Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6.

The CACNA1A gene, encoding the voltage-gated calcium channel subunit α1A, is involved in pre- and postsynaptic Ca(2+) signaling, gene expression, and several genetic neurological disorders. We found that CACNA1A coordinates gene expression using a bicistronic mRNA bearing a cryptic internal ribosomal entry site (IRES). The first cistron encodes the well-characterized α1A subunit. The second expresses a transcription factor, α1ACT, which coordinates expression of a program of genes involved in neural and Purkinje cell development. α1ACT also contains the polyglutamine (polyQ) tract that, when expanded, causes spinocerebellar ataxia type 6 (SCA6). When expressed as an independent polypeptide, α1ACT-bearing an expanded polyQ tract-lacks transcription factor function and neurite outgrowth properties, causes cell death in culture, and leads to ataxia and cerebellar atrophy in transgenic mice. Suppression of CACNA1A IRES function in SCA6 may be a potential therapeutic strategy.

Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B).

OBJECTIVES: Spinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene has recently been recognized as a common cause of late-onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathological abnormalities, and response to 4-aminopyridine in a cohort of 102 patients bearing GAA repeat expansions. METHODS: We compiled a series of patients with SCA27B, recruited from 5 academic centers across the United States. Clinical manifestations and patient demographics were collected retrospectively from clinical records in an unblinded approach using a standardized form. Post-mortem analysis was done on 4 brains of patients with genetically confirmed SCA27B. RESULTS: In our cohort of 102 patients with SCA27B, we found that SCA27B was a late-onset (57 ± 12.5 years) slowly progressive ataxia with an episodic component in 51% of patients. Balance and gait impairment were almost always present at disease onset. The principal finding on post-mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis. Similar to European populations, a high percent of patients 21/28 (75%) reported a positive treatment response with 4-aminopyridine. INTERPRETATION: Our study further estimates prevalence and further expands the clinical, imaging and pathological features of SCA27B, while looking at treatment response, disease progression, and survival in patients with this disease. Testing for SCA27B should be considered in all undiagnosed ataxia patients, especially those with episodic onset. ANN NEUROL 2024.

Standing Balance Conditions and Digital Sway Measures for Clinical Trials of Friedreich's Ataxia.

BACKGROUND: Progressive loss of standing balance is a feature of Friedreich's ataxia (FRDA). OBJECTIVES: This study aimed to identify standing balance conditions and digital postural sway measures that best discriminate between FRDA and healthy controls (HC). We assessed test-retest reliability and correlations between sway measures and clinical scores. METHODS: Twenty-eight subjects with FRDA and 20 HC completed six standing conditions: feet apart, feet together, and feet tandem, both with eyes opened (EO) and eyes closed. Sway was measured using a wearable sensor on the lumbar spine for 30 seconds. Test completion rate, test-retest reliability with intraclass correlation coefficients, and areas under the receiver operating characteristic curves (AUCs) for each measure were compared to identify distinguishable FRDA sway characteristics from HC. Pearson correlations were used to evaluate the relationships between discriminative measures and clinical scores. RESULTS: Three of the six standing conditions had completion rates over 70%. Of these three conditions, natural stance and feet together with EO showed the greatest completion rates. All six of the sway measures' mean values were significantly different between FRDA and HC. Four of these six measures discriminated between groups with >0.9 AUC in all three conditions. The Friedreich Ataxia Rating Scale Upright Stability and Total scores correlated with sway measures with P-values <0.05 and r-values (0.63-0.86) and (0.65-0.81), respectively. CONCLUSION: Digital postural sway measures using wearable sensors are discriminative and reliable for assessing standing balance in individuals with FRDA. Natural stance and feet together stance with EO conditions suggest use in clinical trials for FRDA. © 2024 International Parkinson and Movement Disorder Society.

Digital Measures of Postural Sway Quantify Balance Deficits in Spinocerebellar Ataxia.

BACKGROUND: Maintaining balance is crucial for independence and quality of life. Loss of balance is a hallmark of spinocerebellar ataxia (SCA). OBJECTIVE: The aim of this study was to identify which standing balance conditions and digital measures of body sway were most discriminative, reliable, and valid for quantifying balance in SCA. METHODS: Fifty-three people with SCA (13 SCA1, 13 SCA2, 14 SCA3, and 13 SCA6) and Scale for Assessment and Rating of Ataxia (SARA) scores 9.28 ± 4.36 and 31 healthy controls were recruited. Subjects stood in six test conditions (natural stance, feet together and tandem, each with eyes open [EO] and eyes closed [EC]) with an inertial sensor on their lower back for 30 seconds (×2). We compared test completion rate, test-retest reliability, and areas under the receiver operating characteristic curve (AUC) for seven digital sway measures. Pearson's correlations related sway with the SARA and the Patient-Reported Outcome Measure of Ataxia (PROM ataxia). RESULTS: Most individuals with SCA (85%-100%) could stand for 30 seconds with natural stance EO or EC, and with feet together EO. The most discriminative digital sway measures (path length, range, area, and root mean square) from the two most reliable and discriminative conditions (natural stance EC and feet together EO) showed intraclass correlation coefficients from 0.70 to 0.91 and AUCs from 0.83 to 0.93. Correlations of sway with SARA were significant (maximum r = 0.65 and 0.73). Correlations with PROM ataxia were mild to moderate (maximum r = 0.56 and 0.34). CONCLUSION: Inertial sensor measures of extent of postural sway in conditions of natural stance EC and feet together stance EO were discriminative, reliable, and valid for monitoring SCA. © 2024 International Parkinson and Movement Disorder Society.

Intermuscular Coherence in Spinocerebellar Ataxias 3 and 6: a Preliminary Study.

Spinocerebellar ataxias (SCAs) are familial neurodegenerative diseases involving the cerebellum and spinocerebellar tracts. While there is variable involvement of corticospinal tracts (CST), dorsal root ganglia, and motor neurons in SCA3, SCA6 is characterized by a pure, late-onset ataxia. Abnormal intermuscular coherence in the beta-gamma frequency range (IMCßγ) implies a lack of integrity of CST or the afferent input from the acting muscles. We test the hypothesis that IMCßγ has the potential to be a biomarker of disease activity in SCA3 but not SCA6. Intermuscular coherence between biceps brachii and brachioradialis muscles was measured from surface EMG waveforms in SCA3 (N = 16) and SCA6 (N = 20) patients and in neurotypical subjects (N = 23). IMC peak frequencies were present in the ß range in SCA patients and in the γ range in neurotypical subjects. The difference between IMC amplitudes in the γ and ß ranges was significant when comparing neurotypical control subjects to SCA3 (p < 0.01) and SCA6 (p = 0.01) patients. IMCßγ amplitude was smaller in SCA3 patients compared to neurotypical subjects (p < 0.05), but not different between SCA3 and SCA6 patients or between SCA6 and neurotypical subjects. IMC metrics can differentiate SCA patients from normal controls.

Early-Life Social Determinants of SCA6 Age at Onset, Severity, and Progression.

SCA6 patients with the same size CAG repeat allele can vary significantly in age at onset (AAO) and clinical progression. The specific external factors affecting SCA6 have yet to be investigated. We assessed the effect of early life events on AAO, severity, and progression in SCA6 patients using a social determinant of health approach. We performed a survey of biological and social factors in SCA6 patients enrolled in the SCA6 Network at the University of Chicago. AAO of ataxia symptoms and patient-reported outcome measure (PROM) of ataxia were used as primary outcome measures. Least absolute shrinkage and selection operation (LASSO) regressions were used to identify which early life factors are predictive of SCA6 AAO, severity, and progression. Multiple linear regression models were then used to assess the degree to which these determinants influence SCA6 health outcomes. A total of 105 participants with genetically confirmed SCA6 completed the assessments. SCA6 participants with maternal difficulty during pregnancy, active participation in school sports, and/or longer CAG repeats were determined to have earlier AAO. We found a 13.44-year earlier AAO for those with maternal difficulty in pregnancy than those without (p = 0.008) and a 12.31-year earlier AAO for those active in school sports than those who were not (p < 0.001). Higher education attainment was associated with decreased SCA6 severity and slower progression. Early life biological and social factors can have a strong influence on the SCA6 disease course, indicating that non-genetic factors can contribute significantly to SCA6 health outcomes.

The Cerebellar Cognitive Affective/Schmahmann Syndrome Scale in Spinocerebellar Ataxias.

The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) manifests as impaired executive control, linguistic processing, visual spatial function, and affect regulation. The CCAS has been described in the spinocerebellar ataxias (SCAs), but its prevalence is unknown. We analyzed results of the CCAS/Schmahmann Scale (CCAS-S), developed to detect and quantify CCAS, in two natural history studies of 309 individuals Symptomatic for SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8, 26 individuals Pre-symptomatic for SCA1 or SCA3, and 37 Controls. We compared total raw scores, domain scores, and total fail scores between Symptomatic, Pre-symptomatic, and Control cohorts, and between SCA types. We calculated scale sensitivity and selectivity based on CCAS category designation among Symptomatic individuals and Controls, and correlated CCAS-S performance against age and education, and in Symptomatic patients, against genetic repeat length, onset age, disease duration, motor ataxia, depression, and fatigue. Definite CCAS was identified in 46% of the Symptomatic group. False positive rate among Controls was 5.4%. Symptomatic individuals had poorer global CCAS-S performance than Controls, accounting for age and education. The domains of semantic fluency, phonemic fluency, and category switching that tap executive function and linguistic processing consistently separated Symptomatic individuals from Controls. CCAS-S scores correlated most closely with motor ataxia. Controls were similar to Pre-symptomatic individuals whose nearness to symptom onset was unknown. The use of the CCAS-S identifies a high CCAS prevalence in a large cohort of SCA patients, underscoring the utility of the scale and the notion that the CCAS is the third cornerstone of clinical ataxiology.

De Novo variants in EEF2 cause a neurodevelopmental disorder with benign external hydrocephalus.

Eukaryotic translation elongation factor 2 (eEF2) is a key regulatory factor in gene expression that catalyzes the elongation stage of translation. A functionally impaired eEF2, due to a heterozygous missense variant in the EEF2 gene, was previously reported in one family with spinocerebellar ataxia-26 (SCA26), an autosomal dominant adult-onset pure cerebellar ataxia. Clinical exome sequencing identified de novo EEF2 variants in three unrelated children presenting with a neurodevelopmental disorder (NDD). Individuals shared a mild phenotype comprising motor delay and relative macrocephaly associated with ventriculomegaly. Populational data and bioinformatic analysis underscored the pathogenicity of all de novo missense variants. The eEF2 yeast model strains demonstrated that patient-derived variants affect cellular growth, sensitivity to translation inhibitors and translational fidelity. Consequently, we propose that pathogenic variants in the EEF2 gene, so far exclusively associated with late-onset SCA26, can cause a broader spectrum of neurologic disorders, including childhood-onset NDDs and benign external hydrocephalus.

The Transcription Factor, α1ACT, Acts Through a MicroRNA Network to Regulate Neurogenesis and Cell Death During Neonatal Cerebellar Development.

MicroRNAs, a class of small RNA regulators, function throughout neurodevelopment, from neural stem cell neurogenesis to neuronal maturation, synaptic formation, and plasticity. α1ACT, a transcription factor (TF), plays a critical role in neonatal cerebellar development by regulating an ensemble of genes. Of these, ChIP-seq analysis matched near 50% genes directly regulated by α1ACT. Yet, more than half the regulated transcripts lacked direct interaction with α1ACT. To investigate whether α1ACT acts through a microRNA network, we studied α1ACT-associated simultaneous miRNA:mRNA transcriptome profiles, using miRNA-seq paired with RNA-seq. Thirty-one differentially expressed miRNAs (DEMs) associated with α1ACT-regulated differentially expressed genes (DEGs) were profiled in α1ACT-overexpressing PC12 cells and were further validated in neonatal transgenic mouse cerebellum overexpressing α1ACT in a context-dependent manner. Here, we also demonstrated that α1ACT facilitates neurogenesis and development of dendritic synapses and is partially a result of the downregulation of the miR-99 cluster, miR-143, miR-23, miR-146, miR-363, and miR-484. On the other hand, the miR-181, miR-125, and miR-708 clusters were upregulated by α1ACT, which inhibit MAPK signaling and cell death pathways by targeting Ask1, Odc1, Atf4, and Nuf2 for decreased expression. MiR-181a-5p was verified as the most abundant DEM in neonatal cerebellum, which was further induced by α1ACT. Overall, under α1ACT modulation, up-/downregulated miRNA clusters with their paired target genes may form a regulatory network controlling the balance between the neuronal proliferation, differentiation, and cell death in the cerebellum to promote neonatal development. Our findings concerning the α1ACT-related miRNA/mRNA expression profiles in neonatal cerebellum may inform future investigations for cerebellar development.

Quantitative Gait and Balance Outcomes for Ataxia Trials: Consensus Recommendations by the Ataxia Global Initiative Working Group on Digital-Motor Biomarkers.

With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid, finely granulated, digital health measures are highly warranted to augment clinical and patient-reported outcome measures. Gait and balance disturbances most often present as the first signs of degenerative cerebellar ataxia and are the most reported disabling features in disease progression. Thus, digital gait and balance measures constitute promising and relevant performance outcomes for clinical trials.This narrative review with embedded consensus will describe evidence for the sensitivity of digital gait and balance measures for evaluating ataxia severity and progression, propose a consensus protocol for establishing gait and balance metrics in natural history studies and clinical trials, and discuss relevant issues for their use as performance outcomes.

The S-Factor, a New Measure of Disease Severity in Spinocerebellar Ataxia: Findings and Implications.

Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders, but there is no metric that predicts disease severity over time. We hypothesized that by developing a new metric, the Severity Factor (S-Factor) using immutable disease parameters, it would be possible to capture disease severity independent of clinical rating scales. Extracting data from the CRC-SCA and READISCA natural history studies, we calculated the S-Factor for 438 participants with symptomatic SCA1, SCA2, SCA3, or SCA6, as follows: ((length of CAG repeat expansion - maximum normal repeat length) /maximum normal repeat length) × (current age - age at disease onset) × 10). Within each SCA type, the S-Factor at the first Scale for the Assessment and Rating of Ataxia (SARA) visit (baseline) was correlated against scores on SARA and other motor and cognitive assessments. In 281 participants with longitudinal data, the slope of the S-Factor over time was correlated against slopes of scores on SARA and other motor rating scales. At baseline, the S-Factor showed moderate-to-strong correlations with SARA and other motor rating scales at the group level, but not with cognitive performance. Longitudinally the S-Factor slope showed no consistent association with the slope of performance on motor scales. Approximately 30% of SARA slopes reflected a trend of non-progression in motor symptoms. The S-Factor is an observer-independent metric of disease burden in SCAs. It may be useful at the group level to compare cohorts at baseline in clinical studies. Derivation and examination of the S-factor highlighted challenges in the use of clinical rating scales in this population.

Pontine stroke in a patient with Chronic Progressive External Ophthalmoplegia (CPEO): a case report.

BACKGROUND: Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease with slowly progressive bilateral ptosis and symmetric ophthalmoplegia due to a genetic mutation that results in defective oxidative phosphorylation. Common genes that are implicated in CPEO include POLG, RRM2B, ANT1 and PEO1/TWNK. Here, we report a case of a patient diagnosed with CPEO caused by a novel mutation in PEO/TWNK after suffering a right pontine stroke. CASE PRESENTATION: A 70-year-old man with history of chronic progressive bilateral ptosis and ophthalmoplegia, as well as similar ocular symptoms in his father and grandfather, presented with acute onset of right hemifacial weakness and dysarthria. Brain MRI revealed an acute ischemic stroke in the right dorsal pons. The patient did not experience diplopia due to severe baseline ophthalmoplegia. Creatine kinase was elevated to 6,080 U/L upon admission and normalized over the course of one week; electromyography revealed a myopathic process. Genetic testing revealed a novel mutation c.1510G > A (p. Ala504Thr) in a pathogenic "hot spot" of the C10ORF2 gene (TWNK/PEO1), which is associated with CPEO. The mutation appears to be deleterious using several pathogenicity prediction tools. CONCLUSIONS: This case report describes a patient with late-onset CPEO caused by a novel, likely pathogenic, mutation in the TWNK gene. Although the patient presented with a pontine stroke, it manifested with solely new onset facial palsy, as he had a severe underlying ophthalmoplegia secondary to his CPEO.

Loss-of-function BK channel mutation causes impaired mitochondria and progressive cerebellar ataxia.

Despite a growing number of ion channel genes implicated in hereditary ataxia, it remains unclear how ion channel mutations lead to loss-of-function or death of cerebellar neurons. Mutations in the gene KCNMA1, encoding the α-subunit of the BK channel have emerged as responsible for a variety of neurological phenotypes. We describe a mutation (BKG354S) in KCNMA1, in a child with congenital and progressive cerebellar ataxia with cognitive impairment. The mutation in the BK channel selectivity filter dramatically reduced single-channel conductance and ion selectivity. The BKG354S channel trafficked normally to plasma, nuclear, and mitochondrial membranes, but caused reduced neurite outgrowth, cell viability, and mitochondrial content. Small interfering RNA (siRNA) knockdown of endogenous BK channels had similar effects. The BK activator, NS1619, rescued BKG354S cells but not siRNA-treated cells, by selectively blocking the mutant channels. When expressed in cerebellum via adenoassociated virus (AAV) viral transfection in mice, the mutant BKG354S channel, but not the BKWT channel, caused progressive impairment of several gait parameters consistent with cerebellar dysfunction from 40- to 80-d-old mice. Finally, treatment of the patient with chlorzoxazone, a BK/SK channel activator, partially improved motor function, but ataxia continued to progress. These studies indicate that a loss-of-function BK channel mutation causes ataxia and acts by reducing mitochondrial and subsequently cellular viability.

HER2 c-Terminal Fragments Are Expressed via Internal Translation of the HER2 mRNA.

The HER2/neu signaling pathway is one of the most frequently mutated in human cancer. Although therapeutics targeting this pathway have good efficacy, cancer cells frequently develop resistance. The HER2 gene encodes the full-length HER2 protein, as well as smaller c-terminal fragments (CTFs), which have been shown to be a cause of resistance. Here, we show that HER2 CTFs, exclusive from the full-length HER2 protein, are generated via internal translation of the full-length HER2 mRNA and identify regions which are required for this mechanism to occur. These regions of the HER2 mRNA may present novel sites for therapeutic intervention via small molecules or antisense oligonucleotides (ASOs).

Gait Variability in Spinocerebellar Ataxia Assessed Using Wearable Inertial Sensors.

BACKGROUND: Quantitative assessment of severity of ataxia-specific gait impairments from wearable technology could provide sensitive performance outcome measures with high face validity to power clinical trials. OBJECTIVES: The aim of this study was to identify a set of gait measures from body-worn inertial sensors that best discriminate between people with prodromal or manifest spinocerebellar ataxia (SCA) and age-matched, healthy control subjects (HC) and determine how these measures relate to disease severity. METHODS: One hundred and sixty-three people with SCA (subtypes 1, 2, 3, and 6), 42 people with prodromal SCA, and 96 HC wore 6 inertial sensors while performing a natural pace, 2-minute walk. Areas under the receiver operating characteristic curves (AUC) were compared for 25 gait measures, including standard deviations as variability, to discriminate between ataxic and normal gait. Pearson's correlation coefficient assessed the relationships between the gait measures and severity of ataxia. RESULTS: Increased gait variability was the most discriminative gait feature of SCA; toe-out angle variability (AUC = 0.936; sensitivity = 0.871; specificity = 0.896) and double-support time variability (AUC = 0.932; sensitivity = 0.834; specificity = 0.865) were the most sensitive and specific measures. These variability measures were also significantly correlated with the scale for the assessment and rating of ataxia (SARA) and disease duration. The same gait measures discriminated gait of people with prodromal SCA from the gait of HC (AUC = 0.610, and 0.670, respectively). CONCLUSIONS: Wearable inertial sensors provide sensitive and specific measures of excessive gait variability in both manifest and prodromal SCAs that are reliable and related to the severity of the disease, suggesting they may be useful as clinical trial performance outcome measures. © 2021 International Parkinson and Movement Disorder Society.

Prodromal Spinocerebellar Ataxia Type 2 Subjects Have Quantifiable Gait and Postural Sway Deficits.

BACKGROUND: The search for valid preclinical biomarkers of cerebellar dysfunction is a key research goal for the upcoming era of early interventional approaches in spinocerebellar ataxias. This study aims to describe novel preclinical biomarkers of subtle gait and postural sway abnormalities in prodromal spinocerebellar ataxia type 2 (pre-SCA2). METHODS: Thirty pre-SCA2 patients and their matched healthy controls underwent quantitative assessments of gait and postural sway using a wearable sensor-based system and semiquantitative evaluation of cerebellar features by SARA (Scale for the Assessment and Rating of Ataxia) score. RESULTS: Quantitative analysis of natural gait showed a significantly larger variability of the swing period, toe-off angle and toe-out angle in pre-SCA2, and larger mean coronal and transverse ranges of motion of the trunk at the lumbar location and of the sagittal range of motion of the trunk at the sternum location compared to controls. During tandem gait, pre-SCA2 subjects showed larger lumbar, trunk, and arm ranges of motion than controls. Postural sway analysis showed excessive body oscillation that was increased in tandem stance. Overall, these abnormalities were detected in pre-SCA2 patients without clinical evidence of abnormalities in SARA. The toe-off angle and swing time variability were significantly correlated with the time to ataxia onset, whereas the toe-off angle and transverse range of motion at trunk position during tandem gait were significantly associated with the SARA score. CONCLUSIONS: This study demonstrates early alteration of gait and postural sway control in prodromal SCA2 using a wearable sensor-based system. This offers new pathophysiological hints into this early disease stage and provides novel potential biomarkers for future clinical trials. © 2020 International Parkinson and Movement Disorder Society.

Mammalian Polycistronic mRNAs and Disease.

Our understanding of gene expression has come far since the 'one-gene one-polypeptide' hypothesis proposed by Beadle and Tatum. In this review, we address the gradual recognition that a growing number of polycistronic genes, originally discovered in viruses, are being identified within the mammalian genome, and that these may provide new insights into disease mechanisms and treatment. We carried out a systematic literature review identifying 13 mammalian genes for which there is evidence for polycistronic expression via translation through an internal ribosome entry site (IRES). Although the canonical mechanism of translation initiation has been studied extensively, here we highlight a process of noncanonical translation, IRES-mediated translation, that is a growing source for understanding complex inheritance, the elucidation of disease mechanisms, and the discovery of novel therapeutic targets. Identification of additional polycistronic genes may provide new insights into disease therapy and allow for new discoveries of both translational and disease mechanisms.

Founder Effects of Spinocerebellar Ataxias in the American Continents and the Caribbean.

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.

Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes.

PURPOSE: To examine the impact of a targeted exome approach for the molecular diagnosis of patients nationwide with a wide range of ataxia-related phenotypes. METHODS: One hundred and seventy patients with ataxia of unknown etiology referred from clinics throughout the United States and Canada were studied using a targeted exome approach. Patients ranged in age from 2 to 88 years. Analysis was focused on 441 curated genes associated with ataxia and ataxia-like conditions. RESULTS: Pathogenic and suspected diagnostic variants were identified in 88 of the 170 patients, providing a positive molecular diagnostic rate of 52%. Forty-six different genes were implicated, with the six most commonly mutated genes being SPG7, SYNE1, ADCK3, CACNA1A, ATP1A3, and SPTBN2, which accounted for >40% of the positive cases. In many cases a diagnosis was provided for conditions that were not suspected and resulted in the broadening of the clinical spectrum of several conditions. CONCLUSION: Exome sequencing with targeted analysis provides a high-yield approach for the genetic diagnosis of ataxia-related conditions. This is the largest targeted exome study performed to date in patients with ataxia and ataxia-like conditions and represents patients with a wide range of ataxia phenotypes typically encountered in neurology and genetics clinics.

Neurochemical abnormalities in premanifest and early spinocerebellar ataxias.

OBJECTIVE: To investigate whether early neurochemical abnormalities are detectable by high-field magnetic resonance spectroscopy (MRS) in individuals with spinocerebellar ataxias (SCAs) 1, 2, 3, and 6, including patients without manifestation of ataxia. METHODS: A cohort of 100 subjects (N = 18-21 in each SCA group, including premanifest mutation carriers; mean score on the Scale for the Assessment and Rating of Ataxia [SARA] <10 for all genotypes, and 22 matched controls) was scanned at 7 Tesla to obtain neurochemical profiles of the cerebellum and brainstem. A novel multivariate approach (distance-weighted discrimination) was used to combine regional profiles into an "MRS score." RESULTS: MRS scores robustly distinguished individuals with SCA from controls, with misclassification rates of 0% (SCA2), 2% (SCA3), 5% (SCA1), and 17% (SCA6). Premanifest mutation carriers with estimated disease onset within 10 years had MRS scores in the range of early-manifest SCA subjects. Levels of neuronal and glial markers significantly correlated with SARA and an Activities of Daily Living score in subjects with SCA. Regional neurochemical alterations were different between SCAs at comparable disease severity, with SCA2 displaying the most extensive neurochemical abnormalities, followed by SCA1, SCA3, and SCA6. INTERPRETATION: Neurochemical abnormalities are detectable in individuals before manifest disease, which may allow premanifest enrollment in future SCA trials. Correlations with ataxia and quality-of-life scores show that neurochemical levels can serve as clinically meaningful endpoints in trials. Ranking of SCA types by degree of neurochemical abnormalities indicates that the neurochemistry may reflect synaptic function or density. Ann Neurol 2018;83:816-829.