[A pilot study of idebenone in the treatment of patients with hereditary myopathies]. / Pilotnoe issledovanie idebenona v lechenii bol'nykh s nasledstvennymi miopatiyami.

OBJECTIVE: To evaluate the efficacy of the energotropic drug idebenon in hereditary neuromuscular pathology. MATERIAL AND METHODS: A total of 9 patients with hereditary myopathies were examined during treatment with idebenone. Determination of muscle strength was carried out on the British medical research Council scale (0 points - no active movements, 5 points - no muscle weakness). The examination was performed before and 1 month after the start of treatment. Treatment regimen: idebenone was prescribed in a daily dose of 90 mg. RESULTS: In the general group of patients with hereditary ataxia, the median strength of the biceps muscle of the shoulder during treatment increased from 3.5 to 4.0 points (p>0.05). The median strength of the ilio-lumbar muscle increased from 3.0 to 4.0 points (p>0.05). Before treatment, the median number of sit-ups was 0, and after 1 month - 2 (p>0.05). CONCLUSION: We used the energotropic drug idebenon, a synthetic analog of the natural substance coenzyme Q10, which is involved in electron transfer in the mitochondrial respiratory chain complex III, for the treatment of patients with hereditary myopathies. In the general group of patients, there was an increase in muscle strength, although it did not reach statistical significance. Before the advent of energotropic drugs, the use of various methods of treating hereditary myopathies did not lead to an increase in muscle strength in patients. Therefore, the identified positive dynamics is of great importance in providing medical care to these patients and improving their quality of life.

[Hereditary spastic paraplegia type 4 (SPG4) in Russian patients]. / Nasledstvennaia spasticheskaia paraplegiia 4-go tipa u rossiiskikh bol'nykh.

AIM: To investigate molecular, clinical and genealogical characteristics of SPG4 in a first representative Russian group, to estimate SPG4 proportion among all DNA-diagnosed spastic paraplegias. MATERIAL AND METHODS: Fifty unrelated Russian families with SPG4 detected in the course of clinical and molecular studies of spastic paraplegias were studied. Clinical, genealogical and several molecular methods were used, i.e. Sanger sequencing of SPAST, massive parallel sequencing MPS (panel 'hereditary paraplegias') and multiplex ligation-dependent amplification MLPA. RESULTS: SPG4 proportion was 56% among all DNA verified SPG cases (90 families/14 forms) and 68% in subgroup of dominant SPG. In 50 families, 43 different SPAST mutations were detected, of which 21 were novel; percentage of large rearrangements was 30% (13 mutations in 15 families). Four mutations were detected in two families each, nonsense mutation c.1291C>T (p.Arg431*) in 4 unrelated families. Proportion of familial cases was 68%, pedigrees with 'missing' disease in elderly carriers pointed to incomplete penetrance. Age of onset varied from one year to 58 years, middle-age onset was common but the proportion of early-onset cases, particularly in male index cases, was also high. Onset age showed marked intrafamilial differences (more than 10 years in 14 pedigrees, up to 50 year in one) and between families with identical mutations. Insidious onset, slow development with most patients ambulant and 'uncomplicated' phenotype were typical. Cases with additional signs were: a family with ataxia in both patients, two families with epilepsy in one of SPG4 patients; three families with mild mental deficiency in one of SPG4 patients. A case described separately is a 29-year-old male patient with indeterminate myalgia and no SPG signs in whom SPAST previously reported mutation p.Ala430Thr de novo was an unexpected MPS finding. CONCLUSION: SPG4 substantially predomimates in SPG structure in Russian families as practically everywhere else. Half of 43 detected SPAST mutations are novel, the proportion of large rearrangements is 30% higher than in most of studies. Clinical inter- and intrafamilial variability concerns mostly age of onset. SPG4 is not exclusively adult-onset as was thought earlier.

[Mitochondrial disorders in multiple sclerosis]. / Mitokhondrial'nye narusheniia pri rasseiannom skleroze.

AIM: To determine the mitochondrial dysfunction in multiple sclerosis (MS). MATERIAL AND METHODS: Fourteen adult patients with MS and 23 healthy people were examined. Cytochemical analysis of lymphocytes in peripheral blood was carried out. The activity of the mitochondrial enzymes involved in metabolism of carbohydrates (lactate dehydrogenase, LDH), amino acids (glutamate dehydrogenase, GDH), fatty acids (alpha-glycerophosphate, α-GPDH) and II complex of the mitochondrial respiratory chain (succinate dehydrogenase, LDH), and the level of lactate in the blood were measured. RESULTS AND CONCLUSION: The activity of α-GPDH was reduced in 62.5% patients and increased in 37.5%. GDH activity in all patients was lowered. LDH activity was reduced in 71.4% patients and compensatory increased in 28.6%. In 66.7% patients, LDH activity was reduced and in 33.3% compensatory increased. Increased blood lactate was observed in 33.3% patients before meal and 44.4% after carbohydrate loading. After carbohydrate loading, in 33.3% patients lactate levels in the blood increased and in 11.1% increased above normal values. Therefore, the enzyme activity have decreased in most patients that suggests the decompensation of mitochondrial function. The results indicate the advisability of administering the energotrophic drugs carnicetin and coenzyme Q10 (idebenone) in patients with MS.

[Outcomes and treatment of myasthenic crisis]. / Iskhody i lechenie miastenicheskogo kriza.

AIM: The analysis of fatal outcomes of myasthenic crisis in patients with myasthenia. MATERIAL AND METHODS: The data on 19 patients with myastheniccrisis admitted at the Moscow Regional Research and Clinical Institute («MONIKI¼) over 12 years (1997-2009) have been summarized. RESULTS AND CONCLUSION: There are more than 600 patients with myasthenia in the Moscow region, including 13% patients with onset after 60 years. Seventeen patients of 19 were in the intensive care unit. Total death occurred in 7 cases (36.6%). Myocardial infarction, bilateral confluent pneumonia and hemorrhagic pulmonary edema caused death. All patients had concomitant diseases: hypertension, myocardial changes, hyperglycemia and others. Steroids and plasmapheresis were used for treatment of myasthenic crisis. The authors believe that methods of treatment of myasthenic crisis that does not lead to complications in elderly age and are suitable for patients with concomitant diseases, who can't be treated with glucocorticoids and plasmapheresis, should be used in clinical neurology. Normal human intravenous immunoglobulin is recommended in these cases.

[Hereditary spastic paraplegia type 4 (SPG4): clinical and molecular-genetic characteristics].

Hereditary spastic paraplegia (HSP), type 4, or SPG4, caused by various mutations in the spastin gene (SPAST) is the most common disorder in a heterogeneous group of autosomal dominant HSP's. We performed a search of SPAST mutations by routine methods (SSCP and subsequent direct sequencing of fragments with modified electrophoretic mobility) in a sample of 26 families with autosomal dominant HSP from different Russian regions. In six families, five of Russian and one of Tatar ethnicity, different SPAST mutations were detected. Three of the mutations, Arg431Stop, Gln280Arg FsX9 and Asn386Ser, were reported previously; the remaining three, Asp555Tyr, Thr369Thr and Asn184Thr, were novel. In the family with the Arg431Stop mutation, a linkage to SPG4 locus was also established, lod scores were 1,66 for D2S352 marker and 1,51 for D2S367. Another large family also showed a linkage to the SPG4 locus (lod scores 1,68 for D2S352, 2,17 for D2S367) but the mutation was not found which may be due to atypical SPAST mutations (large deletions etc) undetectable by routine methods of DNA analysis. Including this family, the proportion of the SPG4 in the sample is 27%, which is less than average literature data (40-45%). Most of our patients presented relatively late-onset "uncompicated" HSP, which was typical for SPG4, though different additional features in SPG4 patients were also known. One of our patients had very early-onset HSP and concomitant epilepsy. In two pedigrees, in which all available relatives were examined, some patients had mild signs of SPG4, even late in life.

[Photopheresis--anew method for treatment of myasthenia]. / Fotoferez--novyi metod lechenia miastenii.

Photopheresis with blood lymphocytes UV radiation exposure was for the first time used in the treatment of patients with myasthenia. Twenty-three patients with generalized form of the disease, aged 23-66 years, were treated. Twenty patients (87%) exhibited clinical improvement after a treatment course (4 sessions). One photopheresis session was shown to be more or less beneficial in 16 out of 23 patients (70%). The treatment resulted in strengthening of all the muscles studied, especially of mimic, platysma, biceps, deltoid, illiopsoas and gastrocnemius. Photopheresis was effective not only in a mild and moderate but in severe form of myasthenia as well. Compared to plasmapheresis, photopheresis exerts a more prolonged effect. Clinical improvement correlated with positive changes in immune status of the patients.

[Acetylcholine receptor antibodies in patients with myasthenia]. / Antitela k retseptoram atsetilkholina pri miastenii.

Acethylcholine receptor (AChR) antibodies in patients with myasthenia were studied for the first time in Russia with radioimmuno-assay application. Seronegative result (antibody titer lower than 0.2 nmol/l) was obtained for 33% of the patients and seropositive one (antibody titer higher than 0.2 nmol/l)--for 67%. AChR antibodies level varied from 1.9 to 115.0 nmol/l. The AChR antibodies were found more frequently and in higher titers in women than in men. Correlation analysis revealed strong correlation between AChR antibodies level and severity of myasthenia.

Congenital myasthenic syndrome (CMS) in three European kinships due to a novel splice mutation (IVS7 - 2 A/G) in the epsilon acetylcholine receptor (AChR) subunit gene.

Mutations in the epsilon-acetylcholine receptor (AChR epsilon) subunit gene cause congenital myasthenic syndromes (CMS) with postsynaptic neural transmission defects. We present 3 male and 2 female patients from three unrelated Croatian, Hungarian, and Russian families with autosomal recessive CMS. All patients manifested with variable degrees of ophthalmoparesis and generalized, fatiguable muscle weakness since birth or early infancy. Electrophysiological studies showed a decremental response in all patients indicating a neuromuscular transmission defect. Pyridostigmine treatment improved the proximal muscle weakness whereas the ophthalmoparesis remained unchanged in all patients. Analysis of the AChR epsilon subunit gene showed homozygosity for a novel splice site mutation of intron 7 epsilon(IVS7-2A/G) in the two Croatian siblings. epsilon-mRNA analysis by RT-PCR and direct sequencing revealed that exon 7 was spliced directly to exon 9 with skipping of exon 8. The Hungarian and Russian patients were heteroallelic carriers of the same mutation epsilon(IVS7-2A/G) and of a frameshifting mutation epsilon 70insG and epsilon 1293insG, respectively. We hypothesize that altered splice products may not be expressed as functional receptors at the cell surface. A haplotype analysis with polymorphic markers revealed a high degree of similarity for the epsilon(IVS7-2A/G) carrying allele in all families and may therefore indicate a common origin of the mutation.

[Antigens of histocompatibility in children with myasthenia gravis]. / Antigeny gistosovmestimosti pri miastenii u detei.

HLA-phenotype was determined in 59 juvenile patients of Russian nationality and in their 50 relatives by means of lymphocytotoxic test. There was a positive association with HLA-A1, B8 and DR3 and the negative one--with HLA-A2, A9, B5, B7, and DR7. The frequencies of HLA-A1, B8, DR3 were higher in boys than in girls with myasthenia. There were no significant changes of HLA frequencies in ocular form of the disease in comparison with the healthy group. The frequencies of HLA-B8 and DR3 were significantly higher in relatives of the patients with juvenile myasthenia than in control population.

[Twin studies of myasthenia]. / Bliznetsovye issledovaniia miastenii.

Twin pairs with one or two myasthenic patients were selected from patients with neuromuscular pathology. 18 couples of twins were included in final selection (9 monozygotic and 9 dizygotic pairs). 4 pairs of monozygotic twins were concordant to myasthenia (MA). All dizygotic pairs were discordant to this disease. Matched concordance of monozygotic twins was 44%. Penetration of pathological gene was 61% assuming the hypothesis about monogenic heredity of MA. The coefficient of heredity was 44%. The conclusion was made about important, but not absolute role of hereditary factors in development of MA. It was necessary the presence of combination of both genetic and environmental factors for MA development.

[Analysis of the association of ABO blood groups and Rhesus factor with myasthenia]. / Analiz assotsiatsii grupp krovi ABO i rezus-faktora s miasteniei.

The distribution of ABO blood groups and rhesus factor was studied in patients with myasthenia as compared with the control. There was a statistically significant association of the diseases with the rhesus-negative phenotype and that of generalized myasthenia concurrent with thymoma with the B (III) blood group. The examination revealed no other determinants of the significant association with the disease. The values of a disease risk were obtained for persons having myasthenia-associated signs. It is concluded that the Rh-negative phenotype shows a 1.3-fold increase in the risk of the disease as compared with those having Rh-positive persons.

[The role of mutagenic factors in the development of diffuse toxic goiter]. / Rol' mutagennykh faktorov v razvitii diffuznogo toksicheskogo zoba.

The role of mutagenic factors in the onset of diffuse toxic goiter (DTG) was studied in 49 families of probands with DTG. The evidence obtained on the order in which the child was born in the proband's family, age of the parents at the time of DTG child delivery, implications of occupational factors in DTG onset does not rule out mutagenic effects in the origin of DTG and thus feasibility of the key gene influence on the disease predisposition.

[Late results of surgical treatment of myasthenia gravis in children]. / Otdalennye rezul'taty khirurgicheskogo lecheniia miastenii u detei.

Thymectomy was carried out in 52 children with the generalized form of myasthenia at the Moscow Regional Research Clinical Institute in 1986-1991. The long-term results were studied in 50 patients in follow-up periods of 6 months to 5 years. The follow-up was studied in all patients, the muscular strength in various groups of muscles was measured according to a 5-point scale, and the function of external respiration, neuromuscular conductivity, and cellular and humoral immunity were studied. After thymectomy the symptoms of myasthenia disappeared completely or diminished significantly, the decrement was 11% on the average instead of 37% as was before the operation, the external respiration values improved, the level of circulating immune complexes and immunoglobulins became normal. The long-term results were appraised according to G. Keanes' scale. Group A was made up of 22 patients, group B of 13, group C of 5, group D of 8, and group E of 2 patients. Thus, the study shows that thymectomy is the most effective method for the treatment of myasthenia in children today.

[Surgical treatment of myasthenia gravis in children]. / Khirurgicheskoe lechenie miastenii u detei.

Thymectomy was included in the complex of therapeutic measures in the management of generalized myasthenia in 41 children. Much attention was given to preoperative management in which plasmapheresis was applied along with the traditional methods. As a result, maximum compensation of the myasthenic disorders was achieved and spontaneous respiration was restored in 9 patients who were given artificial ventilation of the lungs before the operation. The authors describe the techniques of thymectomy and the changes found in the thymus during histological study. No complications occurred. All of the children were discharged from the clinic in an improved condition. The late-term results were studied in 38 children in follow-up periods of 6 months to 4 years. Marked stable improvement was recorded in 31 (77.5%) patients.

[Clinical characteristics of myasthenia gravis in children and the role of plasmapheresis in its complex treatment]. / Klinicheskie osobennosti miastenii u detei i rol' plazmafereza v kompleksnoi terapii.

The authors describe the course of myasthenia in children whose mean age of the disease onset is 10.1 years (7.9 years in boys and 11.2 years in girls). All the children had generalized myasthenia. The use of plasmapheresis produced a beneficial effect in all the cases, especially in children with grave myasthenia.

[Clinical characteristics of hereditary ataxia]. / Klinicheskie osobennosti nasledstvennykh ataksii.

Employing the clinical signs of diseases the authors compared characteristics of different hereditary ataxias (Friedreich's ataxia, familial spastic paraplegia, Marie's disease, olivopontocerebellar atrophy, Roussy-Levy syndrome, and Charcot-Marie neural amyotrophy). It is emphasized that clinico-genealogical examination is essential for the identification of the nosological form of the disease.