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Mental retardation with monogenic diseases

Monogenic diseases are a heterogeneous group of conditions that differ both in the specificity of mutations, the characteristics of pathogenesis, and in the clinical picture. The group of monogenic diseases with mental retardation includes some hereditary metabolic diseases, connective tissue diseases, isolated forms of microcephaly, hydrocephalus and a number of other diseases.

As noted above, among monogenously inherited diseases, a large group consists of hereditary metabolic defects, and in particular enzymopathy or fermentopathy. To the beginning of the XXI century. more than 100 enzymopathies are known, and for more than 40 of them, methods of drug therapy or diet therapy have been fundamentally developed. Early diagnosis and treatment started in a timely manner make it possible in most cases to prevent brain damage (and, therefore, intellectual underdevelopment) at those stages of its formation when it is especially vulnerable. Enzymopathies are most often inherited autosomally recessive or X-linked recessively, their frequency varies widely (from 1: 1000 to 1: 1 000 000).

The central pathogenetic link of enzymopathy is the absence or significant decrease in the activity of one or another enzyme, which blocks or causes a significant insufficiency of a certain biochemical process. Since most enzyme systems are multicomponent, enzyme pathologies are usually represented by several genetic forms. It should also be noted that the enzyme is almost always involved in several metabolic pathways, which makes the disease polysymptomatic and affects several organ systems. Accordingly, isolated intellectual disabilities are rare; from other systems, vision is especially often affected (with galactosemia, homocystinuria, mucopolysaccharidoses, amavrotic idiocy, etc.).

One of the most common (on average 1: 10000) and well-studied enzymes is phenylketonuria (PKU, phenylpyruvic oligophrenia, Foelling's disease). PKU is caused by a deficiency of phenylalanine hydroxylase (of the apoenzyme or coenzyme system - NADPH and dihydrobiopterin). In this case, phenylalanine cannot be converted into tyrosine, its blood content rises (sometimes by 35-40 times), and it is included in the side metabolic pathway (transamination), turning into phenylpyruvic acid, phenylacetic acid and other phenylketone derivatives toxic to the developing nervous system.

The main consequence of the toxic effects of phenylketo acids is mental retardation (in 65% - deep, in 31.8% - moderate and severe, and only 3.2% - mild). Phenylpyruvic acid is excreted in the urine, giving it a special “mouse” (“wolf”) smell.

Tyrosine deficiency affects the formation of the pigment melanin, the exchange of thyroid hormones and catecholamines is less affected. In this regard, in patients with PKU, the skin is depigmented (or weakly pigmented), has an increased sensitivity to ultraviolet radiation, eczema and dermatitis often develop; hair is light and light color of the iris. The skull (especially its brain part) is underdeveloped (secondary microcephaly). Specific ggosa is characteristic: the elbow, hip and knee joints are slightly bent, the trunk is tilted forward. Pathoanatomically detected small brain mass, myelination defects in the cerebral cortex (especially in the frontal and temporal lobes) and other structures (inner capsule, visual pathways), depigmentation of the substantia nigra.

Psychopathologically, in addition to mental retardation, underdevelopment of speech is noted (it is either not at all, or there are individual words that patients do not correlate with objects), the understanding of speech and sound pronunciation are severely impaired.

Neurological symptoms are nonspecific: epileptiform seizures, disturbances in muscle tone, poor coordination of movements, a lot of stereotypy, and other signs of extrapyramidal insufficiency (athetoid, choreiform movements) are common.

The behavior of patients is different. In some cases, it is close to field (motor anxiety, unfocused, uncontrolled movements from object to object, aimless manipulations with objects, etc.). In others, children are passive, listless, don’t show a sense of affection, don’t recognize loved ones, they liven up mostly when they mention food.

In untreated cases, the first manifestations are most often detected 2-3 months after birth (rarely earlier), and in general, the dynamics of the disease do not fit into purely evolutionary patterns.

Impairment of intellectual development is also shown in some heterozygotes - carriers of the PKU gene. With the obviously confirmed fact of heterozygous carriage among parents and siblings of patients, mild intellectual insufficiency was revealed in 4% of cases, and in 6.5% the lower bound of the norm for intellect with the corresponding low level of education, professional and social adaptation.

The beginning of diet therapy (the exclusion of products containing phenylalanine) in the first weeks of life and its conduct for 10-12 years allows in approximately 90% of cases to prevent the development of mental retardation; if treatment begins at an older age, the development of intellectual insolvency cannot be prevented, but the behavior is somewhat normalized, and after-episodic seizures are less common.

The successful use of medical methods and diet therapy in PKU is one of the most striking examples of medical correction and prevention of developmental abnormalities.

Another example of the same group of disorders is homocystinuria, in which the appearance of patients resembles Marfan syndrome. The frequency of homocystinuria is from 1:50 000 to 1: 250 000.

Minimum diagnostic signs: a marfanoid phenotype, an increase in the concentration of methionine and homocystin in the blood plasma in combination with a decrease in the same indicator for cystine, as well as an increase in the excretion of homocystin with urine (homocystinuria).

The pathogenesis of homocystinuria is based on impaired metabolism of sulfur-containing amino acids. Normally, one of these amino acids - methionine - passes through a series of intermediate stages (including homo-cysteine ​​and cystathionine) into cysteine.

At present, 4 forms of homopistinuria are known, and in most cases there is a deficiency of the enzyme cystathionine beta synthase, resulting in increased levels of homocystine (a derivative of homocysteine) in the blood, tissues and urine, and sometimes methionine. An increased concentration of these substances natural for the body causes focal necrosis in the kidneys, spleen, gastric mucosa, and vessels. Damage to the walls of blood vessels, as well as activation of the blood coagulation system, increase thrombosis, which is manifested by thrombosis of the coronary, carotid, renal arteries, generalized venous thrombosis. This can lead to arterial hypertension, various neurological disorders, early death.

Homocystinuria is also characterized by elongation of the tubular bones, funnel-shaped or keeled chest deformity, scoliosis, kyphosis, hallux valgus deformity of the knee and / or feet, flat feet, change in the shape and arrangement of teeth, as well as osteoporosis, tendency to fractures, and limited mobility in the joints. Some patients have a subluxation of the lens, sometimes accompanied by myopia, atrophy of the optic nerve, retinal detachment, and glaucoma.

Neurologically revealed various signs of focal pathology (hemiparesis, hemiplegia, less often cramp), gait disorders. These disorders are often progressive. Poor switching of attention, reduced working capacity, and uncriticality towards oneself and others are also noted. Speech is a limited set of short grammatical phrases, disturbances in pronunciation are common, and vocabulary is reduced. In the vast majority of patients, intelligence is reduced (1Q from 70 to 30, i.e., from mild to severe intellectual failure).

Similar, although more polymorphic, clinical manifestations are characteristic of other forms of homocystinuria due to a violation of coenzyme exchange systems for sulfur-containing amino acids. The disease is inherited autosomally recessively. The homocystinuria gene is located in the long arm of chromosome 21.

In some diseases (they are called “accumulation diseases”), the enzymes of the catabolism of certain substances suffer, as a result of which the latter accumulate in the cells, disrupting all their vital functions. An example is mucopolysaccharide dose, Nyman-Peak disease, etc.

So, with Niman-Peak disease (inherited autosomally recessively, occurs equally often in boys and girls), a deficiency of acid sphingomyelinidase is detected and the metabolism of one of the types of lipids, sphingomyelin, is disturbed. Products of its incomplete decay accumulate in the cells of the liver, spleen, brain, lymph nodes, lymphocytes. There are several forms of the disease that differ clinically (by the time of onset, severity of visceral and neuropsychiatric manifestations), and, apparently, genetically identical. Symptoms common to all are enlarged liver and spleen, generalized enlargement of lymph nodes. At an early onset of the disease, visceral symptoms quickly increase, mental and physical development is roughly delayed, neurological disorders progress rapidly, and patients die at the age of 3-5 years. In the youthful form, in addition to visceral symptoms, signs of damage to the nervous system (convulsions, cerebellar symptoms, etc.) are observed, but they appear late and develop slowly. With the visceral form, damage to the nervous system is not characteristic.

Monogenic forms of oligophrenia include true microcephaly and obstructive hydrocephalus.

Small brain sizes are noted in at least 2.5% of children with intellectual disabilities. The causes of microcephaly can be various, 1/10 of such cases are not associated with exogenous lesions of the intrauterine period and refers to the genetically determined “true” microcephaly, which is inherited autosomally recessively.
These patients, as a rule, have a deep general mental underdevelopment, and often also convulsive seizures, cerebral motor disorders.

The action of the recessive gene of true microcephaly appears in approximately 10% of heterozygous carriers, its signs are a reduced skull size and a slight intellectual defect. Some experts are of the opinion that up to 10% of all cases of clinically identified intellectual deficiency are due to heterozygosity for the true microcephaly gene.

About 1/3 of all cases of congenital hydrocephalus are hereditary obstructive hydrocephalus. Inheritance more often occurs according to the X-linked recessive type (i.e., it occurs only in boys), however, cases of autosomal dominant and autosomal recessive inheritance are known. Regardless of the type of inheritance, the main pathogenetic moment is stenosis of the sylvian aqueduct. The absence of normal conditions for the outflow of cerebrospinal fluid from the first three cerebral ventricles leads to thrombogenous neurological symptoms, and without surgical repair of the defect at an early age, the prognosis is unfavorable.

The hereditary diseases with mental retardation include Martin-Bell syndrome (fragile X-chromosome syndrome). The syndrome is inherited X-linked recessively and occurs mainly in boys, although it is also detected in 1/3 of women who carry the gene. Its frequency is 1: 1250 - 1: 5000 males. At present, the nature of the genetic changes underlying this disease has been clarified. It was shown that the clinical manifestations of the syndrome are associated with an increase in the number of trinucleotide repeats of cytosine-guanine-guanine in a certain section of the long arm of the X chromosome (Xq27.3). Neurologically, muscle hypotension, the phenomena of oral apraxia, and hydrocephalus are most often noted.

In all cases, mental retardation is noted, but its depth is different. So, for sick boys with fragile X-chromosome syndrome, mental underdevelopment can vary from moderate to deep (1 <2 from 70 to 35), while at the same time, only mild intellectual deficiency is noted in women with this pathology.

A frequent feature of patients' speech is cluttering syndrome, in which hasty, illegible speech with dysrhythmia, perseveration, difficulty in finding words, and arranging logical stresses is noted.

Often there is schizophrenia-like symptoms, as well as manifestations of childhood autism. Even in those cases when the leading symptom in the clinical picture is intellectual disturbances, some of the features characteristic of autism (sensitivity, high satiety, insufficient communicative abilities, sometimes the presence of special interests) are very significant, and they must be taken into account in the psychological and pedagogical work. In dynamics, a tendency toward a decrease in the intellectual level is often noted, which, however, requires special study: it is possible that in addition to biological reasons, inadequate teaching and upbringing methods that have been used for a long time (several years) are essential.

Example. In the family, the first child - a boy (at the time of the examination at the age of 18) - suffers from Martin-Bell syndrome. His intelligence corresponds to severe mental retardation, autism is noted; despite officially recognized learning disabilities, in a special institution for children with autism, it was possible to develop speech, writing, reading, and everyday skills; being musical, the child mastered the elementary skills of playing the piano. During the year, he worked as a janitor and a janitor of office premises, satisfactorily coped with the work, but required constant monitoring. The level of his social adaptation excluded the possibility of independent living.

Parents applied for genetic counseling in connection with the desire to have a second child. The probability of birth of a Free child and measures to control the course of pregnancy were determined. Studies during the subsequent pregnancy (male fetus) gave positive results for the presence of fragile X-chromosome syndrome, and the pregnancy was terminated; pathomorphological studies fully confirmed the correctness of prenatal diagnosis.

The third pregnancy, which also took place under medical and genetic control, ended with the birth of a normal girl, and the subsequent five-year follow-up indicates the absence of significant deviations in the child's mental and physical development.

Among the diverse forms of mental retardation of a monogenic nature, the so-called xerodermic forms are distinguished, in which an intellectual defect is combined with skin damage. An example of these diseases are neurofibromatosis and tuberous sclerosis.

The presence of multiple tumors along the peripheral nerves, tumors of the central nervous system, organs of vision, internal organs is characteristic of neurofibromatosis (Recklinghausep disease), skin pigmentation, skin nevi, and bone abnormalities are noted.

An expanded form of neurofibromatosis occurs with a frequency of 1: 2500–1: 3000 newborns, is inherited autosompominantly with 100% penetrance and variable expressivity.

Currently, two forms of neurofibromatosis are distinguished; classical peripheral (neurofibromatosis I), the gene of which is localized on the 17th chromosome, and the central form (neurofibromatosis II), the gene of which is located on the 22nd chromosome.

Minimum diagnostic signs of neurofibromatosis: the presence on the skin of more than 5 spots of "the color of coffee with milk" with a diameter of at least 15 mm; two or more neurofibromas; optic nerve glioma.

The disease manifests itself from birth or in the first decade of life by the formation of age spots on the skin, the size and number of which gradually increase (Fig. XI.5, a). The spots are localized most often in closed areas of the skin (on the back and side sections of the body, as well as in the axillary and inguinal areas). Skin and subcutaneous tumors are located along the peripheral nerves (Fig. XI.5, b). The most characteristic gliomas of the optic nerve, neurofibroma on the eyelids, conjunctiva, cornea, and iris are possible. If tumors arise inside the orbits, then they can provoke ptosis, paralysis of the eye muscles. Skeletal disorders (kyphosis, scoliosis, violations of the tubular bones, etc.) are less likely.

Lesions of the nervous system are diverse in spectrum, severity and dynamics, which is determined by the localization and size of tumors. One of the manifestations of their localization in the central nervous system is a decrease in intelligence, impaired memory, attention, and sometimes convulsive syndrome. Эти признаки могут проявляться не у всех больных, начинаются они с незначительных проявлений, но, постепенно нарастая, приводят к расстройствам речи, ослаблению отдельных высших психических функций и, как следствие, к трудностям обучения. С течением времени во мнотих случаях школьные проблемы нарастают, усугубляются личностными отклонениями и могут приводить к переводу на программы более низкого уровня (и соответственно в специальную (коррекционную) школу VIII вида) и/или индивидуальное обучение.

Характерной особенностью неврофиброматоза II типа является образование опухолей черепномозговых нервов и спинного мозга. В клинической картине на первом плане различные неврологические расстройства, прогрессирующее снижение интеллекта и распад психики в целом. Кожных опухолей и периферических нейрофибром, как правило, нет. Для специальной педагогики этот тип заболевания существенного значения не имеет.

Минимальными диагностическими признаками туберозного склероза (болезнь Бурневилля-Прингла) являются ангиофиброма лица, судороги и умственная отсталость.

Частота туберозного склероза при рождении составляет примерно 1:10 000, среди всего населения — от 1:30 000 до 1:100 000.

80 % случаев связаны с мутацией йе пото, механизм наследования аутосомно-доминантный со 100%-й пенетрантностью и вариабельной экспрессивностью.

Проявляется заболевание в возрасте 2-5 лет чаще всего (93%) судорожными припадками различного типа (большие, малые, салаамовы и др.). Из других неврологических нарушений встречаются гидроцефалия, пирамидные и экстрапирамидные симптомы. В головном мозге — в стенках желудочков, мозжечке, базальных ганглиях обнаруживаются многочисленные кальцификаты. Если говорить о поражениях кожи, то это прежде всего (70% случаев) ангиофиброма щек в виде «бабочки» (красные и розовые папулы), шагреневая кожа, депигментированные пятна, кофейные пятна, подкожные фиброматозные узелки и др. (рис. XI.6). В зрительной системе встречаются опухолевидные изменения сетчатки, иногда глаукома. Значительно чаще, чем в среднем в популяции, встречаются как доброкачественные, так и злокачественные опухоли различных органов. Течение заболевания прогрессирующее, большинство больных умирают в 20-25 лет.

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