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Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a rare disease with diagnosis offered by the Unified Health System in Brazil. Our aim was to investigate the diagnostic delay in an interval of 23 years in a public university hospital, and some potentially determining factors.A retrospective review of the medical records of subjects identified at our institution between 1999 and 2017 was carried out, including residents of Rio Grande do Sul. The diagnostic delay was equivalent to the difference between age at onset of symptoms and age at molecular diagnosis. Calendar years, educational level, sex, distance between the household and the clinics, age and being the index case were studied as modifying factors.SCA3/MJD had a median diagnostic delay of 5 years. Index cases had delays of 6 versus 4 years (p0.001) for subsequent family members. Delay correlated with age (rho=0.346, p0.001), but not with age at disease onset (rho=0.005, p=0.91). No change was observed with the level of education of individuals or with the distance between household and hospital from 1999 to 2017.The diagnostic delay of SCA3/MJD is high in our region, where its occurrence has been reported for years. Failure to change the delay over the years suggests ineffective dissemination to the population, but a smaller lag among younger people can portray the effect of digital inclusion.

Background: Spinocerebellar ataxia type 3/Machado-Joseph Disease (SCA3/MJD) is a genetic disorder characterized by ataxic manifestations. Although dysarthria is the main symptom, validated assessments of speech and voice are lacking. Objectives: We aimed to evaluate reliability of auditory-perceptual and acoustic assessments, collected in-person and by telephone calls, and to raise data on their external validity. Methods: Symptomatic individuals were studied. Arm 1 studied test-retest reliability of in-person speech assessments; arm 2 studied reliability of in-person and remote evaluations. Friedreich's Ataxia Rating Scale (FARS)-adl, demographic, and molecular data were also obtained. The minimum kappa for the five perceptual variables under study to be considered reliable was set at 0.8. The minimum intraclass correlation coefficients (ICC) for the 45 acoustic-instrumental assessments under study to be considered reliable was 0.70, for a p Results: 17 and 20 subjects were included in arms 1 and 2, respectively. All five auditory-perceptual assessments and 30 acoustic-instrumental assessments were considered reliable for the standard in-person use. Four auditory-perceptual and four acoustic assessments have also achieved reliability for use in-person and/or by telephone. Three auditory-perceptual assessments (subsystems: phonation, respiration, and resonance) and two acoustic-instrumental assessments (subsystems: respiration and articulation) correlated with age and disease duration; phonation also correlated FARS-adl. Discussion: A substantial number of assessments of speech were considered reliable for the standard in-person use in SCA3/MJD. Moreover, eight of them were also reliable when used either in-person or remotely. Our results support their use in future studies on this disease.

Although health-related quality of life (HRQoL) has been increasingly valued in healthcare and in clinical trials, there is scarce information about it in spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD). This study describes the HRQoL results obtained from ataxic SCA3/MJD subjects, and their non-ataxic offspring included in the BIGPRO (Biomarkers and genetic modifiers in a study of presymptomatic and symptomatic SCA3/MJD carriers) study. Demographic data, clinical scales, and HRQoL instruments EQ-5D-3L and SF-36 were collected. Subjects at 50% risk were genotyped in a double-blind manner. The time left until the onset of the disease was estimated for mutation carriers with a SARA

Little is known about preclinical stages of Machado-Joseph disease, a polyglutamine disorder characterized by progressive adult-onset ataxia.We aimed to describe the longitudinal progression of clinical and oculomotor variables in the preataxic phase of disease.Carriers and noncarriers were assessed at three visits. Preataxic carriers (Scale for Assessment and Rating of Ataxia score 3) expected to start ataxia in ≤4 years were considered near onset (PAN). Progressions of ataxic and preataxic carriers, considering status at the end of the study, were described according to the start (or its prediction) of gait ataxia (TimeToAfterOnset) and according to the study time.A total of 35 ataxics, 38 preataxics, and 22 noncarriers were included. The "TimeToAfterOnset" timeline showed that Neurological Examination Scale for Spinocerebellar Ataxias (NESSCA; effect size, 0.09), Inventory of Non-Ataxia Symptoms (INAS0.07), and the vestibulo-ocular reflex gain (0.12) progressed in preataxic carriers, and that most slopes accelerate in PAN, turning similar to those of ataxics. In the study time, NESSCA (1.36) and vertical pursuit gain (1.17) significantly worsened in PAN, and 6 of 11 PANs converted to ataxia. For a clinical trial with 80% power and 2-year duration, 57 PANs are needed in each study arm to detect a 50% reduction in the conversion rate.NESSCA, INAS, vestibulo-ocular reflex, and vertical pursuit gains significantly worsened in the preataxic phase. The "TimeToAfterOnset" timeline unveiled that slopes of most variables are small in preataxics but increase and reach the ataxic slopes from 4 years before the onset of ataxia. For future trials in preataxic carriers, we recommend recruiting PANs and using the conversion rate as the primary outcome. © 2022 International Parkinson and Movement Disorder Society.

Calpain-mediated proteolysis has been proposed to modulate the pathogenesis of spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), a disorder due to a CAG repeat expansion (CAGexp) at ATXN3. We aimed to investigate if single-nucleotide polymorphisms (SNPs) at calpain gene CAPN2 and at calpastatin gene CAST modulate the age at onset (AO) and disease progression in SCA3/MJD. A total of 287 SCA3/MJD symptomatic subjects (151 families) were included. AO was analyzed and controlled by the CAG repeat length of expanded allele and family. Candidate polymorphisms were chosen based on the literature and on a priori criteria. The CAG repeat length and SNPs were genotyped according to standard methods. AO of carriers of AA and AG + GGrs1559085 genotypes in CAST and with the median value of 75 repeats at the expanded allele were 34.23 (33.07–35.38) and 36.42 years (34.50–38.34), respectively (p = 0.049, mixed model treating the expanded CAG repeat size as fixed effect and family as random effect). Carriers of haplotype Crs27852/Grs1559085 had mean AO of 37.23 (12.76) and 33.42 years (12.20) (p = 0.047, Student’s t test). Our data suggest an association between allele Grs1559085 and haplotype Crs27852/Grs1559085 at CAST and variations in the AO of SCA3/MJD subjects, independent from the effects of the CAGexp and family. The present results support the potential role of calpain cleavage pathway over modulation of SCA3/MJD phenotype.

Little is known about access of rare disease carriers to health care. To increase this knowledge, the Pan American Hereditary Ataxia Network (PAHAN) conducted an exploratory survey about care for hereditary ataxias in American continents and the Caribbean. A questionnaire was sent to health professionals about the hereditary ataxias identified; access to care; and local teaching and research. The number of ataxics under current care per 100,000 inhabitants was subtracted from the expected overall prevalence of 6/100,000, to estimate the prevalence of uncovered ataxic patients. Local Human Development Indexes (HDI) were used to measure socio-economic factors. Twenty-six sites participated. Twelve sites had very high, 13 had high, and one site had medium HDI. Participants reported on 2239 and 602 patients with spinocerebellar ataxias and recessive forms under current care. The number of patients under current care per inhabitants varied between 0.14 and 12/100,000. The estimated prevalence of uncovered ataxic patients was inversely proportional to HDIs (rho = 0.665, p = 0.003). Access to diagnosis, pre-symptomatic tests, and rehabilitation were associated with HDIs. More and better molecular diagnostic tools, protocols and guidelines, and professional training for ataxia care were the top priorities common to all respondents. Evidence of inequalities was confirmed. Lower HDIs were associated with high potential numbers of uncovered ataxic subjects, and with lack of molecular diagnosis, pre-symptomatic testing, and rehabilitation. More and better diagnostic tools, guidelines, and professional training were priorities to all sites. PAHAN consortium might help with the last two tasks.

Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the ATXN3 gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study (Pearson's correlation coefficient R2 = 0.62). Using a total of 786 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci (P < 1 × 10-5). These loci were enriched for genes involved in vesicle transport, olfactory signaling, and synaptic pathways. Furthermore, associations between AO and the TRIM29 and RAG genes suggests that DNA repair mechanisms might be implicated in MJD pathogenesis. Our study demonstrates the existence of several additional genetic factors, along with CAG expansion, that may lead to a better understanding of the genotype-phenotype correlation in MJD. FA and CL were funded by the Fonds de Recherche du Québec–Santé. SM is funded by FCT (CEECIND/00684/2017) and by NORTE-01-0145- FEDER-000008, supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). FM and LI are funded by Fundaçao de Amparo a Pesquisa do Estado de São Paulo (FAPESP, 2013/07559-3). MLSP and LBJ were funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil (CNPq) and by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). GAR holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences.

Spinocerebellar ataxias (SCAs) comprise a heterogeneous group of autosomal dominant disorders. The relative frequency of the different SCA subtypes varies broadly among different geographical and ethnic groups as result of genetic drifts. This review aims to provide an update regarding SCA founders in the American continents and the Caribbean as well as to discuss characteristics of these populations. Clusters of SCAs were detected in Eastern regions of Cuba for SCA2, in South Brazil for SCA3/MJD, and in Southeast regions of Mexico for SCA7. Prevalence rates were obtained and reached 154 (municipality of Báguano, Cuba), 166 (General Câmara, Brazil), and 423 (Tlaltetela, Mexico) patients/100,000 for SCA2, SCA3/MJD, and SCA7, respectively. In contrast, the scattered families with spinocerebellar ataxia type 10 (SCA10) reported all over North and South Americas have been associated to a common Native American ancestry that may have risen in East Asia and migrated to Americas 10,000 to 20,000 years ago. The comprehensive review showed that for each of these SCAs corresponded at least the development of one study group with a large production of scientific evidence often generalizable to all carriers of these conditions. Clusters of SCA populations in the American continents and the Caribbean provide unusual opportunity to gain insights into clinical and genetic characteristics of these disorders. Furthermore, the presence of large populations of patients living close to study centers can favor the development of meaningful clinical trials, which will impact on therapies and on quality of life of SCA carriers worldwide.

Although health-related quality of life (HRQoL) has been increasingly valued in healthcare and in clinical trials, there is scarce information about it in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). This study describes the HRQoL results obtained from ataxic SCA3/MJD subjects, and their non-ataxic offspring included in the BIGPRO (Biomarkers and genetic modifiers in a study of presymptomatic and symptomatic SCA3/MJD carriers) study. Demographic data, clinical scales, and HRQoL instruments EQ-5D-3L and SF-36 were collected. Subjects at 50% risk were genotyped in a double-blind manner. The time left until the onset of the disease was estimated for mutation carriers with a SARA 3 and combined with disease duration of ataxic subjects (TimeToAfterOnset). Analyses were performed using PASW Statistics version 18.0, R version 4.0.0, and G*Power 3.1, and p 0.05 was considered statistically significant. Twenty-three ataxic carriers, 33 pre-ataxic carriers, and 21 controls were enrolled. Significant differences between ataxic carriers and controls were seen in EQ-VAS, EQ-5D Index, and in some domains of EQ-5D-3L and SF-36. EQ-5D Index showed the best effect size between ataxic and controls (Cohen's d = 2.423). Stepwise changes were seen in pre-ataxic subjects, although not statistically significant. TimeToAfterOnset correlated with EQ-5D Index, EQ-VAS, and SF-36 Physical functioning, Role Physical, Pain, and General Health. EQ-5D Index and EQ-VAS correlated with clinical scales in the ataxic group. These results suggest that HRQoL worsens among carriers since pre-ataxic stages and that they might encompass the underlying disease process. In this cohort, SF-36 Physical Functioning, SF-36 General health, and especially EQ-5D Index and EQ-VAS were the best HRQoL instruments to be used as ancillary evidence to support biological and social meanings for future interventions.

Dominant diseases due to expanded CAG repeat tracts, such as spinocerebellar ataxia type 2 (SCA2), are prone to anticipation and worsening of clinical picture in subsequent generations. There is insufficient data about selective forces acting on the maintenance of these diseases in populations. We made a systematic review and meta-analysis on the effect of the CAG length over age at onset, instability of transmissions, anticipation, de novo or sporadic cases, fitness, segregation of alleles, and ancestral haplotypes. The correlation between CAG expanded and age at onset was r2 = 0.577, and transmission of the mutant allele was associated with an increase of 2.42 CAG repeats in the next generation and an anticipation of 14.62 years per generation, on average. One de novo and 18 sporadic cases were detected. Affected SCA2 individuals seem to have more children than controls. The expanded allele was less segregated than the 22-repeat allele in children of SCA2 subjects. Several ancestral SCA2 haplotypes were published. Data suggest that SCA2 lineages may tend to disappear eventually, due to strong anticipation phenomena. Whether or not the novel cases come from common haplotypes associated with a predisposition to further expansions is a question that needs to be addressed by future studies.

Spinocerebellar ataxia type 10 (SCA10) is a repeat expansion disease occurring mostly in Latin America, suggesting that the mutation spread with the peopling of the Americas, or that Amerindian populations, have a higher ATXN10 mutability. High frequency of large normal alleles is associated with prevalence and relative frequency of other repeat expansion diseases. To test whether the allele distribution of the SCA10-causing ATXN10 microsatellite in an Amerindian Peruvian population differs from that of other populations. The ATXN10 allele distribution in a Quechua Peruvian population from Puno, Peru, is similar to that of Finland. Mean allele size and mode were also similar to those of Mexico, Japan, and white Europeans. ATXN10 allele distribution in a healthy Amerindian population from Peru does not differ from that of other populations.

Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia in Caucasian populations. It is caused by a homozygous GAA expansion in the first intron of the frataxin gene (FXN) (OMIM: 606829) in 96% of the affected individuals. The remaining patients have a GAA expansion in one allele and a point mutation in the other. Little is known about compound heterozygous patients outside Europe and North America. We have thus designed a study to determine the frequency and mutational profile of these patients in Brazil. To accomplish that, we recruited all patients with ataxia and at least one expanded GAA allele at FXN from 3 national reference centers. We identified those subjects with a single expansion and proceeded with further genetic testing (Sanger sequencing and CGH arrays) for those. There were 143 unrelated patients (128 families), five of which had a single expanded allele. We identified point mutations in three out of these five (3/128 = 2.34%). Two patients had the c.157delC variant, whereas one individual had the novel variant c.482+1G>T. These results indicate that FXN point mutations are rare, but exist in Brazilian patients with FRDA. This has obvious implications for diagnostic testing and genetic counseling.

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.

Spinocerebellar ataxia type 7 (SCA7) is a polyglutamine disease that progressively affects the cerebellum, brainstem, and retina. SCA7 is quite rare, and insights into biomarkers and pre-clinical phases are still missing. We aimed to describe neurologic and ophthalmological findings observed in symptomatic and pre-symptomatic SCA7 subjects. Several neurologic scales, visual acuity, visual fields obtained by computer perimetry, and macular thickness in optical coherence tomography (mOCT) were measured in symptomatic carriers and at risk relatives. Molecular analysis of the ATXN7 was done blindly in individuals at risk. Thirteen symptomatic carriers, 3 pre-symptomatic subjects, and 5 related controls were enrolled. Symptomatic carriers presented scores significantly different from those of controls in most neurologic and ophthalmological scores. Gradual changes from controls to pre-symptomatic and then to symptomatic carriers were seen in mean (SD) of visual fields - 1.34 (1.15), - 2.81 (1.66). and - 9.56 (7.26); mOCT - 1.11 (2.6), - 3.48 (3.54), and - 7.73 (2.56) Z scores; and "Spinocerebellar Ataxia Functional Index (SCAFI)" - 1.16 (0.28), 0.65 (0.56), and - 0.61 (0.44), respectively. Visual fields and SCAFI were significantly correlated with time to disease onset (pre-symptomatic)/disease duration (symptomatic carriers). Visual fields, mOCT, and SCAFI stood out as candidates for state biomarkers for SCA7 since pre-symptomatic stages of disease.

Machado-Joseph disease (SCA3/MJD) is the most common spinocerebellar ataxia worldwide, and particularly so in Southern Brazil. Due to an expanded polyglutamine at ataxin-3, SCA3/MJD presents a relentless course with no current disease modifying treatment. Clinical scales used to measure SCA3/MJD progression present moderate effect sizes, a major drawback for their use as main outcomes in clinical trials, given the rarity and slow progression of the disease. This limitation might be overcome by finding good surrogate markers. We present here a review of studies on peripheral and neurophysiological markers in SCA3/MJD that can be candidates for state biomarkers. Data on markers already studied were summarized, giving emphasis on validation against clinical scale, and responsiveness to change. While some biological fluid compounds and neurophysiological parameters showed poor responsiveness, others seemed to be good candidates. Some potential candidates that are waiting for responsiveness studies were serum levels of neuron specific enolase, vestibulo-ocular reflex and video-oculography. Candidates evaluated by RNA and microRNA expression levels need further studies to improve their measurements. Data on peripheral levels of Beclin-1 and DNAJB1 are promising but still incipient. We conclude that several potential candidates should follow onto validating studies for surrogate state biomarkers of SCA3/MJD.

Ataxi A-T elangiectasia (AT) is a multisystem, complex and rare disease inherited in an autosomal recessive manner. Homozygous individuals have a variety of pathological manifestations, however, heterozygotes only present a higher risk of developing cancer. We evaluated the background levels of DNA damage (basal damage) and cell response to bleomycin or ionizing radiation using Comet assay and the cytokinesis-block micronucleus (CBMN) test in individuals with AT, their parents and controls. To evaluate DNA repair, the challenge experiment with ionizing radiation was performed using Comet assay, and different recovery times were evaluated. Results showed that basal MN frequencies differ between patients, parents and controls. Meanwhile, using the Comet assay, the results from the basal analysis do not differ between the groups, but monitoring the kinetics of DNA repair, we verified that the group of patients showed a delay in repair, compared to controls. Another finding was the nuclear bud (NBUD) frequency: spontaneous and induced cell cultures (with bleomycin and radiation) showed clear differences between patients, parents and controls. The CBMN assay and repair measurement with the Comet assay can help in the diagnosis of AT patients and ATM gene carriers, as complementary methods. The use of genomic instability evaluation techniques for the identification of the heterozygotes in families, where at least one member is affected, may be of great clinical importance.

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder caused by disfunction of the ABCD1 gene, which encodes a peroxisomal protein responsible for the transport of the very long-chain fatty acids from the cytosol into the peroxisome, to undergo β-oxidation. The mainly accumulated saturated fatty acids are hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) in tissues and body fluids. This peroxisomal disorder occurs in at least 1 out of 20,000 births. Considering that pathophysiology of this disease is not well characterized yet, and glial cells are widely used in studies of protective mechanisms against neuronal oxidative stress, we investigated oxidative damages and inflammatory effects of vesicles containing lecithin and C26:0, as well as the protection conferred by N-acetyl-L-cysteine (NAC), trolox (TRO), and rosuvastatin (RSV) was assessed. It was verified that glial cells exposed to C26:0 presented oxidative DNA damage (measured by comet assay and endonuclease III repair enzyme), enzymatic oxidative imbalance (high catalase activity), nitrative stress [increased nitric oxide (NO) levels], inflammation [high Interleukin-1beta (IL-1β) levels], and induced lipid peroxidation (increased isoprostane levels) compared to native glial cells without C26:0 exposure. Furthermore, NAC, TRO, and RSV were capable to mitigate some damages caused by the C26:0 in glial cells. The present work yields experimental evidence that inflammation, oxidative, and nitrative stress may be induced by hexacosanoic acid, the main accumulated metabolite in X-ALD, and that antioxidants might be considered as an adjuvant therapy for this severe neurometabolic disease.

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

Objective In spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), the expanded cytosine adenine guanine (CAG) repeat in ATXN3 is the causal mutation, and its length is the main factor in determining the age at onset (AO) of clinical symptoms. However, the contribution of the expanded CAG repeat length to the rate of disease progression after onset has remained a matter of debate, even though an understanding of this factor is crucial for experimental data on disease modifiers and their translation to clinical trials and their design. Methods Eighty-two Dutch patients with SCA3/MJD were evaluated annually for 15 years using the International Cooperative Ataxia Rating Scale (ICARS). Using linear growth curve models, ICARS progression rates were calculated and tested for their relation to the length of the CAG repeat expansion and to the residual age at onset (RAO): The difference between the observed AO and the AO predicted on the basis of the CAG repeat length. Results On average, ICARS scores increased 2.57 points/year of disease. The length of the CAG repeat was positively correlated with a more rapid ICARS progression, explaining 30% of the differences between patients. Combining both the length of the CAG repeat and RAO as comodifiers explained up to 47% of the interpatient variation in ICARS progression. Interpretation Our data imply that the length of the expanded CAG repeat in ATXN3 is a major determinant of clinical decline, which suggests that CAG-dependent molecular mechanisms similar to those responsible for disease onset also contribute to the rate of disease progression in SCA3/MJD. ANN NEUROL 2021;89:66-73.

Background The pathological burden of spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), accumulates before the beginning of symptoms. Our study aims at validating biomarkers for disease progression since pre-ataxic periods. We report on baseline findings of clinical scales and oculomotor neurophysiology. Methods Ataxic (Scale for the Assessment and Rating of Ataxia > 2.5) and at 50% risk subjects were included. The latter were subdivided into noncarriers, pre-ataxic carriers near (PAN), or pre-ataxic carriers far from (PAFF) ataxia onset (AO), with 4 years from the predicted age at onset being the cutoff. The subjects were assessed by Neurological Examination Score for Spinocerebellar Ataxia (NESSCA), International Cooperative Ataxia Rating Scale (ICARS), Inventory of Non-Ataxic Signs (INAScount), Composite Cerebellar Functions Score and SCA Functional Index, and video-oculography, including the regression slope of vestibulo-ocular reflex gain (VORr), main sequence of volitional and reflexive vertical saccades, slow-phase velocity of central and gaze-evoked (SPV-GE) nystagmus, and vertical pursuit gain. Correction for multiple comparisons was performed; the threshold for statistical significance was P Results A total of 35 ataxic, 14 PAN, 24 PAFF, and 22 noncarriers were included. All variables showed significant differences between groups and correlated to time to onset or time after onset, among all 73 SCA3/MJD carriers; none significantly changed with age in controls. NESSCA, ICARS, INAScount, VORr, main sequence of volitional saccades, and SPV-GE not only distinguished PAN from controls but also correlated with time left to AO. Conclusions Clinical scales and video-oculography variables were already altered in pre-ataxic SCA3/MJD carriers and worsened with time. NESSCA, ICARS, INAScount, VORr, main sequence of vertical volitional saccades, and SPV-GE are good candidates to measure preclinical changes in SCA3/MJD. © 2021 International Parkinson and Movement Disorder Society.

The original version of this article unfortunately contained some mistakes in Table 2. The additional row (just above SCA2) with the following information “SCA1, 1(1), 1, 50, 74, 24, 46 and 0/1” should be inserted.

Background and purpose In spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), the length of CAG repeat expansions in ATXN3 shows an inverse correlation with age at onset (AO). Recently, a formula for predicting AO based on CAG expansion was developed for European carriers. We tested this formula in SCA3/MJD carriers from distinct origins and developed population-specific models to predict AO. Methods This was a parametric survival modelling study. Results The European formula (EF) was tested in 739 independent SCA3/MJD carriers from South Brazil, Taiwan and the Portuguese Azorean islands, and it largely underestimated AO in South Brazilian and Taiwanese test cohorts. This finding challenged the universal use of the EF, leading us to develop and validate population-specific models for AO prediction. Using validation cohorts, we showed that Brazilian and Taiwanese formulas largely outperformed the EF in a population-specific manner. Inversely, the EF was more accurate at predicting AO among Portuguese Azorean patients. Hence, specific prediction models were required for each SCA3/MJD ethnic group. Conclusions Our data strongly support the existence of as yet unknown factors that modulate AO in SCA3/MJD in a population-dependent manner, independent of CAG expansion length. The generated models are made available to the scientific community as they can be useful for future studies on SCA3/MJD carriers from distinct geographical origins.

Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the ATXN3 gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study. Using a total of 786 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci (P < 1 × 10−5). These loci were enriched for genes involved in vesicle transport, olfactory signaling, and synaptic pathways. Furthermore, associations between AO and the TRIM29 and RAG genes suggests that DNA repair mechanisms might be implicated in MJD pathogenesis. Our study demonstrates the existence of several additional genetic factors, along with CAG expansion, that may lead to a better understanding of the genotype-phenotype correlation in MJD.

Summary Background Most patients with Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies do not carry mutations in known disease-causing genes. The aim of this study was to identify a novel gene implicated in the development of these disorders. Methods Our study was done in three stages. First, we did genome-wide linkage analysis of an Italian family with dominantly inherited Parkinson's disease to identify the disease locus. Second, we sequenced the candidate gene in an international multicentre series of unrelated probands who were diagnosed either clinically or pathologically with Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies. As a control, we used gene sequencing data from individuals with abdominal aortic aneurysms (who were not examined neurologically). Third, we enrolled an independent series of patients diagnosed clinically with Parkinson's disease and controls with no signs or family history of Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies from centres in Portugal, Sardinia, and Taiwan, and screened them for specific variants. We also did mRNA and brain pathology studies in three patients from the international multicentre series carrying disease-associated variants, and we did functional protein studies in in-vitro models, including neurons from induced pluripotent stem-like cells. Findings Molecular studies were done between Jan 1, 2008, and Dec 31, 2017. In the initial kindred of ten affected Italian individuals (mean age of disease onset 59·8 years [SD 8·7]), we detected significant linkage of Parkinson's disease to chromosome 14 and nominated LRP10 as the disease-causing gene. Among the international series of 660 probands, we identified eight individuals (four with Parkinson's disease, two with Parkinson's disease dementia, and two with dementia with Lewy bodies) who carried different, rare, potentially pathogenic LRP10 variants; one carrier was found among 645 controls with abdominal aortic aneurysms. In the independent series, two of these eight variants were detected in three additional Parkinson's disease probands (two from Sardinia and one from Taiwan) but in none of the controls. Of the 11 probands from the international and independent cohorts with LRP10 variants, ten had a positive family history of disease and DNA was available from ten affected relatives (in seven of these families). The LRP10 variants were present in nine of these ten relatives, providing independent—albeit limited—evidence of co-segregation with disease. Post-mortem studies in three patients carrying distinct LRP10 variants showed severe Lewy body pathology. Of nine variants identified in total (one in the initial family and eight in stage 2), three severely affected LRP10 expression and mRNA stability (1424+5delG, 1424+5G→A, and Ala212Serfs*17, shown by cDNA analysis), four affected protein stability (Tyr307Asn, Gly603Arg, Arg235Cys, and Pro699Ser, shown by cycloheximide-chase experiments), and two affected protein localisation (Asn517del and Arg533Leu; shown by immunocytochemistry), pointing to loss of LRP10 function as a common pathogenic mechanism. Interpretation Our findings implicate LRP10 gene defects in the development of inherited forms of α-synucleinopathies. Future elucidation of the function of the LRP10 protein and pathways could offer novel insights into mechanisms, biomarkers, and therapeutic targets. Funding Stichting ParkinsonFonds, Dorpmans-Wigmans Stichting, Erasmus Medical Center, ZonMw—Memorabel programme, EU Joint Programme Neurodegenerative Disease Research (JPND), Parkinson's UK, Avtal om Lakarutbildning och Forskning (ALF) and Parkinsonfonden (Sweden), Lijf and Leven foundation, and cross-border grant of Alzheimer Netherlands–Ligue Europeene Contre la Maladie d'Alzheimer (LECMA).

Background Molecular diagnosis of hereditary spastic paraplegias (HSP) is a difficult task due to great clinical and genetic heterogeneity. We aimed to characterize clinical and molecular findings of HSP families from Rio Grande do Sul, Brazil; and to evaluate the diagnostic yield of a next-generation sequencing (NGS) panel with twelve HSP-related genes. Methods A consecutive series of HSP index cases with familial recurrence of spasticity, consanguinity or thin corpus callosum (TCC) were included in this cross-sectional study. Results Among the 29 index cases, 51.7% (15/29) received at least a likely molecular diagnosis, and 48.3% (14/29) a defined diagnosis. NGS panel diagnostic yield was 60% for autosomal dominant HSP (6/10, all SPG4), 47.4% for autosomal recessive HSP (9/19: 5 SPG11, 2 SPG7, 1 SPG5 and 1 cerebrotendinous xanthomatosis), and 50% for patients with TCC (3/6, all SPG11). Remarkably, 2/6 SPG11 patients presented keratoconus, and tendon xanthomas were absent in the patient with cerebrotendinous xanthomatosis. Conclusion A likely molecular diagnosis was obtained for more than half of families with the NGS panel, indicating that this approach could be employed as a first-line investigation for HSP. SPG4 is the most frequent form of autosomal dominant and SPG11 of autosomal recessive HSP in Southern Brazil.