ABSTRACT
RSMD1 is a rare autosomal recessive disorder. Unlike most congenital muscular dystrophies, early motor improvement and normal CPK are typical, while in contrast to structural myopathies there is no specific muscle morphology. Rigid spine, early scoliosis and joint contractures are characteristic. We diagnosed RSMD1 in a 27-year-old Russian female with previous diagnosis of unspecified myopathy. DNA test detected compound heterozygosity for two SEPN1 mutations: already known missence-mutation c.1397G>A (p.Arg466Gln) and novel frame-shift mutation c.683_689dup7 leading to preterm stop-codon.
Subject(s)
Mallory Bodies/pathology , Muscle Proteins/genetics , Muscular Dystrophies/genetics , Scoliosis/genetics , Selenoproteins/genetics , Adult , Codon, Terminator/genetics , Female , Humans , Mallory Bodies/genetics , MutationABSTRACT
AOA are autosomal recessive ataxias with a common feature of oculomotor apraxia (OA) - inability to coordinate eye movements. The group includes AOA1 (APTX gene), relatively common AOA2 (SETX gene) and AOA3 (PIK 3R5 gene) described in 2012 in a Saudi family. OA is typical also for Louis-Bar ataxia-telangiectasia and its variants. Ð first Russian AOA2 case confirmed by DNA test is presented. The disease in a 25-year-old male started in 18 years, in 23 years he lost independent walking due to incoordination and weakness. OA produced few symptoms and was not recorded previously. Sensorimotor axonal polyneuropathy was confirmed by EMG. MRI showed cerebellar atrophy. Alpha-fetoprotein level was tenfold raised. A hereditary ataxia was considered from the disease onset, and a number of genetic tests were performed, but AOA2 was recognized only seven years later. On direct sequencing of SETX exons 6-8 a novel frame-shift mutation Ñ.2623-2626 del 4 in heterozygous state was detected which is sufficient for AOA2 confirmation; the allelic mutation is in search. Recently a first Russian AOA1 case in a 15-year-old girl was also confirmed in our laboratory: compound-heterozygosity for two novel APTX mutations was detected. Evidently AOA are underestimated in clinical diagnostics while DNA testing permits genetic prophylaxis in families. OA should be purposefully searched for in children and young adults suspicious of autosomal recessive ataxias.
Subject(s)
Apraxias/diagnosis , Apraxias/genetics , Ataxia Telangiectasia/diagnosis , Ataxia Telangiectasia/genetics , Hypoalbuminemia/diagnosis , Hypoalbuminemia/genetics , RNA Helicases/genetics , Adolescent , Adult , Cerebellar Ataxia/congenital , DNA/genetics , DNA Helicases , DNA Mutational Analysis , DNA-Binding Proteins/genetics , Exons/genetics , Female , Genetic Carrier Screening , Humans , Magnetic Resonance Imaging , Male , Multifunctional Enzymes , Mutation , Nuclear Proteins/geneticsABSTRACT
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%).
Subject(s)
Chloride Channels/genetics , Mutation , Myotonia Congenita/genetics , Amino Acid Substitution , Female , Humans , Male , Myotonia/genetics , Pedigree , RussiaSubject(s)
Foot Deformities, Congenital/diagnosis , Myotonia Congenita/diagnosis , Adult , Chloride Channels/genetics , DNA Mutational Analysis , Electromyography , Female , Foot Deformities, Congenital/complications , Foot Deformities, Congenital/genetics , Gait Apraxia/etiology , Humans , Myotonia Congenita/complications , Myotonia Congenita/genetics , RNA-Binding Proteins/geneticsABSTRACT
Niemann-Pick disease, type C is a rare hereditary disorder of the group of lisosomal storage diseases, caused by mutations in the genes NPC1 or NPC2. Depending on the onset age, several clinical forms of this disease, which differs by manifestation age, main clinical signs and clinical course, are distinguished. Niemann-Pick disease type C can imitate other hereditary and acquired diseases, which complicates its early diagnostics. Clinical and genetic diversity of this disorder, considered on the clinical cases diagnosed at the FSI "RCMG" of RAMS, are discussed in this review.
Subject(s)
Carrier Proteins/genetics , DNA/genetics , Genetic Therapy/methods , Membrane Glycoproteins/genetics , Mutation , Niemann-Pick Disease, Type C/genetics , Genetic Predisposition to Disease , Genetic Variation , Humans , Niemann-Pick Disease, Type C/therapyABSTRACT
Myoclonic epilepsy of Lafora (EPM2) is a severe autosomal recessive disorder. The onset in adolescence, generalized seizures, severe myoclonus, dementia and a rapid malignant course with death in 4-8 years after the onset are characteristic features of EPM2. The disease has a specific pathological feature, intracellular polyglucosan inclusions (Lafora bodies) in the brain, liver, skin and muscles. Two genetic forms are known, one of which (EPM2A) is caused by mutations in the laforin gene and another (EPM2B)--by mutations in the malin gene. We report a case of EPM2A in a 17-year-old girl of mixed Russian-Ukrainian ethnicity. The disease lasted for almost four years by the time of the examination but the girl still had no dementia. A previously described laforin mutation Tyr86Stop in the homozygous state was detected and Lafora bodies were found in the skin and muscles. Various anticonvulsants produced no effect or a slight and unstable effect. In the following several months, the disease progressed quickly, the girl became severely disabled and demented and died in 19 years old, 5.5 years after the disease onset. This is a first Russian case confirmed by DNA testing.
Subject(s)
Lafora Disease/diagnosis , Anticonvulsants/therapeutic use , DNA/analysis , DNA/genetics , Electroencephalography , Fatal Outcome , Female , Genetic Predisposition to Disease , Humans , Lafora Disease/drug therapy , Lafora Disease/genetics , Lafora Disease/pathology , Mutation , Protein Tyrosine Phosphatases, Non-Receptor/genetics , Sweat Glands/pathology , Young AdultABSTRACT
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.
Subject(s)
Adenosine Triphosphatases/genetics , Spastic Paraplegia, Hereditary/diagnosis , Spastic Paraplegia, Hereditary/genetics , Adolescent , Adult , Aged , Child , Child, Preschool , DNA Mutational Analysis , Female , Humans , Middle Aged , Mutation , Pedigree , Spastic Paraplegia, Hereditary/physiopathology , Spastin , Young AdultABSTRACT
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.
Subject(s)
Calpain/genetics , Muscle Proteins/genetics , Muscular Dystrophies, Limb-Girdle/genetics , Muscular Dystrophies, Limb-Girdle/physiopathology , Adolescent , Adult , Child , Female , Humans , Male , Middle Aged , Muscular Dystrophies, Limb-Girdle/diagnosis , Mutation , Russia , Sequence Deletion , Young AdultABSTRACT
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.
Subject(s)
DNA/genetics , Leigh Disease/genetics , Membrane Proteins/genetics , Mitochondrial Proteins/genetics , Mutation , Child , Child, Preschool , Diagnosis, Differential , Female , Genetic Predisposition to Disease , Genotype , Humans , Infant , Leigh Disease/diagnosis , Leigh Disease/epidemiology , Magnetic Resonance Imaging , Male , Membrane Proteins/metabolism , Mitochondrial Proteins/metabolism , Polymerase Chain Reaction , Prevalence , Russia/epidemiology , Ukraine/epidemiologyABSTRACT
A search for emerin and lamin A/C (LMNA) mutations was performed in a group of 63 unrelated patients with probable Emery-Dreifuss muscular dystrophy (EDMD) and other MD's with concomitant dilated cardiomyopathy (DCMP). Four different emerin mutations and 7 LMNA mutations were found in unrelated patients. One emerin mutation and 2 LMNA mutations, one of the latter being found twice, have been registered earlier; the rest of the mutations are novel. All the patients with emerin mutations and 3 patients with LMNA mutations represented single cases while 4 LMNA-related cases were familial. De novo origin was proved for one emerin and 3 LMNA mutations. Apart from EDMD phenotypes, varying also in age at onset and severity, 2 cases of limb girdle MD type 1B were diagnosed. One patient with LMNA mutation and severe DCMP had subclinical signs of skeletal myopathy only. There was an overlap between DCMP type 1A and MD's. Autosomal dominant EDMD seems to be more common than "classic" X-linked EDMD. We found neither emerin nor LMNA mutations in a subset of families with EDMD-like phenotypes that may imply an existence of other genes causing similar disorders. Taking into account clinical variability of MD's caused by emerin and LMNA mutations, DNA diagnosis should not confine to the "classic" phenotype. DNA diagnosis of EDMD is important boht for medical genetic counseling and for patients' management: timely diagnosis of the disease allows one to prevent fatal cardiologic complications.
Subject(s)
DNA/genetics , Lamin Type A/genetics , Membrane Proteins/genetics , Muscular Dystrophy, Emery-Dreifuss/genetics , Mutation , Nuclear Proteins/genetics , Adolescent , Adult , Child , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Muscular Dystrophy, Emery-Dreifuss/metabolism , Pedigree , Phenotype , Polymorphism, Single-Stranded Conformational , Prognosis , Risk FactorsSubject(s)
Cardiomyopathy, Dilated/genetics , DNA/genetics , Lamin Type A/genetics , Mutation, Missense , Adolescent , Adult , Electrophoresis, Polyacrylamide Gel , Female , Genetic Markers , Humans , Infant , Male , Middle Aged , Pedigree , Polymerase Chain Reaction , Polymorphism, Single-Stranded ConformationalABSTRACT
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.
Subject(s)
Consanguinity , Genetic Diseases, Inborn/epidemiology , Genetic Testing , Genetics, Population , Female , Humans , Male , Population Dynamics , Power Plants , Russia , Surveys and QuestionnairesABSTRACT
Comparing to other mitochondrial diseases, multisystemic lesions in Leber's hereditary optic atrophy (LHOA) occur less frequently. However, in some cases there are concomitant manifestations, especially neurological ones. Out of thirteen patients examined in the study, 5 exhibited MRI-detected neurological symptoms and changes, which may have concern to the underlying disease, namely LHOA caused by 11778A mutation. Literature and author's own data on neurological spectrum of LHOA and its possible relation to multiple sclerosis are summarized. A rare combination of LHOA caused by 14484C mutation and diabetes mellitus, described first-ever in the present study, is emphasized.
Subject(s)
Diabetes Complications , Gene Expression/genetics , Long QT Syndrome/complications , Optic Atrophy, Hereditary, Leber/complications , Optic Atrophy, Hereditary, Leber/genetics , Point Mutation/genetics , Wolff-Parkinson-White Syndrome/complications , Adolescent , Adult , DNA Mutational Analysis , Evoked Potentials, Visual/physiology , Female , Humans , Male , Optic Atrophy, Hereditary, Leber/physiopathology , Visual Acuity/physiologyABSTRACT
Leber's hereditary optic neuropathy (LHON) is a worldwide spread neuro-ophthalmologic disease characterized by immediate pronounced visual reduction with a picture of retrobulbar neuritis, following by optic atrophy. The disease is caused by mitochondrial DNA mutations. Molecular genetic structure of 12 families, including 26 LHON patients, 13 of them being examined, is presented. All of the main primary mutations have been found: the most frequent 11778A (in 10 families), 3460A and 14484C (each in 1 family). In 5 families, the disease was clearly hereditary. Men predominated among the patients, that indicated a reduction of the gene penetrance in women. The most frequent age at the disease onset is 18-25 years. Clinico-genealogical LHON mechanisms correlate with mutation type. Molecular genetic mechanisms of the disease and possible environmental factors, influencing the gene penetrance, are discussed.
Subject(s)
Mutation/genetics , Optic Atrophy, Hereditary, Leber/genetics , Adolescent , Adult , DNA Mutational Analysis , Female , Humans , Male , Middle Aged , Optic Atrophy, Hereditary, Leber/diagnosis , PedigreeABSTRACT
The experience of DNA-diagnosis of X-linked recessive Emery-Dreifuss muscular dystrophy for the first time made in Russia is presented. A search for mutations in emerin gene responsible for the disease has been conducted in 13 blood samples of male patients with clinical diagnosis of various muscular dystrophy. Mutations were found in 2 patients. In one of them clinical diagnosis of Emery-Dreifuss muscular dystrophy was confirmed. In the other, a novel mutation was described that allowed to change a clinical diagnosis of limb girdle muscular dystrophy. X-linked and clinically identical autosomal-dominant forms of Emery-Dreifuss muscular dystrophy are characterized by pronounced clinical polymorphism complicating clinical diagnosis. DNA-diagnosis principally extends possibilities for early diagnosis of this disorder that is extremely important for prevention of severe and frequently lethal heart diseases.
Subject(s)
Membrane Proteins/genetics , Muscular Dystrophy, Emery-Dreifuss/diagnosis , Thymopoietins/genetics , DNA Mutational Analysis , Humans , Male , Membrane Proteins/blood , Muscular Dystrophy, Emery-Dreifuss/genetics , Mutation , Nuclear Proteins , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational , Thymopoietins/bloodABSTRACT
X-linked adrenoleukodystrophy (X-ALD) is a relatively common world spread disease characterized by significant clinical heterogeneity. Clinico-biochemical examination in the Medico-genetic research center identified, 20 X-ALD cases in 17 families over 5 years. Prevalence of children (60%) and adolescence (25%) cerebral forms is explained, in part, by patients referring for medical-genetic counseling. Adrenomyeloneuropathy was diagnosed in one patient. In two healthy siblings presymptomatic stage was found. A main X-ALD biochemical marker is an increase of very long chain fatty acids (VLCFA) level, which does not depend on clinical form of the disease. Most interesting appeared to be a family including 5 patients in 3 generations with intrafamilial combination of childhood and adolescence cerebral forms, and atypically mild disease course in proband. Regarding symptoms of childhood and adolescence cerebral forms, attention has been drawn to 3 patients with tics, which mask organic nature of the disease on its initial stage. X-ALD is so far incurable, but its timely diagnosis provides an adequate medico-genetic help on the base of modern prenatal diagnosis.
Subject(s)
Adrenoleukodystrophy/pathology , Fatty Acids/blood , ATP Binding Cassette Transporter, Subfamily D, Member 1 , ATP-Binding Cassette Transporters/blood , ATP-Binding Cassette Transporters/genetics , Adrenocortical Hyperfunction/diagnosis , Adrenoleukodystrophy/diagnosis , Adrenoleukodystrophy/genetics , Age Factors , Chromosomes, Human, X/genetics , Female , Genetic Linkage , Genetic Testing , Humans , Male , Tics/diagnosisABSTRACT
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.