[Modern opportunities and prospects for studying pathogenesis, diagnosing and treating hereditary optic neuropathies].

OBJECTIVE: To evaluate modern opportunities and prospects for studying pathogenesis and improving diagnostics and treatment of hereditary optic neuropathies (HON). MATERIAL AND METHODS: The article presents summarized data on the pathogenesis, diagnostics, and treatment of HON based on modern methods of assessment. RESULTS: The results of long-term worldwide studies and those performed in the Research Institute of Eye Diseases in collaboration with several other institutions are presented. Genetic testing for mitochondrial and nucleus DNA mutations that have a known association with Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic neuropathy (ADON) allow verification only in half of the cases. Particular features of hereditary diseases, such as incomplete penentrance, variable expression, clinical polymorphism, difficulties in detection of hereditary sings, and genetic heterogeneity, are shown to complicate the diagnosis of HON. Spectral retinal tomography revealed characteristic morphometric changes in the macular region and peripapillary nerve fiber layer in the acute stage of LHON. Hereditary optic neuropathies result from a genetically determined decrease in mitochondrial respiratory chain complexes activity, which is associated with a decrease in ATP production. From that standpoint, studying of mitochondrial oxidative phosphorylation biochemical defects in LHON and ADON is an option for detection of mitochondrial dysfunction. Results of a newly proposed method of mitochondrial membrane potential assessment in skin fibroblasts, which can be used for differential diagnosis of mitochondrial optic nerve diseases, are presented. Possible therapeutic measures for HON are discussed. CONCLUSION: In the prevailing number of cases the described clinical, molecular genetic, and cytological methods ensure proper diagnosis of hereditary optic neuropathies. Prospects of HON treatment, rather ambiguous, are associated with further studying of pathogenesis, development of drugs and gene therapy.

[Ataxia with oculomotor apraxia: clinical-genetic characteristics and DNA-diagnostic].

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. А 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 с.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.

[A case report of Byler's syndrome].

The case report describes a progressive familial intrahepatic cholestasis II type Byler's syndrome with structural abnormality of the bile canalicular membrane. A child with a rare hereditary pathology,who is on the waiting list for liver transplantation, on the background of complex treatment, including diet therapy, drug therapy achieved a positive dynamics of clinical and laboratory parameters, acceleration of physical, psychomotor and intellectual development, that in general has improved the surgery prognosis and quality of life of the patient.

[Molecular genetics and clinical aspects of monogenic diabetes mellitus].

The paper is dedicated to clinical and laboratory aspects of Diabetes Mellitus non-immune forms, such as neonatal Diabetes Mellitus, Maturity Onset Diabetes of young (MODY), DIDMOAD-syndrome, Wolframe syndrome, Alstrom syndrome and its determinating genes. The analysis of proper clinical results are present in this paper.

[Clinical and genetic special features of Niemann-Pick disease, type C].

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.

[Myoclonic epilepsy of Lafora: a case report].

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.

[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.

[Clinical and molecular genetic diagnosis of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation in children].

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a recently described disorder with autosomal recessive model of inheritance. Mutations in the DARS2 gene, which encode mitochondrial aspartyl-tRNA synthetase, have been found. We present 31 cases with characteristic clinical and neuroimaging findings of this disorder. Patients have been stratified into two groups (early and late forms) by age-at-onset and clinical symptoms. The early form was characterized clinically by progressive pyramidal dysfunction, cerebellar and intellectual problems appeared later. Patients with the late form had cerebellar and sensitive ataxia, disturbances of muscle tonus, spastic type, mostly in the low extremities, polyneuropathic and rarely - psychoorganic syndrome. The brain MRI of all patients was characterized by inhomogeneous T2W signal abnormalities in the periventricular and deep white matter and a strikingly selective involvement of certain brainstem and spinal tracts. Most of the patients were compound-heterozygous for common mutations in the DARS2. We found 4 new mutations associated with LBSL. This is the first clinical and molecular-genetic investigation of this rare leukoencephalopathy in Russia.

[Glutaric aciduria type 1: clinical presentations, diagnostics and treatment.].

Glutaric aciduria type I is a rare autosomic recessive neurometabolic disease, which develops in the first year of life and is characterized by progressive extrapyramidal disorders as a result of the basal ganglia damage. We describe first cases of this disease in Russian population. The clinical observations are compared to the literature data. The disease usually develops after infections and features by seizures, vomiting, metabolic acidosis and deprivation of consciousness up to coma. These crises lead to the development of necroses of the basal ganglia that results in dystonias, dyskinesias and choreoatethosis. The secondary complications of the disease are difficulties with feeding, speech delay, chronic aspiration syndrome and severe delay of movement development. Diagnostics of the disease is based on urine and blood tests using methods of tandem mass spectrometry and gas chromatography. Treatment is based on dietary lysine or protein restriction and supplementation with carnitine. The data on the treatment of this disease are presented.

[Leber's hereditary optic atrophy: neurological and other non-optic appearances]. / Nasledstvennaia atrofiia zritel'nykh nervov Lebera: nevrologicheskie i drugie vneglaznye proiavleniia.

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.

[Leber's hereditary optic neuropathy: DNA-diagnosis and clinico-genetic comparisons in 12 families]. / Nasledstvennaia atrofiia zritel'nykh nervov Leber: DNK-diagnostika i kliniko-geneticheskie sopostavleniia v 12 sem'iakh.

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.

[Clinical heterogeneity of X-linked adrenoleukodystrophy ]. / Klinicheskoe raznoobrazie X-stseplennoi adrenoleikodistrofii.

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.

[Program for diagnosis and prevention of inherited metabolic diseases of cellular organelles]. / Prgramma diagnostiki i profilaktiki nasledstvennykh boleznei obmena kletochnykh organell.

A programme for diagnosis and prevention of lysosomal, peroxisomal, and mitochondrial [respiratory chain diseases (RCD)] diseases was developed on clinical, biochemical, and molecular approaches. The authors made postnatal diagnosis was made in 674 patients from 516 families and prenatal diagnosis in 124 fetuses in 94 families at risk. DNA analysis of mutant alleles in the mucopolysaccharidoses (MPS) I, II, and VI revealed 14, 13, and 4 new mutant alleles in IDS, ASB, IDUA genes, respectively. The pressure of a mutation process played a major role in the distribution of mutant alleles leading to MPS I and VI, but along with this factor genetic drift and migration undoubtedly influenced the observed spectrum of IDUA alleles in Russia. A clinical phenotype of patients with different MPS was analyzed on the basis of uniform registration of 167 symptoms and signs in 249 patients. Special statistical approaches were developed to characterize early manifestations of different MPS and "unique" signs and symptoms for many of them and "phenotypic distances" between them. The similar problems were solved for RCD through uniform registration of 110 symptoms and signs in 54 patients with different syndromes: pathognomonic symptoms for the whole RCD and "unique" symptoms for syndromes were defined.

[Analysis of hydroxypyridine cross-links of collagen from human rib cartilage]. / Analiz gidroksipiridinovykh sshivok kollagena rebernogo khriashcha cheloveka.

Ion-paired reversed-phase high performance liquid chromatography (HPLC) has been used for the analysis of the content of mature collagen crosslinks--hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) in biopsy specimens of human rib cartilage from healthy donors (n = 14) and patients with inherited diseases of the connective tissue complicated with funnel chest (n = 17). Analysis of normal tissues reveal the presence of LP (alongside with HP) in embryonal rib cartilage. LP has been found in the rib cartilage of 4 out of 6 patients with funnel chest (FC) associated with Ehlers-Danlos syndrome (EDS); with no signs of this pathology detected in individuals with isolated FC. In rib cartilage of 2 patients with recurrent isolated FC LP has been discovered alongside with the presence of type I collagen. A significant increase of LP content in rib cartilage in a child with clinical phenotype of EDS type VI has been discovered.