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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.

Genes associated with non-syndromic hearing loss (NSHL) are frequently included in panels for reproductive genetic carrier screening (RGCS), despite a lack of consensus on whether NSHL is a condition appropriate for inclusion in RGCS. We conducted a national online survey using a questionnaire to explore the views of clinicians who facilitate RGCS or provide care to deaf individuals in Australia and New Zealand regarding the inclusion of such genes in RGCS. Results were analysed descriptively, and free-text responses were analysed thematically. The questionnaire was completed by 386 respondents including genetic healthcare providers, obstetricians, ear nose and throat specialists, and general practitioners. The majority of respondents agreed that genes associated with NSHL should be included in RGCS, but there were differences between the groups. 74% of clinicians working in a hearing clinic agreed these genes should be included compared to 67% of genetic healthcare providers, 54% of reproductive care healthcare providers, and 44% of general practitioners. A majority of respondents agreed that moderate to profound deafness is a serious disability, although genetic healthcare providers were less likely to agree than other groups. Overall, respondents agreed that including NSHL in RGCS upholds prospective parents’ right to information. However, they also identified major challenges, including concern that screening may express a discriminatory attitude towards those living with deafness. They also identified the complexity of defining the severity of deafness.

To evaluate the performance of cell-free DNA (cfDNA) screening for common fetal aneuploidies, choice of prenatal procedure, and chromosome conditions identified during pregnancy after low-risk cfDNA screening.A single-centre prenatal cfDNA screening test was employed to detect trisomies 21, 18 and 13 (T21, T18, T13) and sex chromosome aneuploidies (SCAs). Test performance, choice of prenatal procedure, and cytogenetic results in pregnancies with low-risk cfDNA screening were reviewed.CfDNA screening of 38,289 consecutive samples identified 720 (1.9%) pregnancies at increased risk for aneuploidy. Positive predictive values (PPVs) for high-risk singleton pregnancies were 98.5% (T21), 92.5% (T18) and 55.2% (T13). PPVs for SCAs ranged from 30.6-95.2%. Most women elected chorionic villus sampling for prenatal diagnosis of T21, T18 and T13; amniocentesis and/or postnatal testing were commonly chosen for SCAs. Cytogenetic tests from 616 screen-negative pregnancies identified 64 cases (12.7%) with chromosome conditions not detected by cfDNA screening, including triploidy (n=30) and pathogenic and likely pathogenic copy number variants (n=34). Fifteen (0.04%) false-negative common aneuploidy results were identified.CfDNA screening was highly accurate for detecting fetal aneuploidy in this general-risk obstetric population. Fetal ultrasound and prenatal diagnostic testing were important in identifying chromosome conditions in pregnancies screened as low-risk. This article is protected by copyright. All rights reserved.

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.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.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.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.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.

OBJECTIVE: Reproductive genetic carrier screening (RGCS) panels often include genes associated with non-syndromic hearing loss (NSHL) despite a lack of evidence of acceptability. Although some couples take steps to avoid having a child who is deaf, there are effective interventions for children who are deaf. There is no consensus whether deafness is considered a disabling condition. METHOD: This study explored views of people who had RGCS, without genes for NSHL, about this topic. Online surveys were sent to 2186 people who had a low chance RGCS result and 655 completed the survey (participation rate 30%). RESULTS: Sixty-three percent (N = 412) think deafness is a serious health condition. The majority agreed (60%, N = 391) that with support (i.e. hearing aids/cochlear implants) deafness is a minor condition in children. Most (84%, N = 545) agreed genes for NSHL should be included in RGCS. Thirty-five percent (N = 231) indicated they would make different reproductive decisions if they had an increased chance of having a child born deaf; 31% would not change their reproductive plans and 34% were unsure what they would do. CONCLUSION: While the majority support inclusion of genes associated with NSHL in RGCS, there was uncertainty about the severity of deafness as a health condition and there was no consensus on whether it is a health condition that warrants changing reproductive decisions.

We aim to create a bank of clinical grade cord blood-derived induced pluripotent stem cell lines in order to facilitate clinical research leading to the development of new cellular therapies. Here we present a clear pathway toward the creation of such a resource, within a strong quality framework, and with the appropriate regulatory, government and ethics approvals, along with a dynamic follow-up and re-consent process of cord blood donors from the public BMDI Cord Blood Bank. Interrogation of the cord blood bank inventory and next generation sequencing was used to identify and confirm 18 donors with suitable HLA homozygous haplotypes. Regulatory challenges that may affect global acceptance of the cell lines, along with the quality standards required to operate as part of a global network, are being met by working in collaboration with bodies such as the International Stem Cell Banking Initiative (ISCBI) and the Global Alliance for iPSC Therapies (GAiT). Ethics approval was granted by an Institutional Human Research Ethics Committee, and government approval has been obtained to use banked cord blood for this purpose. New issues of whole-genome sequencing and the relevant donor safeguards and protections were considered with input from clinical genetics services, including the rights and information flow to donors, and commercialization aspects. The success of these processes has confirmed feasibility and utility of using banked cord blood to produce clinical-grade iPSC lines for potential cellular therapies.

Genes associated with nonsyndromic hearing loss are commonly included in reproductive carrier screening panels, which are now routinely offered in preconception and prenatal care in many countries. However, there is debate whether hearing loss should be considered a medical condition appropriate for screening. This systematic review assessed research on opinions of those with a lived experience of deafness and the general public regarding genetic testing for deafness in the reproductive setting.Search of 5 online databases yielded 423 articles, 20 of which met inclusion criteria. We assessed the quality of each study, extracted data, and performed thematic analysis on qualitative studies.Most studies indicated interest in the use of prenatal diagnosis for deafness. However, there were mixed views, and sometimes strongly held views, expressed regarding the reproductive options that should be available to those with an increased chance of having a child with deafness. Studies were small, from a limited number of countries, and most were too old to include views regarding preimplantation genetic testing.There is a broad range of views regarding the use of reproductive options for deafness. Further research is essential to explore the benefits and harms of including nonsyndromic hearing loss genes in carrier screening.

Australian life insurance companies can legally use genetic test results in underwriting, which can lead to genetic discrimination. In 2019, the Financial Services Council (Australian life insurance industry governing body) introduced a partial moratorium restricting the use of genetic testing in underwriting policies ≤ $500,000 (active 2019–2024). Health professionals (HPs), especially clinical geneticists and genetic counsellors, often discuss the implications of genetic testing with patients, and provide critical insights into the effectiveness of the moratorium. Using a sequential explanatory mixed methods design, we interviewed 23 Australian HPs, who regularly discuss genetic testing with patients and had previously completed an online survey about genetic testing and life insurance. Interviews explored views and experiences about the moratorium, and regulation, in greater depth. Interview transcripts were analysed using thematic analysis. Two key themes emerged from views expressed by HPs during interviews (about matters reported to or observed by them): 1) benefits of the moratorium, and 2) concerns about the moratorium. While HPs reported that the moratorium reassures some consumers, concerns include industry self-regulation, uncertainty created by the temporary time period, and the inadequacy of the moratorium’s financial limits for patients’ financial needs. Although a minority of HPs felt the current industry self-regulated moratorium is an adequate solution to genetic discrimination, the vast majority (19/23) expressed concern with industry self-regulation and most felt government regulation is required to adequately protect consumers. HPs in Australia are concerned about the adequacy of the FSC moratorium with regards to consumer protections, and suggest government regulation is required.

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 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.

Fears of genetic discrimination in life insurance continue to deter some Australians from genetic testing. In July 2019, the life insurance industry introduced a partial, self-regulated moratorium restricting the use of genetic results in underwriting, applicable to policies up to certain limits (eg AUD$500,000 for death cover).We administered an online survey to consumers who had taken, or been offered, clinical genetic testing for adult-onset conditions, to gather views and experiences about the moratorium and the use of genetic results in life insurance, including its regulation.Most respondents (n = 367) had undertaken a genetic test (89%), and had a positive test result (76%; n = 243/321). Almost 30% (n = 94/326) reported testing after 1 July 2019. Relatively few respondents reported knowing about the moratorium (16%; n = 54/340) or that use of genetic results in life insurance underwriting is legal (17%; n = 60/348). Only 4% (n = 14/350) consider this practice should be allowed. Some respondents reported ongoing difficulties accessing life insurance products, even after the moratorium. Further, discrimination concerns continue to affect some consumers’ decision-making about having clinical testing and applying for life insurance products, despite the Moratorium being in place. Most respondents (88%; n = 298/340) support the introduction of legislation by the Australian government to regulate this issue.Despite the introduction of a partial moratorium in Australia, fears of genetic discrimination persist, and continue to deter people from genetic testing. Consumers overwhelmingly consider life insurers should not be allowed to use genetic results in underwriting, and that federal legislation is required to regulate this area.

BackgroundDigital biomarkers continue to make headway in the clinic and clinical trials for neurological conditions. Speech is a domain with great promise.ObjectivesUsing Friedreich ataxia (FRDA) as an exemplar population, we aimed to align objective measures of speech with markers of disease severity, speech related quality of life and subjective judgements of speech using supervised machine learning techniques.Methods132 participants with genetically confirmed diagnosis of FRDA were assessed using digital speech tests, disease severity scores (Friedreich Ataxia Rating Scale, FARS) and speech related quality of life ratings over a 10-year period. Speech was analyzed perceptually by expert listeners for intelligibility (ability to be understood) and naturalness (deviance from healthy norm) and acoustically across 344 features. Features were selected and presented into a random forest and a support vector machine classifier in a standard supervised learning setup designed to replicate expert-produced scores.ResultsWe demonstrate a subset of measures are strongly associated with all four clinical scales. Objective speech data replicated experts’ assessments of naturalness and intelligibility. These scores represent a lower level of variability than observed between subjective listener ratings. Findings provide evidence there are specific objective markers of speech that change over time and reflect clinical aspects of the disease.DiscussionThe use of a large dataset yielded a speech assay capable of accurately approximating expert listener ratings of key clinical aspects of dysarthria severity. Distinct but complementary subsets align with disease severity and speech related quality of life.

Cerebellar ataxia (CA) is concerned with the incoordination of movement caused by cerebellar dysfunction. Movements of the eyes, speech, trunk, and limbs are affected. Conventional machine learning approaches utilizing centralised databases have been used to objectively diagnose and quantify the severity of CA. Although these approaches achieved high accuracy, large scale deployment will require large clinics and raises privacy concerns. In this study, we propose an image transformation-based approach to leverage the advantages of state-of-the-art deep learning with federated learning in diagnosing CA. We use motion capture sensors during the performance of a standard neurological balance test obtained from four geographically separated clinics. The recurrence plot, melspectrogram, and poincaré plot are three transformation techniques explored. Experimental results indicate that the recurrence plot yields the highest validation accuracy (86.69%) with MobileNetV2 model in diagnosing CA. The proposed scheme provides a practical solution with high diagnosis accuracy, removing the need for feature engineering and preserving data privacy for a large-scale deployment.

Several neurological disorders, such as myotonic dystrophy are caused by expansions of short tandem repeats (STRs) which can be difficult to detect by molecular tools. Methodological advances have made repeat expansion (RE) detection with whole genome sequencing (WGS) feasible. We recruited a multi-generational family (family A) ascertained for genetic studies of autism spectrum disorder. WGS was performed on seven children from four nuclear families from family A and analyzed for REs of STRs known to cause neurological disorders. We detected an expansion of a heterozygous intronic CCTG STR in CNBP in two siblings. This STR causes myotonic dystrophy type 2 (DM2). The expansion did not segregate with the ASD phenotype. Repeat-primed PCR showed that the DM2 CCTG motif was expanded above the pathogenic threshold in both children and their mother. On subsequent examination, the mother had mild features of DM2. We show that screening of STRs in WGS datasets has diagnostic utility, both in the clinical and research domain, with potential management and genetic counseling implications.

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. Refereed/Peer-reviewed

BackgroundClinical exome sequencing typically achieves diagnostic yields of 30%–57.5% in individuals with monogenic rare diseases. Undiagnosed diseases programmes implement strategies to improve diagnostic outcomes for these individuals.AimWe share the lessons learnt from the first 3 years of the Undiagnosed Diseases Program-Victoria, an Australian programme embedded within a clinical genetics service in the state of Victoria with a focus on paediatric rare diseases.MethodsWe enrolled families who remained without a diagnosis after clinical genomic (panel, exome or genome) sequencing between 2016 and 2018. We used family-based exome sequencing (family ES), family-based genome sequencing (family GS), RNA sequencing (RNA-seq) and high-resolution chromosomal microarray (CMA) with research-based analysis.ResultsIn 150 families, we achieved a diagnosis or strong candidate in 64 (42.7%) (37 in known genes with a consistent phenotype, 3 in known genes with a novel phenotype and 24 in novel disease genes). Fifty-four diagnoses or strong candidates were made by family ES, six by family GS with RNA-seq, two by high-resolution CMA and two by data reanalysis.ConclusionWe share our lessons learnt from the programme. Flexible implementation of multiple strategies allowed for scalability and response to the availability of new technologies. Broad implementation of family ES with research-based analysis showed promising yields post a negative clinical singleton ES. RNA-seq offered multiple benefits in family ES-negative populations. International data sharing strategies were critical in facilitating collaborations to establish novel disease–gene associations. Finally, the integrated approach of a multiskilled, multidisciplinary team was fundamental to having diverse perspectives and strategic decision-making.

Noninvasive prenatal testing (NIPT) is a screening test for fetal chromosomal aneuploidy using cell-free DNA derived from maternal blood. It has been rapidly accepted into obstetric practice because of its application from 10-weeks' gestation, and its high sensitivity and specificity. NIPT results can be influenced by several factors including placental or maternal mosaicism and co-twin demise; cell-free DNA from a maternal origin can also complicate interpretation, with evidence that NIPT can detect previously unsuspected malignancies. This study aimed to develop management guidelines for women with NIPT results suspicious of maternal malignancy. The Peter MacCallum Cancer Center's experience of seven cases where abnormal NIPT results led to investigation for maternal malignancy between 2016 and 2019 were reviewed, along with the published literature. Six of the seven women (86%) referred for investigation were diagnosed with advanced malignancies, including colorectal cancer, breast cancer, melanoma, and Hodgkin lymphoma. Based on our single-center experience, as well as the available literature, guidelines for the investigation of women with NIPT results suspicious of malignancy are proposed, including utilization of fluorodeoxyglucose positron emission tomography-computed tomography, which had a high concordance with other investigations and diagnoses. These guidelines include maternal and fetal investigations, as well as consideration of the complex medical, psychologic, social, and ethical needs of these patients and their families.

Reproductive genetic carrier screening (RGCS) may be offered to all individuals and couples, regardless of family history or ethnicity. “Mackenzie’s Mission” (MM) is an Australian RGCS pilot study, evaluating the offer of couple-based screening for ~1300 genes associated with around 750 autosomal and X-linked recessive childhood-onset conditions. Each member of the couple makes an individual decision about RGCS and provides consent. We developed a decision aid (RGCS-DA) to support informed decision-making in MM, suitable for couples who were either non-pregnant or in early pregnancy. A Delphi approach invited experts to review values statements related to various concepts of RGCS. Three review rounds were completed, seeking consensus for relevance and clarity of statements, incorporating recommended modifications in subsequent iterations. The final RGCS-DA contains 14 statements that achieved Delphi consensus plus the attitude scale of the measure of informed choice. This was then evaluated in cognitive talk aloud interviews with potential users to assess face and content validity. Minimal wording changes were required at this stage. After this process, the RGCS-DA was piloted with 15 couples participating in MM who were then interviewed about their decision-making. The RGCS-DA prompted discussion within couples and facilitated in depth consideration of screening. There was reassurance when values aligned and a sense of shared decision-making within the couple. This RGCS-DA may become a very useful tool in supporting couples’ decision making and contribute to RGCS being feasible for scaled-up implementation.

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.

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 [18 F]-FEMPA, a marker of glial activation, together with the quantification of blood plasma inflammatory cytokines. RESULTS [18 F]-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 [18 F]-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

The FMR1 premutation (PM:55-199 CGG) is associated with fragile X-associated tremor/ataxia syndrome (FXTAS) and when maternally transmitted is at risk of expansion to a hypermethylated full mutation (FM: ≥ 200 CGG) that causes fragile X syndrome (FXS). We describe a maternally transmitted PM (77 CGG) that was passed to a son (103 CGG), and to a daughter (220-1822 CGG), who were affected with FXTAS and FXS, respectively. The male with the PM showed low-level mosaicism for normal size of 30 and 37 CGG. This male had two offspring: one female mosaic for PM and FM (56, 157, >200 CGG) and another with only a 37 CGG allele detected in multiple tissues, neither with a clinical phenotype. The female with the 37 CGG allele showed normal levels of FMR1 methylation and mRNA and passed this 37 CGG allele to one of her daughters, who was also unaffected. These findings show that post-zygotic paternal retraction can lead to low-level mosaicism for normal size alleles, with these normal alleles being functional when passed over two generations.

Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified a novel intronic GAA repeat expansion in the gene encoding Fibroblast Growth Factor 14 (FGF14). Genetic analysis identified 4/95 previously unresolved Australian affected individuals (4.2%) with (GAA)>335and a further nine individuals with (GAA)>250. Notably, PCR and long-read sequence analysis revealed these were pure GAA repeats. In comparison, no controls had (GAA)>300and only 2/311 control individuals (0.6%) encoded a pure (GAA)>250. In a German validation cohort 9/104 (8.7%) of affected individuals had (GAA)>335and a further six had (GAA)>250. In comparison no controls had (GAA)>335and 10/190 (5.3%) encoded (GAA)>250. The combined data suggests (GAA)>335are disease-causing and fully penetrant [P-value 6.0×10−8, OR 72 (95% CI=4.3-1227)], while (GAA)>250is likely pathogenic, albeit with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with a clinical phenotype that may include vestibular impairment, hyper-reflexia and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2=0.44 p=0.00045, slope = -0.12). This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansion loci via model free, genome-wide analysis and identifies SCA50/ATX-FGF14 is a frequent cause of adult-onset ataxia.

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.

Reproductive genetic carrier screening (RGCS) provides people with information about their chance of having children with autosomal recessive or X-linked genetic conditions, enabling informed reproductive decision-making. RGCS is recommended to be offered to all couples during preconception or in early pregnancy. However, cost and a lack of awareness may prevent access. To address this, the Australian Government funded Mackenzie’s Mission—the Australian Reproductive Genetic Carrier Screening Project. Mackenzie’s Mission aims to assess the acceptability and feasibility of an easily accessible RGCS program, provided free of charge to the participant. In study Phase 1, implementation needs were mapped, and key study elements were developed. In Phase 2, RGCS is being offered by healthcare providers educated by the study team. Reproductive couples who provide consent are screened for over 1200 genes associated with >750 serious, childhood-onset genetic conditions. Those with an increased chance result are provided comprehensive genetic counseling support. Reproductive couples, recruiting healthcare providers, and study team members are also invited to complete surveys and/or interviews. In Phase 3, a mixed-methods analysis will be undertaken to assess the program outcomes, psychosocial implications and implementation considerations alongside an ongoing bioethical analysis and a health economic evaluation. Findings will inform the implementation of an ethically robust RGCS program.

BACKGROUND AND OBJECTIVES: Discussing population-based cancer risk and screening is common in general practice. Patients with an inherited cancer syndrome, however, may need more nuanced discussions. Li-Fraumeni syndrome (LFS) is a rare, inherited cancer syndrome that affects many organ systems from birth and requires intensive, whole-body cancer risk management. The aim of this study was to explore the risk management experiences of young people (aged 15-39 years) with, or at risk of, LFS. METHOD: Using an interpretive description design, semi-structured interviews were conducted with young people diagnosed with, or at risk of, LFS from across Australia. Interview transcripts were analysed with team-based, codebook thematic analysis. RESULTS: Thirty young people (mean age 25.5 years) participated. Participants described intensive screening and risk-reducing mastectomy (for women) as their 'best shot' to control their cancer risks with LFS. Engaging in these options as a young person came with a slew of psychosocial implications. DISCUSSION: General practitioners may help to improve care for young people with inherited cancer syndromes by acknowledging the benefits and complex burdens of their risk management.

RationaleThe natural history of Friedreich Ataxia (FRDA) is being investigated in a multi-center longitudinal study designated the Friedreich Ataxia Clinical Outcome Measures Study (FA-COMS). To understand the utility of this natural history dataset in analysis of clinical trials, we performed a propensity-matched comparison of the data from the open-label MOXIe Extension (omaveloxolone) with that from FA-COMS.MethodsAll MOXIe Extension patients who had at least one post-baseline assessment were matched to FA-COMS 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. Selection of covariates was based on clinical relevance (i.e., factors considered prognostic for disease progression) and availability. The change from baseline in mFARS at Year 3 for the MOXIe Extension patients compared to the matched FA-COMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis.ResultsData from the MOXIe Extension show that omaveloxolone provides persistent benefit over three years when compared to an untreated, rigorously matched cohort from FA-COMS. At each year, and in all analysis populations, patients in the MOXIe Extension experienced a smaller change from baseline in mFARS score than the matched FA-COMS patients. In the Primary Pooled Population (136 patients in each group) by Year 3, patients in the FA-COMS 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). Thus, progression in mFARS was slowed by 55% with omaveloxolone treatment.ConclusionsThese results suggest a clinically meaningful slowing of FRDA progression with omaveloxolone, and consequently details how propensity-matched analysis contributes to the understanding of the effects of therapeutic agents. This demonstrates the direct value of natural history studies in the evaluation of clinical trials.

Orphanet journal of rare diseases : OJRD 17, 415 (2022). doi:10.1186/s13023-022-02568-3, Published by BioMed Central, London

Prenatal screening for sex chromosome aneuploidies (SCAs) is increasingly available through expanded non-invasive prenatal testing (NIPT). NIPT for SCAs raises complex ethical issues for clinical providers, prospective parents and future children. This paper discusses the ethical issues that arise around NIPT for SCAs and current guidelines and protocols for management. The first section outlines current practice and the limitations of NIPT for SCAs. It then outlines key guidelines before discussing the ethical issues raised by this use of NIPT. We conclude that while screening for SCAs should be made available for people seeking to use NIPT, its implementation requires careful consideration of what, when and how information is provided to users.

Objective The objective of this study was to characterize the incidence and progression of scoliosis in the natural history of Friedreich’s ataxia (FRDA) and document the factors leading to the requirement for corrective surgery. Methods Data on the prevalence of scoliosis and scoliosis surgery from up to 17 years of follow‐up collected during a large natural history study in FRDA (1116 patients at 4928 visits) were summarized descriptively and subjected to time to event analyses. Results Well over 90% of early or typical FRDA patients (as determined by age of onset) developed intermediate to severe scoliosis, while patients with a later onset (>14 years) had no or much lower prevalence of scoliosis. Diagnosis of scoliosis occurs during the onset of ataxia and in rare cases even prior to that. Major progression follows throughout the growth phase and puberty, leading to the need for surgical intervention in more than 50% of individuals in the most severe subgroup. The youngest patients appear to delay surgery until the end of the growth period, leading to further progression before surgical intervention. Age of onset of FRDA before or after reaching 15 years sharply separated severe and relatively mild incidence and progression of scoliosis. Interpretation Scoliosis is an important comorbidity of FRDA. Our comprehensive documentation of scoliosis progression in this natural history study provides a baseline for comparison as novel treatments become available.

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. 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. 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. Heterogeneity in Friedreich ataxia progression is observed at the neurobiological level, with evidence of earlier cerebellar and later cerebral degeneration.