Reverse Phase Protein Array Reveals Correlation of Retinoic Acid Metabolism With Cardiomyopathy in Friedreich's Ataxia.

Identifying biomarkers is important for assessment of disease progression, prediction of symptom development, and determination of treatment effectiveness. While unbiased analyses of differential gene expression using next-generation sequencing methods are now routinely conducted, proteomics studies are more challenging because of traditional methods predominantly being low throughput and offering a limited dynamic range for simultaneous detection of hundreds of proteins that drastically differ in their intracellular abundance. We utilized a sensitive and high-throughput proteomic technique, reverse phase protein array (RPPA), to attain protein expression profiles of primary fibroblasts obtained from patients with Friedreich's ataxia (FRDA) and unaffected controls (CTRLs). The RPPA was designed to detect 217 proteins or phosphorylated proteins by individual antibody, and the specificity of each antibody was validated prior to the experiment. Among 62 fibroblast samples (44 FRDA and 18 CTRLs) analyzed, 30 proteins/phosphoproteins were significantly changed in FRDA fibroblasts compared with CTRL cells (p < 0.05), mostly representing signaling molecules and metabolic enzymes. As expected, frataxin was significantly downregulated in FRDA samples, thus serving as an internal CTRL for assay integrity. Extensive bioinformatics analyses were conducted to correlate differentially expressed proteins with critical disease parameters (e.g., selected symptoms, age of onset, guanine-adenine-adenine sizes, frataxin levels, and Functional Assessment Rating Scale scores). Members of the integrin family of proteins specifically associated with hearing loss in FRDA. Also, RPPA data, combined with results of transcriptome profiling, uncovered defects in the retinoic acid metabolism pathway in FRDA samples. Moreover, expression of aldehyde dehydrogenase family 1 member A3 differed significantly between cardiomyopathy-positive and cardiomyopathy-negative FRDA cohorts, demonstrating that metabolites such as retinol, retinal, or retinoic acid could become potential predictive biomarkers of cardiac presentation in FRDA.

The Responsiveness of Gait and Balance Outcomes to Disease Progression in Friedreich Ataxia.

To identify gait and balance measures that are responsive to change during the timeline of a clinical trial in Friedreich ataxia (FRDA), we administered a battery of potential measures three times over a 12-month period. Sixty-one ambulant individuals with FRDA underwent assessment of gait and balance at baseline, 6 months and 12 months. Outcomes included GAITRite® spatiotemporal gait parameters; Biodex Balance System Postural Stability Test (PST) and Limits of Stability; Berg Balance Scale (BBS); Timed 25-Foot Walk Test; Dynamic Gait Index (DGI); SenseWear MF Armband step and energy activity; and the Friedreich Ataxia Rating Scale Upright Stability Subscale (FARS USS). The standardised response mean (SRM) or correlation coefficients were reported as effect size indices for comparison of internal responsiveness. Internal responsiveness was also analysed in subgroups. SenseWear Armband daily step count had the largest effect size of all the variables over 6 months (SRM = -0.615), while the PST medial-lateral index had the largest effect size (SRM = 0.829) over 12 months. The FARS USS (SRM = 0.824) and BBS (SRM = -0.720) were the only outcomes able to detect change over 12 months in all subgroups. The DGI was the most responsive outcome in children, detecting a mean change of -2.59 (95% CI -3.52 to -1.66, p < 0.001, SRM = -1.429). In conclusion, the FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich's ataxia patients.

Transcriptional changes in Friedreich's ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, have been studied in affected but inaccessible tissues-such as dorsal root ganglia, sensory neurons and cerebellum-in animal models or small patient series. However, transcriptional changes induced by FRDA in peripheral blood, a readily accessible tissue, have not been characterized in a large sample. We used differential expression, association with disability stage, network analysis and enrichment analysis to characterize the peripheral blood transcriptome and identify genes that were differentially expressed in FRDA patients (n = 418) compared with both heterozygous expansion carriers (n = 228) and controls (n = 93 739 individuals in total), or were associated with disease progression, resulting in a disease signature for FRDA. We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression.

Expanded GAA repeats impede transcription elongation through the FXN gene and induce transcriptional silencing that is restricted to the FXN locus.

Friedreich's ataxia (FRDA) is a severe neurodegenerative disease caused by homozygous expansion of the guanine-adenine-adenine (GAA) repeats in intron 1 of the FXN gene leading to transcriptional repression of frataxin expression. Post-translational histone modifications that typify heterochromatin are enriched in the vicinity of the repeats, whereas active chromatin marks in this region are underrepresented in FRDA samples. Yet, the immediate effect of the expanded repeats on transcription progression through FXN and their long-range effect on the surrounding genomic context are two critical questions that remain unanswered in the molecular pathogenesis of FRDA. To address these questions, we conducted next-generation RNA sequencing of a large cohort of FRDA and control primary fibroblasts. This comprehensive analysis revealed that the GAA-induced silencing effect does not influence expression of neighboring genes upstream or downstream of FXN. Furthermore, no long-range silencing effects were detected across a large portion of chromosome 9. Additionally, results of chromatin immunoprecipitation studies confirmed that histone modifications associated with repressed transcription are confined to the FXN locus. Finally, deep sequencing of FXN pre-mRNA molecules revealed a pronounced defect in the transcription elongation rate in FRDA cells when compared with controls. These results indicate that approaches aimed to reactivate frataxin expression should simultaneously address deficits in transcription initiation and elongation at the FXN locus.

N-Heteroarylation of Optically Pure α-Amino Esters using the Pd-PEPPSI-IPentCl -o-picoline Pre-Catalyst.

A robust, mild, and efficient method for the Pd-catalyzed N-heteroarylation of optically pure α-amino esters was developed. Dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](o-picoline)palladium(II) (Pd-PEPPSI-IPentCl -o-picoline; PEPPSI=pyridine enhanced pre-catalyst preparation, stabilization, and initiation) was shown to effectively couple a variety of amino acids as the tert-butyl ester with heteroaryl chlorides in high yields and with excellent stereoretention of the acidic proton adjacent to the ester. Control experiments revealed that racemization is base-mediated, with no evidence of Pd-mediated ß-hydride elimination when using Pd-PEPPSI-IPentCl , and that racemization occurs only after the product is formed, that is, the non-arylated starting amino ester does not deprotonate under our reaction conditions. Studies also revealed that increasing the steric bulk of the ester moiety on the amino acid (e.g., ethyl to tert-butyl) drastically slows racemization of the product.

Solvent choice and kinetic isotope effects (KIEs) dramatically alter regioselectivity in the directed ortho metalation (DoM) of 1,5-dichloro-2,4-dimethoxybenzene.

The regioselective formation of the 6-lithio derivative of 1,5-dichloro-2,4-dimethoxybenzene (i.e., 12) by directed ortho metalation (DoM) with nBuLi in THF is described. Although literature reports suggest direct deprotonation at C6, a series of time-course and labelling studies has revealed that deprotonation rather occurs exclusively at C3 followed by isomerization of the anion to C6. By contrast, when DoM was performed in Et2 O, deprotonation again occurred selectively at C3, but now no isomerization occurs, and electrophilic capture produces the regioisomer of that produced in THF. In these labeling studies, it has been found that deuterium has an enormous kinetic isotope effect (KIE) that suppresses not only the original DoM reaction at C3 when deuterium is present there, but also suppresses isomerization to C6 when the label is at that site. Remarkably, this "protecting-group" role of the deuterium is unique to THF; in ether, full deprotonation of the deuterium at C3 was observed.

[(IPent)PdCl2(morpholine)]: a readily activated precatalyst for room-temperature, additive-free carbon-sulfur coupling.

A series of new, easily activated NHC-Pd(II) precatalysts featuring a trans-oriented morpholine ligand were prepared and evaluated for activity in carbon-sulfur cross-coupling chemistry. [(IPent)PdCl2(morpholine)] (IPent=1,3-bis(2,6-di(3-pentyl)phenyl)imidazol-2-ylidene) was identified as the most active precatalyst and was shown to effectively couple a wide variety of deactivated aryl halides with both aryl and alkyl thiols at or near ambient temperature, without the need for additives, external activators, or pre-activation steps. Mechanistic studies revealed that, in contrast to other common NHC-Pd(II) precatalysts, these complexes are rapidly reduced to the active NHC-Pd(0) species at ambient temperature in the presence of KOtBu, thus avoiding the formation of deleterious off-cycle Pd(II)-thiolate resting states.

Environmental gestagens activate fathead minnow (Pimephales promelas) nuclear progesterone and androgen receptors in vitro.

Gestagen is a collective term for endogenous and synthetic progesterone receptor (PR) ligands. In teleost fishes, 17α,20ß-dihydroxy-4-pregnen-3-one (DHP) and 17α,20ß,21-trihydroxy-4-pregnen-3-one (20ß-S) are the predominant progestogens, whereas in other vertebrates the major progestogen is progesterone (P4). Progestins are components of human contraceptives and hormone replacement pharmaceuticals and, with P4, can enter the environment and alter fish and amphibian reproductive health. In this study, our primary objectives were to clone the fathead minnow (FHM) nuclear PR (nPR), to develop an in vitro assay for FHM nPR transactivation, and to screen eight gestagens for their ability to transactivate FHM nPR. We also investigated the ability of these gestagens to transactivate FHM androgen receptor (AR). Fish progestogens activated FHM nPR, with DHP being more potent than 20ß-S. The progestin drospirenone and P4 transactivated the FHM nPR, whereas five progestins and P4 transactivated FHM AR, all at environmentally relevant concentrations. Progestins are designed to activate human PR, but older generation progestins have unwanted androgenic side effects in humans. In FHMs, several progestins proved to be strong agonists of AR. Here, we present the first mechanistic evidence that environmental gestagens can activate FHM nPR and AR, suggesting that gestagens may affect phenotype through nPR- and AR-mediated pathways.

Room-temperature amination of deactivated aniline and aryl halide partners with carbonate base using a Pd-PEPPSI-IPentCl-o-picoline catalyst.

Current state-of-the-art protocols for the coupling of unreactive amines (e.g., electron-poor anilines) with deactivated oxidative-addition partners (e.g., electron-rich and/or hindered aryl chlorides) involve strong heating (usually >100°C) and/or tert-butoxide base, and even then not all couplings are successful. The aggressive base tert-butoxide reacts with and in many instances destroys the typical functional groups that are necessary for the function of most organic molecules, such as carbonyl groups, esters, nitriles, amides, alcohols, and amines. The new catalyst described herein, Pd-PEPPSI-IPentCl-o-picoline, is able to aminate profoundly deactivated coupling partners when using only carbonate base at room temperature.

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.

Safety, pharmacokinetics, and pharmacodynamics of nomlabofusp (CTI-1601) in Friedreich's ataxia.

OBJECTIVE: Current treatments for Friedreich's ataxia, a neurodegenerative disorder characterized by decreased intramitochondrial frataxin, do not address low frataxin concentrations. Nomlabofusp (previously CTI-1601) is a frataxin replacement therapy with a unique mechanism of action that directly addresses this underlying frataxin deficiency. Phase 1 studies assessed the safety, pharmacokinetic, and pharmacodynamic profiles of subcutaneously administered nomlabofusp in adults with Friedreich's ataxia. METHODS: Patients were enrolled in two Phase 1, double-blind, placebo-controlled studies. The single ascending-dose (SAD) study (NCT04176991) evaluated single doses of nomlabofusp (25, 50, 75, or 100 mg) or placebo. The multiple ascending-dose (MAD) study (NCT04519567) evaluated nomlabofusp (25 mg daily for 4 days then every third day, 50 mg daily for 7 days then every 2 days, or 100 mg daily) or placebo for 13 days. RESULTS: Patients aged 19-69 years were enrolled (SAD, N = 28; MAD, N = 27). Nomlabofusp was generally well tolerated through 13 days. Most adverse events were mild and resolved quickly. No serious adverse events or deaths were reported. Peak nomlabofusp plasma concentrations occurred 15 min after subcutaneous administration. Nomlabofusp plasma exposures increased with increasing doses and daily administration and decreased with reduced dosing frequency. Increased frataxin concentrations were observed in buccal cells, skin, and platelets with higher and more frequent nomlabofusp administration. INTERPRETATION: Results from this study support a favorable safety profile for nomlabofusp. Subcutaneous nomlabofusp injections were quickly absorbed; higher doses and daily administration resulted in increased tissue frataxin concentrations. Future studies will evaluate longer-term safety and possible efficacy of nomlabofusp.

Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data.

OBJECTIVE: The natural history of Friedreich ataxia is being investigated in a multi-center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity-matched comparison of data from the open-label MOXIe extension (omaveloxolone) to that from FACOMS. METHODS: MOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis. RESULTS: Data from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = -3.6; nominal p value = 0.0001). INTERPRETATION: These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity-matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.

Common data elements for clinical research in Friedreich's ataxia.

To reduce study start-up time, increase data sharing, and assist investigators conducting clinical studies, the National Institute of Neurological Disorders and Stroke embarked on an initiative to create common data elements for neuroscience clinical research. The Common Data Element Team developed general common data elements, which are commonly collected in clinical studies regardless of therapeutic area, such as demographics. In the present project, we applied such approaches to data collection in Friedreich's ataxia (FRDA), a neurological disorder that involves multiple organ systems. To develop FRDA common data elements, FRDA experts formed a working group and subgroups to define elements in the following: ataxia and performance measures; biomarkers; cardiac and other clinical outcomes; and demographics, laboratory tests, and medical history. The basic development process included identification of international experts in FRDA clinical research, meeting by teleconference to develop a draft of standardized common data elements recommendations, vetting of recommendations across the subgroups, and dissemination of recommendations to the research community for public comment. The full recommendations were published online in September 2011 at http://www.commondataelements.ninds.nih.gov/FA.aspx. The subgroups' recommendations are classified as core, supplemental, or exploratory. Template case report forms were created for many of the core tests. The present set of data elements should ideally lead to decreased initiation time for clinical research studies and greater ability to compare and analyze data across studies. Their incorporation into new, ongoing studies will be assessed in an ongoing fashion to define their utility in FRDA.

Regioselective cross-coupling of allylboronic acid pinacol ester derivatives with aryl halides via Pd-PEPPSI-IPent.

The cross-coupling reactions of allylboronic acid pinacol ester derivatives with aryl and heteroaryl halides occurred with high selectivity (>97%) at the α-carbon of the allylboron reagent in the presence of Pd-PEPPSI-IPent precatalyst and 5 M KOH in refluxing THF. In the case of trisubstituted allylboronates with different substituents on the olefin, minor olefin geometry isomerization was observed (E/Z ≈ 80/20).

A program evaluation of the Innovative Teen Pregnancy Prevention Programs (iTP3) Project.

BACKGROUND: Teen pregnancy prevention in the United States has traditionally focused on the development, testing, and subsequent implementation of a set of evidence-based programs (EBPs), recommended nationally. However, these existing EBPs often do not prioritize the most at-risk or vulnerable populations. METHODS: The Innovative Teen Pregnancy Prevention Programs (iTP3) project was funded to facilitate the development of new, innovative programs to reach disparate populations. Through a mixed methods design, iTP3 evaluated the process and resulting innovative programs from five iterative cohorts of funded organizations, referred to as Innovators. iTP3 utilized both a traditional funding model with more traditional methods of capacity building assistance, but transitioned over time to a design-focused funding model in which organizations and individuals developed innovative programs through an intensive human centered design process. RESULTS: Evaluation results showed that the resulting portfolio of programs had differences in the types of programs resulting from the differing funding models. Notable differences among programs from the two funding models include program length, along with personnel, time, and resources needed to develop and manage. CONCLUSION: Both traditional and design funding models led to innovative programs, with notable differences in the development process and resulting programs.

Clinical management guidelines for Friedreich ataxia: best practice in rare diseases.

BACKGROUND: Individuals with Friedreich ataxia (FRDA) can find it difficult to access specialized clinical care. To facilitate best practice in delivering healthcare for FRDA, clinical management guidelines (CMGs) were developed in 2014. However, the lack of high-certainty evidence and the inadequacy of accepted metrics to measure health status continues to present challenges in FRDA and other rare diseases. To overcome these challenges, the Grading of Recommendations Assessment and Evaluation (GRADE) framework for rare diseases developed by the RARE-Bestpractices Working Group was adopted to update the clinical guidelines for FRDA. This approach incorporates additional strategies to the GRADE framework to support the strength of recommendations, such as review of literature in similar conditions, the systematic collection of expert opinion and patient perceptions, and use of natural history data. METHODS: A panel representing international clinical experts, stakeholders and consumer groups provided oversight to guideline development within the GRADE framework. Invited expert authors generated the Patient, Intervention, Comparison, Outcome (PICO) questions to guide the literature search (2014 to June 2020). Evidence profiles in tandem with feedback from individuals living with FRDA, natural history registry data and expert clinical observations contributed to the final recommendations. Authors also developed best practice statements for clinical care points that were considered self-evident or were not amenable to the GRADE process. RESULTS: Seventy clinical experts contributed to fifteen topic-specific chapters with clinical recommendations and/or best practice statements. New topics since 2014 include emergency medicine, digital and assistive technologies and a stand-alone section on mental health. Evidence was evaluated according to GRADE criteria and 130 new recommendations and 95 best practice statements were generated. DISCUSSION AND CONCLUSION: Evidence-based CMGs are required to ensure the best clinical care for people with FRDA. Adopting the GRADE rare-disease framework enabled the development of higher quality CMGs for FRDA and allows individual topics to be updated as new evidence emerges. While the primary goal of these guidelines is better outcomes for people living with FRDA, the process of developing the guidelines may also help inform the development of clinical guidelines in other rare diseases.

A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol.

INTRODUCTION: Drug development for neurodegenerative diseases such as Friedreich's ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers of pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been limited by their small sample sizes and limited follow up. TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to address these shortcomings by enabling better understanding of underlying pathology and identifying sensitive, clinical trial ready, neuroimaging biomarkers for FRDA. METHODS: 200 individuals with FRDA and 104 control participants will be recruited across seven international study sites. Inclusion criteria for participants with genetically confirmed FRDA involves, age of disease onset ≤ 25 years, Friedreich's Ataxia Rating Scale (FARS) functional staging score of ≤ 5, and a total modified FARS (mFARS) score of ≤ 65 upon enrolment. The control cohort is matched to the FRDA cohort for age, sex, handedness, and years of education. Participants will be evaluated at three study visits over two years. Each visit comprises of a harmonized multimodal Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) scan of the brain and spinal cord; clinical, cognitive, mood and speech assessments and collection of a blood sample. Primary outcome measures, informed by previous neuroimaging studies, include measures of: spinal cord and brain morphometry, spinal cord and brain microstructure (measured using diffusion MRI), brain iron accumulation (using Quantitative Susceptibility Mapping) and spinal cord biochemistry (using MRS). Secondary and exploratory outcome measures include clinical, cognitive assessments and blood biomarkers. DISCUSSION: Prioritising immediate areas of need, TRACK-FA aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease trajectory. Once validated, these potential pharmacodynamic biomarkers can be used to measure the efficacy of new therapeutics in forestalling disease progression. CLINICAL TRIAL REGISTRATION: ClinicalTrails.gov Identifier: NCT04349514.

Results of a randomized double-blind study evaluating luvadaxistat in adults with Friedreich ataxia.

OBJECTIVES: Friedreich ataxia (FRDA) is a rare disorder with progressive neurodegeneration and cardiomyopathy. Luvadaxistat (also known as TAK-831; NBI-1065844), an inhibitor of the enzyme d-amino acid oxidase, has demonstrated beneficial effects in preclinical models relevant to FRDA. This phase 2, randomized, double-blind, placebo-controlled, parallel-arm study evaluated the efficacy and safety of oral luvadaxistat in adults with FRDA. METHODS: Adult patients with FRDA were randomized 2:1:2 to placebo, luvadaxistat 75 mg twice daily (BID), or luvadaxistat 300 mg BID for 12 weeks. The primary endpoint changed from baseline at week 12 on the inverse of the time to complete the nine-hole peg test (9-HPT-1 ), a performance-based measure of the function of the upper extremities and manual dexterity. Comparisons between luvadaxistat and placebo were made using a mixed model for repeated measures. RESULTS: Of 67 randomized patients, 63 (94%) completed the study. For the primary endpoint, there was no statistically significant difference in change from baseline on the 9-HPT-1 (seconds-1 ) at week 12 between placebo (0.00029) and luvadaxistat 75 mg BID (-0.00031) or luvadaxistat 300 mg BID (-0.00059); least squares mean differences versus placebo (standard error) were -0.00054 (0.000746) for the 75 mg dose and -0.00069 (0.000616) for the 300 mg dose. Luvadaxistat was safe and well tolerated; the majority of reported adverse events were mild in intensity. INTERPRETATION: Luvadaxistat was safe and well tolerated in this cohort of adults with FRDA; however, it did not demonstrate efficacy as a treatment for this condition.

Body Mass Index and Height in the Friedreich Ataxia Clinical Outcome Measures Study.

BACKGROUND AND OBJECTIVES: Body mass index (BMI) and height are important indices of health. We tested the association between these outcomes and clinical characteristics in Friedreich ataxia (FRDA), a progressive neuromuscular disorder. METHODS: Participants (N = 961) were enrolled in a prospective natural history study (Friedreich Ataxia Clinical Outcome Measure Study). Age- and sex-specific BMI and height Z-scores were calculated using CDC 2000 references for participants younger than 18 years. For adults aged 18 years or older, height Z-scores were also calculated, and absolute BMI was reported. Univariate and multivariate linear regression analyses tested the associations between exposures, covariates, and BMI or height measured at the baseline visit. In children, the superimposition by translation and rotation analysis method was used to compare linear growth trajectories between FRDA and a healthy reference cohort, the Bone Mineral Density in Childhood Study (n = 1,535 used for analysis). RESULTS: Median age at the baseline was 20 years (IQR, 13-33 years); 49% (n = 475) were women. A substantial proportion of children (17%) were underweight (BMI-Z < fifth percentile), and female sex was associated with lower BMI-Z (ß = -0.34, p < 0.05). In adults, older age was associated with higher BMI (ß = 0.09, p < 0.05). Regarding height, in children, older age (ß -0.06, p < 0.05) and worse modified Friedreich Ataxia Rating Scale (mFARS) scores (ß = -1.05 for fourth quartile vs first quartile, p < 0.01) were associated with shorter stature. In girls, the magnitude of the pubertal growth spurt was less, and in boys, the pubertal growth spurt occurred later (p < 0.001 for both) than in a healthy reference cohort. In adults, in unadjusted analyses, both earlier age of FRDA symptom onset (=0.09, p < 0.05) and longer guanine-adenine-adenine repeat length (shorter of the 2 GAA repeats, ß = -0.12, p < 0.01) were associated with shorter stature. Both adults and children with higher mFARS scores and/or who were nonambulatory were less likely to have height and weight measurements recorded at clinical visits. DISCUSSION: FRDA affects both weight gain and linear growth. These insights will inform assessments of affected individuals in both research and clinical settings.