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Metabolic diseases of the central nervous system



Many metabolic diseases are inherited in an autosomal recessive manner, and some of them in an X-linked, recessive manner (see chapter 8). Hereditary metabolic defects disrupt the metabolism of many substances: lipids, carbohydrates, glycosaminoglycans (mucopolysaccharides), amino acids and trace elements. In some metabolic diseases, pathological changes begin with the central nervous system, in others, other organs and systems are involved in the process, although such diseases are accompanied by a secondarily reduced neuronal metabolism. Most of the described diseases occur in children, often during the first days of life.

The complexity of metabolic processes in the central nervous system determines its dependence on the functional integrity of other body systems. Therefore, it is not surprising that secondary metabolic effects on the central nervous system often serve as manifestations of a systemic disease. In many cases, clinical manifestations are reversible and are accompanied by minimal morphological changes. However, with severe and prolonged symptoms, structural disturbances are also significant.

Primary (hereditary) metabolic diseases. They arise due to the deficiency of certain lysosomal enzymes (see chapter 8), which play an important role in the breakdown of numerous normal metabolites or cellular products. As a result, undigested substrates accumulate in the enlarged lysosomes of some cells, and the types of affected cells are closely related to the types of enzyme deficiency. This is how lysosomal storage diseases develop. In some of these diseases, neurons are affected, which increase in size and acquire a balloonized appearance. Accumulated material can be detected using histochemical techniques. Electron microscopy shows enlarged lysosomes filled with an undigested substrate. Diagnosis is based on an assessment of the content of lysosomal enzymes in the blood, urine, cultured white blood cells, or fibroblasts. A brain biopsy is rarely used. Diseases of lysosomal accumulation of the brain and spinal cord can be divided into two groups: accumulation disorders affecting neurons (neuronal accumulation diseases), and those changes that affect white matter (leukodystrophy). Such a separation is convenient, but not universal, since in some diseases neurons and the white matter of the brain can be affected simultaneously.

Neural accumulation diseases. These include sphingolipidoses and mucopolysaccharidoses. The most important group of hereditary metabolic diseases affecting the central nervous system are sphingolipidoses. Sphingolipids include gangliosides, cerebrosides, sulfatides and sphingomyelins. Each of these substances is an important component of normal cells. One of the most common accumulation diseases affecting neurons is Tay-Sachs syndrome, a classic childhood type of amavrotic family idiocy (a progressive decline in intelligence and vision).

Leukodystrophy. They constitute a complex group of rather rare diseases, which are characterized by diffuse symmetric demyelination and gliosis of the white matter of the cerebral hemispheres, as well as the cerebellum, brain stem and spinal cord. Clinically, these diseases are manifested by various combinations of mental degradation, motor failure, and peripheral neuropathy. Leukodystrophy is often referred to as the so-called dysmyelinating disease, since myelin, before undergoing degeneration, becomes biochemically abnormal. At the same time, in primary demyelinating diseases, demyelination undergoes normal myelin in composition.

Krabbe's disease (KHKrabbe; globoid cell leukodystrophy, diffuse infantile sclerosis). The disease is inherited in an autosomal recessive manner, occurs when p-galactosidase galactocerebroside is insufficient, an enzyme necessary for the conversion of galactocerebroside to ceramide and galactose. The lack of galactocerebrosidase does not cause the accumulation of galactocerebroside either in neurons or in white matter. Instead, an alternative way is used: fatty acid is removed from the molecules of galactocerebrosides and psychosine (galactosylsphingosine) is formed - a cytotoxic substance that damages oligodendrocytes.

Crabbe disease progresses rapidly. Sick children rarely live up to 2 years. The first symptoms appear at the age of 3-6 months: this is stiffness, weakness and gradually increasing difficulties with feeding. Since peripheral nerves are involved in the process, morphological examination of the biopsy specimen may facilitate clinical diagnosis. In addition to the nervous system, other tissues and organs are not affected. Especially valuable is the biochemical confirmation of enzyme deficiency. With a pathomorphological study, there is a gradual loss of myelin and oligodendrocytes in the central nervous system, as well as similar changes in the peripheral nerves. Neurons and axons remain relatively intact. Accumulations of macrophages around blood vessels are considered characteristic signs for Crabbe disease. Many of these macrophages take the form of multinucleated cells, called globoid cells. These macrophages contain the above accumulation material, which, under an electron microscope, looks like linear cytoplasmic inclusions.

Metachromatic leukodystrophy. The disease is inherited in an autosomal recessive manner, it is based on aryl sulfatase A deficiency. This enzyme, contained in many tissues, cleaves the sulfuric acid salt from sulfate-containing lipids (sulfatides) - the first phase of their splitting. Aryl sulfatase A deficiency is accompanied by an accumulation of sulfatides, especially cerebrazide sulfate. How the latter leads to the breakdown of myelin is not clear. Currently known clinical subtypes of the disease include: hereditary form, late infantile form (the most common), juvenile form and adult form. The gene encoding arylsulfatase A and located on the long arm of chromosome 22 near the ql3 band has been identified. The method of treatment is unknown, but bone marrow transplantation gives good results.

Under the microscope, it is seen that the destruction of myelin in the white matter of the brain is accompanied by gliosis. Macrophages with vacuolated cytoplasm are scattered throughout the white matter. Vacuoles associated with plasmolemma contain complex crystalloid structures of sulfatides. The latter, when stained with histological sections (for example, toluidine blue), give metachromasia (dye color change) from blue to light tan. Similar changes are found in the peripheral nerves. The detection of metachromatic substances in a urinary centrifuge is also a reliable diagnostic marker.

Peliceus-Merzbacher disease (F. Pelizaeus, L. Merzbacher). It is an X-linked leukodystrophy. Of the constant clinical signs of the disease, the pendulum (rocking) nystagmus (involuntary rhythmic biphasic eye movements) and symptoms of widespread damage to the white matter of the brain should be mentioned. It is shown that this disease is the result of a mutation of the gene encoding the proteolipid protein (PLP), the main myelin protein in the central nervous system [according to MacSween RNM, Whaley K., 1994]. Despite the almost complete loss of myelin in the cerebral hemispheres, a pattern of tigroid changes in myelin-stained tissue is observed in separate and fairly numerous areas.

Canavan Disease (M. Canavan). The disease is inherited in an autosomal recessive manner, manifested by spongy (spongy) degeneration of white matter using Alzheimer's cells (type II) (see the beginning of the chapter). In the affected members of one family, aspartoacylase deficiency is noted, which is regarded as the pathogenetic basis of the disease. Due to this deficiency, metabolic changes in peroxisomes lead to leukodystrophy.

Mitochondrial encephalomyopathy.
JIu disease (ADLeigh; hereditary encephalomyelopathy). The disease is inherited in an autosomal recessive manner, characterized by a delay in psychomotor development, difficulty in feeding, epileptic seizures, muscle weakness and hypotension, paralysis of various cranial nerves, except for the oculomotor nerve. Lee's disease progresses in children up to the 3rd year of life and ends in death most often from paralysis of the respiratory center. One of the leading laboratory diagnostic signs is lactic acidosis (lactacidemia, i.e. the accumulation of lactic acid in the blood). In addition, various biochemical abnormalities were found in sick children, each of which indicates a dysfunction of the mitochondria in the conversion of pyruvate to ATP. A morphological study in the brain reveals bilateral foci of tissue destruction, as well as proliferation in the area of ​​these foci of small blood vessels. As a rule, such changes are distinguished by the symmetry of localization and the involvement of the periventricular gray matter in the midbrain, the cap of the brain bridge (Varolian bridge) and the periventricular zones of the thalamus and hypothalamus.

Other mitochondrial encephalomyopathies. Myoclonic epilepsy (myoclonus epilepsy) with torn (or coarse) red fibers (MERRF) is associated with a mutation of the mtDNA gene for mitochondrial-specific transport RNA (tRNA). It is believed that the disease is the result of a change in the function of several oxidative complexes. A similar type of mutation of the tRNA gene was found in combination pathologies - mitochondrial encephalomyopathy, lactic acidosis and seizures similar to brain strokes (MELAS). Possible causes of complex lesions due to changes in the vascular bed are associated with the pathology of mitochondria in the cells of brain vessels. Another example of a disease already associated with changes in mtDNA and point mutation of a gene encoding a single enzyme is hereditary degenerative neuropathy of the optic nerve Leber (Th. Leber).

Other congenital metabolic defects affecting the central nervous system. We mention only three groups of such defects. Hypothyroidism of newborns, phenylketonuria (a hereditary metabolic disorder of phenylalanine, manifested in physical and mental maldevelopment) and galactosemia (a hereditary metabolic disorder of carbohydrate) are the first and most important group of congenital diseases. In recognizing these diseases in children, it is sometimes possible to prevent or “mitigate” brain damage using replacement therapy or by eliminating the appropriate precursor substances from foods. Hepatolenticular degeneration [Wilson’s disease (SAKWilson), hepatocerebral dystrophy, Wilson-Konovalov’s disease (N.V. Konovalov)] is inherited in an autosomal recessive manner, manifested in a violation of copper metabolism. Mostly the liver and striatum of the brain are affected. Along with the liver, in which cirrhosis develops, copper accumulates in putamen and the caudate nucleus of the brain. These formations are first moistened, then wrinkled and turn into cystic cavities. Of the clinical symptoms, muscle rigidity and spasticity (increased tone), tremor (trembling), hyperkinesis, and progressive dementia can be distinguished. The central nervous system, as a rule, is involved in the pathological process even in the presence of cirrhosis.

Secondary metabolic diseases. They can develop with liver failure and diabetes mellitus (see chapter 17), uremia and renal dialysis (see chapter 18), transplantation, hyper- and hypothyroidism (see chapter 23), acidosis and alkalosis, hypoxia, poisoning with oxide and dioxide carbon.

Hepatic encephalopathy. The disease occurs with severe liver failure. Vast zones of necrosis can appear in the liver, which is usually accompanied by a rapidly onset coma. However, with cirrhosis of the liver [in particular, accompanied by portal hypertension (see chapter 17)], a chronic form of hepatic encephalopathy is noted. Even with an acute form of complication in the central nervous system, there may be no clear histological changes. But in the chronic form, in some patients, clusters of astrocytes are revealed, randomly dispersed in the gray matter of the brain. It is believed that such clusters appear in response to the effects of neurotoxic substances circulating in the blood in severe liver failure.

Bilirubin encephalopathy (nuclear jaundice, kernicterus). Basically, the disease occurs in the perinatal period. It is known that bilirubin is secreted by the placenta in the fetus. Therefore, with this pathology, jaundice reaches a severe degree only after the birth of a child. In turn, with severe jaundice in infancy, there is a risk of damage to brain tissue. If this happens, then in the area of ​​the hippocampus and basal nuclei, under the microscope, zones are found not only for necrosis of neurons, but also for staining of tissue with bile. If the lesions do not lead to death, then they are more likely to cause the development of choreoathetosis (a combination of choreic hyperkinesis, i.e., automatic sweeping and erratic movements due to involuntary muscle contractions in a state of hypotension, with athetosis, i.e. hyperkinesis with stereotypical fanciful movements ), as well as spasticity and often mental inferiority.

Bilirubin encephalopathy can occur when the plasma level of indirect (free) bilirubin exceeds 250 mmol / L (see chapter 17). However, the more common cause of such encephalopathy in full-term babies of the white race is hemolytic anemia, due to incompatibility in the Rh factor of the fetus and mother. In other racial and ethnic groups, hemolysis caused by glucose-6-phosphate dehydrogenase deficiency also serves as an important etiological factor (see chapter 12). Other causes of bilirubin encephalopathy include functional immaturity of the liver in premature infants, liver damage of various nature, genetically determined defects in bilirubin binding. Among the conditions conducive to this encephalopathy, hypoxia, which can develop during childbirth and severe anemia, as well as an excess of (artificially introduced) vitamin K analogues, which can aggravate hemolysis and, thus, contribute to the occurrence of jaundice, should be mentioned.

Non-metastatic (distant) effects on the central nervous system by malignant tumors (see chapter 7). Some malignant neoplasms, such as bronchial carcinomas and malignant lymphomas, can have an indirect effect on the nervous system. In approximately 6% of patients with some form of cancer, neurological symptoms are noted. However, there is no definite relationship between the degree of neurological impairment and the stage of tumor progression. In rare cases, such disorders precede other oncological symptoms.

The most common distant effect of a malignant neoplasm is manifested in the nervous system in the form of peripheral neuropathy, which can have a motor, sensory or mixed character. Among other forms of non-metastatic effects, myasthenic syndrome and diffuse encephalomyelitis should be mentioned. The latter mainly affects the middle parts of the temporal lobes of the brain and is characterized by the presence of perivascular lymphocytic couplings. Subacute cerebellar atrophy is also occasionally noted, in which there is a noticeable loss of pear-shaped cerebellar neurocytes (Purkinje cells), as well as degeneration of the long motor and sensory tracts in the spinal cord. The etiology of these processes is unknown. With regard to encephalomyelitis, a causative role of the neurotropic virus is suggested, but an antigen-antibody type reaction is not excluded, since in some patients with encephalomyelitis specific antibodies to nerve tissue were isolated.

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Metabolic diseases of the central nervous system

  1. Degenerative diseases of the central nervous system.
    Degenerative diseases of the central nervous system is a heterogeneous group of diseases characterized by a progressive loss of neurons with secondary changes in white matter and a concomitant glial-proliferative reaction. Most neurodegenerative diseases occur in the 5-6th decades of life and at a later age. Macroscopically determined atrophy of certain
  2. Demyelinating diseases of the central nervous system.
    Demyelinating diseases of the central nervous system are characterized by the predominant destruction of the myelin (Schwann) membrane with the relative preservation of the axon. Шванновские клетки образуют шванновскую оболочку, или невролемму, окружающую аксоны и дендриты периферической нервной системы, клеточные тела в сенсорных ганглиях и нервные волокна в белом веществе центральной нервной
  3. Вирусные заболевания центральной нервной системы.
    Вирусные менингиты протекают доброкачественнее, чем бактериальные. Более чем в 70% случаев вирусного менингита выявляют энтеровирусы. Все представители энтеровирусов вызывают менингиты, но наиболее часто вирусы Коксаки, ЕСНО и непаралитического полиомиелита. При исследовании ликвора отмечается лимфоцитарный состав, а уровень белка и сахара существенно не изменяется. Макроскопическая картина
  4. Системные заболевания центральной нервной системы
    Это сборная группа заболеваний, многие из которых имеют семейный характер и сопровождаются прогрессивной дегенерацией нейронов и их отростков центральной нервной системы в определенных зонах. У больных встречаются поражения чувствительных или двигательных (моторных) систем с мозжечковой атаксией и непроизвольными движениями или деменцией. Синдром Паркинсона (паркинсонизм, дрожательный паралич,
  5. ИНФЕКЦИОННЫЕ ЗАБОЛЕВАНИЯ ЦЕНТРАЛЬНОЙ НЕРВНОЙ СИСТЕМЫ
    К группе учеников, подлежащих переводу в специальные школы, в большинстве случаев относят детей, перенесших менингиты, энцефалиты, менингоэнцефалиты и другие формы нейроинфекций. В отдельных случаях встречаются дети с теми или иными формами поражения нервной системы в результате перенесенного сифилиса, туберкулеза, а также ревматизма. Возбудителями болезней являются различные виды микробов и
  6. ЦЕНТРАЛЬНАЯ НЕРВНАЯ СИСТЕМА И ОРГАНЫ ЧУВСТВ. ЛЕЧЕНИЕ ЗАБОЛЕВАНИЙ
    Между центральной нервной системой и сердечно-сосудистой существует удивительное сходство. В последней одна подсистема (венозная) возвращает кровь к сердцу, а другая (артериальная) гонит кровь по сосудам от сердца. Аналогично, центральная нервная система (ЦНС) имеет два сугубо отличных друг от друга вида нервов, которые соединены с мозгом, а мозг, в свою очередь, играет первостепенную роль в ЦНС,
  7. Инфекционные заболевания центральной нервной системы.
    Классификация инфекционных заболеваний ЦНС учитывает этиологию, локализацию, характер морфологических изменений, особенности клинического течения поражения. По этиологии выделяют бактериальные, вирусные, грибковые, прионовые, паразитарные заболевания, по локализации воспалительных изменений — менингит (арахноидит, лептоменингит, пахименингит); энцефалит; миелит; энцефаломиелит; менингомиелит;
  8. Инфекционные заболевания центральной нервной системы
    Инфекционные заболевания центральной нервной
  9. Diseases of the nervous system. Diseases accompanied by an increase in intracranial pressure. Cerebrovascular disease. Cerebral infarction. Spontaneous intracranial hemorrhage. Infectious lesions of the central nervous system. Alzheimer's disease. Multiple sclerosis.
    1. The earliest changes in neurons during blood flow arrest 1. cytolysis 4. microvacuolization 2. tigrolysis 5. wrinkling of neurons 3. hyperchromatosis 2. The most common causes of cerebral infarction 1. stenotic atherosclerosis 2. thromboembolism 3. true polycythemia 4. thrombosis 5. embolism fatty with a fracture of the tubular bones 3. Cerebral edema of the cytotoxic type occurs at 1.
  10. ЦЕНТРАЛЬНЫЙ ОТДЕЛ НЕРВНОЙ СИСТЕМЫ, ИЛИ ЦЕНТРАЛЬНАЯ НЕРВНАЯ СИСТЕМА
    В состав центрального отдела нервной системы входят головной и спинной мозг с их ганглиями. Спинномозговые ганглии —- округлые тельца, располагающиеся вдоль спинного мозга, справа и слева от него. Лежат они вместе со спинным мозгом внутри позвоночного канала. Число ганглиев соответствует числу сегментов. Гистологически ганглии состоят из стромы и нервных клеток с их отростками. Снаружи
  11. DISEASES OF THE CENTRAL NERVOUS SYSTEM, PERIPHERAL NERVES, EYES AND EARS
    DISEASES OF THE CENTRAL NERVOUS SYSTEM, PERIPHERAL NERVES, EYES AND
  12. Заболевания центральной нервной системы, связанные с различными видами недостаточности, интоксикации и лучевой терапии
    Витаминная недостаточность. Витаминные дефициты являются довольно частой причиной неврологических заболеваний. Последствия таких поражений, однажды возникнув, часто остаются навсегда. Несмотря на то что витаминные дефициты могут развиваться у лиц, в прочих отношениях здоровых, они все же встречаются в основном у людей с нарушениями питания или пищеварения. Недостаточность тиамина (витамина В1).
  13. ЦЕНТРАЛЬНАЯ НЕРВНАЯ СИСТЕМА
    К центральной нервной системе (ЦНС) относятся спинной и головной мозг, которые состоят из серого и белого вещества. Серое вещество спинного и головного мозга — это скопление нервных клеток вместе с ближайшими разветвлениями их отростков. Белое вещество — это нервные волокна, отростки нервных клеток, которые имеют миели-новую оболочку (она придает волокнам белый цвет). Нервные волокна входят в
  14. АЛИМЕНТАРНЫЕ И МЕТАБОЛИЧЕСКИЕ БОЛЕЗНИ НЕРВНОЙ СИСТЕМЫ
    М. Виктор, Дж. Б. Мартин (М. Victor, J. В. Martin) Данная глава посвящена широкому кругу разнообразных приобретенных и врожденных неврологических заболеваний. Особое внимание здесь будет уделено приобретенным заболеваниям, поскольку они составляют существенную группу патологических состояний взрослых лиц и представляют большой интерес как для терапевтов, так и для неврологов.
  15. Опухоли центральной нервной системы.
    В 1999 г. в США диагностировано 16800 новых случаев внутричерепных опухолей, а умерло 13100 больных с новообразованиями ЦНС. По данным клиники Мэйо (США), в период с 1950 по 1989 г. ежегодная заболеваемость опухолями ЦНС составила 19,1 на 100 тыс. населения. Кроме того, ежегодно только в США погибают около 100 тыс. больных с метастазами в головной мозг. Точно установленным этиологическим фактором
  16. ВИРУСНЫЕ ЗАБОЛЕВАНИЯ ЦЕНТРАЛЬНОЙ НЕРВНОЙ
    СИСТЕМЫ: АСЕПТИЧЕСКИЙ МЕНИНГИТ И ЭНЦЕФАЛИТ Д. X. Хартер, Р. Г. Петерсдорф (D. Я. Harter, RG Petersdorf) Существует несколько путей поражения центральной нервной системы (ЦНС) вирусами. Хотя о природе и репликации вирусов известно много, корреляция между свойствами вирусов и типом неврологического поражения несоразмерная и неполная. Вирусы, значительно различающиеся между собой по
  17. БОЛЕЗНИ ЦЕНТРАЛЬНОЙ НЕРВНОЙ СИСТЕМЫ
    Болезни нервной системы характеризуются чрезвычайным разнообразием и играют важную роль в патологии человека. Так, например, цереброваскулярные заболевания занимают одно из первых мест среди причин смерти в г. Москве. Классификация болезней центральной нервной системы (ЦНС) учитывает: 1) влияние наследственных и приобретенных факторов — наследственные и приобретенные болезни ЦНС; 2)
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