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Thomsen's and Becker's diseases are the most prevalent nondystrophic myotonias. Their frequency varies, according to different sources, from 1 : 100 000 to 1 : 10 000. Thomsen's myotonia is autosomal dominant, and Becker's myotonia is autosomal recessive. Both diseases result from mutations of the CLCN1 gene encoding chloride ion channels of skeletal muscles. Molecular genetic analysis of the CLCN1 gene has been performed in patients with diagnoses of nondystrophic Thomsen's and Becker's myotonias living in the Russian Federation. A sample of 79 unrelated probands with nondystrophic Thomsen's and Becker's myotonias and 44 their relatives has been formed in the Laboratory of DNA Diagnosis of the Medical Genetic Research Center of the Russian Academy of Medical Sciences. Forty CLCN1 gene mutations have been found in a total of 118 chromosomes of 66 probands, including 21 familial and 45 sporadic cases. About half the mutations detected (45%) have been found for the first time; they are not described in the SNP database (ncbi.nlm.nih.gov). The following mutations (substitutions) have been detected in more than one chromosome, accounting for a total of 59.3% of chromosomes with mutations: Glyl90Ser (5.9%), c.1437-1450del14 (9.3%), Ala493Glu (5.1%), Thr550Met (3.4%), Tyr686Stop (5.1%), and Arg894Stop (30.5%).

Syndrome Leigh (SL) or subacute necrotizing encephalomyelopathy - is a rare hereditary genetically heterogeneous disease from the group of mitochondrial encephalomyopathies. Twenty-seven children with SL were examined using clinical, laboratory (measuring lactate levels), MRI and molecular-genetic (polymerase chain reaction genotyping of 9 exons of the SURF1 gene) studies. The mean age of manifestation was 11,6 months. The main manifestations of SL were: delay of psychomotor development, diffuse muscle hypertonic, cerebellar syndrome, ophthalmoparesis, hypertrichosis. The disease had a progressive course with the loss of acquired skills. The blood lactate concentration was increased on average up to 3,1 mM/ml (from 1,9 to 5,1 mM/ml) compared to normal values (1,8 mM/ml). Brain MRI revealed the subcortical and cortical atrophy (80% of cases), symmetrical distinctly delineated hyperintense lesions on T2-weighted images (demyelization) in the basal ganglia and the brain stem (50%), as well as in the cerebellum (25%). Genotyping identified 7 different mutations. The most frequent (64,8%) was the deletion of 2 nucleotides (845delCT) in exon 8 that was in line with early data of Polish researchers thus indicating the Slavic origin of this mutation. Other mutations (574-575insCTGT, 311-321del10insAT and IVS8-1G>) were also frequent in the Russian population.

We present the results of the molecular genetic study of 26 patients, aged from 12 to 60 years, from 24 unrelated families with limb girdle-muscular dystrophy (LGMD) type 2A. The disease duration varied from 6 months to 30 years. The diagnosis of LGMD 2capital A, Cyrillic was confirmed by molecular genetic methods basing on the presence of a CAPN3 mutation in homozygous, compound-heterozygous and heterozygous state. The Leyden-Moebius variant that is characterized by the primary affection of muscles of pelvic girdle and shin with the gradual progression of the pathological process in shoulder girdle muscles was the most frequent in the Russian population. Tip-toe walking or difficulties in walking upstairs and running were the first symptoms reported by patients. In contrast to criteria of the European Neuromuscular Center, the characteristic symptoms of the disease were early contractures of ankle joints and pseudohypertrophy of gastrocnemius muscles. The major c.550delA mutation in the CAPN3 gene was identified in 70% of Russian patients.

We have analyzed mitochondrial DNA sequence in 15 Russian LHON patients and found the new mtDNA sequence variant in one family (2 patients) who showed 100% penetrance of the disease in men. This family has a T14484C primary mutation, and four secondary mutations (T4216C, G13708A, G15812A, G15257A), which belong to the European haplogroup J. The new sequence variant of A9016G in the ATPase 6 gene changed highly conserved amino acid of isoleucine to valine, has not been found in the rest of 13 LHON patients and controls. This novel sequence variant may contribute to the 100% penetration of LHON disorder in men of this family.

An integrated medical genetic an population genetic study has been performed in two raions (administrative districts) of the Tver oblast (region) of Russia: the Udomlya raion located in the zone affected by the Kalininskaya Nuclear Power Plant and the Ostashkov raion, which served as a control district. No significant differences has been found with respect to the genetic parameters studied. The values of these parameters in the populations of the town of Udomlya, the town of Ostashkov, the Udomlya raion, and the Ostashkov raion, respectively, are the following: random inbreeding, 0.00006, 0.00011, 0.000167, and 0.000366; endogamy index, 0.05, 0.43, 0.30, and 0.42; local inbreeding, 0.0003, 0.00045, 0.0009, and 0.0011; the degree of isolation by distance, 0.0003, 0.00045, 0.0009, and 0.0005; sigma, 2098, 1338, 1473, and 1189; the load of autosomal dominant (AD) diseases, 0.71, 0.92, 0.92, and 1.37; the load of autosomal recessive (AR) diseases, 0.68, 0.69, 0.67, and 0.82; and the load of X-linked diseases, 0.18, 0.64, 0.83, and 0.27.

The first population genetic study of hereditary disorders of the nervous system (HDNS) in Vladimir oblast was carried out. A total of 1,622,900 subjects, including 1,306,200 from the urban and 316,700 from the rural population, were tested. The population examined was characterized by virtually homogenous ethnic structure, with Russians constituting 95.76%. Pooled prevalence of HDNS in Vladimir oblast corresponded to the average prevalence for other Russian populations. Substantial differences between urban and rural populations in respect of the population load of HDNS and its nosological structure were not observed. A total of 22 nosological forms of HDNS were revealed, including thirteen autosomal dominant (193 families with 272 affected individuals), seven autosomal recessive (59 families with 66 affected individuals), and two X-linked (15 families with 17 affected individuals) diseases. The composition of the HDNS spectrum "nucleus" in Vladimir oblast displayed a number of differences from that in the majority of other populations examined. The HDNS in different regions of the area tested were characterized by different prevalence and spectrum. The data obtained may constitute a basis for regional registration of HDNS in Vladimir oblast.

Comprehensive population genetic and medical genetic studies were performed in three raions (districts) of Chuvashia. The population of these districts is more than 90% Chuvash. About 70% of the families that completed reproduction had two or three children. The proportion of families with four or more children was 18%. The duration of generation was 27.6 years. The differential fertility and differential mortality indices in the Chuvash population were estimated at 0.33 and 0.076, respectively. The total index of differential selection was 0.403, which is typical of modern urbanized populations. Mean values of local inbreeding calculated from Malecot's model of isolation by distance were 0.00124 and 0.00377 for the urban and rural populations, respectively, of the districts studied. The prevalence rates of autosomal dominant (AD), autosomal recessive (AR), and X-linked diseases were found to be 0.47, 0.52, and 0.35 per 1000, respectively, in the urban population and 1.62, 1.14, and 0.31 per 1000, respectively, in the rural population. Significant correlation between the local inbreeding and prevalence rates of AD and AR diseases was found. A total of 43 AD and 43 AR diseases were identified. Some of them were not found in previous studies on other populations.

A summary of the medical genetic studies of the Marii El population is presented. A total of 276,900 people, 110,894 and 166,006 urban and rural inhabitants, respectively, were examined. Regarding the ethnic composition, the studied population was mostly Mari (61.96%) and Russian (32.04%). Medical genetic examination revealed 480 subjects from 260 families with autosomal dominant (AD) diseases, 234 subjects from 184 families with autosomal recessive (AR) diseases, and 49 subjects from 41 families with x-linked diseases. Segregation analysis revealed a good agreement between the expected and observed segregation frequencies for families with AR and AD diseases and allowed the frequency of hereditary diseases in the urban and rural, as well as the Russian and Mari, populations, to be estimated. The total frequency of AD diseases in Maris was approximately twice as high as in Russians (1.99 and 0.97%, respectively); substantial differences between district populations were found. The total frequency of AR diseases was also two times higher in Maris than in Russians (1.00 and 0.54%, respectively). The frequencies of AR and AD diseases in different districts were correlated with the levels of random and local inbreeding, population size, and the index of maximum selection.

The spectrum and prevalence rate of hereditary pathology in Kanevskii and Bryukhovetskii raions (districts) of Krasnodar krai (territory) were analyzed. The total size of the studied population was 145,937. The prevalence rate of monogenic hereditary pathology was estimated. This value was 1.08 +/- 0.08, 0.72 +/- 0.07, and 0.20 +/- 0.06 per 1000 people for autosomal dominant (AD), autosomal recessive (AR), and X-linked (XL) recessive diseases, respectively. Forty-two AD (158 affected persons in 82 families), 32 AR (105 affected persons in 82 families), and 6 XL disease entities (13 affected persons in 8 families) were found. A slight genetic subdivision was found in the populations of Kanevskii and Bryukhovetskii raions. However, it was not found to affect the prevalence of hereditary pathology.

The diversity of Mendelian hereditary pathology was studied in Marii El Republic. In total, 276,900 subjects, including 171,151 Maris and 88,714 Russians, living in seven raions (districts) were studied. Fifty-five autosomal dominant disease entities were found, with more than ten diseases having a frequency of 1:50,000 people or higher. In Maris, autosomal recessive hypotrichosis was observed at a relatively high frequency (1:15,337); this disease was not revealed in the Russian population studied earlier. Conversely, no phenylketonuria (PKU) was found in Maris, while it was a relatively common autosomal recessive disease in Russians. Regarding autosomal dominant pathology, 76 disease entities were revealed, with 21 diseases being observed at a frequency of at least 1:50,000. Ten X-linked diseases were found. The numbers of both autosomal recessive and autosomal dominant diseases exhibited a linear relationship with the number of subjects examined. The genetic structure of the Mari population was studied on the basis of data on the genes of recessive diseases. A matrix of Nei's genetic distances was calculated from the frequencies of 45 recessive diseases found in the seven districts studied. The average genetic distance calculated for the 45 loci of autosomal recessive diseases was 0.006175 x 10(-3). Similarly, matrix of genetic distances for five Mari populations was obtained (Medvedevskii and Zvenigovskii raions were not included) based on a total of 32 allelic frequencies for ten polymorphic immune and biochemical loci. The average genetic distance calculated from the ten polymorphic loci was 0.001930, i.e., 2.5 orders of magnitude greater than the average genetic distance for recessive diseases. The matrices of genetic distances for the five Mari populations calculated from the gene frequencies for recessive diseases and for the ten polymorphic systems were largely similar to each other. Thus, the main elements of the genetic structure of the Mari population can be estimated on the basis of gene frequencies for hereditary diseases. In this case, the characteristics of individual populations, which are more or less isolated, and of their interaction are the same as in the case of studying genetic structure with the use of polymorphic biological markers.

A medical genetic study of Orshanskii, Morkinskii, Sovetskii, and Semurskii raions (districts) of the Marii El Republic was performed. The total number of subjects examined was 115,743. Meadow Maris and Russians accounted for the most part of the populations of the districts studied. A total of 147 families with presumably autosomal dominant (AD) pathology and 150 families with presumably autosomal recessive (AR) or X-linked pathology (270 and 169 affected persons, respectively) were revealed. Segregation analysis demonstrated a good agreement between the observed and expected segregation frequencies for both AR and AD diseases, as well as a considerable number of sporadic cases of presumably AD diseases. The incidence of hereditary diseases was estimated separately for different population groups. Significant differences in this incidence were revealed between the urban and rural, as well as between the Russian and Mari populations; the average incidence was 2.33 affected subjects per 1000 people. The incidence of AR diseases was significantly higher in Maris than in Russians (1.34 x 10(-3) and 0.82 x 10(-3), respectively). The populations studied exhibited a significant, high correlation between the incidence of AR diseases and the levels of random and local inbreeding. The incidence of X-linked recessive diseases was approximately the same as in Russian populations studied earlier. Its average value was 0.5 per 1000 men; the incidence in the Mari and Russian populations did not differ significantly. The higher AD incidence in the total population studied and the higher AR incidence in the Meadow Mari population compared to the populations studied earlier are discussed.

The population of Gornomariiskii raion, Marii El Republic, primarily made up of mountain Marii, was subjected to medical genetic examination. The size of the entire population is 54853. Estimates of hereditary pathology in urban and rural populations of the raion were obtained. They were 0.68 and 1.11, respectively, for autosomal dominant pathology (AD); 0.55 and 0.81 for autosomal recessive pathology (AR); and 0.45 and 0.20 for X-linked pathology. Twenty-two, 25, and six nosologic forms of autosomal dominant, autosomal recessive, and X-linked diseases were revealed, respectively. We attempted to compare the sample under consideration with previously studied Russian and Finnish populations for rare pathologic recessive genes.

A population genetic study of spinal amyotrophy (SMA) in six Russian and three Central Asian regions was carried out. In total, 29 patients with autosomal recessive (AR) infantile proximal SMA (SMA I-III) and four patients with rare SMA forms with an unspecified type of inheritance were revealed. In Russian populations, the prevalence of SMA I-III is similar (1.5-2.5/100000), it is one of the most common hereditary neurological diseases. A tendency toward nonuniform territorial SMA prevalence is observed in genetically subdivided populations. The lesser SMA I-III prevalence in Central Asian populations might be due in part to inbreeding depression. A segregation frequency of 0.21 is in accordance with AR inheritance; the proportion of sporadic cases is 3%. Clinical genealogical data support the genetic unity of forms I-III. The origin of pedigrees with SMA in distant relatives is discussed.

15 families (27 patients) with hereditary spastic paraplegia (HSP) were found in the course of monogenic disorders investigation in 6 Russian populations. High HSP prevalence (7.21+1.61) x 10(-5) was found in Kirov Province [the frequency of the gene of autosomal-dominant form was (3.61 +/- 1.14) x 10(-5), autosomal-recessive-(64.5 +/- 9.74)- 10(-6)]. The pronounced interfamilial polymorphism of HSP was observed. Two families with rare autosomal-recessive variation of "clear" HSP as well as two families with HSP associated with peroneal amyotrophies were revealed. Accumulation of cases with unusual combination of autosomal-dominant HSP together with mental deficiency was remarkable in Kirov Province.

All the cases of hereditary motor and sensory neuropathy (HMSN) in an eastern part of Kirov region (Russian north-east) were ascertained (N = 42 including 11 persons with pre/subclinical forms; m: f = 1). HMSN prevalence is 15.95 +/- 2.47.10(-5) being higher in rural than in urban populations. The distribution of HMSN families (total 16) in 9 districts of the region is uneven. HMSN is the most common of all hereditary muscular disorders in the region. Autosomal dominant inheritance was established in 12 families, AD gene frequency is 10.90 +/- 2.90.10(-5) gene penetrance being 90%. Sporadic cases were few (N = 4; 9.76%). No proven autosomal recessive or X-linked inheritance was found out.

The main purpose of this report is to present the nosological spectrum of hereditary diseases in 9 Districts of Kirov Province and to compare it with that studies earlier in other Russian populations. This comparison is undertaken in an attempt to define a "nucleus" of hereditary diseases in the Russian population studied. During this study 343 families with 546 affected were registered. The spectrum covered 55 different autosomal dominant, 14 autosomal recessive and 11 X-linked recessive hereditary disorders in the population under study. Some of these forms could be considered as common forms for the whole Russian population, because they were met in all Russian populations which were analysed. This conclusion is proved by the cluster analysis of genetic distances calculated on the basis of gene frequencies for autosomal recessive hereditary disorders.

Medical-genetic study was carried out in the population of Kirov Province (population size about 120.000). 203 families with 334 affected with hereditary disorders were registered. The correctness of pathology classification for the inheritance type was confirmed by segregational analysis. The load of hereditary diseases in the population was: 1.25 +/- 0.06 for autosomal dominant, 1.37 +/- 0.07 for autosomal recessive and 0.22 +/- 0.06 for X-linked recessive disorders. It is suggested that variability in the values of the load of autosomal recessive disorders is determined to the large extent by genetic structure of the population.

Data on the prevalence of hereditary diseases in five regions of the Kostroma province were obtained and analysed. 28 autosomal recessive, 25 autosomal dominant and 4 X-linked recessive disorders were found. Segregation analysis proved the rightness of the material subdivision, according to the type of inheritance. The load of hereditary diseases in five regions was: 0.86 +/- 0.09 X 10(3) for autosomal recessive, 0.97 +/- 0.1 X 10(3) for autosomal dominant and 0.36 +/- 0.09 X 10(3) for X-linked recessive disorders. The problems of prevalence of hereditary diseases connected with population structure is discussed.

The diversity of hereditary pathology in Kostroma was studied. An attempt was made to classify all isolated cases by genetic and clinical analysis. 57 nosological forms of autosomal dominants, 41 autosomal recessive and 14 X-linked recessive disorders were found. The analysis of marriage distances in the whole population and in the families of the probands was carried out. The spectra of hereditary pathology in Kostroma and Kostroma Province were compared. The sources of the load of hereditary pathology in Kostroma are discussed.