Andersen's disease (glycogenosis type IV, amylopectinosis) occurs due to deficiency of the 1,4-a-glucan branching enzyme, which leads to the accumulation of abnormal, poorly soluble glycogen.

This disease is called amylopectinosis because glycogen in such cases is less branched and has longer linear sections containing α-1,4-glycosidic bonds, which is characteristic of the structure of amylopectin.

Andersen's disease is inherited in an autosomal recessive manner. The 1,4-a-glucan branching enzyme gene is located on chromosome 3; Its mutations underlying the disease are known, and their characteristics in each individual case make it possible to predict the clinical picture of the disease.

Symptoms of Andersen's disease

Amylopectinosis is clinically heterogeneous. Its most common classical form is characterized by progressive cirrhosis of the liver. Initial signs - hepatosplenomegaly and poor development - appear in the first 18 months. life. Portal hypertension, ascites, esophageal varices, and liver failure gradually develop, from which patients die by the age of 5. In rare cases, liver damage does not progress.

There are also reports of a neuromuscular form of Andersen's disease. Its manifestations are varied:

• severe hypotension, muscle atrophy; neuronal damage from birth; death occurs in the neonatal period;
• myopathy and myocardial damage in older children;

diffuse damage to the central, peripheral nervous system, accompanied by the accumulation of polyglucosan bodies in neurons (the so-called polyglucosan body disease) The diagnosis in the latter case requires determination of the activity of the 1,4-a-glucan-branching enzyme in leukocytes or biopsies of nervous tissue, since its deficiency is limited precisely these cells.

Diagnosis of Andersen's disease

Deposition of atypical glycogen is found in the liver, heart, muscles, skin, intestines, brain and spinal cord, and peripheral nerves. Small nodular cirrhosis develops in the liver. When examined, weakly stained basophilic inclusions are visible in hepatocytes, which are coarse-grained PAS-positive deposits, partially resistant to amylase. Electron microscopy reveals, in addition to glycogen particles, fibrous aggregates characteristic of amylopectin. The characteristic staining of cytoplasmic inclusions and the electron microscopic picture could be of diagnostic value, but similar histological features were observed in polysaccharidoses without deficiency of the 1,4-a-glucan branching enzyme. To confirm the diagnosis, it is necessary to establish a deficiency of this particular enzyme in the liver, muscles, cultured skin fibroblasts or leukocytes. For the purpose of prenatal diagnosis, the activity of 1,4-a-glucan branching enzyme is determined in cultured amniocytes or chorionic villi.

described by American pathologist Dorothy H. Andersen, 1901–1964; synonyms - glycogenosis, type IV, amylopectinosis) is a rare hereditary disease from the class of storage diseases, caused by the lack of 1,4-alpha-glucan-branching enzyme, which leads to the accumulation of atypical poorly soluble glycogen. Main clinical manifestations: hepatosplenomegaly in the first years of life, progressive portal fibrosis with the development of liver cirrhosis, ascites, esophageal varices, liver failure; muscle hypotension; myocardial damage and heart failure. The diagnosis is clarified by examining the activity of the 1,4-alpha-glucan branching enzyme in the liver, muscles, etc. The type of inheritance is autosomal recessive. Treatment is symptomatic; the use of glucocorticoids can promote temporary remission. The prognosis of the disease is unfavorable, death occurs in childhood, usually due to liver failure.

D. H. Andersen. Familial cirrhosis of the liver with storage of abnormal glycogen. Laboratory Investigation, Baltimore, 1956; 5: 11–20.

ANDERSEN SYNDROME

described by the Danish physician E. D. Andersen) – a rare hereditary disease: prolonged Q-T interval, ventricular extrasystole, muscle hypotension; characterized by craniofacial features - macrocephaly (increase in the size of the skull by more than 10% of the age norm), dolichocephaly (elongation of the skull in the anteroposterior direction due to premature ossification of the sagittal suture), scaphocephaly (long skull with a protruding forehead and occiput, a raised vault, reminiscent of an overturned boat), low-lying ears, hypertelorism (widely spaced eyes), micrognathia (small size of the upper jaw), brachydactyly (short fingers), clinodactyly of the fifth fingers (lateral or medial curvature). The type of inheritance is autosomal dominant. Most of the reported cases are sporadic. Treatment is symptomatic.

E. D. Andersen, P. A. Krasilnikoff, H. Overad. Intermittent muscular weakness, extrasystoles and multiple developmental abnormalities: a new syndrome? Acta paediatrica Scandinavica, Stockholm, 1971; 60:559–564.

What is glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)- a hereditary disease that is caused by a deficiency of enzymes involved in glycogen metabolism; characterized by a violation of the structure of glycogen, its insufficient or excessive accumulation in various organs and tissues.

What provokes glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Andersen's disease occurs as a result of mutations in the microsomal amylo-1,4:1,6-glucan transferase gene, leading to its deficiency in the liver, muscles, leukocytes, erythrocytes and fibroblasts. The gene is mapped on chromosome 3p 12. The mode of inheritance is autosomal recessive.

Pathogenesis (what happens?) during glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Amylo-1,4:1,6-glucan transferase is involved in glycogen synthesis at branch points of the glycogen tree. The enzyme connects a session of at least six α-1,4-linked glycosidic residues of the outer glycogen chains to the glycogen “tree” via an α-1,6-glycosidic linkage. When the enzyme is deficient, amylopectin is deposited in liver and muscle cells, which leads to cell damage. The glycogen concentration in the liver does not exceed 5%.

Symptoms of glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Disease manifests itself in the first year of life with nonspecific gastrointestinal symptoms: vomiting, diarrhea. As the disease progresses, hepatosplenomegaly, progressive liver failure, generalized muscle hypotonia and atrophy, and severe cardiomyopathy occur. Death of patients usually occurs before 3-5 years of age due to chronic liver failure, rarely in older childhood (up to 8 years).

Diagnosis of glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Laboratory diagnostics based on the detection of glycogen with an altered structure in liver biopsy and a decrease in the activity of amylo-1,4:1,6-glucan transferase.

Treatment of glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Treatment is aimed at combating metabolic disorders, incl. with acidosis. In some cases, the use of glucagon, anabolic hormones and glucocorticoids is effective. Frequent meals high in easily digestible carbohydrates are necessary for hypoglycemia. In muscular forms of glycogenosis, improvement is noted by following a diet high in protein, administering fructose (50-100 g orally per day), multivitamins, and ATP. Attempts are being made to administer missing enzymes to patients.

Patients with glycogenosis are subject to dispensary observation by a doctor at the medical genetic center and a pediatrician (therapist) at the clinic.

Prevention of glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Prevention has not been developed. To prevent the birth of a child with glycogenosis in families where there were similar patients, medical and genetic counseling is carried out.

Which doctors should you contact if you have glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

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The clinical picture of the disease was first described by Andersen in 1956. The disease is inherited in an autosomal recessive manner. In type IV glycogenosis, there is a defect in the enzyme amylo-1,4 → 1,6-transglucosidase, which is involved in the formation of branch points in the glycogen molecule:

In type IV glycogenosis, abnormal glycogen, similar to amylopectin (a component of starch in plant cells), is synthesized in the affected organs. The abnormal glycogen molecule has a reduced number of branch points and longer external and internal chains compared to the norm.

The disease is rare and is generalized (cardiac and skeletal muscles and liver are most often affected). Clinically, the disease is manifested by hepatosplenomegaly, ascites, mental development is not affected. Progressive portal fibrosis of the liver leads to cirrhosis. Cirrhosis probably develops as a result of the accumulation of amyl-like glycogen.

Death in childhood from liver failure. A pathological examination reveals an increase in the size of the kidneys, liver, and spleen. Hepatocytes are enlarged and contain amylopectin-like polysaccharide.

Lafora disease- cerebral glycogenosis (myoclonic epilepsy). In this disease, an accumulation of abnormal glycogen is detected in the brain, resembling the properties of the polymer in type IV glycogenosis. The activity of the branching enzyme is not changed in this disease.

Glycogenosis type V (McArdle disease)

First described by B. McArdle in 1951. Autosomal recessive type of inheritance. Characterized by deficiency of muscle phosphorylase in skeletal muscles. The absence of muscle phosphorylase is not combined with a violation of hepatic phosphorylase (controlled by various genes). The activity of phosphorylase of leukocytes, erythrocytes, and platelets in McArdle disease is not changed.

With this disease, up to 3-4% of glycogen that is normal in structure accumulates in the muscle fibers. Excess glycogen is deposited under the sarcolemma in the cytoplasm. At rest, energy needs are provided by myocyte glucose. During muscular work, the need for energy supply is not met due to an enzymatic defect, which causes pain and cramps in this type of glycogenosis.

McArdle disease is heterogeneous. Clinical signs more often appear in adults; in childhood, the symptoms of the disease are not pronounced. The disease occurs in 3 stages:

1. In childhood and adolescence, muscle weakness, fatigue, and possible myoglobinuria are observed.

2. Between the ages of 20 and 40, muscle pain becomes more intense, and cramps appear after physical activity.

3. After 40 years, progressive weakness occurs due to muscular dystrophy.

It has been established that phosphorylase activity decreases sharply with vitamin B6 deficiency (60% of pyridoxine in skeletal muscles is associated with phosphorylase). Therefore, phosphorylase deficiency affects the content of pyridoxine in the body. The prognosis for type V glycogenosis is favorable.

13. Priori S. G., Napolitano C., Grillo M. Concealed arrhythmogenic syndromes: The hidden substrate of idiopathic ventricular fibrillation? // Cardiovasc. Res. - 2001. - Vol. 50.

14. Priori S. G., Napolitano C., Memmi M. Clinical and molecular characterization of patients with cathecholaminergic polymorphic ventricular tachycardia // Circulation. - 2002.

Vol. 106. - P. 69-74.

15. Priori S. G., Napolitano C., Tiso N. et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie cathecholaminergic polymorphic ventricular tachycardia // Ibid.

2000. - Vol. 103. - P. 196-200.

16. Spurgeon D. Sudden cardiac deaths rise 10% in young Americans // Brit. Med. J. - 2001. - Vol. 322. - P. 573 (Abstract).

17. Sumitomo N., Harada K., Nagashima M. et al. Cathecholaminergic polymorphic ventricular tachycardia:

© S. M. KRUPIANKO, T. T. KAKUCHAYA, 2005 UDC 616.12-008.6

ANDERSEN'S SYNDROME

S. M. Krupyanko, T. T. Kakuchaya

Scientific Center for Cardiovascular Surgery named after. A.

RAMS, Moscow

Andersen syndrome is a rare hereditary pathology characterized by transient muscle paralysis, prolongation of the QT interval, often combined with the appearance of high-amplitude U waves, ventricular arrhythmias and signs of dysmorphogenesis - low-set ears, micrognathia (abnormally small jaws, especially the lower jaw), wide forehead, clinodactyly -ey (persistent deformation of one or more fingers), syndactyly (fusion or the presence of membranes between the toes or hands), hypertelorism (increased distance between two paired organs), short stature, scoliosis, etc. In 1971, E. Andersen et al. reported that an 8-year-old patient had short stature, hypertelorism (widely spaced eyes), jaw hypoplasia, wide base of the nose, cleft palate, scaphocephalic skull (a long narrow skull with a ridge along the ossified sagittal suture) and clinodactyly of the fifth digit. In 1994, R. Tawil et al. first used the term “Andersen syndrome” to describe a clinical case with three characteristic features (clinical triad): potassium-sensitive cyclic paralysis, ventricular rhythm disturbances and signs of dysmorphogenesis, observed by Andersen in 1971. The literature also often contains the definition of “Andersen-Tawil syndrome” (Andersen-Tawil syn-

Electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death // Heart. - 2003.

Vol. 89, No. 1. - P. 66-70.

18. Swan H, Laitinen P. J., Kontula K. et al. Calcium channel antagonism reduces exercise-induced ventricular arrhythmias in cathecholaminergic polymorphic ventricular tachycardia patients with RYR2 mutations // J. Cardiovasc. Electrophysiol. - 2005. - Vol. 16, No. 2. - P. 162-166 (Abstract).

19. Swan H., Piippo K., Viitasalo M. et al. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts // J. Amer. Coll. Cardiol. - 1999. - Vol. 34, no. 7.

20. Tan H. L., Hofman N., Van Langen I. M. et al. Sudden unexplained death. Heritability and diagnostic yield of cardiological and genetic examination in surviving relatives // Circulation. - 2005. - Vol. 112. - P. 207-213.

N. Bakuleva (director - Academician of the Russian Academy of Medical Sciences L. A. Bokeria)

drome, abbreviated as ATS). This syndrome should not be confused with Andersen's disease, which belongs to glycogenosis - diseases of glycogen storage (due to a deficiency of glycogen-converting enzyme, a pathological amount of glycogen accumulates in the liver, muscles and other tissues). Andersen syndrome was the first pathology described in the section on channelopathies - pathologies of ion channels. Andersen syndrome is inherited in an autosomal dominant manner, although there are reports of sporadic cases. The probability of passing it on by inheritance is more than 50%. The severity of the disease can vary within one family - one child may have severe damage, while another may be clinically asymptomatic. The penetrance of the disease is widely variable, and not all patients exhibit the full range of clinical features of this syndrome. Rhythm disturbances accompany any attack of muscle paralysis, occurring secondarily and caused by sharp fluctuations in the level of potassium in the patient’s blood serum (Fig. 1). However, the literature describes cases where rhythm disturbances were the first clinical manifestation of Andersen syndrome and preceded episodes of muscle paresis and paralysis. In this disease phenotype, a prolonged QT interval was later identified. Cases of sudden cardiac death have also been reported in Andersen syndrome.

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III AVF V3 * V6 Serum K+=2.9

III AVF V3 V6 Serum K+=3.4

Rice. 1. An episode of ventricular bigeminy in a 16-year-old girl with Andersen’s syndrome against the background of hypokalemia (a) (asterisks indicate ventricular extrasystoles); b - normalization of the level of potassium in the blood led to the disappearance of arrhythmia.

Serum K+ - serum potassium.

Despite its low prevalence in the population, Andersen syndrome is of great scientific and practical interest for modern medicine, since it is the only one among all genetically determined channelopathies that affects both striated (skeletal) muscles and the heart muscle. Other diseases that manifest as muscle paresis and paralysis are caused by mutations in genes responsible for the transport of sodium, calcium and potassium ions in skeletal muscle cells, while various forms of long QT syndrome are caused by mutations in genes encoding the transport of sodium and potassium ions only in cardiomyocytes. Previous studies excluded the possibility of allelic genesis of Andersen syndrome. However, in 2001, N. Plaster et al. When conducting a molecular genetic study in a large family (15 individuals), we discovered a connection between the likelihood of inheriting Andersen syndrome and the pathology of the 17q locus of chromosome 23 and identified a heterozygous missense mutation of the KCNJ2 gene (the 17q locus of chromosome 23 intersects with the KCNJ2 gene locus - 17q23.1-17q24 .2) . Mutations of the KCNJ2 gene have been found in more than 50% of patients with Andersen syndrome, thus confirming the fact that the KCNJ2 gene is responsible for the development of this pathology. Currently, more than 20 heterozygous missense mutations of the KCNJ2 gene have been identified that cause Andersen syndrome (Fig. 2). KCNJ family genes are widely expressed in various tissues: muscle (KCNJ2, KCNJ11), heart (KCNJ2, KCNJ3, KCNJ5, KCNJ11), brain (KCNJ3, KCNJ6, KCNJ9, KCNJ11), epithelium (KCNJ1, KCNJ2) and many others. Mutations in the KCNJ gene family can lead to the development of three inherited diseases in humans and one disease in mice. Thus, mutations of the KCNJ1 (Kir1.1) gene lead to the development of Bart-ter syndrome, an autosomal recessive disease characterized by hypokalemia and sodium loss in the human body; mutations of the KCNJ11 (Kir6.2) gene and the associated protein SUR1 lead to the development of permanent hyperinsulinemic hypo-

Rice. 2. Structure of the Kir2.1 channel subunit.

Pore ​​- central hole (time); M1, M2 - transmembrane domains; extracellular - extracellular; intracellular - intracellular.

The gray boxes indicate the 20 mutations currently identified in patients with Andersen syndrome; the white square indicates the mutation identified in short QT syndrome.

glycemia in children, mutations of Kir3.2 (GIRK2) - to an autosomal recessive pathology in mice, manifested by loss of neurons and severe ataxia, and finally, mutations of the KCNJ2 gene are associated with the development of Andersen syndrome. KCNJ2 encodes the synthesis of the Kir2.1 protein, which is part of the potassium channel in cells capable of excitability, including cardiomyocytes, cells of striated muscle and brain. Kir2.1 channels are the most important regulators of the resting membrane potential of cardiac and skeletal muscles and, thus, the excitability of cells in these tissues in general, since they ensure the release of potassium ions from cells with a hyperpolarized membrane during the final repolarization phase of the action potential. The Kir2.1 protein consists of 427 amino acids with two transmembrane domains (M1, M2) and a central hole (pore) (H5) and regulates the IK1 component of the potassium current with delayed rectification of the repolarization phase (see Fig. 2). Northern blot analysis revealed a 5.5-kb transcript of the KCNJ2 gene with high levels of Kir2.1 in the heart, brain, placenta, lungs, and skeletal muscle and lower levels in the kidneys. In the heart, Kir2.1 channels predominate in the atria, ventricles (with high IK1 current conduction velocity), and Purkinje fibers and are less common in nodal cells. Kir2.1 subunits, encoded by the KCNJ2 gene, combine into a tetramer within the cell wall of cardiomyocytes, forming a functioning channel; they can also combine with other subunits of the Kir2.1 family as heteromultimers, indicating their functional complexity and diversity. Most KCNJ2 gene mutations are missense mutations.

having a dominant-negative effect, which leads to a decrease in IK1 current, a decrease in repolarization and an increase in the duration of the action potential. As a result of the above processes, depolarization and destabilization of the resting membrane potential occurs, which initiates the appearance of ventricular arrhythmias or myotonic contractions of skeletal muscles. Moreover, the researchers suggest that dysfunction of the Kir2.1 channel and a decrease in IK1 current play an important role in the development of signaling dysfunctions in non-excitable tissues, which may explain the manifestations of dysmorphogenesis in patients with Andersen syndrome. M. Tristani-Firouzi et al. studied the functional consequences of mutations in Andersen syndrome by expressing the altered protein in vitro. Significant impairment of Kir2.1 channel function has been observed in all types of mutations identified to date.

The clinical manifestations of Andersen syndrome are extremely variable, which is explained by the existence of various mutations that contribute to the manifestation of different phenotypes of the disease. It is likely that defects in other ion channels are also important in the etiology of Andersen syndrome. Recurrent muscle paralysis can be caused by pathology of the calcium, sodium and potassium channels of myocytes. Patients experience short-term episodes of weakness in the arms and legs, up to generalized paresis and paralysis of the limbs. Such attacks can occur at rest, after exercise, or upon waking in the morning. It should be noted that the triggering factors for the disease are different. Currently, not all nutritional factors that provoke an attack of muscle paralysis in Andersen syndrome are known. Triggers are likely to include foods rich in potassium and glucose. Other factors that provoke the occurrence of periodic muscle paralysis may be: a change in activities - rest after physical activity, physical activity after a long period of sitting, waking up after sleep, a long walk on an empty stomach, a large meal. Any cold can also cause muscle paralysis; There are reports in the literature of cases where the triggers were inhaled gases - carbon dioxide, gasoline vapors, or even the smell of oil paint. In the Tristani-Firuozi study, cyclic muscle paralysis was observed in 23 (64%) of 36 patients with KCNJ2 gene mutations. Rest after physical activity was the most common trigger for the occurrence of muscle paralysis, as in classical variants of this type.

conditions, with the majority (55%) of patients having hypokalemia (serum potassium concentration less than or equal to 3.4 mEq/L), hyperkalemia was observed in 22%, and normokalemia in 10% of patients. However, in Andersen's syndrome, hypokalemic conditions were not preceded by the ingestion of carbohydrates, as is the case with classic variants of hypokalemic muscle paralysis. Muscle biopsy performed in 12 patients revealed nonspecific changes - minor myopathies and/or tubular aggregates observed in other forms of cyclic muscle paresis or paralysis. Carbon anhydrase inhibitors were effective in reducing the frequency of attacks of paralysis in Andersen syndrome, as well as in classical forms of muscle paralysis.

The most characteristic changes on the ECG in patients with Andersen syndrome are prolongation of the OT interval and high-amplitude waves and (Fig. 3). Currently, there are conflicting opinions among researchers regarding the involvement of Andersen syndrome in one of the variants of the long OT interval syndrome. Since Andersen's syndrome is considered as a genetically determined pathology of muscle cell repolarization, it began to be classified as long OT interval syndrome (LTS), namely type 7 (LOTS). Currently, 5 genes have been identified, mutations in which are reliably responsible for the development of typical clinical manifestations of the long OT interval syndrome: KSYO1 (SHT1), IEAO (KSYN2, SHT2), SSY5L (SHT3), KSYO1 (SHT5), KSYO2 (SHT6). Similar to other forms of congenital prolonged OT syndrome, the primary manifestation is side-

Rice. 3. The most typical electrocardiographic changes and rhythm disturbances detected in patients with Andersen syndrome. a - lengthening of the OT interval; b - short run of unstable polymorphic ventricular tachycardia followed by ventricular bigeminy; c - bidirectional ventricular tachycardia; d - arrows indicate protruding teeth and.

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The main feature of the cardiovascular system in Andersen syndrome was the prolongation of the OT interval, identified in 71% of all carriers of the KSH2 gene. The average value of the corrected OT interval (OTI) in male and female probands with Andersen syndrome was 479 and 493 ms, respectively, while in other forms of long OT syndrome it was 497 and 510 ms, respectively. Due to the presence of an extended OT interval and the possibility of developing life-threatening ventricular arrhythmias, some researchers consider Andersen syndrome as one of the subtypes of congenital prolonged OT syndrome. However, as it turned out, despite the frequent occurrence of ventricular arrhythmias (ventricular extrasystoles and runs of unsustained ventricular tachycardias, including bidirectional ventricular tachycardias, see Fig. 3) - in 64% of patients in the study M. Il81ash-R1goi21, the risk of sudden cardiac mortality in Andersen syndrome was lower than in long OT interval syndrome and other hereditary channelopathies. To identify the mechanisms of occurrence of ventricular arrhythmias in Andersen syndrome, the authors simulated the suppression of the function of the Yu2.1 channel of cardiomyocytes of the ventricle of the heart in an experiment. It turned out that suppression of the Yu2.1 channel function against the background of hypokalemia led to a prolongation of the final phase of the action potential of the cardiac muscle, the occurrence of delayed afterdepolarizations due to the induction of Ca+/Ca2+ exchange and the development of spontaneous arrhythmias. The authors concluded

that the substrate for the occurrence of ventricular arrhythmias in Andersen syndrome differs from that in other forms of congenital long OT interval syndrome and is closer to arrhythmias resulting from Ca2+ overload or digitalis intoxication (such as bidirectional and polymorphic ventricular tachycardia). Thus, with Andersen syndrome, the clinical manifestations of congenital long OT interval syndrome and familial (catecholaminergic) polymorphic ventricular tachycardia are combined (with the latter, as a rule, an extended OT interval is not observed). The range of rhythm disturbances found in Andersen syndrome is presented in the table.

The high amplitude of the waves is a specific finding in Andersen syndrome and is recorded mainly in the anterior chest leads (see Fig. 3). This trait was detected in 76% of probands and 47% of carriers of mutant KSH2 genes according to M. ln81at-Igou21. It should be noted that normally in healthy people the wave and can be recorded at a rare heart rate, while in probands with Andersen syndrome in the study of M. ln81at-Igoi21 the average heart rate was 84±17 beats/min (from 52 to 115 beats/min). min). It is known that with hypokalemia, the amplitude of the wave can also be high, however, we could not find any studies reporting the level of potassium in the blood serum in patients with high-amplitude waves, so the role of hypokalemia in the genesis of high-amplitude waves and in Andersen syndrome cannot be excluded. Auto-

Clinical manifestations of Andersen syndrome in probands with the mutant KSP gene

Mutation Cluster Gender Heart rate Duration OT, ms Rhythm disturbances

D71V 4415 F 100 513 Not detected

A95-98 (A-deletion) 3328 F 83 475 Bigeminy, polymorphic VT

8136B 6634 F 68 500 Bigeminia

P186b 7246 M 94 PBPNPG* Polymorphic VT

R218W 2401 F 100 560 Bigeminy, non-fatal cardiac arrest, 1st degree AV block, fibrillation, ventricular flutter

R218W 2679 M 68 510 Bigeminia, polymorphic VT

R218W 2681 F 75 488 Bigeminy, polymorphic VT

R218W 7480 M 94 525 Bigeminia

R218W 6515 M 52 416 Bigeminia, polymorphic VT

R218Q 6562 M 70 469 Not detected

G300V 3677 F 100 480 Bigeminia, polymorphic VT

V302M 2682 M 79 PBPNPG* Bigeminia

E303K 2281 F 85 495 Frequent ventricular extrasystoles

A314-315 5768 F 115 471 Fibrillation, ventricular flutter, monomorphic VT

* Complete right bundle branch block prevented accurate measurement of the OT interval.

The researchers also assessed the relationship between the severity of mutations (severity of Kr2.1 channel dysfunction) and the severity of clinical manifestations (prolongation of TPV, arrhythmias, neuromuscular symptoms, dysmorphogenesis) of Andersen syndrome. It turned out that the clinical phenotype of the disease did not correlate with the degree of dominant-negative suppression of the K1r2.1 channel function.

G. Andelfinge et al. identified the heterozygous missense mutation R67W of the KSH2 gene in 41 blood relatives, and it turned out that the inheritance of ventricular arrhythmias and periodic muscle paralysis differed by gender: for example, ventricular arrhythmias predominated in women (13 out of 16, or 81%), and neuromuscular symptoms - in men (10 out of 25, or 40%). At the same time, ventricular arrhythmias began to appear after the age of 10 years, and they were less frequent during pregnancy (while with other types of KSH2 gene mutations in women, rhythm disturbances were more frequent during pregnancy) and after 55 years (during menopause ). Notably, there was no prolongation of the OT interval in this pedigree. In this group of patients, three had a history of syncope; one patient who survived sudden cardiac death was implanted with a cardioverter defibrillator. In 8 male patients, episodes of muscle weakness or paralysis were noted after exercise, and in 2 there was hypokalemia. Hypertelorism was observed in 4 individuals, small mandible in 10, syndactyly of fingers or toes in 9, clinodactyly in 12. Signs of dysmorphogenesis were equally common in males and females. One male patient underwent surgical treatment for scoliosis, and one female patient for cleft palate. Very unusual was the identification in the studied pedigree of unilateral renal dysplasia and valvular pathology of the heart - pulmonary valve stenosis (diagnosed in one patient at the age of 6 months), bicuspid aortic valve (in 3 patients) and bicuspid aortic valve with coarctation of the aorta (in 1 patient ). Such abnormalities were first identified in patients with Andersen syndrome. In addition, there was a report of the death of a newborn with an unknown heart defect. First degree atrioventricular (AV) block was observed in 4 men and one woman in combination with left bundle branch block. No individual had all the manifestations characteristic of Andersen syndrome at the same time. Pleiotropy of phenotypic manifestations in Andersen syndrome within

This pedigree (Fig. 4) can be explained either by the specific effect of the R67W mutation, or by variation in the expression of alleles, or by the modifying effect of external factors.

There are few descriptions of treatments used for Andersen syndrome. As an example, we cite the report of J. Junker et al. : in a 6-year-old patient without a family history of hereditary or cardiovascular diseases, recurrent episodes of atonic paresis began to occur for the first time. At the age of 10 years, she was suspected of poststreptococcal myocarditis due to a high level of serum creatinease (up to 447 U/L) and asymptomatic polymorphic ventricular extrasystoles (PVCs) recorded on the ECG. Due to spontaneously stopping attacks of muscle weakness, doctors did not exclude the possibility of their psychogenic origin. At the age of 15 years, the patient experienced an episode of ventricular fibrillation (VF), and cardiopulmonary resuscitation was successfully performed. Programmed electrical stimulation induced sustained ventricular tachycardia, with a QTc of 0.45 s. The patient was implanted with a cardioverter-defibrillator (ICD). After a year, daily attacks of VF began to occur, requiring ICD shocks, and episodes of severe muscle weakness (even muscle paralysis) were observed. Among the features that attracted attention during the physical examination were: a wide base of the nose, clinodactyly, scoliosis and short stature. Atonic muscle paralysis covered different muscle groups of the upper and lower extremities, arose suddenly, lasted several hours or days and stopped on their own. Serum potassium and creatine kinase levels were normal. Attacks of weakness were induced by hyperkalemia or cold, and exercise was accompanied by a decrease in muscle action potential. Muscle biopsy revealed tubular aggregates and several vacuoles. The clinical diagnosis of the sporadic variant of Andersen syndrome was confirmed after a molecular genetic study that revealed a heterozygous missense mutation R218W of the KCNJ2 gene in the girl, but not in her parents. Sotalol and class I antiarrhythmic drugs (AAAs), including flecainide and propafenone, were ineffective. Amiodarone was added to the therapy with captopril, nadolol and digitoxin at a loading dose of 200 mg per day. Ventricular arrhythmias quickly disappeared, and attacks of muscle weakness continued to recur. After 2 months, acetazolamide (Diamox) was added to the above therapy at a dose of 750 mg per day. Over the next 2 years, the patient

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1 report either the failure of therapy with amiodarone and acetazolamide in patients with Andersen syndrome, or the need to discontinue it due to the development of side effects. On the other hand, there may be a pharmacogenetic interaction between the R218W mutation and the therapeutic response to amiodarone and acetazolamide, which requires confirmation in other patients. Since amiodarone inhibits IK1 current, it is logical to assume that it inhibits the hyperexcitability of the heart muscle by slowing the function of sodium and calcium channels, as well as beta-adrenergic receptors.

ditch, thereby correcting changes caused by the loss of function of the South2.1 channel. However, due to the potential for significant side effects, amiodarone may be recommended in patients with symptomatic arrhythmias. Acetazolamide, a drug that changes the acidity of the blood, can prevent attacks of periodic muscle paralysis of any origin due to the selective opening of muscle Ksa2+ channels, which may compensate for the dysfunction of the IK1 current and prevent a drop in the membrane potential of the muscles in Andersen syndrome. Patients with hypokalemic forms of muscle paresis can take potassium chloride dissolved in an unsweetened solution (symptoms usually disappear within an hour); they should avoid foods rich in carbohydrates and excessive exercise. Patients with hyperkalemic forms of muscle paralysis can prevent these attacks by eating frequent meals rich in carbohydrates and low in potassium.

Thus, we have presented the most comprehensive review to date on the clinical picture, diagnosis and treatment of Andersen syndrome, one of the unique pathologies among hereditary channelopathies due to the unusual combination of phenotypic manifestations of the cardiac and musculoskeletal systems in combination with various

figurative signs of dysmorphogenesis, the mechanism of occurrence of which still remains unclear. Similar to the discovery of new variants of such genetically determined diseases as long or short QT syndrome, further research in the field of molecular genetics will help identify new forms of Andersen syndrome and study more deeply the mechanisms of action of mutations (mutations can disrupt the functions of ion channels and transmembrane proteins at different levels of their interaction ) and explain the unusual phenotypic manifestations of this disease, and pharmacogenetic studies will help develop new treatment methods.

LITERATURE

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mutations of KCNJ2 suppress the native inward rectifier

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UDC 616.124.3:616.127]-07-08

DIAGNOSIS, COURSE AND TREATMENT OF AUTOSOMAL DOMINANT ARRHYTHMOGENIC CARDIOMYOPATHY/DYSPLASIA OF THE RIGHT VENTRICLE

L. A. Bockeria, V. A. Bazaev, A. Kh. Melikulov, U. T. Kabaev, O. L. Bockeria, R. V. Viskov,

A G. Filatov, A N. Gritsai, V. V. Chumakov

Scientific Center for Cardiovascular Surgery named after. A. N. Bakuleva (director - Academician of the Russian Academy of Medical Sciences L. A. Bockeria) RAMS, Moscow

rhythmogenic dysplasia of the right ventricle, or arrhythmogenic right ventricular cardiomyopathy/dysplasia - a pathology of unknown etiology, often hereditary, characterized by life-threatening

thick or fibrofatty infiltration of the myocardium, predominantly in the pancreas, accompanied by ventricular arrhythmias of varying severity, including ventricular fibrillation.

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