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.

Characterization of Cardiac-Onset Initial Presentation in Friedreich Ataxia.

We examined the clinical features of Friedreich ataxia (FRDA) patients who present first with cardiac disease in order to understand the earliest features of the diagnostic journey in FRDA. We identified a group of subjects in the FACOMS natural history study whose first identified clinical feature was cardiac. Only 0.5% of the total cohort belonged to this group, which was younger on average at the time of presentation. Their cardiac symptoms ranged from asymptomatic features to heart failure with severe systolic dysfunction. Two of those individuals with severe dysfunction proceeded to heart transplantation, but others spontaneously recovered. In most cases, diagnosis of FRDA was not made until well after cardiac presentation. The present study shows that some FRDA patients present based on cardiac features, suggesting that earlier identification of FRDA might occur through enhancing awareness of FRDA among pediatric cardiologists who see such patients. This is important in the context of newly identified therapies for FRDA.

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.

Brief assessment of cognitive function in myotonic dystrophy: Multicenter longitudinal study using computer-assisted evaluation.

INTRODUCTION/AIMS: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Pain as a significant symptom in patients with periodic paralysis-A cross-sectional survey.

INTRODUCTION: Periodic paralysis (PP) is thought to be limited to episodes of muscle weakness, but there are reports of fibromyalgia-like pain in PP. We aimed to evaluate pain and comorbid sleep, fatigue, and mood disorders in PP patients. METHODS: We administered a cross-sectional survey to PP patients at the 2019 Periodic Paralysis Conference. The survey consisted of the Brief Pain Inventory, Widespread Pain Index, Pittsburgh Sleep Quality Index, Modified Fatigue Impact Scale, and ten-question Center for Epidemiologic Studies Depression Scale (CESD-10). Descriptive statistics for PP patients were calculated and compared with earlier studies. RESULTS: Forty-four individuals with PP took the survey. Of these patients, 52.3% reported a moderate to severe interference of pain on their lives, and 45.5% met the study criteria for fibromyalgia. Patients with SCN4A mutations had higher rates of fibromyalgia than the next most prevalent gene mutation, CACNA1S. In patients with pain, there were increased rates of comorbid fatigue, depression, and poor sleep quality. DISCUSSION: Pain, akin to fibromyalgia, is a significant symptom of PP and can affect quality of life. Pain in PP was more prevalent than in the general population, at a rate comparable with other chronic neuromuscular disease groups. PP patients could benefit from a multidisciplinary approach to assess their pain, sleep, fatigue, and mood.

Gauging Gait Disorders with a Method Inspired by Motor Control Theories: A Pilot Study in Friedreich's Ataxia.

To date, it has been challenging for clinicians and researchers alike to use the multiple outcome measures available to create a meaningful clinical picture and perform effective longitudinal follow-up. It has been found that instrumented gait analysis can provide information associated with a patient's performance and help to remedy the shortcomings of the currently available outcome measures. The goal of this methodological article is to set the background and justify a new outcome measure inspired by the motor control theories to analyze gait using spatiotemporal parameters. The method is applied in a population of individuals living with Friedreich's ataxia (FRDA), a neurodegenerative disease. The sample population consisted of 19 subjects, 11 to 65 years of age with FRDA, who either ambulated independently, with a cane, or with a rollator. Three scores based on the distance from healthy normative data were used: Organization Score, Variability Score, and an overall measurement, the Global Ambulation Score. The scores were then compared to the Scale for Assessment and Rating of Ataxia (SARA) Gait Score (SARA-GS), a clinical scale currently being used for gait analysis in FRDA. Organization Scores demonstrated a longitudinal deterioration in the gait characteristics from independent ambulators to those who ambulated with a rollator. Variability Scores mostly reflected dynamic instability, which became greater as the requirement of an ambulation aid or the switch from a cane to a rollator was imminent. The global value given by the Global Ambulation Score, which takes into consideration both the Organization Score, the Variability Score, and the level of assistive device, demonstrated a logarithmic relationship with the SARA-GS. Overall, these results highlight that both components introduced should be analyzed concurrently and suggest that the Global Ambulation Score may be a valuable outcome measure for longitudinal disease progression.

Temporal but not spatial dysmetria relates to disease severity in FA.

Friedreich's ataxia (FA) is an inherited disease that causes degeneration of the nervous system. Features of FA include proprioceptive and cerebellar deficits leading to impaired muscle coordination and, consequently, dysmetria in force and time of movement. The aim of this study is to characterize dysmetria and its association to disease severity. Also, we examine the neural mechanisms of dysmetria by quantifying the EMG burst area, duration, and time-to-peak of the agonist muscle. Twenty-seven individuals with FA and 13 healthy controls (HCs) performed the modified Functional Ataxia Rating Scale and goal-directed movements with the ankle. Dysmetria was quantified as position and time error during dorsiflexion. FA individuals exhibited greater time but not position error than HCs. Moreover, time error correlated with disease severity and was related to increased agonist EMG burst. Temporal dysmetria is associated to disease severity, likely due to altered activation of the agonist muscle.NEW & NOTEWORTHY For the first time, we quantified spatial and temporal dysmetria and its relation to disease severity in Friedreich's ataxia (FA). We found that FA individuals exhibit temporal but not spatial dysmetria relative to healthy controls. Temporal dysmetria correlated to disease severity in FA and was predicted from an altered activation of the agonist muscle. Therefore, these results provide novel evidence that FA exhibit temporal but not spatial dysmetria, which is different from previous findings on SCA6.

Sleep disorders in myotonic dystrophies.

Myotonic dystrophies (DM), the most common muscular dystrophies, are known to have significant sleep disturbances. We analyzed the literature on sleep and excessive daytime sleepiness (EDS) in DM over the past 30 years. In this review we provide a brief overview of sleep, sleep disorders, and methods of assessment. We also analyze data regarding major sleep disorders in DM patients, including: sleep-disordered breathing (SDB), with both central and obstructive sleep apneas (CSA,OSA); EDS; sleep-related movement disorders; and poor sleep quality. We review the possible pathogenesis of these disorders and outline management strategies. We also consider possible future avenues for research. The findings highlight the complex set of sleep-related problems, including the primary abnormality of sleep control in myotonic dystrophies. In individual patients the roles of poor sleep hygiene, SDB, primary hypersomnia, and excess fatigue require careful assessment for appropriate management.

Evaluating mFARS in pediatric Friedreich's ataxia: Insights from the FACHILD study.

OBJECTIVES: Friedreich ataxia (FRDA) is a rare genetic disorder caused by mutations in the FXN gene, leading to progressive coordination loss and other symptoms. The recently approved omaveloxolone targets this condition but is limited to patients over 16 years of age, highlighting the need for pediatric treatments due to the disorder's early onset and more rapid progression in children. This population also experiences increased non-neurological complications; the FACHILD study aimed to augment and expand the knowledge about the natural history of the disease and clinical outcome assessments for trials in children in FRDA. METHODS: The study enrolled 108 individuals aged 7-18 years with a confirmed FRDA diagnosis, with visits occurring from October 2017 to November 2022 across three institutions. Several measures were introduced to minimize the impact of the COVID-19 pandemic, including virtual visits. Outcome measures centered on the mFARS score and its subscores, and data were analyzed using mixed models for repeated measures. For context and to avoid misinterpretation, the analysis was augmented with data from patients enrolled in the Friedreich's Ataxia Clinical Outcome Measures Study. RESULTS: Results confirmed the general usefulness of the mFARS score in children, but also highlighted issues, particularly with the upper limb subscore (FARS B). Increased variability, limited homogeneity across study subgroups, and potential training effects might limit mFARS application in clinical trials in pediatric populations. INTERPRETATION: The FARS E (Upright Stability) score might be a preferred outcome measure in this patient population.

Roussy-Lévy Syndrome: Pes Cavus, Tendon Areflexia, Amyotrophy, Gait Ataxia, and Upper Limb Tremor in a Patient with CMT Neuropathy.

Background: Roussy-Lévy syndrome (RLS) is characterized by postural hand tremor seen in patients with familial autosomal dominant Charcot-Marie-Tooth (CMT) neuropathy. Phenomenology Shown: This video demonstrates irregular, jerky bilateral kinetic, postural, rest tremor affecting the right > left hand, along with pes cavus and gait ataxia in a patient with CMT disease. Educational Value: Pes cavus, tendon areflexia, sensory ataxia, and upper limb tremor should prompt consideration of CMT neuropathy. Highlights: This video abstract depicts a bilateral hand tremor characteristic of Roussy-Lévy syndrome seen in patients with Charcot-Marie-Tooth disease neuropathy. The significance of the abstract lies in the phenomenology and the physiology of the tremor seen in patients with genetically confirmed duplication of PMP22 gene.

Assessing Long-Term Neurologic Outcomes in SAMD9L-Related Ataxia-Pancytopenia Syndrome.

BACKGROUND: Most published reports on SAMD9L-related ataxia-pancytopenia syndrome (ATXPC) have emphasized the hematologic findings. Fewer details are known about the progression of neurologic manifestations and methods for monitoring them. CASES: We present six individuals from two families transmitting a heterozygous variant in SAMD9L, exhibiting clinical variations in their hematologic and neurologic findings. Serial motor function testing was used to monitor motor proficiency over a 2 to 3 year period in the proband and his father from Family 1. CONCLUSIONS: Our case series focuses on the neurologic progression in patients with heterozygous variants in SAMD9L. Patients with ATXPC should be followed to evaluate a wide range of neurologic manifestations. Serial motor function testing using a standardized method is helpful to track changes in balance and coordination in children and adults with ATXPC and could aid in a future extended natural history study.

Perspectives of the Friedreich ataxia community on gene therapy clinical trials.

Gene therapy is a potential treatment for Friedreich ataxia, with multiple programs on the horizon. The purpose of this study was to collect opinions about gene therapy from individuals 14 years or older with Friedreich ataxia or parents/caregivers of Friedreich ataxia patients who were diagnosed as children 17 or younger. Participants were asked to complete a survey after reading brief educational materials regarding gene therapy. Most of the patients captured in this survey have an early-onset (classical) presentation of the disease. Participants expressed urgency in participating in gene therapy clinical trials despite the associated risks. About half of the respondents believed that gene therapy would cease progression or minimize symptoms, whereas nearly one-fourth expected to be cured. The survey also revealed how participants perceive their symptom burden, because a substantial majority reported that balance/walking issues most interfere with their quality of life and would be the symptom they would prioritize treating. Although not statistically significant, more caregivers prioritized treating cardiomyopathy than patients. This study provides valuable information on priorities, beliefs, and expectations regarding gene therapy and serves to guide future gene therapy opinion studies and gene therapy trial design.

Rare ACTN2 Frameshift Variants Resulting in Protein Extension Cause Distal Myopathy and Hypertrophic Cardiomyopathy through Protein Aggregation.

Distal myopathies are a group of rare, inherited muscular disorders characterized by progressive loss of muscle fibers that begins in the distal parts of arms and legs. Recently, variants in a new disease gene, ACTN2 , have been shown to cause distal myopathy. ACTN2 , a gene previously only associated with cardiomyopathies, encodes alpha-actinin-2, a protein expressed in both cardiac and skeletal sarcomeres. The primary function of alpha-actinin-2 is to link actin and titin to the sarcomere Z-disk. New ACTN2 variants are continuously discovered, however, the clinical significance of many variants remains unknown. Thus, lack of clear genotype-phenotype correlations in ACTN2 -related diseases, actininopathies, persists. Objective: The objective of the study is to characterize the pathomechanisms underlying actininopathies. Methods: Functional characterization in C2C12 cell models of several ACTN2 variants is conducted, including frameshift and missense variants associated with dominant actininopathies. We assess the genotype-phenotype correlations of actininopathies using clinical data from several patients carrying these variants. Results: The results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha-actinin-2 aggregates in the cell model. Conversely, dominant frameshift variants causing a protein extension do produce alpha-actinin-2 aggregates. Interpretation: The results suggest that alpha-actinin-2 aggregation is the disease mechanism underlying some dominant actininopathies, and thus we recommend that protein-extending frameshift variants in ACTN2 should be classified as pathogenic. However, this mechanism is likely elicited by only a limited number of variants. Alternative functional characterization methods should be explored to further investigate other molecular mechanisms underlying actininopathies.

Fatigue Impacts Quality of Life in People with Spinocerebellar Ataxias.

BACKGROUND: Fatigue is a prevalent and debilitating symptom in neurological disorders, including spinocerebellar ataxias (SCAs). However, the risk factors of fatigue in the SCAs as well as its impact have not been well investigated. OBJECTIVES: To study the prevalence of fatigue in SCAs, the factors contributing to fatigue, and the influence of fatigue on quality of life. METHODS: Fatigue was assessed in 418 participants with SCA1, SCA2, SCA3, and SCA6 from the Clinical Research Consortium for the Study of Cerebellar Ataxia using the Fatigue Severity Scale. We conducted multi-variable linear regression models to examine the factors contributing to fatigue as well as the association between fatigue and quality of life. RESULTS: Fatigue was most prevalent in SCA3 (52.6%), followed by SCA1 (36.7%), SCA6 (35.7%), and SCA2 (35.6%). SCA cases with fatigue had more severe ataxia and worse depressive symptoms. In SCA3, those with fatigue had a longer disease duration and longer pathological CAG repeat numbers. In multi-variable models, depressive symptoms, but not ataxia severity, were associated with more severe fatigue. Fatigue, independent of ataxia and depression, contributed to worse quality of life in SCA3 and SCA6 at baseline, and fatigue continued affecting quality of life throughout the disease course in all types of SCA. CONCLUSIONS: Fatigue is a common symptom in SCAs and is closely related to depression. Fatigue significantly impacts patients' quality of life. Therefore, screening for fatigue should be considered a part of standard clinical care for SCAs.

Baseline Clinical and Blood Biomarkers in Patients With Preataxic and Early-Stage Disease Spinocerebellar Ataxia 1 and 3.

BACKGROUND AND OBJECTIVES: In spinocerebellar ataxia, ataxia onset can be preceded by mild clinical manifestation, cerebellar and/or brainstem alterations, or biomarker modifications. READISCA is a prospective, longitudinal observational study of patients with spinocerebellar ataxia type 1 (SCA1) and 3 (SCA3) to provide essential markers for therapeutic interventions. We looked for clinical, imaging, or biological markers that are present at an early stage of the disease. METHODS: We enrolled carriers of a pathologic ATXN1 or ATXN3 expansion and controls from 18 US and 2 European ataxia referral centers. Clinical, cognitive, quantitative motor, neuropsychological measures and plasma neurofilament light chain (NfL) measurements were compared between expansion carriers with and without ataxia and controls. RESULTS: We enrolled 200 participants: 45 carriers of a pathologic ATXN1 expansion (31 patients with ataxia [median Scale for the Assessment and Rating of Ataxia: 9; 7-10] and 14 expansion carriers without ataxia [1; 0-2]) and 116 carriers of a pathologic ATXN3 expansion (80 patients with ataxia [7; 6-9] and 36 expansion carriers without ataxia [1; 0-2]). In addition, we enrolled 39 controls who did not carry a pathologic expansion in ATXN1 or ATXN3. Plasma NfL levels were significantly higher in expansion carriers without ataxia than controls, despite similar mean age (controls: 5.7 pg/mL, SCA1: 18.0 pg/mL [p < 0.0001], SCA3: 19.8 pg/mL [p < 0.0001]). Expansion carriers without ataxia differed from controls by significantly more upper motor signs (SCA1 p = 0.0003, SCA3 p = 0.003) and by the presence of sensor impairment and diplopia in SCA3 (p = 0.0448 and 0.0445, respectively). Functional scales, fatigue and depression scores, swallowing difficulties, and cognitive impairment were worse in expansion carriers with ataxia than those without ataxia. Ataxic SCA3 participants showed extrapyramidal signs, urinary dysfunction, and lower motor neuron signs significantly more often than expansion carriers without ataxia. DISCUSSION: READISCA showed the feasibility of harmonized data acquisition in a multinational network. NfL alterations, early sensory ataxia, and corticospinal signs were quantifiable between preataxic participants and controls. Patients with ataxia differed in many parameters from controls and expansion carriers without ataxia, with a graded increase of abnormal measures from control to preataxic to ataxic cohorts. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT03487367.

Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia.

OBJECTIVES: Friedreich ataxia is (FRDA) an autosomal recessive neurodegenerative disorder associated with intrinsic oxidative damage, suggesting that decreasing lipid peroxidation (LPO) might ameliorate disease progression. The present study tested the ability of RT001, a deuterated form of linoleic acid (D2-LA), to alter disease severity in patients with FRDA in a double-blind placebo-controlled trial. METHODS: Sixty-five subjects were recruited across six sites and received either placebo or active drug for an 11-month study. Subjects were evaluated at 0, 4, 9, and 11 months, with the primary outcome measure being maximum oxygen consumption (MVO2) during cardiopulmonary exercise testing (CPET). A key secondary outcome measure was a composite statistical test using results from the timed 1-min walk (T1MW), peak workload, and MVO2. RESULTS: Forty-five subjects completed the protocol. RT001 was well tolerated, with no serious adverse events related to drug. Plasma and red blood cell (RBC) membrane levels of D2-LA and its primary metabolite deuterated arachidonic acid (D2-AA) achieved steady-state concentrations by 4 months. No significant changes in MVO2 were observed for RT001 compared to placebo. Similarly, no differences between the groups were found in secondary or exploratory outcome measures. Post hoc evaluations also suggested minimal effects of RT001 at the dosages used in this study. INTERPRETATIONS: The results of this study provide no evidence for a significant benefit of RT001 at the dosages tested in this Friedreich ataxia patient population.

Patient-Reported Impact of Symptoms in Friedreich Ataxia.

BACKGROUND AND OBJECTIVES: To determine the prevalence and relative importance of symptoms experienced by children and adults with Friedreich ataxia (FA) and to identify factors associated with a higher burden of disease. METHODS: We conducted qualitative interviews with individuals with FA and caregivers of pediatric individuals with FA to identify potential symptoms of importance to those living with FA. We subsequently performed a cross-sectional study to assess which symptoms have the highest prevalence and importance in FA and to determine which factors are associated with a higher burden of disease. RESULTS: Thirty-nine participants provided 2,527 quotes regarding the symptomatic burden of FA. Two hundred two individuals (153 individuals with FA and 49 caregivers) participated in a subsequent cross-sectional study. Individuals with FA and caregivers identified impaired coordination, limitations with mobility and walking, inability to do activities, fatigue, and lower extremity weakness as the most prevalent and life-altering symptomatic themes in FA. Muscle stiffness and functional staging for ataxia were associated with the prevalence of symptomatic themes in FA. In addition, the length of smaller GAA expansion and the mean length of both GAA expansions were strongly associated with the onset of symptoms in FA. DISCUSSION: There are a wide variety of symptoms that affect the lives of individuals with FA. These symptoms, many underrecognized, have different levels of importance and occur at different rates in the FA population. The most common and life altering of these symptoms represent potential targets for future therapeutic interventions.

Friedreich's Ataxia-Health Index: Development and Validation of a Novel Disease-Specific Patient-Reported Outcome Measure.

Background and Objectives: To develop a valid, disease-specific, patient-reported outcome (PRO) measure for adolescents and adults with Friedreich ataxia (FA) for use in therapeutic trials. Methods: We conducted semistructured qualitative interviews and a national cross-sectional study of individuals with FA to determine the most prevalent and burdensome symptoms and symptomatic themes to this population. These symptoms and symptomatic themes were included as questions in the first version of the Friedreich's Ataxia-Health Index (FA-HI). We subsequently used factor analysis, beta interviews with 17 individuals with FA, and test-retest reliability assessments with 20 individuals with FA to evaluate, refine, and optimize the FA-HI. Finally, we determined the capability of the FA-HI to differentiate between subgroups of FA participants with varying levels of disease severity. Results: Participants with FA identified 18 symptomatic themes of importance to be included as subscales in the FA-HI. The FA-HI demonstrates high internal consistency and test-retest reliability, and it was identified by participants as highly relevant, comprehensive, and easy to complete. FA-HI total and subscale scores statistically differentiated between subgroups of participants with varying levels of disease burden. Discussion: Initial evaluation of the FA-HI supports its validity and reliability as a PRO for assessing how individuals with FA feel and function.

Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial.

BACKGROUND: Myotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert deleterious effects. Antisense oligonucleotides (ASOs) provide a promising approach to treatment of myotonic dystrophy type 1 because they reduce toxic RNA levels. We aimed to investigate the safety of baliforsen (ISIS 598769), an ASO targeting DMPK mRNA. METHODS: In this dose-escalation phase 1/2a trial, adults aged 20-55 years with myotonic dystrophy type 1 were enrolled at seven tertiary referral centres in the USA and randomly assigned via an interactive web or phone response system to subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomisation at each dose level), or to baliforsen 400 mg or 600 mg, or placebo (10:2 randomisation at each dose level), on days 1, 3, 5, 8, 15, 22, 29, and 36. Sponsor personnel directly involved with the trial, participants, and all study personnel were masked to treatment assignments. The primary outcome measure was safety in all participants who received at least one dose of study drug up to day 134. This trial is registered with ClinicalTrials.gov (NCT02312011), and is complete. FINDINGS: Between Dec 12, 2014, and Feb 22, 2016, 49 participants were enrolled and randomly assigned to baliforsen 100 mg (n=7, one patient not dosed), 200 mg (n=6), 300 mg (n=6), 400 mg (n=10), 600 mg (n=10), or placebo (n=10). The safety population comprised 48 participants who received at least one dose of study drug. Treatment-emergent adverse events were reported for 36 (95%) of 38 participants assigned to baliforsen and nine (90%) of ten participants assigned to placebo. Aside from injection-site reactions, common treatment-emergent adverse events were headache (baliforsen: ten [26%] of 38 participants; placebo: four [40%] of ten participants), contusion (baliforsen: seven [18%] of 38; placebo: one [10%] of ten), and nausea (baliforsen: six [16%] of 38; placebo: two [20%] of ten). Most adverse events (baliforsen: 425 [86%] of 494; placebo: 62 [85%] of 73) were mild in severity. One participant (baliforsen 600 mg) developed transient thrombocytopenia considered potentially treatment related. Baliforsen concentrations in skeletal muscle increased with dose. INTERPRETATION: Baliforsen was generally well tolerated. However, skeletal muscle drug concentrations were below levels predicted to achieve substantial target reduction. These results support the further investigation of ASOs as a therapeutic approach for myotonic dystrophy type 1, but suggest improved drug delivery to muscle is needed. FUNDING: Ionis Pharmaceuticals, Biogen.

Inherited Ataxias in Children.

The purpose of this review is to describe the current diagnostic approach to inherited ataxias during childhood. With the expanding use and availability of gene testing technologies including large sequencing panels, the ability to arrive at a precise genetic diagnosis in this group of disorders has been improving. We have reviewed all the gene sequencing studies of ataxias available by a comprehensive literature search and summarize their results. We provide a logical algorithm for a diagnostic approach in the context of this evolving information. We stress the fact that both autosomal recessive and autosomal dominant mutations can occur in children with ataxias and the need for keeping in mind nucleotide repeat expansions, which cannot be detected by sequencing technologies, as a possible cause of progressive ataxias in children. We discuss the traditional phenotype-based diagnostic approach in the context of gene testing technologies. Finally, we summarize those disorders in which a specific therapy may be indicated.