indicate that metachromatic leukodystrophy involves the peripheral nervous system. In the final phase of the disease, hyperthermia, bulbar disorders, tetraplegia, and decerebrate rigidity are noted. Death occurs at the age of 3-7 years from intercurrent diseases. The most important diagnostic criterion is the decrease or absence of sulfatase activity in the urine (staining urine with blue toluidine gives a golden brown color).
Spongy degeneration of white matter. In the white matter of the brain, demyelination is observed in the absence or sharp decrease of phospholipids, cerebrosides, and sphingomyelins. This form of leukodystrophy occurs in the prenatal period. At birth, adynamia, anorexia, and convulsions are observed. Characterized by optic nerve atrophy, hydrocephalus, hypotonia of the neck muscles, increased tone in the limbs, dementia, and hearing loss. In the terminal phase, decerebrate rigidity and tabloid symptoms are noted. The duration of the disease is up to 2 years.
Krabbe leukodystrophy (globoid type). Characterized by diffuse demyelination and sclerosis. The deep sections of the cortex, U-shaped fibers are in a pongy state. Large globoid naked nuclei appear in the cortex and white matter, resembling the second type of Alzheimer's glia. The disease develops in infancy (from the 4th-5th month), affects almost exclusively boys and is manifested by increased excitability, tearfulness, and convulsions. The neurological status includes muscle hypertension, atrophy of the optic nerves, hearing loss, and bulbar symptoms. Increased protein content in the cerebrospinal fluid. A study of nerve conduction velocity shows that in the Krabbe form, the peripheral nervous system is also involved in the process. The disease progresses rapidly. By the end of the first year, children die from cachexia and aspiration pneumonia.
Adrenoleukodystrophy: manifests itself in the form of progressive paralysis of the legs and loss of their sensitivity, insufficiency of the functioning of the adrenal glands and small compared to normal sizes of the gonads; typical childhood form with onset of symptoms between 4 and 10 years of age.
Arylsulfatase A deficiency, or fat storage disease: at the age of 2-5 years, the gait of a sick child is impaired; the disease gradually progresses, and by the age of 10 the child is manifested by ataxia (impaired coordination of movements), increased muscle tone, destruction of central and peripheral nerves and loss of all contacts with the outside world; The patient's life expectancy depends on careful care and feeding through a nasal tube (a flexible tube passed through the nose into the stomach) or through a gastrostomy (an artificially created opening in the anterior abdominal wall and stomach to allow the patient to be fed through this anastomosis).

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Treatment of the disease

Treatment is prescribed based on biochemical data, clinical symptoms, CT and MRI data of the brain.

Carried out by influencing lipid metabolism:

introduction of missing factors - blood transfusion, plasma, administration of tissue extracts, enzyme preparations, vitamins;
introduction of drugs that block synthesis processes;
antagonists of folic acid and cytostatic agents - aminopterin, methotrexate, alkylating agents - ThioTEF, etc.;
the use of drugs that affect metabolic processes (thyroid hormones, ACTH), nicotinic acid, unsaturated fatty acids;
Symptomatic treatment is mostly anticonvulsant.

In fact, the only effective treatment for this disease is allogeneic (donor cells are introduced) transplantation of bone marrow (or umbilical cord blood) from a healthy donor - the level of the missing protein is normalized. It leads to an increase in life expectancy and quality of life. Thus, there are known cases of using transplantations for the treatment of adrenoleukodystrophy, metachromatic leukodystrophy and globoid cell leukodystrophy.

At the same time, the use of transplantations for leukodystrophies is associated with serious limitations. It is very important to perform transplantation as early as possible, before significant neurological impairment develops. Indeed, transplantation does not allow to “correct” existing lesions of the central nervous system, but only stops or slows down their further progression. But it is also necessary to take into account the rate of development of neurological lesions.

Thus, with the most rapidly developing forms of leukodystrophies, it is often impossible to avoid death or severe disability of the patient even after transplantation. This is due to the fact that after transplantation some more time passes (for example, in some leukodystrophies we can talk about 12 or even 24 months) until the work of the donor cells leads to normal functioning of myelin. And all this time the development of the disease will continue. Therefore, in forms with a very early onset of the disease, hopes are associated mainly with those transplantations that were performed before the appearance of clinical symptoms (for example, if the eldest child in the family had already been diagnosed with leukodystrophy and therefore the younger child was diagnosed early). With a slower progression of the disease, the chances of success increase.

As with any allogeneic bone marrow transplant, serious risk factors for the patient's life include graft-versus-host disease, the possibility of infectious and other complications, and graft rejection.

If bone marrow transplantation is not possible or recommended, then palliative therapy aimed at alleviating the symptoms of the disease remains. New treatment approaches are constantly being developed, but for now they remain experimental.

There is an opinion that it is possible to slightly slow down the development of adrenoleukodystrophy (including while waiting for a transplant) with the help of a special diet. Sometimes Lorenzo's oil is also used, a remedy developed by the parents of a boy with adrenoleukodystrophy. However, it is still unclear how effective this remedy is. Loading form..." data-toggle="modal" data-form-id="42" data-slogan-idbgd="7309" data-slogan-id-popup="10615" data-slogan-on-click= "Tell me the prices AB_Slogan2 ID_GDB_7309 http://prntscr.com/merhat" class="center-block btn btn-lg btn-primary gf-button-form" id="gf_button_get_form_691004">Tell me the prices

Diagnosis of the disease

Analysis of the medical history and complaints (at what age did the symptoms of the disease first appear, how quickly did they grow and change).
Analysis of family history - whether this disease has previously occurred in close relatives.
General examination - evaluate muscle tone, tendon reflexes (muscle contraction in response to tendon irritation) - their severity and symmetry, evaluate gait and coordination of movements.
Observation of clinical symptoms (whether they are present and how they change over time): hearing impairment, vision impairment, trembling of the limbs, nystagmus (involuntary rapid rhythmic movements of the eyeballs), mental retardation, etc.
Analysis of cerebrospinal fluid: using a thick needle, a puncture is made in the lumbar region, entering the spinal canal (the puncture site is chosen in such a way that the spinal cord is not injured), cerebrospinal fluid is drawn through the inserted needle for further analysis - its color is assessed and transparency (normally, cerebrospinal fluid is clear and colorless), pressure, the presence and number of cells (cytosis), the amount of protein (increased when brain cells are destroyed), glucose and chlorine salts.
Biochemical tests - measuring the levels of enzymes whose synthesis or transport is impaired in a particular disease, or detecting those substances that accumulate in this disease.
CT (computed tomography) and MRI (magnetic resonance imaging) of the brain. Molecular genetic examination.
For metachromatic, globoid cell and adrenoleukodystrophy, there are methods of prenatal (before birth) diagnosis.
It is also possible to consult a pediatric neurologist or medical geneticist.

Leukodystrophy (progressive sclerosis of the brain) is a group of hereditary diseases of the nervous system. In patients with leukodystrophy, myelin deficiency leads to defenselessness and damage to the white matter of the brain, resulting in dementia. Symptoms appear gradually, and leukodystrophy itself can begin to develop in infancy or from 3 years, less often in adolescence.

Leukodystrophies are genetically determined diseases, and the probability of a child becoming ill is 25% if both parents are carriers of the disease.

Leukodystrophies belong to the group; however, there is both a diagnostic and therapeutic arsenal for this disease.

Symptoms of leukodystrophy:

extreme irritability
spasms in various parts of the body,
weight loss,
impaired control and coordination of movements,
muscle paralysis or paresis,
decreased vision,
gradual slowdown in general development, memory and intelligence,
mental disorder.

Symptoms vary depending on the specific type of leukodystrophy and are sometimes difficult to recognize in the early stages of the disease: adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy, or Krabbe disease. Diagnosis of leukodystrophy in Germany is aimed at determining the type of leukodystrophy and selecting appropriate therapy in each individual case.

Diagnosis of leukodystrophy in Germany

Analysis of family history of diseases in three generations.
Clinical examination.
MRI of the brain (reveals white matter lesions characteristic of leukodystrophies).
Computed tomography of the brain.
Electromyography (with myelin deficiency, the impulse conduction time increases).
Blood and urine analysis.
Cerebrospinal fluid examination.
Biochemical tests, measurement of enzyme levels (to clarify the type of leukodystrophy).
Molecular genetic examination.
Prenatal (antenatal) diagnostics. Possible for metachromatic, globoid cell and adrenoleukodystrophy.

Treatment of leukodystrophy in Germany

The main treatment method for leukodystrophies in Germany is currently bone marrow (or umbilical cord blood) transplantation in the early stages of the disease. In a favorable case, the operation can lead to normalization of the level of the missing protein, and in the future – to an improvement in the quality of life and an increase in its duration. Bone marrow transplantation stops the progression of the disease and allows one to preserve motor and intellectual functions.

If bone marrow transplantation is not possible or recommended, then therapy aimed at alleviating the symptoms of the disease remains. Treatment for most patients with leukodystrophy is supportive and includes German medications, a special diet, physical fitness activities, communication programs, and neurological rehabilitation.

The effectiveness of treatment of leukodystrophy in German clinics is due to the fact that over the past decades, special attention has been paid to the study of and. Doctors are aimed at providing effective assistance to everyone who turns to them. You will receive high-quality diagnostics, professional advice and support from specialists.