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• Measurable changes detected in swallowing function in 12 months. • Decline in function observed at three anatomical sites considered important for safe swallowing. • Individual anatomical sites may be precursors to widespread functional decline in swallowing. Friedreich ataxia (FRDA) is a multisystem neurodegenerative disorder and the most common hereditary ataxia. Dysphagia (swallowing impairment) is present in 98% of individuals with FRDA and is characterized by lingual and pharyngeal dysfunction (manifesting in impaired bolus preparation and transfer, and post-swallow residue in the mouth and pharynx), delayed swallow initiation, and entry of material into the airway (penetration/aspiration). Dysphagia severity correlates with disease severity and duration however no longitudinal studies describe changes in function in FRDA. The aim of this study was to investigate the progression of dysphagia in FRDA over one year. Fifty-nine individuals with FRDA and confirmed dysphagia were recruited and 23 of them underwent a second assessment 12 months later. Assessments of swallowing related quality of life, oral motor function (Frenchay Dysarthria Assessment 2nd Ed [FDA-2]) and functional swallowing via videofluoroscopy were conducted. Trials of thin liquid, puree and biscuit were interpreted using the Bethlehem Assessment Scale and the Penetration-Aspiration Scale by two blinded raters. Data from the videofluoroscopy revealed a decline in tongue function, pharyngeal clearance and cricopharyngeal function on solid food. However, severity of penetration/aspiration did not increase. Swallowing-related quality of life and oral-motor function remained stable. A decline in function was observed at three anatomical sites considered important for safe and effective swallowing (tongue, pharyngeal, and cricopharyngeal). However, these deficits did not translate into any meaningful functional decline in swallowing related health over 12 months for individuals with FRDA. [ABSTRACT FROM AUTHOR]

Scientists and pharmaceutical companies are working toward delivering gene therapy (GT) for Friedreich ataxia (FRDA). Understanding the views of people with lived experience of FRDA and their parents toward GT is essential to inform trial design and identify potential barriers to participation in clinical trials. The goals of this study were to identify the attitudes toward GT held by individuals with FRDA and parents of individuals with FRDA, and to explore how these may impact future trials for this condition. Audiorecorded, semistructured, qualitative interviews with 19 Australians explored experiences of FRDA, knowledge about clinical trials, views on GT, including risks and benefits, and potential barriers to participation in trials. Participants included thirteen individuals living with FRDA aged between 15–43 years, and six parents of children with FRDA aged 4–12 years of age. Thematic analysis of the interviews identified six main themes. Findings from this study indicate there is strong desire for information regarding GT in FRDA, however the current level of uncertainty around GT makes decision making challenging. The desire to maintain functional status and avoid additional risk of deterioration from an investigational treatment was apparent. Importantly, neurological targets were identified as preferred for GT trials. Further research is required to identify if attitudes and perceptions differ according to geographical location and disease stage. [ABSTRACT FROM AUTHOR]

Highlights from the article: We would like to thank Tibben et al. for reporting their experience of identifying intermediate alleles (IA) reduced penetrance alleles (RPA) or, in one case, a fully penetrant allele (FPA) in the partners of individuals who had undertaken or requested pre-natal diagnosis for Huntington's disease (HD) [[1]]. They conclude that the guidelines for predictive testing [[2]] should be altered to include routinely offering to test the unaffected partner for the presence of these alleles and presumably adding a direct assessment of the CAG repeat length when undertaking prenatal diagnosis (PND) or pre-implantation genetic diagnosis (PGD).

Since the discovery in 1989 that mutations in cystic fibrosis transmembrane conductance regulator (CFTR) underlie cystic fibrosis (CF), the most common life shortening genetic disorder in Caucasians, it has been possible to identify heterozygous mutation carriers at risk of having affected children. The Human Genetics Society of Australasia has produced a position statement with recommendations in relation to population-based screening for CF. These include: (1) that screening should be offered to all relatives of people with or carriers of CF (cascade testing) as well as to all couples planning to have children or who are pregnant; (2) the minimum CFTR mutation panel to be tested consists of 17 mutations which are those mutations that are associated with typical CF and occur with a frequency of 0.1% or higher among individuals diagnosed with CF in Australasia; (3) that genetic counselling is offered to all couples where both members are known to have one or two CFTR mutations and that such couples are given the opportunity to meet with a physician with expertise in the management of CF as well as a family/individual affected by the condition. [ABSTRACT FROM PUBLISHER]

ABSTRACT Background Friedreich ataxia (FRDA) generally results from reduced frataxin, a mitochondrial protein involved in iron metabolism. We assessed whether HFE p.C282Y and/or p.H63D heterozygosity modifies age at disease onset or disease severity in individuals with FRDA. Methods One hundred seventy individuals with FRDA were assessed for the association of HFE p.C282Y and p.H63D with (1) age at disease onset and (2) Friedreich Ataxia Rating Scale (FARS) score. Results After adjusting for the smaller FXN GAA repeat size and sex, individuals with FRDA and heterozygous for p.C282Y had disease onset on average 3.72 years earlier than those homozygous for the wild-type amino acid ( P = 0.02). Neither mutation affected disease severity as measured by FARS. Conclusions It is hypothesized that the association between p.C282Y heterozygosity and an earlier age at FRDA onset relates to exacerbation of the already dysregulated iron metabolism that plays a major role in the pathogenesis of FRDA. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Friedreich ataxia (FRDA) generally results from reduced frataxin, a mitochondrial protein involved in iron metabolism. We assessed whether HFE p.C282Y and/or p.H63D heterozygosity modifies age at disease onset or disease severity in individuals with FRDA. Methods: One hundred seventy individuals with FRDA were assessed for the association of HFE p.C282Y and p.H63D with (1) age at disease onset and (2) Friedreich Ataxia Rating Scale (FARS) score. Results: After adjusting for the smaller FXN GAA repeat size and sex, individuals with FRDA and heterozygous for p.C282Y had disease onset on average 3.72 years earlier than those homozygous for the wildtype amino acid (P=0.02). Neither mutation affected disease severity as measured by FARS. Conclusions: It is hypothesized that the association between p.C282Y heterozygosity and an earlier age at FRDA onset relates to exacerbation of the already dysregulated iron metabolism that plays a major role in the pathogenesis of FRDA. [ABSTRACT FROM AUTHOR]

Friedreich ataxia, the most common hereditary ataxia, affects approximately 1 per 29,000 white individuals. In about 98% of these individuals, it is due to homozygosity for a GAA trinucleotide repeat expansion in intron 1 of FXN; in the other 2%, it is due to compound heterozygosity for a GAA expansion and point mutation or deletion. The condition affects multiple sites in the central and peripheral nervous system as well as a number of other organ systems, resulting in multiple signs and symptoms. Onset of this autosomal recessive condition is usually in the first 2 decades of life. Major clinical features include progressive ataxia, absent lower limb reflexes, upgoing plantar responses, and peripheral sensory neuropathy. The main nonneurological sites of morbidity are the heart, resulting in cardiomyopathy, and the pancreas, resulting in diabetes mellitus. In this review, we provide an overview of the clinical features of Friedreich ataxia and discuss differential diagnoses. [ABSTRACT FROM AUTHOR]

The ever‐increasing body of ataxia research provides opportunities for large‐scale meta‐analyses, systematic reviews, and data aggregation. Because multiple standardized scales are used to quantify ataxia severity, harmonization of these measures is necessary for quantitative data pooling. We applied the modified Friedreich Ataxia Rating Scale (mFARS), the Scale for the Assessment and Rating of Ataxia (SARA), and the International Cooperative Ataxia Rating Scale (ICARS) to a large cohort of people with Friedreich's ataxia. We provide regression coefficients for scale interconversion and discuss the reliability of this approach, together with insights into the differential sensitivities of mFARS and SARA to disease progression. [ABSTRACT FROM AUTHOR]

As the results of the Human Genome Project are realised, screening for genetic mutations that predispose to preventable disease is becoming increasingly possible. How and where such screening should best be offered are critical, unanswered questions. This study aimed to assess the acceptability and feasibility of genetic screening for preventable disease, using the model of hereditary haemochromatosis, in high-school students. Screening was offered for the HFE C282Y substitution to 17 638 students. Questionnaires were administered at the time of screening (Q1) and approximately 1 month after results were communicated (Q2). Outcomes assessed were uptake of screening, change in scores of validated anxiety, affect and health perception scales from Q1 to Q2, knowledge and iron indices in C282Y homozygous individuals. A total of 5757 (32.6%) students had screening and 28 C282Y-homozygous individuals (1 in 206) were identified, and none of the 27 individuals who had iron indices measures had significant iron overload. There was no significant change in measures of anxiety, affect or health perception in C282Y homozygous or non-homozygous individuals. Over 86% of students answered each of five knowledge questions correctly at Q1. Genetic population-based screening for a preventable disease can be offered in schools in a way that results in minimal morbidity for those identified at high risk of disease. The results of this study are not only relevant for haemochromatosis, but for other genetic markers of preventable disease such as those for cardiovascular disease and cancer. [ABSTRACT FROM AUTHOR]

Sustained volitional attention and working memory capacity was examined for the first time in people with Friedreich ataxia (FRDA). We administered subtests of the Test of Everyday Attention to 16 individuals with molecularly confirmed FRDA and gender-, age-, and IQ-matched controls. Clinically significant impairment in working memory and sustained volitional attention was evident. Working memory deficits correlated significantly with GAA repeat number on the shorter allele of the FXN gene, and separately, with disease severity, as measured by the Friedreich Ataxia Rating Scale score. Sustained volitional attention was not correlated with disease parameters, suggesting that this impairment may not be related to the disease process in a simple way. The deficits observed may be the result of disruption to corticocerebellar pathways, or directly related to the cortical and/or cerebellar pathology evident in people with FRDA. (JINS, 2011, 17, 000–000) [ABSTRACT FROM PUBLISHER]

Sustained volitional attention and working memory capacity was examined for the first time in people with Friedreich ataxia (FRDA). We administered subtests of the Test of Everyday Attention to 16 individuals with molecularly confirmed FRDA and gender-, age-, and IQ-matched controls. Clinically significant impairment in working memory and sustained volitional attention was evident. Working memory deficits correlated significantly with GAA repeat number on the shorter allele of the FXN gene, and separately, with disease severity, as measured by the Friedreich Ataxia Rating Scale score. Sustained volitional attention was not correlated with disease parameters, suggesting that this impairment may not be related to the disease process in a simple way. The deficits observed may be the result of disruption to corticocerebellar pathways, or directly related to the cortical and/or cerebellar pathology evident in people with FRDA. (JINS, 2011, 17, 000–000) [ABSTRACT FROM AUTHOR]

The cerebellar and spinocerebellar dysfunction seen in Friedreich ataxia (FRDA) has known effects on motor function. Recently, it was suggested that people with FRDA may also have impairment in motor planning, either because of cortical pathology or because of cerebello-cortical projections. Fifteen adults with FRDA and 15 matched controls completed a task requiring reciprocating movements between two buttons on a tapping board. Occasionally there was one of three “oddball” stimuli requiring reprogramming of movement. These were change in (1) direction, (2) extent or (3) direction and extent. We hypothesized that people with FRDA would have prolonged movement times due to their movement disorder, and that changes in preparation time would be affected in a way similar to controls, unless there was impairment in motor planning in FRDA. Movement execution and, to a lesser degree, movement preparation were impaired in individuals with FRDA. We argue this points to disturbed cortical function. There was a significant negative correlation between age of onset and all three reprogramming conditions, suggesting an impact of FRDA on developing motor planning. Future studies will be required to establish whether this dysfunction is due to cerebellar impairment interrupting cerebro-ponto-cerebello-thalamo-cerebral loops, primary cortical pathology or a combination of the two. [ABSTRACT FROM AUTHOR]

Abstract: Mutation of the parkin gene (parkin) is the most common cause of early-onset Parkinson’s disease and to date over 100 different mutations have been described. However, screening of parkin is complicated by its genomic architecture and context. Notably, dosage alterations in parkin account for greater than 50% of mutations detected in some cohort studies. To improve the accuracy and reproducibility of parkin genomic dosage assays we have identified and analysed cell lines with chromosomal abnormalities affecting 6q26. FISH and real-time PCR analysis identified cell lines with reduced or increased copy number spanning the entire parkin locus. These cell lines represent a valuable resource to facilitate accurate copy number determination of any parkin exon. The reagents are easily obtainable and are compatible with current quantitative technologies and platforms. [Copyright &y& Elsevier]

Abstract As the results of the Human Genome Project are realized, it has become technically possible to identify carriers of numerous autosomal and X-linked recessive disorders. Couples at risk of having a child with one of these conditions have a number of reproductive options to avoid having a child with the condition should they wish. In Australia the haemoglobinopathies are the only group of conditions for which population screening is widely offered and which is government funded. In some Australian states there are also population screening programs for cystic fibrosis and autosomal recessive conditions more common in Ashkenazi Jewish individuals which are generally offered on a user pays basis. It is predicted that as consumer demand increases and testing becomes cheaper, that many people planning or in the early stages of pregnancy will have carrier screening for multiple genetic conditions. This will have significant implications for genetic counseling, laboratory and prenatal testing resources. In addition such screening raises a number of ethical issues including the value of lives of those born with genetic conditions for which screening is available. [ABSTRACT FROM AUTHOR]

Carrier screening for cystic fibrosis has been recommended for pregnant women and their partners, individuals and couples prior to conception, and for people with a family history. Many pilot programmes offering cystic fibrosis carrier screening, most commonly in the prenatal setting, have shown that uptake and acceptability are high. This article explores perspectives of the Victorian community regarding carrier screening for cystic fibrosis prior to offering screening. In particular whether or not such carrier screening should be offered, the best time for offering carrier screening, the information required for making a decision about carrier screening, and how this information can best be provided. A qualitative approach was taken to enable exploration of the views of stakeholders. Four focus groups and 32 interviews were conducted with a total of 68 participants. Participants were in agreement that cystic fibrosis carrier screening should be made available to everyone. However, potential consumers viewed cystic fibrosis carrier screening as ‘not in my world’ and were unlikely to request such screening unless it was offered by a health professional, or they had a family history. The best time for carrier screening was seen to be an individual preference and an information brochure was perceived to be useful when considering carrier screening. Lack of knowledge around the irrelevance of family history is a barrier to cystic fibrosis carrier screening. This study highlights the importance of community consultation, with stakeholders, prior to implementation of carrier screening programmes.European Journal of Human Genetics (2008) 16, 435–444; doi:10.1038/sj.ejhg.5201965; published online 5 December 2007 [ABSTRACT FROM AUTHOR]

This article aims to review ethical and clinical guidelines and policies addressing the communication of genetic information in families. Websites of national and regional bioethics committees, national human genetics societies, international health organisations, genetic interest groups and legal recommendations committees were searched for guidelines and policies. The databases Medline, Web of Science and Google Scholar were also utilised to search for additional guidelines relating to the communication of genetic information in families. The guidelines and policies included in this review are limited to those available in English. The search resulted in guidelines from 18 international, regional and national organisations from six countries pertaining to family communication of genetic information. The following ideals were common in their guidelines: (1) individuals have a moral obligation to communicate genetic information to their family members; (2) genetic health professionals should encourage individuals to communicate this information to their family members; and (3) genetic health professionals should support individuals throughout the communication process. The difference between the organisations' guidelines was the inclusion of information about the role of the health professional in supporting clients during the process of communicating genetic information to their family members. Only two recommendations suggested that the health professional should support their clients by identifying at-risk family members, but more guidelines recommended that directive counselling should be undertaken to encourage clients to communicate genetic information to their family members. In conclusion, the guidelines provide an overview of the role that genetic health professionals may undertake; however, there are gaps that need to be addressed.European Journal of Human Genetics (2007) 15, 612–618. doi:10.1038/sj.ejhg.5201822; published online 28 March 2007 [ABSTRACT FROM AUTHOR]

Implementation of population genetic screening programmes requires consideration of strategies for reaching the greatest proportion of the target population in order to achieve maximum awareness. This article reviews the current strategy of school-based population genetic screening programmes. The school environment is an ideal setting for offering relevant genetic screening programmes as it provides an opportunity to engage people at a time when they are exposed to a range of educational experiences and are sufficiently mature to be involved in decision-making processes. Such programmes allow all students, not only those studying biology, an opportunity to be educated and experience genetic screening in a supportive environment, ultimately increasing understanding and empowering students. While the major form of genetic screening in schools has been for reproductive health information (eg carrier screening for TaySachs disease and cystic fibrosis), genetic screening in schools for other conditions may be a timely proposition.European Journal of Human Genetics (2006) 14, 384–389. doi:10.1038/sj.ejhg.5201581; published online 15 February 2006 [ABSTRACT FROM AUTHOR]

Background: The left ventricular (LV) changes which occur in Friedreich ataxia (FRDA) are incompletely understood. Methods: Cardiac magnetic resonance (CMR) imaging was performed using a 1.5T scanner in subjects with FRDA who are homozygous for an expansion of an intron 1 GAA repeat in the FXN gene. Standard measurements were performed of LV mass (LVM), LV end-diastolic volume (LVEDV) and LV ejection fraction (LVEF). Native T1 relaxation time and the extracellular volume fraction (ECV) were utilised as markers of left ventricular (LV) diffuse myocardial fibrosis and late gadolinium enhancement (LGE) was utilised as a marker of LV replacement fibrosis. FRDA genetic severity was assessed using the shorter FXN GAA repeat length (GAA1). Results: There were 93 subjects with FRDA (63 adults, 30 children, 54% males), 9 of whom had a reduced LVEF (<55%). A LVEDV below the normal range was present in 39%, a LVM above the normal range in 22%, and an increased LVM/LVEDV ratio in 89% subjects. In adults with a normal LVEF, there was an independent positive correlation of LVM with GAA1, and a negative correlation with age, but no similar relationships were seen in children. GAA1 was positively correlated with native T1 time in both adults and children, and with ECV in adults, all these associations independent of LVM and LVEDV. LGE was present in 21% of subjects, including both adults and children, and subjects with and without a reduced LVEF. None of GAA1, LVM or LVEDV were predictors of LGE. Conclusion: An association between diffuse interstitial LV myocardial fibrosis and genetic severity in FRDA was present independently of FRDA-related LV structural changes. Localised replacement fibrosis was found in a minority of subjects with FRDA and was not associated with LV structural change or FRDA genetic severity in subjects with a normal LVEF. [ABSTRACT FROM AUTHOR]

Friedreich ataxia is the most common of the hereditary ataxias. It is due to homozygous/compound heterozygous mutations in FXN. This gene encodes frataxin, a protein largely localized to mitochondria. In about 96% of affected individuals there is homozygosity for a GAA repeat expansion in intron 1 of the FXN gene. Studies of people with Friedreich ataxia and of animal and cell models, have provided much insight into the pathogenesis of this disorder. The expanded GAA repeat leads to transcriptional deficiency of the FXN gene. The consequent deficiency of frataxin protein leads to reduced iron-sulfur cluster biogenesis and mitochondrial ATP production, elevated mitochondrial iron, and oxidative stress. More recently, a role for inflammation has emerged as being important in the pathogenesis of Friedreich ataxia. These findings have led to a number of potential therapies that have been subjected to clinical trials or are being developed toward human studies. Therapies that have been proposed include pharmaceuticals that increase frataxin levels, protein and gene replacement therapies, antioxidants, iron chelators and modulators of inflammation. Whilst no therapies have yet been approved for Friedreich ataxia, there is much optimism that the advances in the understanding of the pathogenesis of this disorder since the discovery its genetic basis, will result in approved disease modifying therapies in the near future. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions The dentate nuclei of the cerebellum are key sites of neuropathology in Friedreich ataxia (FRDA). Reduced dentate nucleus volume and increased mean magnetic susceptibility, a proxy of iron concentration, have been reported by magnetic resonance imaging studies in people with FRDA. Here, we investigate whether these changes are regionally heterogeneous.Quantitative susceptibility mapping data were acquired from 49 people with FRDA and 46 healthy controls. The dentate nuclei were manually segmented and analyzed using three dimensional vertex‐based shape modeling and voxel‐based assessments to identify regional changes in morphometry and susceptibility, respectively.Individuals with FRDA, relative to healthy controls, showed significant bilateral surface contraction most strongly at the rostral and caudal boundaries of the dentate nuclei. The magnitude of this surface contraction correlated with disease duration, and to a lesser extent, ataxia severity. Significantly greater susceptibility was also evident in the FRDA cohort relative to controls, but was instead localized to bilateral dorsomedial areas, and also correlated with disease duration and ataxia severity.Changes in the structure of the dentate nuclei in FRDA are not spatially uniform. Atrophy is greatest in areas with high gray matter density, whereas increases in susceptibility—reflecting iron concentration, demyelination, and/or gliosis—predominate in the medial white matter. These findings converge with established histological reports and indicate that regional measures of dentate nucleus substructure are more sensitive measures of disease expression than full‐structure averages. Biomarker development and therapeutic strategies that directly target the dentate nuclei, such as gene therapies, may be optimized by targeting these areas of maximal pathology. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

• Six SMA individuals homozygous for SMN1 disease-associated sequence variants are reported. • A diagnosis of SMA may be missed if only SMN1 copy number analysis is performed. • In individuals with suspected SMA with 2 SMN1 copies and consanguinity, SMN1 sequencing is indicated. • Whole exome sequencing does not reliably detect sequence variants in SMN1. • A response to disease-modifying treatment is seen in these individuals with homozygous SMN1 disease associated sequence variants. 5q-associated spinal muscular atrophy (SMA) is the most common autosomal recessive neurological disease. Depletion in functional SMN protein leads to dysfunction and irreversible degeneration of the motor neurons. Over 95 % of individuals with SMA have homozygous exon 7 deletions in the SMN1 gene. Most of the remaining 4–5 % are compound heterozygous for deletion and a disease-associated sequence variant in the non-deleted allele. Individuals with SMA due to bi-allelic SMN1 sequence variants have rarely been reported. Data regarding their clinical phenotype, disease progression, outcome and treatment response are sparse. This study describes six individuals from three families, all with homozygous sequence variants in SMN1 , and four of whom received treatment with disease-modifying therapies. We also describe the challenges faced during the diagnostic process and intrafamilial phenotypic variability observed between siblings. [ABSTRACT FROM AUTHOR]

Background: The neurological phenotype of Friedreich ataxia (FRDA) is characterized by neurodegeneration and neuroinflammation in the cerebellum and brainstem. Novel neuroimaging approaches quantifying brain free‐water using diffusion magnetic resonance imaging (dMRI) are potentially more sensitive to these processes than standard imaging markers. Objectives: To quantify the extent of free‐water and microstructural change in FRDA‐relevant brain regions using neurite orientation dispersion and density imaging (NODDI), and bitensor diffusion tensor imaging (btDTI). Method: Multi‐shell dMRI was acquired from 14 individuals with FRDA and 14 controls. Free‐water measures from NODDI (FISO) and btDTI (FW) were compared between groups in the cerebellar cortex, dentate nuclei, cerebellar peduncles, and brainstem. The relative sensitivity of the free‐water measures to group differences was compared to microstructural measures of NODDI intracellular volume, free‐water corrected fractional anisotropy, and conventional uncorrected fractional anisotropy. Results: In individuals with FRDA, FW was elevated in the cerebellar cortex, peduncles (excluding middle), dentate, and brainstem (P < 0.005). FISO was elevated primarily in the cerebellar lobules (P < 0.001). On average, FW effect sizes were larger than all other markers (mean ηρ2 = 0.43), although microstructural measures also had very large effects in the superior and inferior cerebellar peduncles and brainstem (ηρ2 > 0.37). Across all regions and metrics, effect sizes were largest in the superior cerebellar peduncles (ηρ2 > 0.46). Conclusions: Multi‐compartment diffusion measures of free‐water and neurite integrity distinguish FRDA from controls with large effects. Free‐water magnitude in the brainstem and cerebellum provided the greatest distinction between groups. This study supports further applications of multi‐compartment diffusion modeling, and investigations of free‐water as a measure of disease expression and progression in FRDA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objective: Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA. Methods: We conducted an international, double‐blind, randomized, placebo‐controlled, parallel‐group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015‐002762‐23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks. Results: One hundred fifty‐five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (−1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of –2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone. Interpretation: In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212–225 [ABSTRACT FROM AUTHOR]

Background: ATL1102 is a 2'MOE gapmer antisense oligonucleotide to the CD49d alpha subunit of VLA-4, inhibiting expression of CD49d on lymphocytes, reducing survival, activation and migration to sites of inflammation. Children with DMD have dystrophin deficient muscles susceptible to contraction induced injury, which triggers the immune system, exacerbating muscle damage. CD49d is a biomarker of disease severity in DMD, with increased numbers of high CD49d expressing T cells correlating with more severe and progressive weakess, despite corticosteroid treatment. Methods: This Phase 2 open label study assessed the safety, efficacy and pharmacokinetic profile of ATL1102 administered as 25 mg weekly by subcutaneous injection for 24 weeks in 9 non-ambulatory boys with DMD aged 10–18 years. The main objective was to assess safety and tolerability of ATL1102. Secondary objectives included the effect of ATL1102 on lymphocyte numbers in the blood, functional changes in upper limb function as assessed by Performance of Upper Limb test (PUL 2.0) and upper limb strength using MyoGrip and MyoPinch compared to baseline. Results: Eight out of nine participants were on a stable dose of corticosteroids. ATL1102 was generally safe and well tolerated. No serious adverse events were reported. There were no participant withdrawals from the study. The most commonly reported adverse events were injection site erythema and skin discoloration. There was no statistically significant change in lymphocyte count from baseline to week 8, 12 or 24 of dosing however, the CD3+CD49d+ T lymphocytes were statistically significantly higher at week 28 compared to week 24, four weeks past the last dose (mean change 0.40x109/L 95%CI 0.05, 0.74; p = 0.030). Functional muscle strength, as measured by the PUL2.0, EK2 and Myoset grip and pinch measures, and MRI fat fraction of the forearm muscles were stable throughout the trial period. Conclusion: ATL1102, a novel antisense drug being developed for the treatment of inflammation that exacerbates muscle fibre damage in DMD, appears to be safe and well tolerated in non-ambulant boys with DMD. The apparent stabilisation observed on multiple muscle disease progression parameters assessed over the study duration support the continued development of ATL1102 for the treatment of DMD. Trial registration: Clinical Trial Registration. Australian New Zealand Clinical Trials Registry Number: ACTRN12618000970246. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Friedreich ataxia is a progressive neurodegenerative disorder with reported abnormalities in cerebellar, brainstem, and cerebral white matter. White matter structure can be measured using in vivo neuroimaging indices sensitive to different white matter features. For the first time, we examined the relative sensitivity and relationship between multiple white matter indices in Friedreich ataxia to more richly characterize disease expression and infer possible mechanisms underlying the observed white matter abnormalities. Diffusion‐tensor, magnetization transfer, and T1‐weighted structural images were acquired from 31 individuals with Friedreich ataxia and 36 controls. Six white matter indices were extracted: fractional anisotropy, diffusivity (mean, axial, radial), magnetization transfer ratio (microstructure), and volume (macrostructure). For each index, whole‐brain voxel‐wise between‐group comparisons and correlations with disease severity, onset age, and gene triplet‐repeat length were undertaken. Correlations between pairs of indices were assessed in the Friedreich ataxia cohort. Spatial similarities in the voxel‐level pattern of between‐group differences across the indices were also assessed. Microstructural abnormalities were maximal in cerebellar and brainstem regions, but evident throughout the brain, while macroscopic abnormalities were restricted to the brainstem. Poorer microstructure and reduced macrostructural volume correlated with greater disease severity and earlier onset, particularly in peri‐dentate nuclei and brainstem regions. Microstructural and macrostructural abnormalities were largely independent. Reduced fractional anisotropy was most strongly associated with axial diffusivity in cerebral tracts, and magnetization transfer in cerebellar tracts. Multiple mechanisms likely underpin white matter abnormalities in Friedreich ataxia, with differential impacts in cerebellar and cerebral pathways. [ABSTRACT FROM AUTHOR]

In this article, the author discusses the predictive genetic testing in children. It is mentioned that the follow-up period required for predictive testing in young children is very long. Also discussed is the commentary of Clarke A. J. on predictive testing. Genetic study of mature minors rather than immature minors is also suggested.

The article presents information on new findings related to lissencephaly. It was found that for approximately 80% of cases of typical lissencephaly and subcortical band heterotopia, mutations in either LIS1 or DCX are responsible. It sates that the new findings implies that around 10% of additional individuals with isolated lissencephaly sequence and 5% of additional individuals with subcortical band heterotopia will now be able to have the cause of their brain malformation diagnosed.

Friedreich ataxia (FRDA) is a rare, inherited neurodegenerative disease characterised in most cases by progressive and debilitating motor dysfunction. Degeneration of cerebellar white matter pathways have been previously reported, alongside indications of cerebello-cerebral functional alterations. In this work, we examine resting-state functional connectivity changes within cerebello-cerebral circuits, and their associations with disease severity (Scale for the Assessment and Rating of Ataxia [SARA]), psychomotor function (speeded and paced finger tapping), and white matter integrity (diffusion tensor imaging) in 35 adults with FRDA and 45 age and sex-matched controls. Voxel-wise seed-based functional connectivity was assessed for three cerebellar cortical regions (anterior lobe, lobules I-V; superior posterior lobe, lobules VI-VIIB; inferior posterior lobe, lobules VIIIA-IX) and two dentate nucleus seeds (dorsal and ventral). Compared to controls, people with FRDA showed significantly reduced connectivity between the anterior cerebellum and bilateral pre/postcentral gyri, and between the superior posterior cerebellum and left dorsolateral PFC. Greater disease severity correlated with lower connectivity in these circuits. Lower anterior cerebellum-motor cortex functional connectivity also correlated with slower speeded finger tapping and less fractional anisotropy in the superior cerebellar peduncles, internal capsule, and precentral white matter in the FRDA cohort. There were no significant between-group differences in inferior posterior cerebellar or dentate nucleus connectivity. This study indicates that altered cerebello-cerebral functional connectivity is associated with functional status and white matter damage in cerebellar efferent pathways in people with FRDA, particularly in motor circuits. [ABSTRACT FROM AUTHOR]

Background: Friedreich ataxia is characterized by progressive motor incoordination that is linked to peripheral, spinal, and cerebellar neuropathology. Cerebral abnormalities are also reported in Friedreich ataxia, but their role in disease expression remains unclear.Methods: In this cross-sectional functional magnetic resonance imaging study, 25 individuals with Friedreich ataxia and 33 healthy controls performed simple (self-paced single-finger) and complex (visually cued multifinger) tapping tasks to respectively gauge basic and attentionally demanding motor behavior. For each task, whole brain functional activations were compared between groups and correlated with disease severity and offline measures of motor dexterity.Results: During simple finger tapping, cerebral hyperactivation in individuals with Friedreich ataxia at the lower end of clinical severity and cerebral hypoactivation in those more severely affected was observed in premotor/ventral attention brain regions, including the supplementary motor area and anterior insula. Greater activation in this network correlated with greater offline finger tapping precision. Complex, attentionally demanding finger tapping was also associated with cerebral hyperactivation, but in this case within dorsolateral prefrontal regions of the executive control network and superior parietal regions of the dorsal attention system. Greater offline motor precision was associated with less activation in the dorsal attention network.Discussion: Compensatory activity is evident in the cerebral cortex in individuals with Friedreich ataxia. Early compensation followed by later decline in premotor/ventral attention systems demonstrates capacity-limited neural reserve, while the additional engagement of higher order brain networks is indicative of compensatory task strategies. Network-level changes in cerebral brain function thus potentially serve to mitigate the impact of motor impairments in Friedreich ataxia. © 2017 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The scope of noninvasive prenatal testing (NIPT) could expand in the future to include detailed analysis of the fetal genome. This will allow for the testing for virtually any trait with a genetic contribution, including "non-medical" traits. Here we discuss the potential use of NIPT for these traits. We outline a scenario which highlights possible inconsistencies with ethical decision-making. We then discuss the case against permitting these uses. The objections include practical problems; increasing inequities; increasing the burden of choice; negative impacts on the child, family, and society; and issues with implementation. We then outline the case for permitting the use of NIPT for these traits. These include arguments for reproductive liberty and autonomy; questioning the labeling of traits as "non-medical"; and the principle of procreative beneficence. This summary of the case for and against can serve as a basis for the development of a consistent and coherent ethical framework. [ABSTRACT FROM AUTHOR]

Background: MOXIe was a two‐part study evaluating the safety and efficacy of omaveloxolone in patients with Friedreich's ataxia, a rare, progressive neurological disease with no proven therapy. MOXIe part 2, a randomized double‐blind placebo‐controlled trial, showed omaveloxolone significantly improved modified Friedreich's Ataxia Rating Scale (mFARS) scores relative to placebo. Patients who completed part 1 or 2 were eligible to receive omaveloxolone in an open‐label extension study. Objective: The delayed‐start study compared mFARS scores at the end of MOXIe part 2 with those at 72 weeks in the open‐label extension period (up to 144 weeks) for patients initially randomized to omaveloxolone versus those initially randomized to placebo. Methods: We performed a noninferiority test to compare the difference between treatment groups (placebo to omaveloxolone versus omaveloxolone to omaveloxolone) using a single mixed model repeated measures (MMRM) model. In addition, slopes of the change in mFARS scores were compared between both groups in the open‐label extension. Results: The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo‐controlled MOXIe part 2 (−2.17 ± 1.09 points) was preserved after 72 weeks in the extension (−2.91 ± 1.44 points). In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks. Conclusions: These results support the positive results of MOXIe part 2 and indicate a persistent benefit of omaveloxolone treatment on disease course in Friedreich's ataxia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Autosomal dominant mutations of DYNC1H1 cause a range of neurogenetic diseases, including mental retardation with cortical malformations, hereditary spastic paraplegia and spinal muscular atrophy. Using SNP array, linkage analysis and next generation sequencing, we identified two families and one isolated proband sharing a known spinal muscular atrophy, lower extremity predominant (SMALED) causing mutation DYNC1H1 c.1792C>T, p.Arg598Cys, and another family harbouring a c.2327C>T, p.Pro776Leu mutation. Here, we present a detailed clinical and pathological examination of these patients, and show that patients with DYNC1H1 mutations may present with a phenotype mimicking a congenital myopathy. We also highlight features that increase the phenotypic overlap with BICD2 , which causes SMALED2. Serial muscle biopsies were available for several patients, spanning from infancy and early childhood to middle age. These provide a unique insight into the developmental and pathological origins of SMALED, suggesting in utero denervation with reinnervation by surrounding intact motor neurons and segmental anterior horn cell deficits. We characterise biopsy features that may make diagnosis of this condition easier in the future. [ABSTRACT FROM AUTHOR]

Hyperferritinaemia is commonly found in clinical practice. In assessing the cause of hyperferritinaemia, it is important to identify if there is true iron overload or not as hyperferritinaemia may be seen in other conditions such as excess alcohol intake, inflammation and non-alcoholic fatty liver disease. Assessment of whether the serum ferritin level is elevated or not should take into account body mass index, gender and age. This review article provides an overview of the different causes of hyperferritinaemia, differentiating those due to iron overload from those not due to iron overload, and provides an algorithm for clinicians to use in clinical practice to carry out appropriate investigations and management. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Beta-ureidopropionase deficiency, caused by variants in UPB1 , has been reported in association with various neurodevelopmental phenotypes including intellectual disability, seizures and autism. We aimed to reassess the relationship between variants in UPB1 and a clinical phenotype. Literature review, calculation of carrier frequencies from population databases, long-term follow-up of a previously published case and reporting of additional cases. Fifty-three published cases were identified, and two additional cases are reported here. Of these, 14 were asymptomatic and four had transient neurological features; clinical features in the remainder were variable and included non-neurological presentations. Several of the variants previously reported as pathogenic are present in population databases at frequencies higher than expected for a rare condition. In particular, the variant most frequently reported as pathogenic, p.Arg326Gln, is very common among East Asians, with a carrier frequency of 1 in 19 and 1 in 907 being homozygous for the variant in gnomAD v2.1.1. Pending the availability of further evidence, UPB1 should be considered a 'gene of uncertain clinical significance'. Caution should be used in ascribing clinical significance to biochemical features of beta-ureidopropionase deficiency and/or UPB1 variants in patients with neurodevelopmental phenotypes. UPB1 is not currently suitable for inclusion in gene panels for reproductive genetic carrier screening. The relationship between beta-ureidopropionase deficiency due to UPB1 variants and clinical phenotypes is uncertain. • The relationship between damaging UPB1 variants and human phenotypes is uncertain. • Described beta-ureidopropionase deficiency cases do not have a consistent phenotype. • Loss of function UPB1 variants are common in the general population. • Care must be used in ascribing diagnostic value to variants in UPB1. • UPB1 should not be included on carrier screening panels. [ABSTRACT FROM AUTHOR]

Background: A high proportion of patients with neurofibromatosis type 1 (NF1) present with functional hearing deficiency as a result of neural abnormality in the late auditory brainstem. Methods: In this randomized, two-period crossover study, we investigated the hypothesis that remote-microphone listening devices can ameliorate hearing and communication deficits in affected school-aged children (7–17 years). Speech perception ability in background noise was evaluated in device-active and inactive conditions using the CNC-word test. Participants were then randomized to one of two treatment sequences: (1) inactive device for two weeks (placebo), followed by active device use for two weeks, or (2) active device for 2 weeks, followed by inactive device for 2 weeks. Listening and communication ratings (LIFE-R Questionnaire) were obtained at baseline and at the end of each treatment phase. Results: Each participant demonstrated functional hearing benefits with remote-microphone use. All showed a speech perception in noise increase when the device was activated with a mean phoneme-score difference of 16.4% (p < 0.001) and reported improved listening/communication abilities in the school classroom (mean difference: 23.4%; p = 0.017). Discussion: Conventional hearing aids are typically ineffective as a treatment for auditory neural dysfunction, making sounds louder, but not clearer for affected individuals. In this study, we demonstrate that remote-microphone technologies are acceptable/tolerable in pediatric patients with NF1 and can ameliorate their hearing deficits. Conclusion: Remote-microphone listening systems offer a viable treatment option for children with auditory deficits associated with NF1. [ABSTRACT FROM AUTHOR]

Friedreich ataxia (FRDA) is the most common of the inherited ataxias. It is an autosomal recessive disease characterised by degeneration of peripheral sensory neurons, regions of the central nervous system and cardiomyopathy. FRDA is usually due to homozygosity for trinucleotide GAA repeat expansions found within first intron of the FRATAXIN ( FXN ) gene, which results in reduced levels of the mitochondrial protein FXN. Reduced FXN protein results in mitochondrial dysfunction and iron accumulation leading to increased oxidative stress and cell death in the nervous system and heart. Yet the precise functions of FXN and the underlying mechanisms leading to disease pathology remain elusive. This is particularly true of the cardiac aspect of FRDA, which remains largely uncharacterized at the cellular level. Here, we summarise current knowledge on experimental models in which to study FRDA cardiomyopathy, with a particular focus on the use of human pluripotent stem cells as a disease model. [ABSTRACT FROM AUTHOR]

Advances in the speed and accessibility of genomic sequencing are broadening the application of this technology to rapid, acute care diagnostics and pre‐conception carrier screening. In both circumstances, genetic counselling plays a critical role in preparing couples for the strengths and limitations of the testing. For pre‐conception carrier screening in particular, it is important that parents and clinicians are aware that even in the absence of an identified risk for recessive disease, a baby with a genetic condition may still be conceived. As an example, we present the genomic journey of a couple who underwent pre‐conception carrier screening and following a low‐risk result, delivered a baby boy who was diagnosed with Type 1 Bartter syndrome. Ultra‐rapid, post‐natal, trio whole genome sequencing resolved both parents as carriers of pathogenic variants in SLC12A1, a gene not included in the original pre‐conception screening panel. This family's story highlights (i) the intricacy of gene selection for pre‐conception screening panels, (ii) the benefits of high‐quality pre‐test genetic counselling in supporting families through adverse genomic findings and (iii) the role rapid genomics can play in resolving uncertainty for families and clinicians in circumstances where suspicion of genetic disease exists. This article is accompanied by a Patient Voice perspective written by the child's parents, placing emphasis on the essential role genetic counselling played in their journey. [ABSTRACT FROM AUTHOR]

Objective We conducted a 6-month, randomized, double-blind, placebo-controlled study to assess safety, tolerability, and efficacy of deferiprone in Friedreich ataxia (FRDA). Methods Seventy-two patients were treated with deferiprone 20, 40, or 60mg/kg/day or placebo, divided into 2 daily doses. Safety was the primary objective; secondary objectives included standardized neurological assessments (Friedreich Ataxia Rating Scale [FARS], International Cooperative Ataxia Rating Scale [ICARS], 9-Hole Peg Test [9HPT], Timed 25-Foot Walk, Low-Contrast Letter Acuity), general functional status (Activities of Daily Living), and cardiac assessments. Results Deferiprone was well tolerated at 20mg/kg/day, whereas more adverse events occurred in the 40mg/kg/day than in the placebo group. The 60mg/kg/day dose was discontinued due to worsening of ataxia in 2 patients. One patient on deferiprone 20mg/kg/day experienced reversible neutropenia, but none developed agranulocytosis. Deferiprone-treated patients receiving 20 or 40mg/kg/day showed a decline in the left ventricular mass index, compared to an increase in the placebo-treated patients. Patients receiving 20mg/kg/day of deferiprone had no significant change in FARS, similar to the placebo-treated patients, whereas those receiving 40mg/kg/day had worsening in FARS and ICARS scores. The lack of deterioration in the placebo arm impaired the ability to detect any potential protective effect of deferiprone. However, subgroup analyses in patients with less severe disease suggested a benefit of deferiprone 20mg/kg/day on ICARS, FARS, kinetic function, and 9HPT. Interpretation This study demonstrated an acceptable safety profile of deferiprone at 20mg/kg/day for the treatment of patients with FRDA. Subgroup analyses raise the possibility that, in patients with less severe disease, deferiprone 20mg/kg/day may reduce disease progression, whereas higher doses appear to worsen ataxia. Ann Neurol 2014;76:509-521 [ABSTRACT FROM AUTHOR]

Friedreich ataxia (FRDA) is a progressive autosomal recessive disease. While motor dysfunction is the primary neurological hallmark, little is known about the underlying neurobiological changes associated with motor deficits over the course of disease. We investigated the hypothesis that progressive functional changes in both the cerebellum and cerebrum are related to longitudinal changes in performance on complex motor tasks in individuals with FRDA. Twenty-two individuals with FRDA and 28 controls participated over 24 months. The longitudinal investigation included finger tapping tasks with different levels of complexity (i.e., visually cued, multi-finger; self-paced, single finger), performed in conjunction with fMRI acquisitions, to interrogate changes in the neurobiology of motor and attentional brain networks including the cerebellum and cerebrum. We demonstrated evidence for significant longitudinal decreased cerebral fMRI activity over time in individuals with FRDA, relative to controls, during an attentionally-demanding motor task (visually cued tapping of multiple fingers) in six cerebral regions: right and left superior frontal gyri, right superior temporal gyrus, right primary somatosensory area, right anterior cingulate cortex, and right medial frontal gyrus. Importantly, longitudinal decreased activity was associated with more severe disease status at baseline, higher GAA1 repeat length and earlier age of onset. These findings suggest a dynamic pattern of neuronal activity in motor, attention and executive control networks over time in individuals with FRDA, which is associated with increased disease severity at baseline, increased GAA1 repeat length and earlier age at onset. [ABSTRACT FROM AUTHOR]

Cerebellar pathology engenders the disturbance of movement that characterizes Friedreich ataxia (FRDA), yet the impact of cerebellar pathology on cognition in FRDA remains unclear. Numerous studies have unequivocally demonstrated the role of the cerebellar pathology in disturbed cognitive, language and affective regulation, referred to as Cerebellar Cognitive Affective Syndrome (CCAS), and quantified by the CCAS-Scale (CCAS-S). The presence of dysarthria in many individuals with ataxia, particularly FRDA, may confound results on some items of the CCAS-S resulting in false-positive scores. This study explored the relationship between performance on the CCAS-S and clinical metrics of disease severity in 57 adults with FRDA. In addition, this study explored the relationship between measures of intelligibility and naturalness of speech and scores on the CCAS-S in a subgroup of 39 individuals with FRDA. We demonstrated a significant relationship between clinical metrics and performance on the CCAS-S. In addition, we confirmed the items that returned the greatest rate of failure were based on Verbal Fluency Tasks, revealing a significant relationship between these items and measures of speech. Measures of speech explained over half of the variance in the CCAS-S score suggesting the role of dysarthria in the performance on the CCAS-S is not clear. Further work is required prior to adopting the CCAS-S as a cognitive screening tool for individuals with FRDA. [ABSTRACT FROM AUTHOR]

The reproductive decision-making of young people (aged 15–39 years) with Li-Fraumeni syndrome (LFS), an early onset inherited cancer syndrome, has not been studied in depth. Using interpretive description methodology, we conducted semi-structured interviews with 30 young Australians (mean age 25.5 years) diagnosed with LFS or at 50% genetic risk. With reflexive thematic analysis, we show how young people's reproductive decision-making and ideals for family formation were shaped by a sense of genetic responsibility to ensure the health of future biological kin. Reproductive technology provided choices for family formation in the context of LFS and also complicated reproductive decisions, as these choices were difficult to understand, make, or carry out. We uphold that reproductive decision-making when living with LFS is a profoundly moral practice that may pose significant challenges for young people navigating their formative years. We offer genetic counseling practice recommendations to support individuals with LFS when making reproductive decisions. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is proposed to accompany, or even contribute to, neuropathology in Friedreich ataxia (FRDA), with implications for disease treatment and tracking. Objectives: To examine brain glial activation and systemic immune dysfunction in people with FRDA and quantify their relationship with symptom severity, duration, and onset age. Methods: Fifteen individuals with FRDA and 13 healthy controls underwent brain positron emission tomography using the translocator protein (TSPO) radioligand [18F]‐FEMPA, a marker of glial activation, together with the quantification of blood plasma inflammatory cytokines. Results: [18F]‐FEMPA binding was significantly increased in the dentate nuclei (d = 0.67), superior cerebellar peduncles (d = 0.74), and midbrain (d = 0.87), alongside increased plasma interleukin‐6 (IL‐6) (d = 0.73), in individuals with FRDA compared to controls. Increased [18F]‐FEMPA binding in the dentate nuclei, brainstem, and cerebellar anterior lobe correlated with earlier age of symptom onset (controlling for the genetic triplet repeat expansion length; all rpart < −0.6), and in the pons and anterior lobe with shorter disease duration (r = −0.66; −0.73). Conclusions: Neuroinflammation is evident in brain regions implicated in FRDA neuropathology. Increased neuroimmune activity may be related to earlier disease onset and attenuate over the course of the illness. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Friedreich ataxia is an inherited neurodegenerative disease, with cerebral and cerebellar pathology evident. Despite an increased understanding of its neuropathology, disease progression in this disease remains poorly understood. This study aimed to characterise longitudinal change in brain structure using a multi-modal approach across cerebral and cerebellar grey and white matter. Methods: T1-weighted, diffusion-tensor, and magnetisation transfer magnetic resonance images were obtained from 28 individuals with Friedreich ataxia and 29 age- and gender-matched controls at two time-points, 2 years apart. Region-of-interest and exploratory between-group comparisons assessed changes in brain macrostructure (cerebellar lobule volume, cerebral cortical thickness/gyrification, brain white matter volume) and microstructure (white matter fractional anisotropy, mean/axial/radial diffusivity, magnetisation transfer ratio). Rates of change were correlated against change in neurological severity, Time 1 severity, and onset age. Results: Individuals with Friedreich ataxia had a greater rate of white matter volume loss than controls in the superior cerebellar peduncles and right peri-thalamic/posterior cerebral regions, and greater reduction in left primary motor cortex gyrification. Greater cerebellar/brainstem white matter volume loss and right dorsal premotor gyrification loss was observed amongst individuals with less severe neurological symptoms at Time 1. Conversely, cerebral atrophy and changes in axial diffusivity were observed in individuals with more severe Time 1 symptoms. Progression in radial diffusivity was more pronounced amongst individuals with earlier disease onset. Greater right ventral premotor gyrification loss correlated with greater neurological progression. Conclusion: Heterogeneity in Friedreich ataxia progression is observed at the neurobiological level, with evidence of earlier cerebellar and later cerebral degeneration. [ABSTRACT FROM AUTHOR]