[Rare forms of autosomal recessive spinocerebellar ataxia associated with mutations in the ANO10 (ATX-ANO10) and SYNE1 (ATX-SYNE1) genes]. / Redkie formy autosomno-retsessivnykh spinotserebellyarnykh ataksii, assotsiirovannye s mutatsiyami v genakh ANO10 (ATX-ANO10) i SYNE1 (ATX-SYNE1).

OBJECTIVE: To analyze clinical and genetic characteristics of patients with the verified rare forms of autosomal recessive spinocerebellar ataxias, ATX-ANO10 and ATX-SYNE1. MATERIAL AND METHODS: Six unrelated patients with established diagnoses were examined: 4 patients with ATX-ANO10 and 2 patients with ATX-SYNE1. Brain MRI and nerve conduction study were performed. To screen for cognitive impairment, the scale for the Assessment and Rating of Ataxia (SARA), and the Montreal Cognitive Assessment Scale (MoCA) were used. Mutation screening included panel sequencing on the Illumina MiSeq platform. RESULTS: Six variants were found in the ANO10 gene: the previously described pathogenic nonsense mutations c.G1025A (p.W342X) and c.C1244G (p.S415X), as well as novel probably pathogenic variants c.1477-2A>G and c.G101T (p.W34L) and missense mutations c.A110C (p.N37T) and c.T104C (p.L35P) of undetermined significance. A novel nonsense mutation c.C8911T (p.Q2971X) and a previously described pathogenic variant c.C4939T (p.Q1647X) were found in the SYNE1 gene. The clinical presentation of the ATX-ANO10 and ATX-SYNE1 was typical presenting with slowly progressive cerebellar ataxia with pyramidal signs, with young onset and cerebellar atrophy according to brain MRI study. CONCLUSION: We provided first-ever data on clinical features and mutation spectrum In Russian patients with ATX-ANO10 and ATX-SYNE1. The phenotype of these ataxias is nonspecific, so the method of choice for molecular diagnostics is massive parallel sequencing.

[Neurological manifestations of hypoparathyroidism: diagnostic difficulties. Case report].

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 hand¼) 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.

[Cerebellar degeneration associated with HIV infection]. / Mozzhechkovye degeneratsii, assotsiirovannye s VICh-infektsiei.

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.

[Spinocerebellar ataxia type 8 in Russian patients]. / Spinotserebellyarnaya ataksiya 8-go tipa u rossiiskikh bol'nykh.

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.

[Neurogenic overactive bladder: focus on cognitive function].

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.

[Diagnostic algorithm for autosomal recessive ataxia]. / Algoritm diagnostiki autosomno-retsessivnykh ataksii.

AIM: To develop a complex algorithm for autosomal recessive ataxia (ARA) diagnosis applicable for Russian patients with degenerative ataxias. MATERIAL AND METHODS: 48 patients with of presumably degenerative ataxias were examined. Clinical evaluation was performed with the use of the SARA and ICARS scales (for ataxia) and MoCA (cognitive functions), and a set of laboratory tests was carried out, including electromyography, brain MRI, and DNA analysis of mutations responsible for Friedreich's disease and spinocerebellar ataxias (SCAs) types 1, 2, 3, 6 and 17. 28 patients underwent mutation screening using a multigenic MPS panel. RESULTS: 8 patients (16.7%) with non-hereditary causes of ataxia were identified: cerebellar alcoholic degeneration (n = 6) and multiple system atrophy of cerebellar type (n = 2); 3 patients (6.3%) with genetic ataxias were identified using routine DNA tests, such as with SCA type 1, 2 and 17, and 9 (18.8%) patients with Friedreich's disease. The MPS panel enabled molecular diagnosis of ARA in 8 patients (28.6%): ataxia-telangiectasia (n = 2), SANDO syndrome (n = 2), ataxia with oculomotor apraxia type 2 (n = 1), SCAR10 (n = 1), SCAR16 (n = 1), and atypical form of neuroaxonal dystrophy (n = 1). The diagnosis was not established in 20 patients. CONCLUSION: We have proposed an appropriate algorithm for degenerative ataxia diagnosis which is recommended to be used when examining patients with sporadic and autosomal recessive cases of the disorders with dyscoordination of movements.

[Mutation del 1,02kb in the CLN3 gene and extrapyramidal syndrome]. / Mutatsiya del 1,02 kb v gene CLN3 i sindrom ekstrapiramidnykh rasstroistv.

Mutations in the GBA and SMPD1 genes, which lead to the development of lysosomal storage diseases, are high risk factors for Parkinson's disease and dementia with Lewy bodies. We screened the mutations in the GALC and CLN3 genes in patients with Parkinson's disease and control subjects. A heterozygous CLN3 mutation (del 1.02 kb) carrier with clinical features of the unusual extrapyramidal syndrome was identified. A role of CLN3 mutations in the development of neurodegenerative disorders is discussed.

Increased plasma oligomeric alpha-synuclein in patients with lysosomal storage diseases.

A link between lysosomal storage diseases (LSDs) and neurodegenerative disorders associated with accumulation of presynaptic protein alpha-synuclein has been shown. Particularly, Gaucher disease (GD) patients with a deficiency of the lysosomal enzyme glucocerebrosidase (GBA) and carriers of GBA mutations are at increased risk of Parkinson's disease (PD). It remains unclear whether this link is due to increased alpha-synuclein oligomerization. Here we show that level of oligomeric alpha-synuclein form, associated with PD development, is increased in plasma of GD patients (n=41, median=22.9pg/mL, range1.57-444.58pg/mL; controls (n=40, median=6.02pg/mL, range 1.05-103.14pg/mL, p<0.0001). This difference is absent in GD patients receiving enzyme replacement therapy (ERT) for more than 5 years. Moreover, the levels of alpha-synuclein oligomers in plasma are also higher in patients with other LSDs (Niemann-Pick type C, Krabbe disease, Wolman disease) compared to the median value in controls. Therefore, we suggest that mutations in the GBA gene and at least in several other LSDs genes may be associated with an increase in oligomeric alpha-synuclein in plasma. ERT applied for recovering of GBA functions in GD treatment might decrease formation of plasma oligomeric alpha-synuclein.