In modern neurology, one of the acute and current problems For which only palliative solutions currently exist, the group of spinal muscular atrophies (SMA) remains. It's about about hereditary diseases in which, due to a defect in one of the genes, the so-called nutritional mechanism is initially disrupted. motor neurons spinal cord – nerve cells responsible for contractile activity muscular structures of the body, which leads to their gradual death.

Fortunately, this pathology is quite rare, but among hereditary diseases it is one of the most frequently encountered. Statistics on spinal muscular atrophy vary from source to source (approximately one case per 6-8 thousand). It is reliably known that the probability of having a sick child when both parents carry a faulty gene is 1/4 (25%); It has also been established that if the atrophic process is “started” from birth, the chances of surviving to the age of two do not exceed 50%. However, SMA can begin at any age, usually between 20-50 years.

There are four types of spinal muscular atrophy. Kennedy syndrome (spinobulbar muscular atrophy, SBMA) is an adult mixed form that has a number of distinctive features. In particular, SBMA is more common and more severe in men than in women; this is due to the fact that the defective gene is located on the X chromosome.

2. Reasons

The additional word “bulbar” in the name of this type of muscular atrophy is due to the fact that in pathological process In addition to spinal motor neurons, neural tissue is involved medulla oblongata(outwardly this part of the brain looks like an onion, hence its outdated Latin name bulbus). With gradual degeneration, its functional viability is inevitably lost, which leads to the development of specific paralytic symptoms. With this type of SMA, it is combined, complex in nature; the functions of the medulla oblongata are such that any bulbar lesions (trauma, tumors, atrophy, etc.) are manifested primarily by disturbances in muscle activity and reflexes in the nasopharynx area.

3. Symptoms, diagnosis

The disease usually begins with muscle weakness and paresis (partial paralysis) upper limbs, gradually spreading to the pelvis and legs. Involuntary twitching and contractions of the muscles of the tongue, face and shoulder girdle, finger tremor in the Romberg position. Characteristic of any spinal muscular atrophy is also a decrease in tactile sensitivity. The bulbar component of the symptom complex consists of disturbances and gradual extinction of swallowing, palatal, chewing reflexes, difficulty speaking, and increasing respiratory failure. Often the process also affects the hypothalamus, which causes endocrine disorders: for example, men may develop gynecomastia (increased mammary glands By female type), infertility, testicular atrophy.

Taking into account the sufficient specificity of the clinical picture, an experienced neurologist can establish the diagnosis of SBMA clinically, based on examination, complaints and anamnesis. For a clarifying examination, MRI and electromyography (a method for diagnosing the functional status of the muscular system) are prescribed.

4. Treatment

There is no etiopathogenetic treatment: the mechanisms for triggering SBMA in carriers of the mutated gene are unknown, prevention of chromosomal diseases is also impossible today (which is why reproductive doctors are increasingly recommending consultation with a medical geneticist at the stage of family planning). The progression of spinal muscular atrophy of any type over one to two decades, alas, ends in death.

However, the quality of life of patients and their families today is significantly higher than it was half a century ago. Developed effective schemes supporting and activating therapy, portable (intended for home) devices are used artificial ventilation lungs, which is especially important at the stage of breathing disorders during sleep. However, one should understand and prepare for the fact that at a certain stage of the process, any patient with spinal bulbar muscular atrophy will need total care and care, becoming completely dependent on others.

An increase in the number of CAG triplet repeats (expansion) in the AR gene is the cause of Kennedy's disease (spinal and bulbar muscular atrophy), an X-linked neurological disease.

Synonyms Russian

Spinal and bulbar muscular atrophy (Kennedy disease - CD), AR gene, triplet repeat expansion, genetic testing.

SynonymsEnglish

Spinal and Bulbar Muscular Atrophy (Kennedy’s Disease, SBMA, X-Linked Spinal and Bulbar Muscular Atrophy), gene AR, expansion of CAG (cytosine-adenine-guanine) triplet repeats.

Gene name

Localization of the gene on the chromosome

Locus Xq12.

Research method

Fragment analysis of the AR gene.

What biomaterial can be used for research?

Venous blood.

How to properly prepare for research?

• Do not smoke for 30 minutes before the test.

General information about the study

Spinal and bulbar muscular atrophy (Kennedy disease - CD) is a hereditary progressive neuromuscular disease characterized by the expansion of CAG trinucleotide repeats in the AR gene, located on the X chromosome and encoding the androgen receptor (AR).

CD is an X-linked disease and is inherited in a dominant manner, that is, there is a 50% risk of inheritance of this disease from a sick mother and 100% from her father. CD is characterized by the phenomenon of anticipation. The size of the expansion correlates with the severity of symptoms, the level of penetrance and the time of first manifestations of the disease.

It is believed that Kennedy disease can only be observed in men, although cases have been described in which hetero- or homozygous expansion of CAG repeats in the AR gene led to the appearance of mild symptoms of this disease.

The AP protein is a steroid hormone receptor. In patients with CD, the AR protein has an abnormally long polyglutamine region (CAG repeats encoding the amino acid glutamine), which changes and destabilizes the protein conformation, reduces the functional ability of the receptor, and also leads to gain-of-function mutations.

The occurrence varies greatly and ranges from 1:150,000 to 420:100,000.

Clinical manifestations:

Neurological

• Weakness in the distal and proximal muscles, convulsions, frequent falls and difficulty walking, movement tremor.
• Muscle atrophy of the proximal and distal sections, joint contracture.
• Swallowing and speech disorders, development aspiration pneumonia And respiratory failure against the background of weakness of the respiratory muscles, GERD, constipation.
• Slight sensory impairment in the distal extremities.

Endocrinological:

• Decreased sensitivity to androgens: gynecomastia, testicular atrophy, oligo/azoospermia.

Instrumental examination: MRI of the brain - regional atrophy in the frontal areas of the gray and white matter(including subcortical areas), as well as the dorsal part of the brain stem.

What is the research used for?

In accordance with international clinical guidelines, genetic testing for Kennedy's disease is carried out if the patient has clinical symptoms characteristic of this disease, as well as to the relatives and children of the patient.

When is the study scheduled?

• If Kennedy's disease is suspected;
• in the differential diagnosis of motor neuron disease;
• in the differential diagnosis of muscle weakness;
• in the differential diagnosis of hyper-CPK-emia;
• for differential diagnosis of infertility and gynecomastia;
• at early detection illnesses in relatives;
• when planning a family.

What do the results mean?

Genetic testing is the main method of confirming the diagnosis and is based on counting the number of triple CAG repeats using the fragment analysis method in the AR gene. The diagnostic significance of the detected number of CAG repeats in the AR gene is presented in the table:

What can influence the result?

Although a genetic test is precise method laboratory diagnostics, time clinical manifestations disease (disease penetrance) depends on external environment, individual genetic factors. To assess the nature of inheritance in children and relatives, the risk of disease progression and prescribe treatment, it is recommended to consult a specialist.

Important Notes

• To obtain a conclusion based on the results of the examination, it is necessary to consult a clinical geneticist.

Who orders the study?

Neurologist, psychiatrist, geneticist, urologist, reproductive specialist.

Diagnosis of myasthenia gravis (antibodies to the acetylcholine receptor (AchR))

Determination of the copy number or absence of the PMP22 gene in Charcot-Marie-Tooth disease and hereditary neuropathy with susceptibility to pressure palsy (HNPS)

Gene diagnostics for Duchenne-Becker muscular dystrophy

Literature

• La Spada A. Spinal and Bulbar Muscular Atrophy. 1999 Feb 26. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2018.
• Grunseich C, Rinaldi C, Fischbeck KH. Spinal and bulbar muscular atrophy: pathogenesis and clinical management. Oral Dis 2013;20:6–9.

AS are a heterogeneous group of inherited diseases of peripheral nervous system, which are characterized by pronounced clinical polymorphism.

Spinal muscular atrophy (or SA) is a heterogeneous group of inherited diseases that involve damage and loss of motor neurons in the anterior horns of the spinal cord.

Amyotrophy is a disorder of muscle trophism, accompanied by thinning muscle fibers and a decrease in their contractility, caused by damage to the nervous system: motor neurons (at various levels of the central nervous system - neurons of the motor cortex, brainstem nuclei, anterior horns of the spinal cord) or peripheral nerve fibers. The disease is considered hereditary as a result gene mutations, although if we look at the medical histories, then in many patients there is no family history.

There are hereditary and symptomatic amyotrophies. Neurogenic hereditary amyotrophies are divided into two large groups - spinal and neural amyotrophies. In most cases, more severe are spinal forms. These include: spinal amyotrophy (Werdnig-Hoffmann disease), pseudomyopathic progressive spinal amyotrophy Kugelberg-Welander, rare forms of spinal amyotrophy and undifferentiated forms. Neural amyotrophies: Charcot-Marie-Tooth disease, Dejerine-Sotta hypertrophic neuropathy, Roussy-Lewy syndrome, ataxic polyneuropathy or Refsum disease, as well as undifferentiated forms.

SAs are also divided into adults and children. Proximal AS of childhood include: acute malignant infantile AS Werdnig-Hoffmann (spinal amyotrophy type 1), chronic infantile AS (spinal amyotrophy type 2), juvenile AS (Kugelberg-Welander disease), rare forms of AS in childhood: infantile neuronal degeneration, congenital form of Peliceus-Merzbacher disease, congenital cervical SA, atypical variant of GM gangliosidosis, childhood progressive bulbar palsy(Fazio-Londe syndrome), pontobulbar palsy with deafness (Vialetto-Van Laere syndrome).

Adult SA: Kennedy bulbospinal amyotrophy, distal SA, segmental SA, monomyelic SA, scapuloperoneal Stark-Kaiser SA, facioscapulohumeral SA Fenichel, oculopharyngeal SA. There are also undifferentiated forms of SA with a rapidly progressive, slowly progressive and non-progressive course.

According to the recommendation of the European Consortium for the Study of Neuromuscular Diseases, clinical criteria spinal muscular amyotrophy are: [ 1 ] symmetrical muscle hypotonia and malnutrition, [ 2 ] fasciculations of various muscle groups, [ 3 ] hypo- or areflexia of the muscles of the limbs, [ 4 ] absence of sensory, cerebellar and intellectual disorders.

Please note! There are no pathognomonic changes in spinal muscular amyotrophy. However, it is important to determine the activity of serum creatine kinase: it is believed that exceeding its norm by more than 10 times is characteristic of muscular dystrophy and contradicts the diagnosis of spinal muscular amyotrophy.

read also the post: Creatine kinase (neurologist's reference book)(to website)

Electroneuromyography (ENMG) reveals symptoms of damage to peripheral motor neurons: spontaneous muscle activity, increased duration and amplitude of action potentials of motor units with normal speed of impulse conduction along afferent and efferent fibers peripheral nerves. At histological examination Muscle biopsies reveal signs of denervation muscle atrophy.

Classic adult proximal SA begins in the 3rd decade of life and is inherited in an autosomal recessive manner. SA usually debuts between 40 and 50 years old, however, there are cases with onset in adolescence. The distribution of muscle weakness in the autosomal dominant type is in some cases much wider than in the autosomal recessive type. Proximal muscles are also more severely affected than distal muscles. Symptoms progress slowly, motor functions and the ability to walk in the overwhelming majority of patients remains in adulthood and even in old age. Weakness of the bulbar muscles is not typical. Oculomotor muscles are not affected. Tendon reflexes are depressed or absent. Joint contractures are rare. CPK levels are normal or slightly elevated. Will be considered following forms SA of adults:

1. bulbospinal amyotrophy Kennedy;
2. distal SA;
3. segmental SA;
4. monomyelic SA;
5. Stark-Kaiser scapuloperonial SA;
6. Facioscapulohumeral SA Fenichel;
7. oculopharyngeal spinal amyotrophy.

Bulbospinal amyotrophy Kennedy. A rare X-linked form of spinal amyotrophy; debuts in the 4th decade of life, although cases of first manifestations are occasionally reported at 12–15 years of age. Ken is mapped on the long arm of the X chromosome in the Xq21-22 segment. The mutation affects the androgen receptor gene and represents an expansion of the nucleotide triplet (cytosine - adenine - guanine). The core of the clinical picture of the disease consists of weakness, atrophy and fasciculations in the proximal muscle groups of the extremities, tendon areflexia, weakness facial muscles, atrophy and fasciculations in the tongue, perioral fasciculations, dysarthria and dysphagia (the latter is not a prognostically unfavorable sign), postural tremor and cramps. Rarely, axonal neuropathy develops. Bulbar disorders usually occur 10 years after the onset of the disease. Endocrine disorders are characteristic: gynecomastia (!), testicular atrophy, decreased potency and libido, diabetes mellitus. A third of patients suffer from infertility caused by azoospermia. Manifestations of feminization and hypogonadism are probably associated with the insensitivity of defective androgen receptors to male sex hormones (their levels in patients remain normal). The prognosis of the disease is generally favorable. Walking and the ability to self-care are preserved. Life expectancy is not shortened. However, there is increased risk malignant tumors due to hormonal imbalance(breast cancer), which requires oncological alertness. The disease must be distinguished from ALS. Currently, it is possible to carry out direct DNA diagnosis of the disease, establish heterozygous carriage and carry out prenatal diagnosis.

Distal SA. Autos.-recess. the form can begin in early childhood, while autos.-dominant. form - at 23 - 25 years old. With both types of inheritance, severe clinical forms, and shapes moderate severity. The disease begins with weakness and atrophy of the anterior group of muscles of the legs, which are accompanied by deformities of the feet. Tendon reflexes may be preserved. The clinical picture may resemble NMSI type I, but in AS, sensitivity is not impaired. In case of severe autorecesses. forms, muscle weakness gradually spreads to the proximal muscles of the legs and sometimes the arms. The degree of weakness in the arms varies between different families, but is almost the same among representatives of the same family. Approximately 25% of patients have scoliosis. In some families, affected individuals may exhibit pseudohypertrophy or atrophy calf muscles. ENMG data make it possible to distinguish the disease from peripheral neuropathy: the conduction velocity along motor axons is normal, despite signs of total denervation of the small muscles of the foot. Sensory evoked potentials are also normal. CPK levels are normal, sometimes moderately elevated.

Segmental SA: affects only the hands or only the feet; the disease is characterized by genetic heterogeneity: autos.-dom. inheritance is typical for the adult-onset form; auto.-recess. - for the form that begins in adolescents, mainly boys. Atrophy of the hands, as a rule, is asymmetrical, progresses over 2 to 4 years and sometimes affects the forearms. Fasciculations and cramps are characteristic. Usually the growth of arthophia stops over time, but in some cases the leg muscles are involved.

Monomelic SA: This rare form affects the muscles in the arm or leg. Most cases have been reported in Japan and India. Monomelic SA usually occurs as sporadic cases with a male preponderance of 10:1, suggesting an X-linked recessive pattern of inheritance. The age of debut varies from 10 to 25 years. Weakness and muscle atrophy increase unnoticed. The arm is more often affected than the leg. The weakness may be distributed only proximally, only distally, or involve the entire limb. The atrophy is initially unilateral and observed in muscles innervated by the C7, C8, and Th1 spinal segments. Bilateral muscle weakness usually develops within 2 years. Unilateral or bilateral postural tremor of the hands is often observed. Fasciculations in proximal muscle groups precede the onset of weakness and atrophy. The progression of the disease is slow and after 5 years, as a rule, stabilization occurs. However, after 15 years, another limb may be involved in the pathological process. Other causes of monoplegia must be excluded.

Scapuloperoneal SA Stark-Kaiser. This rare form SA is genetically heterogeneous. Cases inherited in an autosomal dominant manner debut in the 3rd-4th decade of life and have a relatively benign course, while cases with autosomal recessive inheritance debut in 3-5 years. Linkage to the 12q24 locus is suggested. In some patients, a mutation is detected in the SMN gene of chromosome 5, which casts doubt on the nosological independence of a number of cases of scapuloperoneal SA and indicates a unique variant of proximal SA gene expression. Weakness and muscle atrophy predominate in the glenohumeral muscle group and the extensors of the foot. Atrophy may slowly spread to the proximal parts of the legs and the muscles of the pelvic girdle. Differential diagnosis carried out with scapuloperoneal myodystrophy.

Facioscapulohumeral SA Fenichela. A rare autosomal recessive form of SA that begins in the 2nd decade of life. The gene has not yet been mapped. The disease mimics Landouzy-Dejerine facioscapulohumeral myodystrophy, but tendon reflexes are usually absent and muscle strength is slightly reduced. The EMG shows a neuronal-axonal type of lesion. CPK activity is normal. A number of researchers dispute the nosological independence of this form and consider it within the framework of Landouzy-Dejerine disease.

Oculopharyngeal SA. An autosomal dominant mode of inheritance is assumed. The disease usually begins in the 4th decade of life with external ophthalmoplegia, dysphagia and dysarthria. In some cases, weakness occurs in the distal limbs and back muscles. The course is slow and benign. Sometimes the disease is considered within the framework of mitochondrial myopathies.

source: materials from the manual for doctors “Diseases of the Nervous System”, ed. N.N. Yakhno, D.R. Shtulman, ed. 2nd, volume 1; Moscow, "Medicine", 2001 (as well as the articles listed below).

read also:

article " Clinical case late onset of spinal amyotrophy in an adult patient - a stage in the development of amyotrophic lateral sclerosis?” T.B. Burnasheva; Center for Israeli Medicine, Almaty, Kazakhstan (magazine “Medicine” No. 12, 2014) [read];

article “Clinical case of late onset of undifferentiated spinal amyotrophy” Goncharova Y.A., Simonyan V.A., Evtushenko S.K., Belyakova M.S., Evtushenko I.S.; State Institution “Institute of Emergency and Reconstructive Surgery named after. V.K. Gusak NAMS of Ukraine", Donetsk National medical university them. M. Gorky (International Neurological Journal, No. 5, 2012) [read];

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Spinal-bulbar muscular atrophy, or Kennedy's disease (SBMA) is characterized by a late onset (at 40-60 years), slow progression, participation in the process of the bulbar group of cranial nerves, and descending spread of paralysis. The first manifestations of the disease are usually weakness and atrophy of the muscles of the proximal parts of the upper extremities, spontaneous fasciculations (twitching), limited range of active movements in the arms, decreased tendon reflexes in the biceps and triceps brachii muscles. As the disease progresses, bulbar disorders(choking, tongue atrophy, dysarthria, tongue fibrillation), then proximal muscles are involved lower limbs, appear auxiliary techniques when standing up, a “duck” gait develops, pseudohypertrophy of the calf muscles and gynecomastia develop.
The type of inheritance of SBMA is X-linked recessive, i.e. it affects almost exclusively boys, while women with a damaged gene on one of the X chromosomes are carriers of the disease.
Androgen receptor gene (AR), responsible for the development of SBMA, is mapped to the Xq21.3-q22 locus. Exon 1 of this gene contains an unstable sequence of trinucleotide repeats (CAG). Normally, from 11 to 33 CAG repeats are recorded, and in patients with SBMA there are from 40 to 62 CAG repeats. A clear relationship has been identified between the length of this repeat and the severity of SBMA: more The CAG repeats of the mutant allele correspond to more early age onset of the disease, as well as a faster rate of its progression. About 30% of mutant alleles are unstable when hereditary transmission, in this case, both a decrease in the number of triplets and their increase are observed.
The Center for Molecular Genetics performs direct DNA diagnostics of SBMA, which is based on assessing the number of CAG repeats localized in the 1st exon of the gene AR. It is possible to carry out presymptomatic and prenatal diagnostics in families where cases of this disease are observed. To get the most reliable results it is necessary to provide biological material from a sick family member.

Developed by us. The kits are intended for use in molecular genetic diagnostic laboratories.

When conducting prenatal (antenatal) DNA diagnostics in relation to a specific disease, it makes sense to diagnose common aneuploidies (Down, Edwards, Shereshevsky-Turner syndrome, etc.) using existing fetal material, paragraph 54.1. Relevance this study due to the high total frequency of aneuploidy - about 1 in 300 newborns, and the absence of the need for repeated sampling of fetal material.