Mitochondrial DNA maintenance disorders in 102 patients from different parts of Russia: Mutational spectrum and phenotypes.

Currently, pathogenic variants in more than 25 nuclear genes, involved in mtDNA maintenance, are associated with human disorders. mtDNA maintenance disorders manifest with a wide range of phenotypes, from severe infantile-onset forms of myocerebrohepatopathy to late-onset forms of myopathies, chronic progressive external ophthalmoplegia, and parkinsonism. This study represents the results of molecular genetic analysis and phenotypes of 102 probands with mtDNA maintenance disorders. So far, this is the largest Russian cohort for this group of diseases. Mutations were identified in 10 mtDNA maintenance genes: POLG (n = 59), DGUOK (n = 14), TWNK (n = 14), TK2 (n = 8), MPV17 (n = 2), OPA3 (n = 1), FBXL4 (n = 1), RRM2B (n = 1), SUCLG1 (n = 1) and TYMP (n = 1). We review a mutation spectrum for the DGUOK and TWNK genes, that can be specific for the Russian population. In 34 patients we measured the blood mtDNA copy number and showed its significant reduction. Novel variants were found in 41 cases, which significantly expands the mutational landscape of mtDNA maintenance disorders.

Case report: a rare case of Hunter syndrome (type II mucopolysaccharidosis) in a girl.

BACKGROUND: Hunter syndrome (mucopolysaccharidosis type II) is a recessive X-linked disorder due to mutations in the iduronate 2-sulfatase (IDS) gene. The IDS gene encodes a lysosomal enzyme, iduronate 2-sulfatase. The disease occurs almost exclusively in males. However, in the literature, 12 cases of the disease in females are known due to structural anomalies, a non-random chromosome X inactivation or chromosome X monosomy. The purpose of this article is to demonstrate a rare case of Hunter syndrome in a girl caused by a mutation in the IDS gene inherited from the mother and the presence of chromosome X of paternal origin, partially deleted in the long arm region - 46,X,del(X)(q22.1). CASE PRESENTATION: Girl M., 4 years old, entered the hospital with growth retardation, pain in the lower limbs, and joint stiffness, noted from the age of 18 months. After the karyotype analysis, which revealed a partial deletion of the long arm of chromosome X - 46, X, del (X) (q 22.1), Turner syndrome was diagnosed. However, due to the hurler-like facial phenotype, Hurler syndrome or type I mucopolysaccharidosis (MPS) was suspected. The study of lysosomal enzymes showed normal alpha-L-iduronidase activity and a sharp decrease in the activity of iduronate sulfatase in the blood: 0.001 µM/l/h, at a rate of 2.5-50 µM/l/h. Molecular genetic analysis revealed a hemizygous deletion in the IDS gene, which was not registered in the international Human Gene Mutation Database (HGMD) professional. This deletion was not detected in the girl's father, but was detected in her mother in the heterozygous state. CONCLUSIONS: Thus, the girl confirmed comorbidity - Turner syndrome with a partial deletion of the long arm of chromosome X of paternal origin, affecting the Xq28 region (localization of the IDS gene), and Hunter syndrome due to a deletion of the IDS gene inherited from the mother. The structural defect of chromosome X in the girl confirmed the hemizygous state due to the mutation in the IDS gene, which has led to the formation of the clinical phenotype of Hunter syndrome.

[Diagnosis of microcirculation features in intestinal anastomosis to prevent its failure]. / Diagnostika sostoianiia mikrotsirkuliatornogo rusla v oblasti mezhkishechnogo anastomoza.

Laser doppler flowmetry is a way to identify predictors of diseases and complications associated with blood supply disorders. Registration of absolute values for results of this method allows to eliminate the subjective factor. Previous studies demonstrate the possibility of using this technique in clinical practice. The effectiveness for assessing the quality of blood supply of the tissues requires further studying.

[Syndrome Leigh caused by mutations in the SURF1 gene: clinical and molecular-genetic characteristics].

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.

[Comparative diagnostic value of the analysis of the skeletal muscle and lymphocytes in mitochondrial diseases]. / Sravnitel'naia diagnosticheskaia tsennost' analiza skeletnoi myshtsy ilimfotsitov pri mitokhondrial'nykh bolezniakh.

Cytochemical analysis of lymphocytes' enzymes may could be an alternative method to skeletal muscle biopsy in diagnosis of mitochondrial pathology. We investigated biopsies of skeletal muscles and cytochemical status of lymphocytes in 14 children with mitochondrial pathology. Lymphocytes were investigated also in 12 health children. The data on mitochondrial state in the skeletal muscles and peripheral blood lymphocytes were comparable. The less were the size and functional activity of single mitochondria in lymphocytes, the higher was mitochondrial insufficiency in the skeletal muscle. Enzymatic status of peripheral blood lymphocytes is not less indicative of mitochondrial insufficiency in children than mitochondrial characteristics in skeletal muscles. It reflects multisystem mitochondrial insufficiency. The results obtained are determined by both mitochondrial pathological modifications and their compensatory response to pathological process.

[Current problems in diagnosis and treatment of hereditary disturbances of growth and development in children]. / Sovremennye problemy diagnostiki i lecheniia nasledstvennykh naryshenii rosta and razvitiia u detei.

The authors' long-term experience in diagnosing and treating childhood hereditary growth and developmental disturbances, such as genetic diseases of connective tissue, amino acid metabolic disturbances, rickets-like diseases, mitochondrial abnormalities, Rett syndrome, and fragile X syndrome is presented. The findings suggest that multimodality treatment is highly effective in treating children with hereditary growth and developmental disturbances in genetic care.

[The indices of the thrombocyte serotonin system and of the nerve growth factor system in children with hereditary disorders of neuropsychic development]. / Pokazateli serotoninovoi sistemy trombotsitov i sistemy faktora rosta nervov u detei s nasledstvennymi narusheniiami nervno-psikhicheskogo razvitiia.

Indices of both platelet serotoninergic system and the system of nerve growth factor (NGF) were examined in children with neurofibromatosis (15 patients), polygenic oligophrenia (24 patients) and Rett's syndrome (14 ones). There was an increase of both the level of blood serum autoantibodies (aAB) to NGF and the value of specific binding of 3H-imipramine (Bmax) in platelets of patients with oligophrenia. For this group of patients a significant negative correlation exists between the rate of platelet uptake of serotonin (Vmax value) and the degree of mental retardation (r = -0.425, p < 0.03). Decrease of both Vmax and activity of platelet NGF receptors was revealed in patients with neurofibromatosis. In such patients there was positive correlation between sensitivity of platelet NGF receptors to NGF (during their stimulation by test dose of purified NGF) and the degree of mental retardation (r = 0.697, p < 0.04). In patients with Rett's syndrome a significant increase of activity of platelet NGF receptors to NGF was observed. The conclusion was made on the existence of some general mechanism of intellectual defect development. Autoimmune processes considered to be such mechanism.

[Morphological alterations of the skeletal muscles in mitochondrial myopathies in children and their mothers]. / Kharakteristika morfologicheskikh izmenenii skeletnoi myshechnoi tkani pri mitokhondrial'nykh miopatiiakh u detei i ikh materei.

Skeletal muscle biopsies from 18 children and 8 from their mothers were studied in mitochondrial myopathies. It is shown that by means of electron microscopy, histochemistry, and morphometry the correct diagnosis of mitochondrial insufficiency is quite possible.

[Automated genetic register and computer support for the physician's diagnostic decisions]. / Avtomatizirovannyi geneticheskii registr i komp'iuternaia podderzhka diagnosticheskikh reshenii vracha.

Computer-based genetical register "GENREG" allows to carry out a prophylactic medical examination for families with children, having hereditary diseases, multifactorial pathology and congenital developmental defects of various nature, and also epidemiological examination. Automated consultative system for pre-laboratory diagnosis of genetically determined diseases after the phenotypical manifestations "DIAGEN" allows to identify up to 1200 nosologic units; diagnostic value (or weight) of the signs according to physician's evaluation is taken into consideration. The system sorts out a narrow differential-and-diagnostic row and information about specific laboratory and functional changes for every selected diagnosis. Efficiency of the system is over 94% (after the next laboratory findings). The results of computer diagnosis and final physician's diagnosis, and also questionnaire of a child are stored in archives (files) of the "DIAGEN" system. Both of the systems are realized on PC/AT IBM-compatible computer.

[Automated information-diagnostic system for hereditary diseases in childhood]. / Avtomatizirovannaia informatsionno-diagnosticheskaia sistema po nasledstvennym zabolevaniiam v detskom vozraste.

This article describes computer-based information-and-diagnostic system dealing with child hereditary diseases which makes in possible to organize automated consultative service on a wide range of monogene and chromosome syndromes. The system is oriented for sorting out a narrow differential-and-diagnostic row from 1200 of genetically determined diseases at the stage of pre-laboratory child examination. The choice of diagnoses in the system is based on the analysis of the likeness of phenotypical manifestation of the syndromes described in literature with the case under analysis. The system envisages information exchange with a physician in a dialogue using the natural language. The system is based on IBM-370 computer and can be operated from remote video device in the data TV transmitting mode.

[Main trends in the control of hereditary diseases in childhood]. / Osnovnye napravleniia bor'by s nasledstvennymi zabolevaniiami v detskom vozraste.

The results of the activity of the Department for Congenital and Hereditary Diseases of the Moscow Research Institute of Pediatrics and Childhood Surgery of the Ministry of Public Health of the RSFSR point to the efficacy of the work of the Centre for Hereditary Pathology of that Institute in the field of the diagnosis, treatment and prevention of hereditary diseases of children. The prospects of further studies are outlined.

[Diagnosis of histidinemia through using the determination of urocanic acid in the sweat by an enzymatic method]. / Diagnostika gistidinemii s pomoshch'iu opredeleniia urokaninovoi kisloty v pote énzimaticheskim metodom.

A diagnosis of histidinemia was confirmed by estimation of urokaninic acid in sweat using highly purified preparation of urokaninase from rat liver tissue. The content of urokaninic acid was estimated by the method developed and by means of a known chemical method, which involved reduction of urokaninic acid with zinc in a medium containing HCL; seven children with histidinemia and ten healthy children were examined. The diagnosis of histidinemia was confirmed since the content of urokaninic acid was distinctly decreased in sweat of the imparied children as compared with the control group. The method developed was highly sensitive, reproducible and accurate.