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Sporadic, adult-onset cerebellar ataxia is a disease with multiple etiologies. In addition to cortical cerebellar atrophy (CCA), which is often used for the pathological diagnosis, other terms such as idiopathic late-onset cerebellar ataxia (ILOCA) and sporadic adult-onset ataxia of unknown etiology (SAOA) have been used to refer to this disorder. These names describe key features of the disease, including degeneration limited to the cerebellar cortex (with or without secondary involvement of inferior olivary nuclei), a slowly progressive ataxia, and absence of a clear etiology, such as multiple system atrophy, as well as paraneoplastic, autoimmune, infectious and inherited ataxias. In this Point of View article, we describe two patients with sporadic, adult-onset ataxia with rapidly progressive disease course in addition to extracerebellar symptoms resembling prion disease, including the reevaluation of one patient who was previously reported. Pathological findings are mostly consistent with CCA, but also have degenerative changes in the thalamus. Whole genome sequencing in two patients with rapidly progressive CCA did not reveal any pathogenic variants associated with cerebellar ataxia. Although the underlying etiology behind rapidly progressive CCA is unknown, we suggest that the unique combination of clinical and pathological features of CAA with a short disease course defines a new disease entity, rapidly progressive cerebellar cortical and thalamic degeneration. This viewpoint article draws attention to this rare sporadic cerebellar ataxia with the hope that highlighting clinical and pathologic findings in a typical case will lead to improved recognition and research.

An elderly Chinese male patient was diagnosed with compound heterozygous spinocerebellar ataxia type 8; molecular diagnosis found that the (CTA)n(CTG)n repeat unit of his ATXN8/ATXN8OS gene was 134/93. The patient has a 6-year medical history, mainly manifested by ataxia, dysarthria, abnormal eye movements, and pyramidal signs. Magnetic resonance imaging (MRI) showed no obvious abnormalities in the medulla oblongata and cervical spinal cord except for cerebellar atrophy and sulci enlargement. There are heterozygous SCA8 individuals among his family members, but there are significant differences in their onset age and clinical manifestations.This case reminds us that (CTA)n(CTG)n repeats are very prone to dynamic mutations in intergenerational inheritance, and the ATXN8/ATXN8OS gene penetrance is different in different SCA8 individuals, which suggests that genetic detection is of great importance.

Contains fulltext : 292317.pdf (Publisher’s version ) (Open Access) The European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI) is a consortium established with the ambition to set up the largest European longitudinal trial-ready cohort of Spinocerebellar Ataxia Type 3/Machado-Joseph Disease (SCA3/MJD), the most common autosomal dominantly inherited ataxia worldwide. A major focus of ESMI has been the identification of SCA3/MJD biomarkers to enable future interventional studies. As biosample collection and processing variables significantly impact the outcomes of biomarkers studies, biosampling procedures standardisation was done previously to study visit initiation. Here, we describe the ESMI consensus biosampling protocol, developed within the scope of ESMI, that ultimately might be translated to other neurodegenerative disorders, particularly ataxias, being the first step to protocol harmonisation in the field. 01 april 2023

Neurodegenerative diseases (NDs) are characterised by progressive dysfunction of synapses, neurons, glial cells and their networks. Neurodegenerative diseases can be classified according to primary clinical features (e.g., dementia, parkinsonism, or motor neuron disease), anatomic distribution of neurodegeneration (e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), or principal molecular abnormalities. The most common neurodegenerative disorders are amyloidosis, tauopathies, a-synucleinopathy, and TAR DNA-binding protein 43 (TDP-43) proteopathy. The protein abnormalities in these disorders have abnormal conformational properties along with altered cellular mechanisms, and they exhibit motor deficit, mitochondrial malfunction, dysfunctions in autophagic-lysosomal pathways, synaptic toxicity, and more emerging mechanisms such as the roles of stress granule pathways and liquid-phase transitions. Finally, for each ND, microglial cells have been reported to be implicated in neurodegeneration, in particular, because the microglial responses can shift from neuroprotective to a deleterious role. Growing experimental evidence suggests that abnormal protein conformers act as seed material for oligomerization, spreading from cell to cell through anatomically connected neuronal pathways, which may in part explain the specific anatomical patterns observed in brain autopsy sample. In this review, we mention the human pathology of select neurodegenerative disorders, focusing on how neurodegenerative disorders (i.e., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis) represent a great healthcare problem worldwide and are becoming prevalent because of the increasing aged population. Despite many studies have focused on their etiopathology, the exact cause of these diseases is still largely unknown and until now with the only available option of symptomatic treatments. In this review, we aim to report the systematic and clinically correlated potential biomarker candidates. Although future studies are necessary for their use in early detection and progression in humans affected by NDs, the promising results obtained by several groups leads us to this idea that biomarkers could be used to design a potential therapeutic approach and preclinical clinical trials for the treatments of NDs.

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.Genotyping of CTA/CTG repeats inSix patients with SCA8 (1.5%) were identified as carriers of the expansion in theSCA8 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.Оценить частоту встречаемости спиноцеребеллярной атаксии 8-го типа (СЦА8) у пациентов с прогрессирующими мозжечковыми атаксиями, описать клинические особенности фенотипа у пациентов с СЦА8.Генотипирование CTA/CTG-повторов в генеВыявлены 6 (1,5%) пациентов с СЦА8 — носители экспансии в генеСЦА8 является редкой формой аутосомно-доминантной атаксии с преобладанием классического фенотипа. Все выявленные случаи СЦА8 были спорадическими, что необходимо учитывать при планировании генетического тестирования у пациентов с СЦА.

Cerebellar ataxias represent a heterogeneous group of disabling disorders characterized by motor and cognitive disturbances, for which no effective treatment is currently available. In this randomized, double-blind, sham-controlled trial, followed by an open-label phase, we investigated whether treatment with cerebello-spinal transcranial direct current stimulation (tDCS) could improve both motor and cognitive symptoms in patients with neurodegenerative ataxia at short and long-term. Sixty-one patients were randomized in two groups for the first controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS) while Group 2 received anodal cerebellar tDCS and cathodal spinal tDCS (real tDCS) for 5 days/week for 2 weeks (T1), with a 12-week (T2) follow-up (randomized, double-blind, sham controlled phase). At the 12-week follow-up (T2), all patients (Group 1 and Group 2) received a second treatment of anodal cerebellar tDCS and cathodal spinal tDCS (real tDCS) for 5 days/week for 2 weeks, with a 14-week (T3), 24-week (T4), 36-week (T5) and 52-week follow-up (T6) (open-label phase). At each time point, a clinical, neuropsychological and neurophysiological evaluation was performed. Cerebellar-motor cortex connectivity was evaluated using transcranial magnetic stimulation. We observed a significant improvement in all motor scores (scale for the assessment and rating of ataxia, international cooperative ataxia rating scale), in cognition (evaluated with the cerebellar cognitive affective syndrome scale), in quality-of-life scores, in motor cortex excitability and in cerebellar inhibition after real tDCS compared to sham stimulation and compared to baseline (T0), both at short and long-term. We observed an addon-effect after two repeated treatments with real tDCS compared to a single treatment with real tDCS. The improvement at motor and cognitive scores correlated with the restoration of cerebellar inhibition evaluated with transcranial magnetic stimulation. Cerebello-spinal tDCS represents a promising therapeutic approach for both motor and cognitive symptoms in patients with neurodegenerative ataxia, a still orphan disorder of any pharmacological intervention.

Spinocerebellar ataxia type 23 (SCA23) is a late‐onset neurodegenerative disorder characterized by slowly progressive gait and limb ataxia, for which there is no therapy available. It is caused by pathogenic variants in PDYN, which encodes prodynorphin (PDYN). PDYN is processed into the opioid peptides α‐neoendorphin and dynorphins (Dyn) A and B; inhibitory neurotransmitters that function in pain signaling, stress‐induced responses and addiction. Variants causing SCA23 mostly affect Dyn A, leading to loss of secondary structure and increased peptide stability. PDYN R212W mice express human PDYN containing the SCA23 variant p.R212W. These mice show progressive motor deficits from 3 months of age, climbing fiber (CF) deficits from 3 months of age, and Purkinje cell (PC) loss from 12 months of age. A mouse model for SCA1 showed similar CF deficits, and a recent study found additional developmental abnormalities, namely increased GABAergic interneuron connectivity and non‐cell autonomous disruption of PC function. As SCA23 mice show a similar pathology to SCA1 mice in adulthood, we hypothesized that SCA23 may also follow SCA1 pathology during development. Examining PDYN R212W cerebella during development, we uncovered developmental deficits from 2 weeks of age, namely a reduced number of GABAergic synapses on PC soma, possibly leading to the observed delay in early phase CF elimination between 2 and 3 weeks of age. Furthermore, CFs did not reach terminal height, leaving proximal PC dendrites open to be occupied by parallel fibers (PFs). The observed increase in vGlut1 protein—a marker for PF‐PC synapses—indicates that PFs indeed take over CF territory and have increased connectivity with PCs. Additionally, we detected altered expression of several critical Ca2+ channel subunits, potentially contributing to altered Ca2+ transients in PDYN R212W cerebella. These findings indicate that developmental abnormalities contribute to the SCA23 pathology and uncover a developmental role for PDYN in the cerebellum., Cerebellar developmental deficits preceding neurodegeneration in a mouse model of spinocerebellar ataxia type 23. Deficits include reduced basket cell and climbing fiber synapses on Purkinje cells, and increased parallel fiber‐Purkinje cell contact.

Introduction Genetic inheritance plays key roles in patients with ataxia and/or spastic paraplegia in consanguineous families. This study aims to clarify the genetic spectrum of patients with autosomal recessive hereditary ataxia and spastic paraplegias (AR-HA/HSPs) in consanguineous families. Methods A total of 36 AR-HA/HSPs consanguineous pedigrees from China were recruited into this study. Next generation sequencing (NGS), guided by homozygosity mapping (HM), was applied to identify the pathogenic variants in known genes or novel candidate genes. Results We totally made molecular diagnosis in 47.2% (17/36) of AR-HA/HSPs families. Among them, 13 AR-HAs carried pathogenic variants in SETX (n = 4), SACS (n = 2), STUB1, HSD17B4, NEU1, ADCK3, TPP1, PLA2G6 and MTCL1, while four AR-HSPs carried pathogenic variants in SPG11, ZFYVE26, ATP13A2 and ABCD1. One homozygous nonsense mutation in MRPS27 was identified in an AR-HA family, which was potentially a novel candidate gene of AR-HA. Conclusion HM and NGS can serve as an efficient molecular diagnostic tool for AR-HA/HSPs in consanguineous families. Our findings provide a better understanding of genetic architecture of AR-HA/HSPs in consanguinity and broaden the clinical-genetic spectrum of the disease.

Spinocerebellar degenerations (SCDs) are a diverse group of rare and slowly progressive neurological diseases that include spinocerebellar ataxia type 1 (SCA1), SCA2, SCA3, SCA6, SCA7, dentatorubral-pallidoluysian atrophy (DRPLA) and multiple system atrophy (MSA). They are often inherited, and affect the cerebellum and related pathways. The combination of clinical findings and lesion distribution has been the gold-standard for classifying SCDs. This conventional approach has not been very successful in providing a solid framework shared among researchers because their points of views have been quite variable. After identification of genetic abnormalities, classification was overwhelmed by genotyping, replacing the conventional approach far behind. In this review, we describe a stepwise operational approach that we constructed based only on macroscopic findings without microscopy to classify SCDs into three major groups: pure cerebellar type for SCA6 and SCA31; olivopontocerebellar (OPC) type for SCA1, SCA2, SCA7 and MSA; and dentatorubral-pallidoluysian (DRPL) type for SCA1, SCA3, DRPLA and progressive supranuclear palsy (PSP). Spinocerebellar tract involvement distinguishes SCA1 and SCA3 from DRPLA. Degeneration of the internal segment of the pallidum is accentuated in SCA3 and PSP, while degeneration of the external segment is accentuated in SCA1 and DRPLA. These contrasts are helpful in subdividing OPC and DRPL types to predict their genotypes. Lesion distribution represents disease-specific selective vulnerability, which is readily differentiated macroscopically using our stepwise operational approach. Precise prediction of the major genotypes will provide a basis to understand how genetic abnormalities lead to corresponding phenotypes through disease-specific selective vulnerabilities.

Despite recent progress in the field of genetics, sporadic late-onset ( 40 years) cerebellar ataxia (SLOCA) etiology remains frequently elusive, while the optimal diagnostic workup still needs to be determined. We aimed to comprehensively describe the causes of SLOCA and to discuss the relevance of the investigations.We included 205 consecutive patients with SLOCA seen in our referral center. Patients were prospectively investigated using exhaustive clinical assessment, biochemical, genetic, electrophysiological, and imaging explorations.We established a diagnosis in 135 (66%) patients and reported 26 different causes for SLOCA, the most frequent being multiple system atrophy cerebellar type (MSA-C) (41%). Fifty-one patients (25%) had various causes of SLOCA including immune-mediated diseases such as multiple sclerosis or anti-GAD antibody-mediated ataxia; and other causes, such as alcoholic cerebellar degeneration, superficial siderosis, or Creutzfeldt-Jakob disease. We also identified 11 genetic causes in 20 patients, including SPG7 (n = 4), RFC1-associated CANVAS (n = 3), SLC20A2 (n = 3), very-late-onset Friedreich's ataxia (n = 2), FXTAS (n = 2), SCA3 (n = 1), SCA17 (n = 1), DRPLA (n = 1), MYORG (n = 1), MELAS (n = 1), and a mitochondriopathy (n = 1) that were less severe than MSA-C (p 0.001). Remaining patients (34%) had idiopathic late-onset cerebellar ataxia which was less severe than MSA-C (p 0.01).Our prospective study provides an exhaustive picture of the etiology of SLOCA and clues regarding yield of investigations and diagnostic workup. Based on our observations, we established a diagnostic algorithm for SLOCA.

The prevalence estimations of hereditary ataxias are biased since most epidemiological studies are confined to isolated geographical regions and few nationwide studies are available. The study aims to assess the prevalence, distribution, and neurological features of the Cuban population with hereditary ataxias. A nationwide epidemiological study of hereditary ataxias was conducted in Cuba between March 2017 and June 2018. Patients were scheduled at the Cuban ataxia research center, various hospitals, or at their homes. Demographic and clinical variables were obtained through standardized questionnaires and validated clinical tools. Overall, 1001 patients were diagnosed with hereditary ataxias for a nationwide prevalence of 8.91 cases/100.000 inhabitants. Spinocerebellar ataxia type 2 (SCA2) was the commonest subtype, with highest prevalences at Holguín province (47.86/100.000), and a broad dissemination in the whole country. Most of neurological features were common between all SCA cohorts, but the frequencies of some of them varied between distinct subtypes. Within the SCA2 cohort, significant influences of long mutation size and higher disease duration over the muscle atrophy and oculomotor disorders were observed. Besides, higher disease durations were associated with resting tremor and dysphagia, whereas shorter disease durations were associated with hyperreflexia. The spreading of SCA2 to whole country and the documented raising of its prevalence set the rationales for higher-scope medical care and research strategies, supported in collaborative research networks. The wide epidemiological, clinical, and genetic characterization of this founder SCA2 population identifies this homogeneous cohort as an attractive source for the development of future clinical-genetic and therapeutic researches.

Early diagnosis of Niemann-Pick disease type C (NPC) is crucial to slow the progression of neurological manifestations. Different tools were developed to aid diagnosis of NPC, but to date, no study has compared their performance. We aimed to compare the RADIAL algorithm, intended for the differential diagnosis of autosomal recessive cerebellar ataxias (ARCAs) and NPC-specific suspicion indices (SIs). This study was a retrospective analysis of data from 834 patients with molecularly confirmed ARCAs, including 57 NPC cases (RADIAL cohort). We aimed to compare the algorithm performance of RADIAL (Top 1 and Top 3) with that of four SIs (Original, Refined, 2/3 and 2/7) in discriminating NPC cases and non-NPC cases. We also identified ARCAs closely related to NPC as those with low specificity to detect non-NPC cases and described differential and overlapping features with NPC. Overall, excellent sensitivity and specificity (> 0.90) were achieved with both RADIAL and SI tools for NPC cases. The highest sensitivity was attained with the 2/7 SI, Refined SI and Top 3 RADIAL algorithms. Top 1 and Top 3 RADIAL were the most specific tools, followed by the Original SI. The individual comparison of each ARCA revealed that Wilson disease, PLA2G6-associated neurodegeneration, and hypomyelinating leukodystrophy (POLR3A) are frequent NPC false positives (PLA2G6 and POL3A only with the SIs). Both RADIAL and SI diagnostic approaches showed strong discriminatory potential and may be useful screening tools in different clinical contexts.

ObjectiveTo investigate the efficacy of rovatirelin, a thyrotropin-releasing hormone analogue, for ataxias in patients with spinocerebellar degeneration (SCD).MethodsTwo multicentre, randomised, double-blind, placebo-controlled phase 3 studies (KPS1301, KPS1305) enrolled patients with predominant cerebellar ataxia, including SCA6, SCA31 or cortical cerebellar atrophy. KPS1301 enrolled patients with truncal ataxia and KPS1305 enrolled patients with truncal and limb ataxia. Each study included 4 weeks of pretreatment, a 28-week or 24-week treatment period and 4 weeks of follow-up. Patients were randomised (1:1:1) to rovatirelin (1.6 or 2.4 mg) or placebo in KPS1301, and randomised (1:1) to rovatirelin 2.4 mg or placebo in KPS1305. The primary endpoint was change in Scale for the Assessment and Rating of Ataxia (SARA) total scores. Pooled analysis was performed in patients who met the SARA recruitment criteria of KPS1305.ResultsFrom October 2013 to May 2014, KPS1301 enrolled 411 patients; 374 were randomised to rovatirelin 1.6 mg (n=125), rovatirelin 2.4 mg (n=126) or placebo (n=123). From November 2016 to August 2017, KPS1305 enrolled 241 patients; 203 were randomised to rovatirelin 2.4 mg (n=101) or placebo (n=102). The primary endpoint showed no significant difference between rovatirelin and placebo in these two studies. In the pooled analysis (n=278), the difference between rovatirelin 2.4 mg (n=140) and placebo (n=138) was –0.61 (–1.64 vs –1.03; 95% CI –1.16 to –0.06; p=0.029) in the adjusted mean change in the SARA total score.ConclusionsRovatirelin is a potentially effective treatment option for SCD.Trial registration numberNCT01970098; NCT02889302

More frequent use of next-generation sequencing led to a paradigm shift in assessing heredodegenerative diseases. This is particularly notable in progressive myoclonus epilepsy (PME) and progressive myoclonus ataxia (PMA) where a group of disorders linked to novel genetic mutations has now been added to these phenotypical realms. Despite the historical value of Ramsay Hunt's contribution defining the syndrome later known as PMA, recent genetic developments have made this eponym obsolete and a new definition and classification of PMA and PME seem necessary. A rational possibility is to adopt the wider term progressive myoclonus ataxia and epilepsy syndrome (PMAES), which can be subdivided into its main subtypes, PME and PMA, whenever clinical data is sufficient to make that distinction.

Journal of neurology 269(8), 4363-4374 (2022). doi:10.1007/s00415-022-11071-5, Published by Steinkopff, [Darmstadt]

BACKGROUND: Ataxia is a clinical syndrome characterized by coordination problems and postural disorders. OBJECTIVE: This study aimed to examine the effects of functional trunk training on trunk control and upper limb functions in autosomal recessive hereditary ataxia. METHODS: Twenty patients were randomly divided into treatment and control groups. Both groups received trunk stabilization and balance exercises, and the treatment group received additional functional trunk training sessions (3 days/week for 8 weeks). The International Cooperative Ataxia Rating Scale, Trunk Impairment Scale, Modified Functional Reach Test, Nine-Hole Peg Test and Quick-Disabilities of the Arm Shoulder and Hand questionnaire were used for assessments. RESULTS: The treatment group showed an increase in the upper limb performance bilaterally, whereas increased performance was seen only in the dominant upper limb in the control group. While the functional reach improved in the anterior-posterior (AP) and medial-lateral (ML) directions in the treatment group, it was improved only in the AP direction in the control group. Also, the mean changes in outcomes were not significantly different between the groups except for modified functional reach test. CONCLUSIONS: Functional trunk training may be a more effective method to improve upper limb performance and dynamic trunk balance in autosomal recessive hereditary ataxia.

Introduction: Sixteen subjects with biallelic WARS2 variants encoding the tryptophanyl mitochondrial aminoacyl-tRNA synthetase, presenting with a neonatal- or infantile-onset mitochondrial disease, have been reported to date. Here we present six novel cases with WARS2-related diseases and expand the spectrum to later onset phenotypes including dopa-responsive early-onset parkinsonism and progressive myoclonus-ataxia.Methods: Six individuals from four families underwent whole-exome sequencing within research and diagnostic settings. Following the identification of a genetic defect, in-depth phenotyping and protein expression studies were performed.Results: A relatively common (gnomAD MAF = 0.0033) pathogenic p.(Trp13Gly) missense variant in WARS2 was detected in trans in all six affected individuals in combination with different pathogenic alleles (exon 2 deletion in family 1; p.(Leu100del) in family 2; p.(Gly50Asp) in family 3; and p.(Glu208*) in family 4). Two subjects presented with action tremor around age 10-12 years and developed tremor-dominant parkinsonism with prominent neuropsychiatric features later in their 20s. Two subjects presented with a progressive myoclonusataxia dominant phenotype. One subject presented with spasticity, choreo-dystonia, myoclonus, and speech problems. One subject presented with speech problems, ataxia, and tremor. Western blotting analyses in patientderived fibroblasts showed a markedly decreased expression of the full-length WARS2 protein in both subjects carrying p.(Trp13Gly) and an exon-2 deletion in compound heterozygosity.Conclusions: This study expands the spectrum of the disease to later onset phenotypes of early-onset tremordominant parkinsonism and progressive myoclonus-ataxia phenotypes.

ObjectivesNigrostriatal dopaminergic denervation (NSDD) remains poorly characterized in cerebellar multiple system atrophy (MSA-C). We aimed to study NSDD progression in MSA-C and evaluate the capacity for [123I]-FP-CIT-SPECT and parkinsonism to differentiate MSA-C from idiopathic late-onset cerebellar ataxia (ILOCA).MethodsWe included 85 patients successively referred for sporadic late-onset cerebellar ataxia (SLOCA). Every 6 months, SARA, UPDRS-III, and SDFS scores were measured, and MSA-C diagnostic criteria were searched for. Striatal/occipital dopaminergic binding ratio was evaluated every year with [123I]-FP-CIT-scintigraphy.ResultsAfter a mean follow-up of 33.8 months, 33 patients had probable MSA-C, 8 possible MSA-C, and 44 ILOCA. SARA and UPDRS-III scores worsened faster in the probable MSA-C group (p < 0.01) compared with the ILOCA group. The baseline striatal/occipital ratio was lower (2.3 vs 2.97; p < 0.01) and more decreasing among patients with probable MSA-C (p < 0.01). Weighting dysautonomia and parkinsonism and/or NSDD as additional and principal criterion, respectively, in the possible MSA-C diagnostic criteria slightly improved their specificity (81.6% vs 76.9%) and sensitivity (77.8% vs 72.2%) to predict a final diagnosis of probable MSA-C.DiscussionRapid symptom worsening and NSDD existence and progression predict MSA-C among patients with SLOCA. Parkinsonism, NSDD, and dysautonomia should be considered equivalent for possible MSA-C diagnosis.

Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid storage syndrome defined clinically by the triad of progressive neurodegeneration, juvenile cataracts and tendon xanthomas in adults. It is treatable, and a prompt diagnosis can improve outcomes. We describe a patient with this condition who presented with progressive ataxia.

Early diagnosis of MSA-C in patients with late-onset cerebellar ataxia (LOCA) may prove difficult. We therefore describe and evaluate the performance of the new "phalanx sign" (PS), that should be looked for during the nose-finger test to distinguish MSA-C from idiopathic late-onset ataxia (ILOCA).Sensitivity, specificity, positive predictive value, negative predictive value and interrater reliability of PS were assessed in three groups: 21 MSA-C, 23 ILOCA and 20 age-matched healthy subjects.PS was positive for 61.9% of MSA-C patients', 4.3% of ILOCA patients' and in none of healthy subjects' evaluations. PS discriminated MSA-C from ILOCA (p 0.001) with a sensitivity of 61.9%, a specificity of 95.7%, a positive predictive value of 92.9%, a negative predictive value of 73.3% and a substantial interrater reliability (Kappa = 0.7273).PS could be a helpful, easy and reproducible sign for the early diagnosis of MSA-C in patients with LOCA.

Background and purpose Spinocerebellar ataxia 21 (SCA21) is a rare autosomal dominant neurodegenerative disorder caused by TMEM240 gene mutations. To date, SCA21 has been reported only in a limited number of families worldwide. Here, we describe clinical and molecular findings in five additional SCA21 patients from four unrelated families, diagnosed through a multicentre next generation sequencing‐based molecular screening project on a large cohort of patients with degenerative and congenital ataxias. Methods A cohort of 393 patients with ataxia of unknown aetiology was selected. Following the identification of heterozygous pathogenic TMEM240 variants using a target resequencing panel, we carried out an in‐depth phenotyping of the novel SCA21 patients. Results Five patients from four unrelated families, three of Italian and one of Libyan origin, were identified. These patients were carriers of previously reported TMEM240 mutations. Clinically, our SCA21 cohort includes both adult onset, slowly progressive cerebellar ataxias associated with cognitive impairment resembling cerebellar cognitive affective syndrome and early onset forms associated with cognitive delay, neuropsychiatric features, or evidence of hypomyelination on brain magnetic resonance imaging. None of our patients exhibited signs of extrapyramidal involvement. The so‐called “recurrent” c.509C>T (p.Pro170Leu) mutation was detected in two of four families, corroborating its role as a hot spot. Conclusions Our results confirm that SCA21 is present also in Italy, suggesting that it might not be as rare as previously thought. The phenotype of these novel SCA21 patients indicates that slowly progressive cerebellar ataxia, and cognitive and psychiatric symptoms are the most typical clinical features associated with mutations in the TMEM240 gene., Spinocerebellar ataxia 21 (SCA21), caused by heterozygous TMEM240 mutations, so far has been rarely reported. By screening a cohort of 393, mostly Italian, ataxic patients with ataxia of unknown aetiology using a next generation sequencing‐based targeted resequencing approach, we identified five novel SCA21 patients from four unrelated families. In all of them, we detected previously described TMEM240 mutations, with the c.509C>T (p.Pro170Leu) mutation confirmed as a mutational hot spot. Thus, SCA21 might not be as rare as previously thought; slowly progressive cerebellar ataxia, and cognitive and psychiatric symptoms appear to be the most typically associated clinical features. ​

Spinocerebellar ataxia type 8 (SCA8) is a rare autosomal dominant neurodegenerative disease caused by CTA/CTG repeat expansion in the ATXN8/ATXN8OS gene. To analyze the frequency and clinical characteristics of SCA8 patients in mainland China, we combined polymerase chain reaction (PCR) and triplet repeat-primed PCR (TRP-PCR) to detect the CTA/CTG expansion. We studied a cohort of 362 ataxia patients in which the other known causative genes had been previously excluded, from among 1294 index patients. Positive samples were validated by southern blotting. The CTA/CTG expansion was observed in six probands, accounting for approximately 0.46% (6/1294) in all patients, and 1.66% (6/362) in patients without definite molecular diagnosis. Clinically, aside from the typical SCA8 phenotype, some patients carrying the CTA/CTG expansion exhibited the cerebellar form of multisystem atrophy (MSA-C) and ataxia with paroxysmal kinesigenic dyskinesia (PKD). For the first time, we described the PKD phenotype in association with CTA/CTG expansion, suggesting that CTA/CTG expansion might play a role in the pathogenesis of paroxysmal dyskinesia symptoms.

Background Spinocerebellar ataxia type 5 (SCA5), a dominant spinocerebellar ataxia is caused by spectrin beta nonerythrocytic 2 gene (SPTBN2) mutation. It typically consists of a slow progressive cerebellar ataxia with an onset principally in adulthood. Here, we report on the first Japanese patient with infantile-onset SCA5 associated with a novel heterozygous SPTBN2 mutation. Case report The patient, a 6-year-old girl, developed delayed motor development and unsteady arm movement during infancy. She also showed gaze-evoked nystagmus, saccadic eye pursuit, dysarthria, dysmetria, intention tremor and mild intellectual disability. Brain MRI revealed moderate cerebellar atrophy and mild pontine atrophy. Comprehensive target capture sequencing to identify the causative gene identified a novel missense mutation in SPTBN2 (c.1309C Discussion Two patients with infantile-onset SCA5 associated with another novel heterozygous SPTBN2 mutation have recently been reported; these SPTBN2 mutations, which may have a significant impact on protein function, were located in the second spectrin. Our findings indicate that SPTBN2 mutations may be associated with infantile-onset cerebellar ataxia accompanied with global developmental delay.

There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.

Progressive ataxia in adults can be difficult to diagnose, owing to its heterogeneity and the rarity of individual causes. Many patients remain undiagnosed (‘idiopathic’ ataxia). This paper provides suggested diagnostic pathways for the general neurologist, based on Ataxia UK’s guidelines for professionals. MR brain scanning can provide diagnostic clues, as well as identify ‘structural’ causes such as tumours and multiple sclerosis. Advances in molecular genetics, including the wider and cheaper availability of ‘next-generation sequencing’, have enabled clinicians to identify many more cases with a genetic cause. Finally, autoimmunity is probably an under-recognised cause of progressive ataxia: as well as patients with antigliadin antibodies there are smaller numbers with various antibodies, including some associated with cancer. There are a few treatable ataxias, but also symptomatic treatments to help people with the spectrum of complications that might accompany progressive ataxias. Multidisciplinary team involvement and allied health professionals’ input are critical to excellent patient care, including in the palliative phase. We can no longer justify a nihilistic approach to the management of ataxia.

ObjectiveThis review focuses on the possible association between restless legs syndrome (RLS) and movement disorders, including Parkinson disease (PD), other parkinsonian syndromes, essential tremor, choreic and dystonic syndromes, Tourette syndrome, and heredodegenerative ataxias.MethodsReview of PubMed from 1966 to September 2018 and identification of references of interest for the topic. A meta-analysis of eligible studies on the frequency of RLS in patients with PD and controls using Meta-DiSc1.1.1 software and using the PRISMA guidelines was performed.Results and conclusionsAlthough there are substantial clinical, neuroimaging, neuropathologic, and genetic differences between RLS and PD, many reports describe a higher than expected prevalence of RLS in patients with PD, when compared with the general population or with matched control groups; several studies have also suggested that RLS could be an early clinical feature of PD. RLS symptoms are frequent in multiple system atrophy, essential tremor, Tourette syndrome, Friedreich ataxia, and spinocerebellar ataxia type 3 as well. Finally, possible genetic links between PD and RLS (the presence of allele 2 of the complex microsatellite repeat Rep1 within the α-synuclein gene promoter) and between Tourette syndrome and RLS (several variants in the BTBD9 gene) have been reported in 2 case–control association studies, although these data, based on preliminary data with small sample sizes, need to be replicated in further studies.

Background There are few studies reporting characteristics of patients with cerebellar ataxias in the Brazilian population. The aim of this study was to provide a detailed neurological description of patients with hereditary ataxia followed by a neurology outpatient service in Brazil. Methods Neurological and clinical evaluation of patients with hereditary ataxia was performed at a neurology service outpatient clinic of a hospital in Northeast Brazil between October 2013 and January 2015. Results A total of 47 patients had ataxia as the main symptom. A high prevalence of consanguinity was found in the population studied (40.4%). Mean age was 38.4 ± 15.3 years, mean age at disease onset was 25.6 ± 17.3 years, mean disease duration was 12.8 ± 9.7 years, and mean score on the Scale for the Assessment and Rating of Ataxia (SARA) was 18.4 ± 7.7. Patients with recessive pattern of inheritance were younger, had earlier age at disease onset and greater severity of ataxia, measured by the SARA. Diagnosis was confirmed by molecular analysis, laboratory exams or biopsy in 42.56% (n = 20) of these patients. The most prevalent diseases were: Friedreich's ataxia in 35% (n = 7), Niemann-Pick type C (NPC) in 15% (n = 3), and ataxia with oculomotor apraxia type 2 in 15% (n = 3). Conclusions In contrast with other studies, our prevalence of recessive ataxias was much higher than that of dominant ataxias. These findings might be explained by the high number of patients living in rural areas with a higher rate of consanguineous marriages, absence of a dominant ataxia founder effect or difficult access to healthcare system.

Purpose The aim of this study was to evaluate the clinical utility of arterial spin labeling (ASL) magnetic resonance imaging (MRI) for the detection of cerebellar hypoperfusion in patients with spinocerebellar degeneration (SCD). Methods Regional cerebral blood flow (CBF) were obtained from ASL and 123I-IMP single-photon emission computed tomography (SPECT) images by volume-of-interest analysis in patients with SCD (n = 16). Regional CBF were also measured by ASL in age-matched controls (n = 19) and by SPECT in separate controls (n = 17). The cerebellar CBF values were normalized to the CBF values for the whole gray matter (nCBF) in ASL and SPECT. Results The mean cerebellar nCBF measured by ASL was lower in patients with SCD (0.70 ± 0.09) than in the controls (0.91 ± 0.05) (p Conclusions ASL imaging showed decreased cerebellar blood flow, which correlated with that measured by SPECT, in patients with SCD. These findings suggest the clinical utility of noninvasive MRI with ASL for detecting cerebellar hypoperfusion in addition to atrophy, which would aid the diagnosis of SCD.

Ataxia encompasses a large group of rare disorders characterized by irregular movements, decreased coordination, imbalance, kinetic tremor, wide-based stance, and dysarthria. Evaluating ataxia can be challenging considering the volume of disorders and their complex pathologies involving diverse genetic and clinical factors. This is a comprehensive review of the genetic ataxia literature, presenting updated guidelines for differential diagnosis. Age, time course, and family history provide initial guidance for evaluation of ataxia. As genetic testing is increasingly utilized, new genes are discovered and phenotypes for existing disorders are expanded. This review assists physicians by offering a diagnostic roadmap for suspected hereditary ataxia based on the current literature.

BACKGROUND AND PURPOSE Spinocerebellar ataxia 21 (SCA21) is a rare autosomal dominant neurodegenerative disorder caused by TMEM240 gene mutations. To date, SCA21 has been reported only in a limited number of families worldwide. Here, we describe clinical and molecular findings in five additional SCA21 patients from four unrelated families, diagnosed through a multicentre next generation sequencing-based molecular screening project on a large cohort of patients with degenerative and congenital ataxias. METHODS A cohort of 393 patients with ataxia of unknown aetiology was selected. Following the identification of heterozygous pathogenic TMEM240 variants using a target resequencing panel, we carried out an in-depth phenotyping of the novel SCA21 patients. RESULTS Five patients from four unrelated families, three of Italian and one of Libyan origin, were identified. These patients were carriers of previously reported TMEM240 mutations. Clinically, our SCA21 cohort includes both adult onset, slowly progressive cerebellar ataxias associated with cognitive impairment resembling cerebellar cognitive affective syndrome and early onset forms associated with cognitive delay, neuropsychiatric features, or evidence of hypomyelination on brain magnetic resonance imaging. None of our patients exhibited signs of extrapyramidal involvement. The so-called "recurrent" c.509C>T (p.Pro170Leu) mutation was detected in two of four families, corroborating its role as a hot spot. CONCLUSIONS Our results confirm that SCA21 is present also in Italy, suggesting that it might not be as rare as previously thought. The phenotype of these novel SCA21 patients indicates that slowly progressive cerebellar ataxia, and cognitive and psychiatric symptoms are the most typical clinical features associated with mutations in the TMEM240 gene.

Background The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations. Objective To identify the prevalence and genetic structure of hereditary ataxias in the Turkish population. Methods Our cohort consisted of 1296 index cases and 324 affected family members. Polymerase chain reaction followed by Sanger sequencing or fragment analysis were performed to screen for the trinucleotide repeat expansions in families with a dominant inheritance pattern, as well as in sporadic cases. The expansion in the frataxin (FXN) gene was tested in all autosomal recessive cases and in sporadic cases with a compatible phenotype. Whole-exome sequencing was applied to 251 probands, selected based on the family history, age of onset, and phenotype. Results Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole-exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty-eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data. Conclusion With the large sample size recruited across the country, we consider that our results provide an accurate picture of the frequency of hereditary ataxias in Turkey. (c) 2021 International Parkinson and Movement Disorder Society, Suna and Inan Kirac Foundation; Koc UniversityKoc University; Bogazici UniversityBogazici University, This work was supported by funds from Suna and Inan Kirac Foundation, Koc University, Bogazici University.

Background The genetics of cerebellar ataxia is complex. Hundreds of causative genes have been identified, but only a few cause more than single cases. The spectrum of ataxia-causing genes differs considerably between populations. The aim of the study was to investigate the molecular epidemiology of ataxia in the Finnish population. Patients and methods All patients in hospital database were reviewed for the diagnosis of unspecified ataxia. Acquired ataxias and nongenetic ataxias such as those related to infection, trauma or stroke were excluded. Sixty patients with sporadic ataxia with unknown etiology and 36 patients with familial ataxia of unknown etiology were recruited in the study. Repeat expansions in the SCA genes (ATXN1, 2, 3, 7, 8/OS, CACNA1A, TBP), FXN, and RFC1 were determined. Point mutations in POLG, SPG7 and in mitochondrial DNA (mtDNA) were investigated. In addition, DNA from 8 patients was exome sequenced. Results A genetic cause of ataxia was found in 33 patients (34.4%). Seven patients had a dominantly inherited repeat expansion in ATXN8/OS. Ten patients had mitochondrial ataxia resulting from mutations in nuclear mitochondrial genes POLG or RARS2, or from a point mutation m.8561C > G or a single deletion in mtDNA. Interestingly, five patients were biallelic for the recently identified pathogenic repeat expansion in RFC1. All the five patients presented with the phenotype of cerebellar ataxia, neuropathy, and vestibular areflexia (CANVAS). Moreover, screening of 54 patients with Charcot-Marie-Tooth neuropathy revealed four additional patients with biallelic repeat expansion in RFC1, but none of them had cerebellar symptoms. Conclusions Expansion in ATXN8/OS results in the majority of dominant ataxias in Finland, while mutations in RFC1 and POLG are the most common cause of recessive ataxias. Our results suggest that analysis of RFC1 should be included in the routine diagnostics of idiopathic ataxia and Charcot-Marie-Tooth polyneuropathy.

Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.

Spinocerebellar ataxias (SCAs) are a group of dominantly-inherited cerebellar ataxias, among which CAG expansion-related SCAs are most common. These diseases have very high penetrance with defined disease progression, and emerging therapies are being developed to provide either symptomatic or disease-modifying benefits. In clinical trial design, it is crucial to incorporate biomarkers to test target engagement or track disease progression in response to therapies, especially in rare diseases such as SCAs. In this article, we review the available rating scales and recent advances of biomarkers in CAG-repeat SCAs. We divided biomarkers into neuroimaging, body fluid, and physiological studies. Understanding the utility of each biomarker will facilitate the design of robust clinical trials to advance therapies for SCAs.

A variety of missense mutations and a stop mutation in the gene coding for transmembrane protein 240 (TMEM240) have been reported to be the causative mutations of spinocerebellar ataxia 21 (SCA21). We aimed to investigate the expression of TMEM240 protein in mouse brain at the tissue, cellular, and subcellular levels. Immunofluorescence labeling showed TMEM240 to be expressed in various areas of the brain, with the highest levels in the hippocampus, isocortex, and cerebellum. In the cerebellum, TMEM240 was detected in the deep nuclei and the cerebellar cortex. The protein was expressed in all three layers of the cortex and various cerebellar neurons. TMEM240 was localized to climbing, mossy, and parallel fiber afferents projecting to Purkinje cells, as shown by coimmunostaining with VGLUT1 and VGLUT2. Co-immunostaining with synaptophysin, post-synaptic fractionation, and confirmatory electron microscopy showed TMEM240 to be localized to the post-synaptic side of synapses near the Purkinje-cell soma. Similar results were obtained in human cerebellar sections. These data suggest that TMEM240 may be involved in the organization of the cerebellar network, particularly in synaptic inputs converging on Purkinje cells. This study is the first to describe TMEM240 expression in the normal mouse brain., The Cerebellum, Springer, In press, Ahead of print

Introduction Hereditary ataxias demonstrate a high degree of clinical and genetic heterogeneity. Understanding the genetic etiology of hereditary ataxias is crucial for genetic counseling and clinical management. Methods The clinical and genetic data of patients with familial or sporadic ataxias who referred to our tertiary medical center were retrospectively analyzed. Probands in this study underwent SCA repeat expansion panel firstly to screen for repeat expansion SCAs; those with negative results had NGS-targeted panels or WES testing to detect conventional mutations. Results A total of 223 patients were enrolled from 206 families. 5 kinds of coexisting SCA repeat expansions were observed (SCA3/SCA17, SCA3/SCA8, SCA2/SCA8, SCA3/SCA12 and SCA8/SCA12) in 12 patients from 8 families, among which SCA2/SCA8, SCA8/SCA12 and SCA3/SCA12 were reported for the first time. The coexistence of expanded SCA3 with SCA17 alleles was the most common in our study. NGS identified pathogenic/likely pathogenic variants in 12 ataxia causative genes in 13 probands. Spastic paraplegia ataxia was the most common diagnosis. Six novel mutations were detected in five ataxia-related genes. Conclusion Coexistence may not specific to a certain SCA subtype and the frequency might have been underestimated before. SCA repeat expansion panel should be considered in patients with overlapping SCA features. In addition, our study broadened the conventional mutation spectrum in ataxia-related genes. These results facilitate a better understanding of the genetic basis for hereditary ataxias.

Background Mutations in TGM6 gene, encoding for transglutaminase 6 (TG6), have been implicated in the pathogenesis of spinocerebellar ataxia type 35 (SCA35), a rare autosomal dominant disease marked by cerebellar degeneration and characterized by postural instability, incoordination of gait, features of cerebellar dysfunction and pyramidal signs. Case presentation Here we report the case of an Italian patient with late-onset, slowly progressive cerebellar features, including gait ataxia, scanning speech and ocular dysmetria and pyramidal tract signs. Whole exome sequencing revealed the rare heterozygous c.1024C > T (p.R342W) variant of TGM6, located at a highly evolutionary conserved position and predicted as pathogenic by in silico tools. Expression of TG6-R342W mutant in HEK293T cells led to a significant reduction of transamidase activity compared to wild-type TG6. Conclusion This finding extends SCA35 genetic landscape, highlighting the importance of TGM6 screening in undiagnosed late-onset and slowly progressive cerebellar ataxias.

The kinase TTBK1 is predominantly expressed in the central nervous system and has been implicated in neurodegenerative diseases including Alzheimer’s disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis through its ability to phosphorylate the proteins tau and TDP-43. Mutations in the closely related gene TTBK2 cause spinocerebellar ataxia, type 11. However, it remains unknown whether altered TTBK1 activity alone can drive neurodegeneration. In order to characterize the consequences of neuronal TTBK1 upregulation in adult brains, we have generated a transgenic mouse model with inducible pan-neuronal expression of human TTBK1. We find that these inducible TTBK1 transgenic mice (iTTBK1 Tg) exhibit motor and cognitive phenotypes, including decreased grip strength, hyperactivity, limb-clasping, and spatial memory impairment. These behavioral phenotypes occur in conjunction with progressive weight loss, neuroinflammation, and severe cerebellar degeneration with Purkinje neuron loss. Phenotype onset begins weeks after TTBK1 induction, culminating in average mortality around 7 weeks post induction. The iTTBK1 Tg animals lack any obvious accumulation of pathological tau or TDP-43, indicating that TTBK1 expression drives neurodegeneration in the absence of detectable pathological protein deposition. In exploring TTBK1 functions, we identified the autophagy related protein GABARAP to be a novel interacting partner of TTBK1 and show that GABARAP protein levels increase in the brain following induction of TTBK1. These iTTBK1 Tg mice exhibit phenotypes reminiscent of spinocerebellar ataxia, and represent a new model of cerebellar neurodegeneration.

FBXO7 is implicated in the ubiquitin–proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS). Methods: We investigated the disease molecular bases in a child with PPS and brain iron accumulation. Results: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient’s fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly-ubiquitinated proteins. Conclusion: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders., Fundacio La Marato de TV3 [Grants 20143130 to BPD, and 20143131 to CE], by the Instituto de Salud Carlos III (ISCIII) - Subdireccion General de Evaluacion y Fomento de la Investigacion within the framework of the National R + D+I Plan cofunded with ERDF funds [Grants PI18/01319 to BPD and PI18/00147 to CE], and by the Generalitat Valenciana [Grant PROMETEO/2018/ 135 to CE]. Part of the equipment employed in this work has been funded by Generalitat Valenciana and cofinanced with ERDF funds (OP ERDF of Comunitat Valenciana 2014-2020). SFR had a contract funded by the Spanish Foundation Per Amor a l’Art (FPAA). PS had a FPU-PhD fellowship funded by the Spanish Ministry of Education, Culture and Sport Inmunoterapia

Spinocerebellar ataxias (SCAs), formerly known as autosomal dominant cerebellar ataxias (ADCAs), are a group of hereditary heterogeneous neurodegenerative diseases. Gait, progressive ataxia, dysarthria, and eye movement disorder are common symptoms of spinocerebellar ataxias. Other symptoms include peripheral neuropathy, cognitive impairment, psychosis, and seizures. Patients may lose their lives due to out of coordinated respiration and/or swallowing. Neurological signs cover pyramidal or extrapyramidal signs, spasm, ophthalmoplegia, hyperactive deep tendon reflexes, and so on. Different subtypes of SCAs present various clinical features. Spinocerebellar ataxia type 23 (SCA23), one subtype of the SCA family, is characterized by mutant prodynorphin (PDYN) gene. Based on literatures, this review details a series of SCA23, to improve a whole understanding of clinicians and point out the potential research direction of this dysfunction, including a history, pathophysiological mechanism, diagnosis and differential diagnosis, epigenetics, penetrance and prevalence, genetic counseling, treatment and prognosis.

Spinocerebellar ataxia type 21 (SCA21/ATX-TMEM240) is a rare form of cerebellar ataxia that commonly presents with motor, cognitive, and behavioral impairments. Although these features have been identified as part of the clinical manifestations of SCA21, the neurodevelopmental disorders associated with SCA21 have not been well studied or described. Here we present extensive phenotypic data for 3 subjects from an SCA21 family in the United States. Genetic testing demonstrated the c.196 G>A (p.Gly66Arg) variant to be a second recurrent mutation associated with the disorder. Standardized developmental assessment revealed significant deficits in cognition, adaptive function, motor skills, and social communication with 2 of the subjects having diagnoses of autism spectrum disorder, which has never been described in SCA21. Quantitative gait analysis showed markedly abnormal spatiotemporal gait variables indicative of poor gait control and cerebellar as well as noncerebellar dysfunction. Clinical evaluation also highlighted a striking variability in clinical symptoms, with greater ataxia correlating with greater severity of neurodevelopmental disorder diagnoses. Notably, neurodevelopmental outcomes have improved with intervention over time. Taken together, this case series identifies that the manifestation of neurodevelopmental disorders is a key feature of SCA21 and may precede the presence of motor abnormalities. Furthermore, the coexistence of ataxia and neurodevelopmental disorders in these subjects suggests a role for spinocerebellar pathways in both outcomes. The findings in this study highlight the importance of evaluation of neurodevelopmental concerns in the context of progressive motor abnormalities and the need for timely intervention to ultimately improve quality of life for individuals with SCA21.

Objective Premature saccades (PSs) are those made with latencies too short for the direction and amplitude to be specifically programmed. We sought to determine the minimum latency needed to establish accurate direction and amplitude, and observed what occurs when saccades are launched before this minimum latency. Methods In Experiment 1, 249 normal subjects performed the gap saccade task with horizontal targets. In Experiment 2, 28 normal subjects performed the gap saccade task with the targets placed in eight directions. In Experiment 3, 38 normal subjects, 49 patients with Parkinson’s disease (PD), and 10 patients with spinocerebellar degeneration (SCD) performed the gap saccade task with horizontal targets. Results In Experiment 1, it took 100 ms to accurately establish saccade amplitudes and directions. In Experiment 2, however, the latencies needed for accurate amplitude and direction establishment were both approximately 150 ms. In Experiment 3, the frequencies of PSs in patients with PD and SCD were lower than those of normal subjects. Conclusions The saccade amplitudes and directions are determined simultaneously, 100–150 ms after target presentation. PSs may result from prediction of the oncoming target direction or latent saccade activities in the superior colliculus. Significance Saccade direction and amplitude are determined simultaneously.

Relative frequency of hereditary ataxias remains unknown in many regions of Latin America. We described the relative frequency in spinocerebellar ataxias (SCA) due to (CAG)n and to (ATTCT)n expansions, as well as Friedreich ataxia (FRDA), among cases series of ataxic individuals from Peru. Among ataxic index cases from 104 families (38 of them with and 66 without autosomal dominant pattern of inheritance), we identified 22 SCA10, 8 SCA2, 3 SCA6, 2 SCA3, 2 SCA7, 1 SCA1, and 9 FRDA cases (or families). SCA10 was by far the most frequent one. Findings in SCA10 and FRDA families were of note. Affected genitors were not detected in 7 out of 22 SCA10 nuclear families; then overall maximal penetrance of SCA10 was estimated as 85%; in multiplex families, penetrance was 94%. Two out of nine FRDA cases carried only one allele with a GAA expansion. SCA10 was the most frequent hereditary ataxia in Peru. Our data suggested that ATTCT expansions at ATXN10 might not be fully penetrant and/or instability between generations might frequently cross the limits between non-penetrant and penetrant lengths. A unique distribution of inherited ataxias in Peru requires specific screening panels, considering SCA10 as first line of local diagnosis guidelines.

Introduction The spectrum of neurologic disorders associated with HIV infection is very broad, resulting from direct virus invasion, opportunistic infections, malignancies and toxic effects of drugs. Methods Among a large cohort of ataxia patients (N = 1050) evaluated between 2008 and 2017, we detected four patients with HIV-infection who developed a pure progressive cerebellar ataxia syndrome combined with cerebellar atrophy. Results Adverse drug effects, opportunistic infections and malignancies as well as immune-reconstitution syndrome were ruled out based on history and laboratory data. The exact pathophysiological mechanisms of ataxia in HIV patients is not very clear, but seems to be immune-mediated or a direct neurotoxic virus effect leading to apoptosis of Purkinje and granular cells. Conclusion HIV infection should be investigated in adult patients with undetermined sporadic progressive pure ataxia with cerebellar atrophy.

Transcranial magnetic stimulation (TMS) is a valuable technique to assess and modulate human brain function in normal and pathological conditions. This critical review surveys the contributions of TMS to the diagnosis, insight into pathophysiology and treatment of genetically confirmed hereditary ataxias, a heterogeneous group of neurodegenerative disorders that can affect motor cortex and the corticospinal tract. Most studies were conducted on small sample sizes and focused on diagnostic approaches. The available data demonstrate early involvement of the corticospinal tract and motor cortex circuitry, and support the possible efficacy of cerebellar repetitive TMS (rTMS) as therapeutic approach. Further TMS-based studies are warranted, to establish biomarkers for early diagnosis and disease monitoring, explore the involvement of the cerebello-dentato-thalamo-cortical projection, study the effects of rTMS-induced plasticity, and utilize rTMS for treatment.