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Myotonic dystrophy type 1 (DM1) is known to affect cognitive function, but the best methods to assess central nervous system involvement in multicenter studies have not been determined. In this study our primary aim was to evaluate the potential of computerized cognitive tests to assess cognition in DM1.We conducted a prospective, longitudinal, observational study of 113 adults with DM1 at six sites. Psychomotor speed, attention, working memory, and executive functioning were assessed at baseline, 3 months, and 12 months using computerized cognitive tests. Results were compared with assessments of muscle function and patient reported outcomes (PROs), including the Myotonic Dystrophy Health Index (MDHI) and the 5-dimension EuroQol (EQ-5D-5L) questionnaire.Based on intraclass correlation coefficients, computerized cognitive tests had moderate to good reliability for psychomotor speed (0.76), attention (0.82), working memory speed (0.79), working memory accuracy (0.65), and executive functioning (0.87). Performance at baseline was lowest for working memory accuracy (P .0001). Executive function performance improved from baseline to 3 months (P .0001), without further changes over 1 year. There was a moderate correlation between poorer executive function and larger CTG repeat size (r = -0.433). There were some weak associations between PROs and cognitive performance.Computerized tests of cognition are feasible in multicenter studies of DM1. Poor performance was exhibited in working memory, which may be a useful variable in clinical trials. Learning effects may have contributed to the improvement in executive functioning. The relationship between PROs and cognitive impairment in DM1 requires further study.

Non-coding CGG repeat expansions cause multiple neurodegenerative disorders, including fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukodystrophy, and oculopharyngodistal myopathy. The underlying genetic causes of several of these diseases have been identified only in the past 2-3 years. These expansion disorders have substantial overlapping clinical, neuroimaging and histopathological features. The shared features suggest common mechanisms that could have implications for the development of therapies for this group of diseases - similar therapeutic strategies or drugs may be effective for various neurodegenerative disorders induced by non-coding CGG expansions. In this Review, we provide an overview of clinical and pathological features of these CGG repeat expansion diseases and consider the likely pathological mechanisms, including RNA toxicity, CGG repeat-associated non-AUG-initiated translation, protein aggregation and mitochondrial impairment. We then discuss future research needed to improve the identification and diagnosis of CGG repeat expansion diseases, to improve modelling of these diseases and to understand their pathogenesis. We also consider possible therapeutic strategies. Finally, we propose that CGG repeat expansion diseases may represent manifestations of a single underlying neuromyodegenerative syndrome in which different organs are affected to different extents depending on the gene location of the repeat expansion.

Pentanucleotide expansion diseases constitute a special class of neurodegeneration. The repeat expansions occur in non-coding regions, have likely arisen from Alu elements, and often result in autosomal dominant or recessive phenotypes with underlying cerebellar neuropathology. When transcribed (potentially bidirectionally), the expanded RNA forms complex secondary and tertiary structures that can give rise to RNA-mediated toxicity, including protein sequestration, pentapeptide synthesis, and mRNA dysregulation. Since several of these diseases have recently been discovered, our understanding of their pathological mechanisms is limited, and their therapeutic interventions underexplored. This review aims to highlight new in vitro and in vivo insights into these incurable diseases.

Background No comprehensive meta-analysis has ever been performed to assess the value of neurofilament light chain (NfL) as a biomarker in genetic ataxia. Objective We conducted a meta-analysis to summarize NfL concentration and evaluate its utility as a biomarker in genetic ataxia. Methods Studies were included if they reported NfL concentration of genetic ataxia. We used log (mean ± SD) NfL to describe mean raw value of NfL. The effect size of NfL between genetic ataxia and healthy controls (HC) was expressed by mean difference. Correlation between NfL and disease severity was calculated. Results We identified 11 studies of 624 HC and 1006 patients, here referred to as spinocerebellar ataxia (SCA1, 2, 3, 6, and 7), Friedreich ataxia (FRDA), and ataxia telangiectasia (A-T). The concentration of blood NfL (bNfL) elevated with proximity to expected onset, and progressively increased from asymptomatic to preclinical to clinical stage in SCA3. Compared with HC, bNfL levels were significantly higher in SCA1, 2, 3, and 7, FRDA, as well as A-T, and the difference increased with the advancing disease in SCA3. bNfL levels correlated with disease severity in SCA3. There was a significant correlation between bNfL and longitudinal progression in SCA3. Additionally, bNfL increased with age in HC, yet this is probably masked by higher disease-related effects on bNfL in genetic ataxia. Conclusions bNfL can be used as a potential biomarker to predict disease onset, severity, and progression of genetic ataxia. Reference-value setting of bNfL should be divided according to age. © 2021 International Parkinson and Movement Disorder Society.

Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of SCA8, we studied the molecular differences between highly penetrant families and more common sporadic cases (82%) using a large cohort of SCA8 families (n = 77). We show that repeat expansion mutations from individuals with multiple affected family members have CCG•CGG interruptions at a higher frequency than sporadic SCA8 cases and that the number of CCG•CGG interruptions correlates with age at onset. At the molecular level, CCG•CGG interruptions increase RNA hairpin stability, and in cell culture experiments, increase p‐eIF2α and polyAla and polySer RAN protein levels. Additionally, CCG•CGG interruptions, which encode arginine interruptions in the polyGln frame, increase toxicity of the resulting proteins. In summary, SCA8 CCG•CGG interruptions increase polyAla and polySer RAN protein levels, polyGln protein toxicity, and disease penetrance and provide novel insight into the molecular differences between SCA8 families with high vs. low disease penetrance., This study shows CCG•CGG interruptions within the ATXN8OS/ATXN8 CTG•CAG repeat are an important genetic modifier of disease penetrance in spinocerebellar ataxia type 8 (SCA8).

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder in which patients have a slowly progressive cerebellar ataxia, with dysarthria, dysphagia, and epilepsy. The aims of this study were to characterize the phenotypic expression of SCA10 and to examine its genotype-phenotype relationships. Ninety-one Brazilian patients with SCA10 from 16 families were selected. Clinical and epidemiological data were assessed by a standardized protocol, and severity of disease was measured by the Scale for the Assessment and Rating of Ataxia (SARA). The mean age of onset of symptoms was 34.8 ± 9.4 years. Sixty-two (68.2%) patients presented exclusively with pure cerebellar ataxia. Only 6 (6.6%) of the patients presented with epilepsy. Patients with epilepsy had a mean age of onset of symptoms lower than that of patients without epilepsy (23.5 ± 15.5 years vs 35.4 ± 8.7 years, p = 0.021, respectively). All cases of intention tremor were in women from one family. This family also had the lowest mean age of onset of symptoms, and a higher percentage of SCA10 cases in women. There was a positive correlation between duration of disease and severity of ataxia (rho = 0.272, p = 0.016), as quantified by SARA. We did not find a statistically significant correlation between age of onset of symptoms and expansion size (r = - 0.163, p = 0.185). The most common clinical presentation of SCA10 was pure cerebellar ataxia. Our data suggest that patients with epilepsy may have a lower age of onset of symptoms than those who do not have epilepsy. These findings and the description of a family with intention tremor in women with earlier onset of symptoms draw further attention to the phenotypic variability of SCA10.

CAG repeat expansion is the genetic cause of nine incurable polyglutamine (polyQ) diseases with neurodegenerative features. Silencing repeat RNA holds great therapeutic value. Here, we developed a repeat-based RNA-cleaving DNAzyme that catalyzes the destruction of expanded CAG repeat RNA of six polyQ diseases with high potency. DNAzyme preferentially cleaved the expanded allele in spinocerebellar ataxia type 1 (SCA1) cells. While cleavage was non-allele-specific for spinocerebellar ataxia type 3 (SCA3) cells, treatment of DNAzyme leads to improved cell viability without affecting mitochondrial metabolism or p62-dependent aggresome formation. DNAzyme appears to be stable in mouse brain for at least 1 month, and an intermediate dosage of DNAzyme in a SCA3 mouse model leads to a significant reduction of high molecular weight ATXN3 proteins. Our data suggest that DNAzyme is an effective RNA silencing molecule for potential treatment of multiple polyQ diseases. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01075-w.

We are grateful to Diego Sevilla, Victoria Marca, and Olimpio Ortega for lab assistance and logistic support. Research reported in this publication was supported by the Fogarty International Center (FIC) of the National Institutes of Health and the National Institute of Neurological Disorders and Stroke (NINDS) under grant #D43TW009345 awarded to the Northern Pacific Global Health Fellows Program and grant #D43TW009137 awarded to the Interdisciplinary Cerebrovascular Diseases Training Program in South America. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

Background Primary deficiency of coenzyme Q10 deficiency‐4 (COQ10D4) is an autosomal recessive cerebellar ataxia with mitochondrial respiratory chain disfunction. The main clinical manifestation involves early‐onset exercise intolerance, progressive cerebellar ataxia, and movement disorders. COQ8A gene mutations are responsible for this disease. Here, we provide clinical, laboratory, and genetic findings of a patient with cerebellar ataxia caused by compound heterozygous mutations in COQ8A gene. Methods A male patient from a non‐consanguineous Chinese family underwent detailed physical and auxiliary examination. After exclusion of acquired causes of ataxia, Friedreich's Ataxia, and common types of spinocerebellar ataxia, the patient was subjected to whole exome sequencing (WES) followed by confirmation of sequence variants using Sanger sequencing. His asymptomatic parents, two brothers and one sister were genotyped for these variants. Results This patient showed early‐onset exercise intolerance and progressive cerebellar ataxia, wide‐based gait and tremor, accompanied by symptoms of dysautonomia. His serum lactate level was elevated and plasma total Coenzyme Q10 (CoQ10) was decreased. Brain MRI showed cerebellar atrophy, and X‐ray of the spine revealed thoraco‐lumbar scoliosis. Compound heterozygous mutations in the COQ8A gene were identified through WES: c.1844_1845insG, p.Ser616Leufs*114 and c.902G>A, p.Arg301Gln. After treatment with ubidecarenone, 40 mg three times per day for 2 years, the symptoms dramatically improved. Conclusions We identified a patient with COQ10D4 caused by novel COQ8A mutations. Our findings widen the spectrum of COQ8A gene mutations and clinical manifestations., We identified a patient with COQ10D4 caused by novel COQ8A mutations through WES. Our findings widen the spectrum of COQ8A gene mutations and clinical manifestations.

Objective Our goal was to perform detailed clinical and genomic analysis of a large multigenerational Chinese family with 21 individuals showing symptoms of Familial Cortical Myoclonic Tremor with Epilepsy (FCMTE) that we have followed for over 20 years. Methods Patients were subjected to clinical evaluation, routine EEG, and structural magnetic resonance imaging. Whole exome sequencing, repeat‐primed PCR, long‐range PCR, and PacBio sequencing were performed to characterize the disease‐causing mutation in this family. Results All evaluated patients manifested adult‐onset seizures and presented with progressive myoclonic postural tremors starting after the third or fourth decade of life. Seizures typically diminished markedly in frequency with implementation of antiseizure medications but did not completely cease. The electroencephalogram of affected individuals showed generalized or multifocal spikes and slow wave complexes. An expansion of TTTTA motifs with addition of TTTCA motifs in intron 4 of SAMD12 was identified to segregate with the disease phenotype in this family. Furthermore, we found that the mutant allele is unstable and can undergo both contraction and expansion by changes in the number of repeat motifs each time it is passed to the next generation. The size of mutant allele varied from 5 to 5.5 kb with 549‐603 copies of TTTTA and 287‐343 copies of TTTCA repeat motifs in this family. Significance Our study provides a detailed description of clinical progression of FCMTE symptoms and its management with antiseizure medications. Our method of repeat analysis by PacBio sequencing of long‐range PCR products does not require high‐quality DNA and hence can be easily applied to other families to elucidate any correlation between the repeat size and phenotypic variables, such as, age of onset, and severity of symptoms.

Introduction There is a dearth of studies of spinocerebellar ataxias (SCAs) and diffusion tensor magnetic resonance imaging (DTI). Objective To analyze changes observed in DTI parameters and correlate these to clinical findings in SCA3 and SCA10 patients. Methods SCA3 (n = 19) and SCA10 (n = 18) patients were compared with a similar number of controls and assessed clinically and with the scale for the assessment and rating of ataxia (SARA) before undergoing the same MRI protocol. TRACULA (TRActs Constrained by UnderLying Anatomy) software was used to analyze the DTI metrics FA, AD, RD and MD. Results More white matter fiber tracts with changes in diffusivity were found in SCA3 patients than in SCA10 patients. There was a reduction in AD in altered fiber tracts in SCA3 and a greater increase in RD in SCA10. In the SCA3 patients, FA was reduced in the corticospinal tract (CST) and inferior longitudinal fasciculus (ILF), but this was not observed in the SCA10 patients. SARA score was correlated with DTI findings in SCA3 but not in SCA10. Conclusion Changes were observed in DTI for both SCA3 and SCA10 but were more widespread in SCA3. Our finding of myelin-sheath changes in SCA10 and secondary axonal changes in SCA3 may reflect the more rapid, aggressive clinical course of SCA3.

Background Dysphagia is a common symptom and may be a cause of death in patients with spinocerebellar ataxias (SCAs). However, little is known about at which disease stage dysphagia becomes clinically relevant. Therefore, our study aims to investigate the prevalence of dysphagia in different disease stages of SCA 1, 2, 3 and 6. Methods We studied 237 genetically confirmed patients with SCA 1, 2, 3, 6 from the Clinical Research Consortium for SCAs and investigated the prevalence of self-reported dysphagia and the association between dysphagia and other clinical characteristics. We further stratified ataxia severity and studied the prevalence of dysphagia at each disease stage. Results Dysphagia was present in 59.9% of SCA patients. Patients with dysphagia had a longer disease duration and more severe ataxia than patients without dysphagia (patients with dysphagia vs. without dysphagia, disease duration (years): 14.51 ± 8.91 vs. 11.22 ± 7.82, p = .001, scale for the assessment and rating of ataxia [SARA]: 17.90 ± 7.74 vs. 13.04 ± 7.51, p = .000). Dysphagia was most common in SCA1, followed by SCA3, SCA 6, and SCA 2. Dysphagia in SCA1 and 3 was associated robustly with ataxia severity, whereas this association was less obvious in SCA2 and 6, demonstrating genotype-specific clinical variation. Conclusion Dysphagia is a common clinical symptom in SCAs, especially in the severe disease stage. Understanding dysphagia in SCA patients can improve the care of these patients and advance knowledge on the roles of the cerebellum and brainstem control in swallowing.

Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by CAG (encoding glutamine) repeat expansion in the Ataxin-3 (ATXN3) gene. We have shown previously that ATXN3-depleted or pathogenic ATXN3-expressing cells abrogate polynucleotide kinase 3'-phosphatase (PNKP) activity. Here, we report that ATXN3 associates with RNA polymerase II (RNAP II) and the classical nonhomologous end-joining (C-NHEJ) proteins, including PNKP, along with nascent RNAs under physiological conditions. Notably, ATXN3 depletion significantly decreased global transcription, repair of transcribed genes, and error-free double-strand break repair of a 3'-phosphate-containing terminally gapped, linearized reporter plasmid. The missing sequence at the terminal break site was restored in the recircularized plasmid in control cells by using the endogenous homologous transcript as a template, indicating ATXN3's role in PNKP-mediated error-free C-NHEJ. Furthermore, brain extracts from SCA3 patients and mice show significantly lower PNKP activity, elevated p53BP1 level, more abundant strand-breaks in the transcribed genes, and degradation of RNAP II relative to controls. A similar RNAP II degradation is also evident in mutant ATXN3-expressing Drosophila larval brains and eyes. Importantly, SCA3 phenotype in Drosophila was completely amenable to PNKP complementation. Hence, salvaging PNKP's activity can be a promising therapeutic strategy for SCA3.

Large expansions of microsatellite DNA cause several neurological diseases. In Spinocerebellar ataxia type 10 (SCA10), the repeat interruptions change disease phenotype; an (ATTCC)n or a (ATCCT)n/(ATCCC)n interruption within the (ATTCT)n repeat is associated with the robust phenotype of ataxia and epilepsy while mostly pure (ATTCT)n may have reduced penetrance. Large repeat expansions of SCA10, and many other microsatellite expansions, can exceed 10,000 base pairs (bp) in size. Conventional next generation sequencing (NGS) technologies are ineffective in determining internal sequence contents or size of these expanded repeats. Using repeat primed PCR (RP-PCR) in conjunction with a high-sensitivity pulsed-field capillary electrophoresis fragment analyzer (FEMTO-Pulse, Agilent, Santa Clara, CA) (RP-FEMTO hereafter), we successfully determined sequence content of large expansion repeats in genomic DNA of SCA10 patients and transformed yeast artificial chromosomes containing SCA10 repeats. This RP-FEMTO is a simple and economical methodology which could complement emerging NGS for very long sequence reads such as Single Molecule, Real-Time (SMRT) and nanopore sequencing technologies.

Spinocerebellar ataxia (SCA) presents different rates of functional decline depending on the type of ataxia.To compare the progression of disability, imbalance and severity of ataxia in patients with the three most common types of SCA in southern Brazil.126 patients (31-SCA2, 58-SCA3 and 37-SCA10) were stratified into four groups based on disease duration. Progression rates were calculated in each group for ataxia severity (SARA), functioning (FIM-ADL and Lawton-IADL), and balance (Berg Balance Scale).Differences across groups in terms of disease severity revealed a linear pattern of decline in SCA3, with a faster rate over time (p = 0.039) compared to SCA2 and SCA10. The pattern was nonlinear for SCA2 and SCA10, with a twofold faster rate in patients with up to seven years of disease compared to all other periods in SCA10 (p 0.001) and to the longer follow up period in SCA2 (p = 0.049). Differences across groups regarding worsening of balance scores was significantly faster in SCA3 compared to SCA10 (p = 0.028) and SCA2 (p = 0.028). The rate of loss of independence of ADLs tended to diminish over time in the three types of ataxia and was faster in SCA3. Similarly, the rate for loss of independence (IADLs) was faster in SCA3 compared to SCA2 (p = 0.057) and significantly faster compared to SCA10 (p = 0.028).The present findings suggest that the progression of the disease (severity/functioning/balance) varies according to the SCA subtype and the period in disease course. Progression is more linear and aggressive in patients with SCA3.

Myotonic dystrophy type 1 (DM1) is caused by a CTG nucleotide repeat expansion within the 3′ UTR of the Dystrophia Myotonica protein kinase gene. In this study, we explored therapeutic genome editing using CRISPR/Cas9 via targeted deletion of expanded CTG repeats and targeted insertion of polyadenylation signals in the 3′ UTR upstream of the CTG repeats to eliminate toxic RNA CUG repeats. We found paired SpCas9 or SaCas9 guide RNA induced deletion of expanded CTG repeats. However, this approach incurred frequent inversion in both the mutant and normal alleles. In contrast, the insertion of polyadenylation signals in the 3′ UTR upstream of the CTG repeats eliminated toxic RNA CUG repeats, which led to phenotype reversal in differentiated neural stem cells, forebrain neurons, cardiomyocytes, and skeletal muscle myofibers. We concluded that targeted insertion of polyadenylation signals in the 3′ UTR is a viable approach to develop therapeutic genome editing for DM1., Myotonic dystrophy type 1 is caused by toxic RNAs with expanded CUG repeats in the 3′ UTR of the DMPK gene. Wang et al. developed a strategy to eliminate the toxic repeats by insertion of polyadenylation signals upstream of the expanded repeats for personalized cell-based therapy and in vivo therapeutic genome editing.

The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative disorders that present principally with progressive ataxia. Within the past few years, studies of pathogenic mechanisms in the SCAs have led to the development of promising therapeutic strategies, especially for SCAs caused by polyglutamine-coding CAG repeats. Nucleotide-based gene-silencing approaches that target the first steps in the pathogenic cascade are one promising approach not only for polyglutamine SCAs but also for the many other SCAs caused by toxic mutant proteins or RNA. For these and other emerging therapeutic strategies, well-coordinated preparation is needed for fruitful clinical trials. To accomplish this goal, investigators from the United States and Europe are now collaborating to share data from their respective SCA cohorts. Increased knowledge of the natural history of SCAs, including of the premanifest and early symptomatic stages of disease, will improve the prospects for success in clinical trials of disease-modifying drugs. In addition, investigators are seeking validated clinical outcome measures that demonstrate responsiveness to changes in SCA populations. Findings suggest that MRI and magnetic resonance spectroscopy biomarkers will provide objective biological readouts of disease activity and progression, but more work is needed to establish disease-specific biomarkers that track target engagement in therapeutic trials. Together, these efforts suggest that the development of successful therapies for one or more SCAs is not far away.

Cerebellar Purkinje cells (PCs) show conspicuous damages in many ataxic disorders. Targeted delivery of short nucleic acids, such as antisense oligonucleotides, to PCs may be a potential treatment for ataxic disorders, especially spinocerebellar ataxias (SCAs), which are mostly caused by a gain of toxic function of the mutant RNA or protein. However, oligonucleotides do not cross the blood-brain barrier (BBB), necessitating direct delivery into the central nervous system (CNS) through intra-thecal, intra-cisternal, intra-cerebral ventricular, or stereotactic parenchymal administration. We have developed a novel liposome (100 to 200 nm in diameter) formulation, DCL64, composed of dipalmitoyl-phosphatidylcholine, cholesterol, and poloxamer L64, which incorporates oligonucleotides efficiently (≥ 70%). Confocal microscopy showed that DCL64 was selectively taken up by brain microvascular endothelial cells by interacting with low-density lipoprotein receptor (LDLr) family members on cell surface, but not with other types of lipid receptors such as caveolin or scavenger receptor class B type 1. LDLr family members are implicated in brain microvascular endothelial cell endocytosis/transcytosis, and are abundantly localized on cerebellar PCs. Intravenous administration of DCL64 in normal mice showed distribution of oligonucleotides to the brain, preferentially in PCs. Mice that received DCL64 showed no adverse effect on hematological, hepatic, and renal functions in blood tests, and no histopathological abnormalities in major organs. These studies suggest that DCL64 delivers oligonucleotides to PCs across the BBB via intravenous injection with no detectable adverse effects. This property potentially makes DCL64 particularly attractive as a delivery vehicle in treatments of SCAs.

Although the main clinical manifestations of spinocerebellar ataxias (SCAs) result from damage of the cerebellum and its connections, other systems may also be involved. To date, there are no studies on olfactory deficits in SCA type 10 (SCA10). However, although still controversy, olfactory deficits have been reported in other types of hereditary ataxias, especially SCA3, the most prevalent form of SCA worldwide. Olfactory identification was tested in three groups of 30 patients (SCA10, SCA3 and Parkinson’s disease - PD) and a group of 44 healthy controls using the Sniffin’ Sticks (SS16) test. Mean disease duration was 14.2 ± 11 years in the SCA10 group and 11.3 ± 6 years in the SCA3 group. Mean SS16 score was 11.9 ± 2.9 for the SCA10 group, 12.3 ± 1.9 for the SCA3 group, 6.6 ± 2.8 for the PD group and 12.1 ± 2.0 for the control group. Mean SS16 score for the SCA10 group was not significantly different from the scores for the SCA3 and control groups but was significantly higher than the score for the PD group (p < 0.001) when adjusted for age, gender and history of smoking. There was no association between SS16 scores and disease duration in the SCA10 or SCA3 groups (p>0.05) or number of repeat expansions (p = 0.7 for 17 SCA10 patients and p = 0.3 for 14 SCA3 patients). SS16 and Mini Mental State Examination scores were highly correlated in the three groups: SCA10 group (r=0.59, p = 0.001), SCA3 group (r=0.50, p = 0.005) and control group (r=0.40, p = 0.007). We found no significant olfactory deficits in SCA10 in this large series.

Nonmotor symptoms (NMS) have been described in several neurodegenerative diseases but have not been systematically evaluated in spinocerebellar ataxia type 10 (SCA10). The objective of the study is to compare the frequency of NMS in patients with SCA10, Machado-Joseph disease (MJD), and healthy controls. Twenty-eight SCA10, 28 MJD, and 28 healthy subjects were prospectively assessed using validated screening tools for chronic pain, autonomic symptoms, fatigue, sleep disturbances, psychiatric disorders, and cognitive function. Chronic pain was present with similar prevalence among SCA10 patients and healthy controls but was more frequent in MJD. Similarly, autonomic symptoms were found in SCA10 in the same proportion of healthy individuals, while the MJD group had higher frequencies. Restless legs syndrome and REM sleep behavior disorder were uncommon in SCA10. The mean scores of excessive daytime sleepiness were worse in the SCA10 group. Scores of fatigue were higher in the SCA10 sample compared to healthy individuals, but better than in the MJD. Psychiatric disorders were generally more prevalent in both spinocerebellar ataxias than among healthy controls. The cognitive performance of healthy controls was better compared with SCA10 patients and MJD, which showed the worst scores. Although NMS were present among SCA10 patients in a higher proportion compared to healthy controls, they were more frequent and severe in MJD. In spite of these comparisons, we were able to identify NMS with significant functional impact in patients with SCA10, indicating the need for their systematic screening aiming at optimal treatment and improvement in quality of life.

Background For a variety of sporadic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, it is well-established that ethnicity does affect the disease phenotypes. However, how ethnicity contributes to the clinical symptoms and disease progressions in monogenetic disorders, such as spinocerebellar ataxia type 3 (SCA3), remains less studied. Methods We used multivariable linear and logistical regression models in 257 molecularly-confirmed SCA3 patients (66 Caucasians, 43 African Americans, and 148 Asians [composed of 131 Chinese and 17 Asian Americans]) to explore the influence of ethnicity on age at onset (AAO), ataxia severity, and non-ataxia symptoms (i.e. depression, tremor, and dystonia). Results We found that Asians had significantly later AAO, compared to Caucasians (β = 4.75, p = 0.000) and to African Americans (β = 6.64, p = 0.000) after adjusting for the pathological CAG repeat numbers in ATXN3. African Americans exhibited the most severe ataxia as compared to Caucasians (β = 3.81, p = 0.004) and Asians (β = 4.39, p = 0.001) after taking into consideration of the pathological CAG repeat numbers in ATXN3 and disease duration. Caucasians had a higher prevalence of depression than African Americans (β = 1.23, p = 0.040). Ethnicity had no influence on tremor or dystonia. Conclusions Ethnicity plays an important role in clinical presentations of SCA3 patients, which could merit further clinical studies and public health consideration. These results highlight the role of ethnicity in monogenetic, neurodegenerative disorders.

How huntingtin (HTT) triggers neurotoxicity in Huntington’s disease (HD) remains unclear. We report that HTT forms a transcription-coupled DNA repair (TCR) complex with RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair enzyme polynucleotide-kinase-3'-phosphatase (PNKP), and cyclic AMP-response element-binding (CREB) protein (CBP). This complex senses and facilitates DNA damage repair during transcriptional elongation, but its functional integrity is impaired by mutant HTT. Abrogated PNKP activity results in persistent DNA break accumulation, preferentially in actively transcribed genes, and aberrant activation of DNA damage-response ataxia telangiectasia-mutated (ATM) signaling in HD transgenic mouse and cell models. A concomitant decrease in Ataxin-3 activity facilitates CBP ubiquitination and degradation, adversely impacting transcription and DNA repair. Increasing PNKP activity in mutant cells improves genome integrity and cell survival. These findings suggest a potential molecular mechanism of how mutant HTT activates DNA damage-response pro-degenerative pathways and impairs transcription, triggering neurotoxicity and functional decline in HD., eLife digest Our DNA encodes the instructions to make proteins, which then go on to perform many crucial roles in the cell. Breakages and damage to DNA occur over time, and if uncorrected, they can make the instructions illegible or incorrect. A build-up of damages can be harmful – for example, DNA damage from excessive UV light exposure can cause skin cancer. Luckily, cells contain DNA repair complexes, protein machines that surveil DNA and correct errors or breakages. An accumulation of DNA breakages is thought to contribute to the development of Huntington’s disease, a devastating and currently incurable condition where brain cells slowly die. The immediate cause of Huntington’s disease is well known: Huntington’s patients have an abnormal, mutant version of a protein called huntingtin. However, it is still unclear how the mutant huntingtin causes the symptoms of the disease and participates in cell death. Gao et al. carefully studied the proteins that huntingtin physically interacts with. The experiments revealed that huntingtin is part of a newly identified DNA repair complex that fixes breakages in DNA as the molecule is ‘read’ by the cell. The presence of the normal huntingtin protein promoted DNA repair. However, when the healthy huntingtin was replaced with the mutant version found in Huntington’s disease, the activity of the DNA repair complex was greatly reduced. This resulted in a build-up of DNA errors, triggering a series of events that ultimately led to cell death. In addition, in mice engineered to produce the mutant version of huntingtin, the accumulation of DNA damage was particularly important in two brain regions that are severely damaged in patients with Huntington’s disease. There is currently no effective treatment for Huntington’s disease. However, understanding how the mutant huntingtin damages brain cells may provide new targets for future therapies. More broadly, several other brain disorders share similarities with Huntington’s disease, and it remains to be seen whether the same mechanisms could be at work in all these conditions.

Summary Background The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. Methods We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50–0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II–IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. Findings Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. Interpretation At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis. Funding National Institutes of Health, National Institute of Neurological Disorders and Stroke.

BACKGROUND: Cerebellar degenerative pathology has been identified in tremor patients; however, how the degenerative pathology could contribute to tremor remains unclear. If the cerebellar degenerative pathology can directly drive tremor, one would hypothesize that tremor is likely to occur in the diseases of cerebellar ataxia and follows the disease progression in such disorders. METHODS: To further test this hypothesis, we studied the occurrence of tremor in different disease stages of classical cerebellar degenerative disorders: spinocerebellar ataxias (SCAs). We further separately analyzed postural tremor and rest tremor, two forms of tremor that both involve the cerebellum. We also explored tremor in different subtypes of SCAs. RESULTS: We found that 18.1% of SCA patients have tremor. Interestingly, SCA patients with tremor have worse ataxia than those without tremor. When stratifying patients into mild, moderate, and severe disease stages according to the severity of ataxia, moderate and severe SCA patients more commonly have tremor than those with mild ataxia, the effect most prominently observed in postural tremor of SCA3 and SCA6 patients. Finally, tremor can independently contribute to worse functional status in SCA2 patients, even after adjusting for ataxia severity. CONCLUSIONS: Tremor is more likely to occur in the severe stage of cerebellar degeneration when compared to mild stages. Our results partially support the cerebellar degenerative model of tremor.

The goal of this report is to describe the genetic mutations of a patient with cerebellar degeneration who had ataxia and impaired emotional communication that led to damage of family relationships. We extracted genomic DNA from peripheral blood lymphocytes and performed whole exome sequencing (WES) in this patient and his unaffected parents and siblings. Found mutations were confirmed by Sanger sequencing in each individual. We found compound heterozygous mutations in the paraplegin (SPG7) gene. One mutated allele has been previously described as a disease-causing missense mutation for spastic paraplegia type 7 (SPG7) (c.1529C > T, p.Ala510Val). The second mutated allele involved a single nucleotide deletion which results in a frameshift in the coding sequence (c.2271delG, p.Met757fs*65). The second allele is similar to, but unique from, other described, SPG7-linked truncation mutations. The abnormal emotional communication in this patient broadens the phenotypic boundary of SPG7.

Myotonic dystrophy type 1 (DM1) is caused by expanded Cytosine-Thymine-Guanine (CTG) repeats in the 3′-untranslated region (3′ UTR) of the Dystrophia myotonica protein kinase ( DMPK ) gene, for which there is no effective therapy. The objective of this study is to develop genome therapy in human DM1 induced pluripotent stem (iPS) cells to eliminate mutant transcripts and reverse the phenotypes for developing autologous stem cell therapy. The general approach involves targeted insertion of polyA signals (PASs) upstream of DMPK CTG repeats, which will lead to premature termination of transcription and elimination of toxic mutant transcripts. Insertion of PASs was mediated by homologous recombination triggered by site-specific transcription activator-like effector nuclease (TALEN)-induced double-strand break. We found genome-treated DM1 iPS cells continue to maintain pluripotency. The insertion of PASs led to elimination of mutant transcripts and complete disappearance of nuclear RNA foci and reversal of aberrant splicing in linear-differentiated neural stem cells, cardiomyocytes, and teratoma tissues. In conclusion, genome therapy by insertion of PASs upstream of the expanded DMPK CTG repeats prevented the production of toxic mutant transcripts and reversal of phenotypes in DM1 iPS cells and their progeny. These genetically-treated iPS cells will have broad clinical application in developing autologous stem cell therapy for DM1.

Spinocerebellar ataxia type 6 (SCA6) is a genetic disease that causes degeneration of Purkinje cells, and recent evidence points to degeneration of Betz cells in the motor cortex. The relation between functional activity of motor cortex and symptom severity during a hand-grip motor control in vivo has not yet been investigated. This study explored both functional changes in the sensorimotor cortex and cerebellar regions and structural alterations in the cerebellum for SCA6 patients as compared to age-matched healthy controls using a multimodal imaging approach (task-based fMRI, task-based functional connectivity, and free-water diffusion MRI). Further, we tested their relation with the severity of ataxia symptoms. SCA6 patients had reduced functional activity in the sensorimotor cortex, supplementary motor area (SMA), cerebellar vermis, and cerebellar lobules I-VI (corrected P

Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion that results in the in vivo accumulation of CUG RNA foci, an ATG‐initiated polyGln and a polyAla protein expressed by repeat‐associated non‐ATG (RAN) translation. Although RAN proteins have been reported in a growing number of diseases, the mechanisms and role of RAN translation in disease are poorly understood. We report a novel toxic SCA8 polySer protein which accumulates in white matter (WM) regions as aggregates that increase with age and disease severity. WM regions with polySer aggregates show demyelination and axonal degeneration in SCA8 human and mouse brains. Additionally, knockdown of the eukaryotic translation initiation factor eIF3F in cells reduces steady‐state levels of SCA8 polySer and other RAN proteins. Taken together, these data show polySer and WM abnormalities contribute to SCA8 and identify eIF3F as a novel modulator of RAN protein accumulation.

Significance A number of hereditary neurological and neuromuscular diseases are caused by the abnormal expansion of short tandem repeats, or microsatellites, resulting in the expression of repeat expansion RNAs and proteins with pathological properties. Although these microsatellite expansions may occur in either the coding or noncoding regions of the genome, trinucleotide CNG repeats predominate in exonic coding and untranslated regions while intron mutations vary from trinucleotide to hexanucleotide GC-rich, and A/AT-rich, repeats. Here, we use transcriptome analysis combined with complementary experimental approaches to demonstrate that GC-rich intronic expansions are selectively associated with host intron retention. Since these intron retention events are detectable in both affected tissues and peripheral blood, they provide a sensitive and disease-specific diagnostic biomarker.

Friedreich's ataxia (FRDA) is an inherited, progressive neurodegenerative disease that typically affects teenagers and young adults. Therapeutic strategies and disease insight have expanded rapidly over recent years, leading to hope for the FRDA population. There is currently no US FDA-approved treatment for FRDA, but advances in research of its pathogenesis have led to clinical trials of potential treatments. This article reviews emerging therapies and discusses future perspectives, including the need for more precise measures for detecting changes in neurologic symptoms as well as a disease-modifying agent.

Purpose of review This article discusses recent advances in the understanding of clinical and genetic aspects of primary ataxias, including congenital, autosomal recessive, autosomal dominant, episodic, X-linked, and mitochondrial ataxias, as well as idiopathic degenerative and secondary ataxias. Recent findings Many important observations have been published in recent years in connection with primary ataxias, particularly new loci and genes. The most commonly inherited ataxias may present with typical and atypical phenotypes. In the group of idiopathic degenerative ataxias, genes have been found in patients with multiple system atrophy type C. Secondary ataxias represent an important group of sporadic, cerebellar, and afferent/sensory ataxias. Summary Knowledge of primary ataxias has been growing rapidly in recent years. Here we review different forms of primary ataxia, including inherited forms, which are subdivided into congenital, autosomal recessive cerebellar ataxias, autosomal dominant cerebellar ataxias, episodic ataxias, X-linked ataxias, and mitochondrial ataxias, as well as sporadic ataxias and idiopathic degenerative ataxias. Secondary or acquired ataxias are also reviewed and the most common causes are discussed.

Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the 3'-untranslated region (3′ UTR) of the DMPK gene. Correcting the mutation in DM1 stem cells would be an important step toward autologous stem cell therapy. The objective of this study is to demonstrate in vitro genome editing to prevent production of toxic mutant transcripts and reverse phenotypes in DM1 stem cells. Genome editing was performed in DM1 neural stem cells (NSCs) derived from human DM1 induced pluripotent stem (iPS) cells. An editing cassette containing SV40/bGH polyA signals was integrated upstream of the CTG repeats by TALEN-mediated homologous recombination (HR). The expression of mutant CUG repeats transcript was monitored by nuclear RNA foci, the molecular hallmarks of DM1, using RNA fluorescence in situ hybridization. Alternative splicing of microtubule-associated protein tau (MAPT) and muscleblind-like (MBNL) proteins were analyzed to further monitor the phenotype reversal after genome modification. The cassette was successfully inserted into DMPK intron 9 and this genomic modification led to complete disappearance of nuclear RNA foci. MAPT and MBNL 1, 2 aberrant splicing in DM1 NSCs were reversed to normal pattern in genome-modified NSCs. Genome modification by integration of exogenous polyA signals upstream of the DMPK CTG repeat expansion prevents the production of toxic RNA and leads to phenotype reversal in human DM1 iPS-cells derived stem cells. Our data provide proof-of-principle evidence that genome modification may be used to generate genetically modified progenitor cells as a first step toward autologous cell transfer therapy for DM1. Stem Cells 2015;33:1829–1838

Spinocerebellar ataxia type 3(SCA3), also known as Machado-Joseph disease (MJD), is the most frequent subtype of autosomal dominant inherited spinocerebellar ataxias, which caused by the expansion of CAG repeats in the ATXN3 gene. The number of CAG repeats of the abnormal allele determines the rate of disease progression in patients with SCA3/MJD. Markers to assess the clinical severity, to predict the course of illness and to monitor the efficacy of therapeutic measures, can be clinical, biological, and radiological. Here, we aimed to explore whether the serum glial fibrillary acidic protein (GFAP) may act as a biomarker in SCA3/MJD patients and to evaluate the correlation between some markers with the number of CAG repeats in SCA3/MJD patients. We showed that the serum levels of GFAP were significantly higher in SCA3/MJD patients than in controls. There was a strong positive correlation between the age-adjusted GFAP levels with the number of CAG repeats. Age-adjusted International Cooperative Ataxia Rating Scale (ICARS) scores and Scale for the Assessment and Rating of Ataxia (SARA) scores correlated with the number of CAG repeats. Raw scores and disease duration-adjusted GFAP levels, ICARS scores, and SARA scores were not correlated with the number of CAG repeats. Our results reveal novel evidence for the role of the triplet expansion in SCA3/MJD-associated neuronal damage.

Ocular motor abnormalities reflect the varied neuropathology of spinocerebellar ataxias (SCAs) and may serve to clinically distinguish the different SCAs. We analyzed the various eye movement abnormalities detected prospectively at the baseline visit during a large multicenter natural history study of SCAs 1, 2, 3, and 6.The data were prospectively collected from 12 centers in the United States in patients with SCAs 1, 2, 3, and 6, as part of the Clinical Research Consortium for Spinocerebellar Ataxias (NIH-CRC-SCA). Patient characteristics, ataxia rating scales, the Unified Huntington Disease Rating Scale functional examination, and clinical staging were used. Eye movement abnormalities including nystagmus, disorders of saccades and pursuit, and ophthalmoparesis were recorded, and factors influencing their occurrence were examined.A total of 301 patients participated in this study, including 52 patients with SCA 1, 64 with SCA 2, 117 with SCA 3, and 68 with SCA 6. Although no specific ocular motor abnormality was pathognomonic to any SCA, significant differences were noted in their occurrence among different disorders. SCA 6 was characterized by frequent occurrence of nystagmus and abnormal pursuit and rarity of slow saccades and ophthalmoparesis and SCA 2 by the frequent occurrence of slow saccades and infrequent nystagmus and dysmetric saccades. SCA 1 and SCA 3 subjects had a more even distribution of eye movement abnormalities.Prospective data from a large cohort of patients with SCAs 1, 2, 3, and 6 provide statistical validation that the SCAs exhibit distinct eye movement abnormalities that are useful in identifying the genotypes. Many of the abnormalities correlate with greater disease severity measures.

As sleep disturbances have been reported in spinocerebellar ataxias (SCAs), including types SCA1, SCA2, SCA3, SCA6 and SCA13, identification and management of these disturbances can help minimise their impact on SCA patients' overall body functions and quality of life. To our knowledge, there are no studies that investigate sleep disturbances in SCA10. Therefore, the aim of this study was to assess sleep disturbances in patients with SCA10. Twenty-three SCA10 patients and 23 healthy controls were recruited. Patients were evaluated in terms of their demographic and clinical data, including disease severity (Scale for the Assessment and Rating of Ataxia, SARA) and excessive daytime sleepiness (Epworth Sleepiness Scale, ESS), and underwent polysomnography. SCA10 patients had longer rapid eye movement (REM) sleep (p = .04) and more REM arousals than controls (p< .0001). There was a correlation of REM sleep onset with the age of onset of symptoms (r = .459), and with disease duration (r = -.4305). There also was correlation between the respiratory disturbance index (RDI) and SARA (r = -.4013), and a strong indirect correlation between arousal index and age at onset of symptoms (r = -.5756). In conclusion, SCA10 patients had sleep abnormalities that included more REM arousals and higher RDI than controls. Our SCA10 patients had sleep disorders related to shorter disease duration and lower severity of ataxia, in a pattern similar to that of other neurodegenerative diseases.

Background Dystonia is a common feature in spinocerebellar ataxias (SCAs). Whether the presence of dystonia is associated with different rate of ataxia progression is not known. Objectives To study clinical characteristics and ataxia progression in SCAs with and without dystonia. Methods We studied 334 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and compared the clinical characteristics of SCAs with and without dystonia. We repeatedly measured ataxia progression by the Scale for Assessment and Rating of Ataxia every 6 months for 2 years. Regression models were employed to study the association between dystonia and ataxia progression after adjusting for age, sex and pathological CAG repeats. We used logistic regression to analyze the impact of different repeat expansion genes on dystonia in SCAs. Results Dystonia was most commonly observed in SCA3, followed by SCA2, SCA1, and SCA6. Dystonia was associated with longer CAG repeats in SCA3. The CAG repeat number in TBP normal alleles appeared to modify the presence of dystonia in SCA1. The presence of dystonia was associated with higher SARA scores in SCA1, 2, and 3. Although relatively rare in SCA6, the presence of dystonia was associated with slower progression of ataxia. Conclusions The presence of dystonia is associated with greater severity of ataxia in SCA1, 2, and 3, but predictive of a slower progression in SCA6. Complex genetic interactions among repeat expansion genes can lead to diverse clinical symptoms and progression in SCAs.

SCA3 presents with a CAG expansion at 14q24.3- q32 while SCA10 shows an ATTCT expansion at 22q13-qter. SCA10 seems to be less aggressive than SCA3. For an in vivo, noninvasive approach of the correlation between central nervous system and clinical evolution, we can use optic coherence tomography (OCT) to measure retinal nerve fiber (RNFL) and ganglion cell layer (GCL) thickness. To describe OCT findings in SCA10, correlate it with expansion size and disease severity and compare with those of SCA3. We analyzed ten individuals with SCA3 and nine with SCA10 recruited from the neurology service of Hospital de Clínicas of Paraná—Brazil. They were submitted to OCT and clinical evaluation using SARA score. Expansion size, demographic data, time from disease onset, and age of onset were collected. We found no correlation between size of expansion, SARA, and RNFL or GCL thickness in SCA10. RNFL seemed to be thicker in SCA10 (p > 0.05). GCL thickness, SARA, median age, and time from disease onset did not differ between groups. SCA10 individuals had an earlier disease onset. In SCA3, there was a negative correlation between SARA and RNFL thickness in nasal area. To the best of our knowledge, this is the first paper assessing retinal changes by OCT in individuals with SCA10. The lack of correlation between disease progression, age, and time since onset supports the anatomopathological findings which suggest SCA10 is less aggressive than other SCAs. The findings in SCA3 are in accordance with the literature.

The aim of this study is to determine whether the initial symptom associates with motor progression in spinocerebellar ataxias (SCAs). SCAs are clinically heterogeneous and the initial presentation may represent different subtypes of SCA with different motor progression. We studied 317 participants with SCAs1, 2, 3, and 6 from the Clinical Research Consortium for SCAs (CRC-SCA) and repeatedly measured the severity of ataxia for 2 years. SCA patients were divided into gait-onset and non-gait-onset (speech, vision, and hand dexterity) groups based on the initial presentation. In addition to demographic comparison, we employed regression models to study ataxia progression in these two groups after adjusting for age, sex, and pathological CAG repeats. The majority of SCA patients had gait abnormality as an initial presentation. The pathological CAG repeat expansions were similar between the gait-onset and non-gait-onset groups. In SCA1, gait-onset group progressed slower than non-gait-onset group, while gait-onset SCA6 group progressed faster than their counterpart. In addition, the disease presented 9 years later for SCA2 gait-onset group than non-gait-onset group. Initial symptoms of SCA3 did not influence age of onset or disease progression. The initial symptom in each SCA has a different influence on age of onset and motor progression. Therefore, gait and non-gait-onset groups of SCAs might represent different subtypes of the diseases.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder manifested by ataxia with a variable presentation of epileptic seizures, which is caused by a large expansion of an intronic ATTCT pentanucleotide repeat in ATXN10 on 22q13.3. Herein, we report the first description of SCA10 in a Peruvian family, supporting the Amerindian origin of SCA10 and the Panamerican geographical distribution of the disease in North, Central and South America. Moreover, the presence of an interruption motif in the SCA10 expansion along with epileptic seizures in this family supports the correlation between the two, as seen in other families. Finally, this is the first SCA10 patient ever observed outside of America, specifically in Italy. Since this patient is a Peruvian immigrant of Amerindian ancestry, our case report highlights the growing need for awareness amongst clinicians of seemingly geographically restricted rare diseases.

DNA methylation has been reported as an important regulator of genomic structure stability, including large tandem repeats. To test the modulation effect of variants in DNA methylation–related genes on distribution of expanded (CAG)n alleles and age at onset (AO) of patients with Machado-Joseph disease (MJD), we conducted an association analysis on 23 selected SNPs in these genes in 613 patients with MJD and 581 controls. There were significant differences in the distribution of rs12957023 between patients and controls (OR = 1.296, p = 0.007 and OR = 1.206, p = 0.008, for genotype and alleles, respectively). The distribution of (CAG)n size was also different between patients carrying a CC and the other genotypes (TT and TC, p = 0.011 for expanded (CAG)n and p = 0.012 for normal size alleles), indicating that DNA methylation might modulate the (CAG)n instability. We found also that rs13420827 in DNMT3A and rs7354779 in DNMT3L contribute to AO of MJD (p = 0.019 and p = 0.008, respectively). In conclusion, our data provide the first evidence that SNPs in DNA methylation–related genes may contribute to (CAG)n instability and modulate the AO of this disease.

Spinocerebellar ataxia type 10 (SCA10) is a rare form of autosomal dominant ataxia found predominantly in patients from Latin America with Amerindian ancestry. The authors report the history of SCA10 families from the south of Brazil (the states of Paraná and Santa Catarina), emphasizing the Belgian-Amerindian connection. A ataxia espinocerebellar tipo 10 (AEC10) é uma forma rara de ataxia cerebelar autossômica dominante, encontrada predominantemente em pacientes da América Latina, de origem Ameríndia. Os autores relatam a história de famílias com AEC10 do sul do Brasil (estados do Paraná e Santa Catarina), enfatizando a conexão Ameríndia-Belga.

Intensive scientific research devoted in the recent years to understand the molecular mechanisms or neurodegeneration in spinocerebellar ataxias (SCAs) are identifying new pathways and targets providing new insights and a better understanding of the molecular pathogenesis in these diseases. In this consensus manuscript, the authors discuss their current views on the identified molecular processes causing or modulating the neurodegenerative phenotype in spinocerebellar ataxias with the common opinion of translating the new knowledge acquired into candidate targets for therapy. The following topics are discussed: transcription dysregulation, protein aggregation, autophagy, ion channels, the role of mitochondria, RNA toxicity, modulators of neurodegeneration and current therapeutic approaches. Overall point of consensus includes the common vision of neurodegeneration in SCAs as a multifactorial, progressive and reversible process, at least in early stages. Specific points of consensus include the role of the dysregulation of protein folding, transcription, bioenergetics, calcium handling and eventual cell death with apoptotic features of neurons during SCA disease progression. Unresolved questions include how the dysregulation of these pathways triggers the onset of symptoms and mediates disease progression since this understanding may allow effective treatments of SCAs within the window of reversibility to prevent early neuronal damage. Common opinions also include the need for clinical detection of early neuronal dysfunction, for more basic research to decipher the early neurodegenerative process in SCAs in order to give rise to new concepts for treatment strategies and for the translation of the results to preclinical studies and, thereafter, in clinical practice.

The p.Arg420His allelic form of spinocerebellar ataxia type 13 has been reported in a large Filipino kindred, as well as three European index cases, one with an affected offspring. Haplotype analysis has confirmed independent mutational events. All individuals share adult-onset, predominantly cerebellar signs and a slowly progressive course. However, a comprehensive phenotypic description has yet to be published on SCA13p.Arg420His. In this study, we present the results of a detailed neurological clinical and diagnostic testing on 21 mutation-positive members of a four-generation Filipino family to further define this disease, aiding diagnosis and prognosis. Electronic supplementary material The online version of this article (doi:10.1007/s12311-013-0507-6) contains supplementary material, which is available to authorized users.

The onset and symptoms of the myotonic dystrophies are diverse, complicating their diagnoses and limiting a comprehensive approach to their clinical care. This report analyzes the diagnostic delay (time from onset of first symptom to diagnosis) in a large sample of myotonic dystrophy (DM) patients enrolled in the US National Registry [679 DM type 1 (DM1) and 135 DM type 2 (DM2) patients]. Age of onset averaged 34.0 ± 14.1 years in DM2 patients compared to 26.1 ± 13.2 years in DM1 (p < 0.0001). The most common initial symptom in DM2 patients was leg weakness (32.6 %) compared to grip myotonia in DM1 (38.3 %). Pain was reported as the first symptom in 11.1 % of DM2 and 3.0 % of DM1 patients (p < 0.0001). Reaching the correct diagnosis in DM2 took 14 years on average (double the time compared to DM1) and a significantly higher percentage of patients underwent extended workup including electromyography, muscle biopsies, and finally genetic testing. DM patients who were index cases experienced similar diagnostic delays to non-index cases of DM. Further evaluation of how to shorten these diagnostic delays and limit their impact on burdens of disease, family planning, and symptom management is needed.

To use optical coherence tomography (OCT) and contrast letter acuity to characterize vision loss in Friedreich ataxia (FRDA). High- and low-contrast letter acuity and neurological measures were assessed in 507 patients with FRDA. In addition, OCT was performed on 63 FRDA patients to evaluate retinal nerve fiber layer (RNFL) and macular thickness. Both OCT and acuity measures were analyzed in relation to genetic severity, neurologic function, and other disease features. High- and low-contrast letter acuity was significantly predicted by age and GAA repeat length, and highly correlated with neurological outcomes. When tested by OCT, 52.7% of eyes (n = 110) had RNFL thickness values below the fifth percentile for age-matched controls. RNFL thickness was significantly lowest for those with worse scores on the Friedreich ataxia rating scale (FARS), worse performance measure composite Z2 scores, and lower scores for high- and low-contrast acuity. In linear regression analysis, GAA repeat length and age independently predicted RNFL thickness. In a subcohort of participants, 21% of eyes from adult subjects (n = 29 eyes) had macular thickness values below the first percentile for age-matched controls, suggesting that macular abnormalities can also be present in FRDA. Low-contrast acuity and RNFL thickness capture visual and neurologic function in FRDA, and reflect genetic severity and disease progression independently. This suggests that such measures are useful markers of neurologic progression in FRDA.