Objective. To analyze the clinical and genetic characteristics of patients with confirmed diagnoses of rare forms of autosomal recessive spinocerebellar ataxia – ATX-ANO10 and ATX-SYNE1. Materials and methods. Six unrelated patients with established diagnoses were examined, four with ATX-ANO10 and two with ATX-SYNE1. Brain MRI, nerve conduction study , assessment of the main neurological symptoms on the Scale for the Assessment and Rating of Ataxia (SARA), and screening for cognitive impairment on the Monreal Cognitive Assessment Scale (MoCA) were performed. Screening for mutations included panel sequencing on the Illumina MiSeq platform. Results. Panel sequencing detected six nucleotide variants in the ANO10 gene: known pathogenic nonsense mutations c.G1025A (p.W342X) and c.C1244G (p.S415X), likely pathogenic variants c.1477–2A>G and c.G101T (p.W34L), described by us for the first time, as well as missense mutations c.A110C (p.N37T) and c.T104C (p.L35P) of uncertain significance. In the SYNE1 gene, the previously undescribed nonsense mutation c.C8911T (p.Q2971X) and the known pathogenic substitution c.C4939T (p.Q1647X) were detected. The clinical picture of ATX-ANO10 and ATX-SYNE1 was typical, consisting of slowly progressive cerebellar ataxia with pyramidal syndrome, with onset at a young age and cerebellar atrophy seen on brain MRI scans. Conclusions. We report here the first data on the clinical features and spectrum of mutations in Russian patients with ATX-ANO10 and ATX-SYNE1 ataxias. The phenotypes of these diseases were nonspecific, so massive parallel sequencing is the method of choice for DNA diagnostics.

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a hereditary slowly progressive adultonset disorder characterized by sersory and cerebellar ataxia, sensory polyneuropathy and bilateral vestibulopathy. In most cases the cause of this disease is biallelic AAGGG-repeat expansion in the RFC1 gene, encoding eplication factor C subunit 1. Today, CANVAS is one of the most common forms among late-onset hereditary ataxias in the world. The differential diagnosis of this syndrome is carried out with a wide range of hereditary and acquired disorders, which are characterized by a combination of cerebellar and sensory ataxia, polyneuropathy and vestibulopathy. The article describes two clinical cases in which the diagnosis of CANVAS caused several diffculties. The phenotypic diversity of this syndrome and the role of videooculography in the diagnostic algorithm and diagnosis verification are discussed.

Introduction. Superficial hemosiderosis of the central nervous system is a chronic, progressive disease caused by continuous low-volume bleeding into the subarachnoid space and, as a result, subpial deposition of hemoglobin de-tritus. Infratentorial superfi cial hemosiderosis (ISS) is characterized by hemosiderin accumulation primarily on the surface of the cerebellum, brainstem and spinal cord. Early detection of ISS may prevent severe disability and raise the chance of successful medical treatment. The purpose of this study was to analyze clinical, radiological, instrumental, and laboratory findings, based on a series of ISS cases diagnosed at the Research Center of Neurology. Material and methods. Seven patients diagnosed with ISS were included in this study (4 men, 3 women). Evaluation of the clinical findings, disease history, brain and spinal cord MRI, MR-angiography, brainstem auditory evoked potentials, audiometry, abdominal ultrasound, and laboratory iron metabolism tests was performed. Results. The median age of subjects was 63 years, and the median duration of disease was 3 years. We identified the cause of ISS in four patients. The most common clinical symptoms were cerebellar ataxia and sensorineural hearing loss. All patients had a typical ISS pattern on brain MRI images. Conclusion. With the development of neuroimaging, iSS is becoming a more frequent finding. Clinicians should be aware of its causes and optimal management strategy. Further studies of possible iSS treatments are needed to reduce free iron neurotoxicity and minimize clinical manifestations of the disease.

Hypoparathyroidism is a rare condition characterized by reduced production of parathyroid hormone or tissue resistance which leads to hypocalcemia and hyperphosphatemia. Neurological manifestations often occur as the first symptoms of hypoparathyroidism and are characterized by a wide variety of symptoms of both the central and peripheral nervous systems dysfunction, which requires a differential diagnosis with a wide range of neurological diseases. Two clinical cases illustrating the features of subacute and chronic hypoparathyroidism are presented. In the case of subacute hypoparathyroidism, a young woman presented with severe tetany involving the oculomotor muscles (paroxysmal strabismus), laryngeal muscles (respiratory stridor), body muscles (opisthotonus, «obstetrician's hand») and the development of secondary myopathy. In another case with a long-term chronic course of postoperative hypoparathyroidism, the patient's adaptation to severe hypocalcemia was noted; the clinical features were dominated by cerebral syndromes due to brain structures calcification (Fahr's syndrome). Possible reasons for late diagnosis of hypoparathyroidism, the importance of active detection of symptoms of neuromuscular hyperexcitability and laboratory testing of phosphorus and calcium metabolism are discussed.

Background:Hypokalemic periodic paralysis (HypoKPP) is a rare neuromuscular genetic disorder causing recurrent episodes of flaccid paralysis. Most cases are associated with CACNA1S mutation, causing defect of calcium channel and subsequent impairment of muscle functions. Due to defined management approaches early diagnosis is crucial for promptly treatment and prevention new attacks.Materials and methods:We report a case of HypoKPP associated with previously unreported mutation in CACNA1S gene (p.R900M). Molecular modeling of CaV1.1 was applied to evaluate its pathogenicity.Results:As a patient referred between attacks neurological status, laboratory and neurophysiological examination were unremarkable. Molecular modeling predicted that the p.R900M mutation affects the process of calcium channels activation.Conclusion:Novel CACNA1S mutation, associated with HypoKPP was identified. Monte-Carlo energy minimization of the CaV1.1 model supported the association of this mutation with this disease.

Описан клинический случай пациентки с редким фенотипом в виде прогрессирующей мозжечковой атаксии в сочетании с признаками поражения верхнего и нижнего двигательных нейронов. При проведении таргетного панельного секвенирования был выявлен описанный ранее патогенный вариант c.272A>C (p.D91A, rs80265967) в 4-м экзоне гена SOD1. Варианты в данном гене являются частой причиной развития наследственных форм бокового амиотрофического склероза (БАС, MIM #105400). Сочетание клинической картины БАС с мозжечковой атаксией является крайне редким феноменом, а случаев обнаружения данной мутации у пациентов с мозжечковой атаксией ранее описано не было. Представленное клиническое наблюдение и данные литературы расширяют представления о генетическом и фенотипическом «перекресте» наследственных атаксий и болезней двигательного нейрона. В настоящее время проводится активная разработка препаратов для генной терапии SOD1- БАС, в том числе с использованием антисмысловых олигонуклеотидов, направленных на подавление экспрессии гена SOD1. В связи этим необходимо включать исследование гена SOD1 в алгоритмы диагностики наследственных мозжечковых атаксий при наличии характерного клинического фенотипа. We report a clinical case of the patient with a rare phenotype presented by progressive cerebellar ataxia in combination with upper and lower motor neuron involvement. Target panel sequencing revealed the previously described pathogenic mutation c.272A>C (p.D91A, rs80265967) in the 4th exon of the SOD1 gene. Mutations in this gene are a common cause of the hereditary forms of amyotrophic lateral sclerosis (ALS, MIM #105400). The combination of ALS with cerebellar ataxia is an extremely rare, and cases of association of this mutation with cerebellar ataxia have not been previously described. The presented clinical observation and literature data expand the understanding of the genetic and phenotypic “overlap” of hereditary ataxias and motor neuron diseases. The development of drugs for SOD1-ALS gene therapy, including the use of antisense oligonucleotides aimed at suppressing SOD1 gene expression, is currently underway. In this regard, it is necessary to include the study of the SOD1 gene in the algorithms for diagnosing hereditary cerebellar ataxia in the presence of a characteristic clinical phenotype.

Introduction. Paraneoplastic cerebellar degeneration (PCD) is an immune-mediated and rapidly progressive cerebellar syndrome that develops as a result of a cross-immune response to the common antigens for the tumor and cerebellar cells. Timely diagnosis and treatment of PCD improves the functional status and survival of these patients.Objective. To analyze the clinical, laboratory and neuroimaging characteristics of PCD case series in comparison with literature data.Material and methods. 16 patients with PCD (13 women, 3 men) were examined. An assessment of the clinical presentation, brain MRI study, blood and cerebrospinal fl uid laboratory tests were carried out, the data of cancer search and patients follow-up were analyzed.Results. The median age of PCD patients was 55 years, the duration of the disease was 8.5 months (range 4 to 16 months). In 12 patients, PCD was the fi rst manifestation of cancer. The clinical prentation was presented by rapidly progressive cerebellar ataxia, often in combination with oculomotor disturbances, pyramidal and bulbar syndrome, hand tremor and dystonia. An associated cancers were detected in 13 patients (81%). Antineuronal antibodies were found in 14 patients (88%): anti-Yo-1, antibodies to amphiphysin, anti-Hu, anti-CV2 and anti-GAD. Mild atrophic changes of the cerebellum were found in 6 patients, and in 2 cases cerebellar hemiatrophy was observed.Conclusion. PCD is a rare disabling but potentially curable disease. The basis of diagnosis is the analysis of the clinical presentation and neuroimaging data, the detection of antineuronal antibodies and in fl ammatory changes in the cerebrospinal fl uid, as well as a thorough cancer search.

OBJECTIVE:To describe the features of the clinical presentation and evaluate the incidence of HIV-associated cerebellar degeneration in patients with progressive cerebellar ataxia.MATERIAL AND METHODS:Three hundred and seventy-seven patients with progressive cerebellar ataxia were studied. Brain MRI study, assessment by the Scale for the Assessment and Rating of Ataxia (SARA), screening for cognitive impairment by the Montreal Cognitive Assessment Scale (MoCA) were performed. In patients with HIV infection, autoimmune, deficient and other causes of ataxia, as well as opportunistic infections, multiple system atrophy and frequent forms of hereditary spinocerebellar ataxias were excluded.RESULTS:Five patients (1.3%) were identified with a combination of cerebellar ataxia and HIV infection (2 men, 3 women, aged 31 to 52 years). The median duration of HIV infection was 5 years, the duration of ataxia was 1 year. In the clinical findings, in addition to progressive ataxia, pyramidal signs, dysphagia, less often ophthalmoparesis, dystonia, postural hand tremor, affective and mild cognitive impairment were observed. In three patients, brain MRI revealed signs of olivopontocerebellar atrophy, two patients had isolated cerebellar degeneration (mainly of the vermis). All patients received combination of antiretroviral therapy in various regimens, but despite this, ataxia was progressive.CONCLUSION:HIV infection is a rare cause of cerebellar degeneration. This diagnosis remains a diagnosis of exclusion to this day. Cerebellar degeneration can occur and progress even after achieving a stable remission of HIV infection while taking highly active antiretroviral therapy.

— A clinical case of a patient with progressive supranuclear palsy (PSP) and wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome identified using video-oculography and ophthalmological examination is presented. WEBINO syndrome is a combination of bilateral internuclear ophthalmoplegia and exodeviation. Few cases of such oculomotor disorder in PSP patients have been earlier described. However, a closer look at the pathogenesis of co-existing internuclear ophthalmoplegia and strabismus reveals its common features with the origins of typical oculomotor disorders seen in PSP. Therefore, this horizontal eye movement impairment might be not so uncommon in PSP patients. Diplopia as one of the subjective manifestations of WEBINO is a treatable phenomenon. Its management is capable of improving the gait function, severely affected in PSP. Practical recommendations are given for neurologists to improve the detection of horizontal gaze dysfunction in PSP and the role of instrumental methods of examination is explained. Awareness of clinical practitioners of WEBINO syndrome will not only elevate the quality of help for PSP patients, but also expand the understanding of pathogenesis of oculomotor abnormalities in this type of atypical parkinsonism.

OBJECTIVE:To assess the incidence of spinocerebellar ataxia type 8 (SCA8) in patients with progressive cerebellar ataxia and describe the clinical features of the SCA8 phenotype in Russian patients.MATERIAL AND METHODS:Genotyping of CTA/CTG repeats in ATXN8OS gene was carried out in 411 patients with degenerative ataxias using fragment analysis. SCA types 1, 2, 3 and 6 as well as Friedreich's ataxia were preliminarily excluded. All patients underwent brain MRI study. Scale for the Assessment and Rating of Ataxia (SARA), and the Montreal Cognitive Assessment Scale (MoCA) to screen for cognitive impairment were used.RESULTS:Six patients with SCA8 (1.5%) were identified as carriers of the expansion in the ATXN8OS gene (91-152 CTA/CTG repeats). All cases were sporadic. Age of onset ranged from 14 to 42 years. All patients had slowly progressive cerebellar ataxia, oculomotor disturbances, dysarthria, pyramidal signs, and two patients had cognitive impairment. In one patient the clinical presentation corresponded to multiple system atrophy cerebellar type (ataxia, orthostatic hypotension, cerebellum and brainstem atrophy). Brain MRI study in all patients revealed cerebellar atrophy.CONCLUSION:SCA8 is a rare form of autosomal dominant ataxia with a predominance of the classical phenotype. All identified cases of SCA8 were sporadic, which should be taken into account when planning genetic testing in patients with spinocerebellar ataxia.

Hereditary spastic paraplegia (HSP) and spinocerebellar ataxia (SCA) are heterogeneous groups of neurodegenerative disorders with the main clinical manifestations including progressive pyramidal syndrome and cerebellar ataxia. The differential diagnosis of these diseases is difficult owing to the significant genetic and phenotypic polymorphism. The use of massive parallel sequencing (MPS) technologies makes it possible to assess the genetic basis of specific clinical syndromes and to clarify the systematization of these overlapping phenotypes. We examined 70 patients with degenerative cerebellar ataxias who were admitted to the clinic with one of the suspected forms of SCA. Mutation screening included panel sequencing on the Illumina MiSeq platform. In the group of patients with SCA phenotypes, four individuals (5.7%) were identified-carriers of mutations in the HSP genes: SPG5-1 patient, SPG7-1 patient, and SPG11-2 patients. Seven mutations were identified: CYP7B1 (SPG5) gene-p.R63X and p.R486C mutations; SPG7 gene-c.1047dupC (p.G352Rfs*43) and splice site mutation c.1779+1G>T, which was described by us for the first time. Two patients with SPG11 carried a compound heterozygous nonsense mutation p.Q811X in the SPG11 gene; other mutations were c.7168dupC (p.P2390fs) and c.733_734del (p.M245fs). The presented data confirm the concept that HSP and SCA represent a single continuum of spinocerebellar degenerations with a significant phenotypic overlap. To verify the diagnosis in patients with cerebellar and pyramidal syndrome of degenerative genesis, MPS methods should be used.

The article presents two clinical cases of 51 and 57-year-old patients living in regions endemic for tick-borne encephalitis in which the differential diagnosis between progressive supranuclear palsy (PSP) and the extremely rare parkinsonian variant of chronic tick-borne encephalitis (CTBE) resulted in a diagnostic challenge. In both cases there was a clinical presentation of progressive symmetric levodopa-resistant parkinsonism with vertical gaze palsy, cognitive impairment of the executive type, frontal lobe signs, focal dystonia and in one case — early onset of postural instability, which corresponds to the diagnosis of probable PSP. The parkinsonian variant of CTBE was supported by the lack of tick-borne encephalitis virus IgG-antibodies negativity in the blood for several years, intrathecal oligoclonal antibody synthesis in one patient, the absence of typical neuroimaging signs of PSP, and delayed disease onset after a tick bite. Difficulties in diagnosis and possible mechanisms of the pathogenesis of primary progressive CTBE, as well as the similarity of the clinical and pathomorphological presentation of PSP, von Economo encephalitis lethargica, and postencephalitic parkinsonism are discussed.

The article presents a description of the family case of rare hereditary prion disease – Gerstmann–Sträussler–Scheinker syndrome with a verified p.P102L mutation in the PRNP gene. The clinical picture was represented by progressive cerebellar ataxia, pyramidal signs, bulbar syndrome, and neuropathy, which made it possible to establish a preliminary diagnosis of autosomal dominant spinocerebellar ataxia. Subsequently, the final diagnosis was verified using the massive parallel sequencing technology. The features of this observation are the variable age of onset within the family, with the unusually early age of the disease onset in the proband (age of 25 years), the absence of cognitive impairment, as well as the absence of pathological changes in the electroencephalography and brain MRI study. The possible modifying role of polymorphism in codon 129 of the PRNP gene (129Val) in the disease phenotype formation, as well as the clinical findings and diagnostic methods of this syndrome are discussed.

BACKGROUND:An overactive bladder and cognitive impairment are two medical and social problems, which have an outmost importance, affecting the quality of life. Both disorders are common in the practice of a urologist, neurologist, internist, and other physicians. Parkinsons disease and multiple sclerosis are the most common neurological diseases, which often manifest by pelvic dysfunction and cognitive dysfunction. The clinician needs to understand the pathogenesis of the underlying disease and the pharmacologic properties of drugs, which can be used both in neurology and urology, as well as in other related specialties. AIM:To evaluate cognitive functions in patients with neurogenic overactive bladder treated with trospium chloride. MATERIALS AND METHODS:A total of 45 patients with neurological disease (28 with Parkinsons disease [group 1] and 17 with multiple sclerosis [group 2]) were included in the study. All patients had symptoms of an overactive bladder. Trospium chloride was administered in an individually adjusted dose for 12 weeks. Cognitive functions were assessed using the international Montreal Cognitive Assessment (MoCA) before and after the therapy. A change of total scores over time was assessed using the paired Wilcoxon test. The level of significance of <0.05 was used (confidence level of 95%). RESULTS:A significant decrease in all studied parameters of an overactive bladder in both groups was seen. The baseline evaluation of the total score on the MoCA scale prior to the start of taking trospium chloride revealed the presence of moderate cognitive impairment (21.3+/-2.9 points) in patients of the group 1. After 12 weeks of therapy, no significant change in cognitive functions was observed (21.7+/-3.1 points; p>0.05). In group 2, moderate cognitive impairment (MoCA 22.5+/-3.7 points) was found at baseline. After taking trospium chloride, no significant changes were noted (MoCA 22.9+/-4.1 points) (p>0.05). No central nervous system side effects were reported in any group. CONCLUSION:Trospium chloride is an effective drug, which does not affect cognitive functions in patients with neurogenic overactive bladder. This drug is safe to use in both Parkinsons disease and multiple sclerosis, considering the low risk of cognitive impairment in polypharmacy.

Introduction. Epilepsy is a common feature of mitochondrial disorders, including those associated with mutations in the POLG gene. Nevertheless, brain electrical activity features of POLG-related disorders in adult patients have not been adequately studied. Objective. To study the features and characteristics of the electroencephalography (EEG) pattern in adult patients with POLG-related disorders. Material and methods. Eight patients were examined: 7 with SANDO (Sensory Ataxic Neuropathy, Dysarthria, Ophthalmoparesis) syndrome, and 1 with MEMSA (Myoclonic Epilepsy Myopathy Sensory Ataxia) syndrome; median age was 32.5 years. All patients underwent routine EEG monitoring using a 19-channel electroencephalograph according to the generally accepted method. Results. Epileptic seizures were found in 3 patients, for 2 of them – as the first manifestation of the disease. In 6 patients, theta waves predominated in the occipital regions. Of those 6 patients, in 5 bilateral synchronous bursts of theta and delta wave groups were identified being more prominent in the frontocentral regions; 4 patients had transient non-lateralized delta activity in the occipital and parieto-occipital brain regions. In all patients, opening eyes led to the depression of rhythms and burst suppression. After photostimulation, in 2 cases bilateral synchronous bursts of delta and theta wave groups were recorded predominantly in frontal lobes. In 3 patients during hyperventilation an increase in delta activity in the occipital lobes and bilateral synchronous bursts of delta wave groups were observed. Epileptiform activity was recorded in 2 cases. Conclusion. In adult patients with POLG-related disorders, regardless of the clinical manifestation, typical EEG features include generalized background slowing, theta and delta bursts in occipital lobes with their suppression by opening eyes.

Синдром CANVAS (мозжечковая атаксия, невропатия и вестибулярная арефлексия) - аутосомно-рецессивная атаксия с поздним дебютом, обусловленная носительством биаллельной экспансии (AAGGG)n во 2-м интроне гена RFC1. До настоящего момента отсутствуют сведения о распространенности данного заболевания в российских семьях. Нами был проведен поиск биаллельной экспансии AAGGG-повторов у 35 российских пациентов с поздней мозжечковой атаксией. Верифицированы 5 пациентов (14,3%) с синдромом CANVAS и характерной клинической картиной. CANVAS (cerebellar ataxia, neuropathy and vestibular areflexia) is a late-onset autosomal recessive ataxia due to biallelic (AAGGG)n repeat expansion in the 2nd intron of the RFC1 gene. There is no information on the CANVAS prevalence in Russian families. We searched for biallelic expansion of AAGGG repeats in 35 Russian patients with late-onset cerebellar ataxia. Five patients (14.3%) with CANVAS syndrome and a characteristic clinical picture were verified.

Anti-glutamic acid decarboxylase (GAD) antibody-associated ataxia is a rarely diagnosed but potentially curable disease associated with autoimmune damage to and death of Purkinje cells in the cerebellar cortex. In Russia, the authors have provided for the first time descriptions of three own observations of this disease, which had a number of clinical features, such as slow progression, mild ataxia, stroke-like episodes with stem symptoms, concomitant gluten sensitivity, onset of ataxia after hepatitis C with cerebellar hemiataxia and hemiatrophy. In the all patients, the diagnosis was verified based on the determination of high anti-GAD antibody titers in serum and cerebrospinal fluid. All the patients lacked intrathecal synthesis of oligoclonal antibodies; protein levels and cytosis were normal. Pulse therapy with methylprednisolone at a total dose of 3–5 g led to a slight reduction in ataxia in one case (a female patient with subacute onset of the disease); the treatment was ineffective in two other cases (patients with a primary chronic course). The paper analyzes the literature covering the pathogenesis and clinical presentations of this type of ataxia, and difficulties in its diagnosis and treatment.

Introduction . Ataxia with impaired DNA repair is a group of inherited diseases with a wide range of neurological and extraneural manifestations. There are some difficulties in the differential diagnosis of this group of ataxias due to significant clinical polymorphism. Objective . To analyze the clinical presentation, laboratory and instrumental examinations data of a series of genetically confirmed cases of ataxia with impaired DNA repair in adult patients. Material and methods . 55 patients with ataxia of degenerative origin were examined. Clinical evaluation, nerve velocity study, brain MRI, alpha-fetoprotein, immunoglobulins, cholesterol and albumin, creatine phosphokinase activity were performed. Massive parallel sequencing (MPS) was used for genotyping, including the original multigene panel. Results . 8 (14.5%) patients with various forms of ataxia with impaired DNA repair were verified: 5 patients with ataxia-telangiectasia, 3 — with ataxia with oculomotor apraxia types 1 and 2. The clinical features of this forms are characterized, the prevalence of atypical forms of ataxia-telangiectasia in a sample of Russian adult patients is revealed. Phenotypes of ataxia with oculomotor apraxia of the 1 and 2 types corresponded to the classical presentation. Several identified mutations in the ATM and SETX genes are described for the first time. Conclusion . Ataxia with impaired DNA repair is a common group of ataxias in adult Russian patients. They are represented by ataxia-telangiectasia, ataxia with oculomotor apraxia types 1 and 2, often due to new mutations. MPS is the method of choice for genotyping of these forms of ataxia.