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To determine the interrater reliability of the Scale for the Assessment and Rating of Ataxia (SARA), Berg Balance Scale (BBS), and motor domain of the FIM (m-FIM) administered by physiotherapists in individuals with a hereditary cerebellar ataxia (HCA). Participants were assessed by 1 of 4 physiotherapists. Assessments were video-recorded and the remaining 3 physiotherapists scored the scales for each participant. Raters were blinded to each other's scores. Assessments were administered at 3 clinical locations in separate states in Australia. Twenty-one individuals (mean age=47.63 years; SD=18.42; 13 male and 8 female) living in the community with an HCA were recruited (N=21). Total and single-item scores of the SARA, BBS, and m-FIM were examined. The m-FIM was conducted by interview. Intraclass coefficients (2,1) for the total scores of the m-FIM (0.92; 95% confidence interval [CI], 0.85-0.96), SARA (0.92; 95% CI, 0.86-0.96), and BBS (0.99; 95% CI, 0.98-0.99) indicated excellent interrater reliability. However, there was inconsistent agreement with the individual items, with SARA item 5 (right side) and item 7 (both sides) demonstrating poor interrater reliability and items 1 and 2 demonstrating excellent reliability. The m-FIM (by interview), SARA, and BBS have excellent interrater reliability for use when assessing individuals with an HCA. Physiotherapists could be considered for administration of the SARA in clinical trials. However, further work is required to improve the agreement of the single-item scores and to examine the other psychometric properties of these scales. [ABSTRACT FROM AUTHOR]

• 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]

• Friedreich ataxia (FRDA) has a significant detrimental effect on hand function. • We quantified muscle strength, spasticity and joint range in 19 people with FRDA. • We identified spasticity and contracture in at least one joint of either hand. • Spasticity and weakness are significant predictors of reduced function. • This study suggests a multifactorial source of hand dysfunction in people with FRDA. Friedreich ataxia (FRDA) has a significant effect on hand function which in turn, may compromise independence and quality of life. This study sought to identify the extent of muscle weakness, spasticity and changes in joint range in the hands of individuals with FRDA. We used the Modified Tardieu Scale (MTS), testing of muscle strength and goniometry to examine hand function in 19 individuals with FRDA. Relationships between clinical measures of disease severity, functional independence and measures of hand function were also explored. We found evidence for both upper and lower motor neuron impairment in this population. Thirteen (68.0%) participants had spasticity in the dominant wrist and finger flexors, and seven (36.8%) had contracture in at least one joint of either hand. Sixteen (84.3%) participants demonstrated weakness in the intrinsic musculature of the hands and the majority demonstrated some degree of hyperextension at the metacarpophalangeal joints of either hand. Significant correlations were found between functional independence capacity and clinical parameters, and components of spasticity and weakness in both the dominant and non-dominant hands. Moreover, spasticity and weakness in the dominant hand were shown to be significant predictors of reduced functional independence capacity. This study highlights for the first time the incidence of upper limb spasticity which, in combination with weakness and contracture, suggests a multifactorial source of hand dysfunction in people with FRDA. [ABSTRACT FROM AUTHOR]

Lower limb spasticity compromises the independence of people with Friedreich’s ataxia (FRDA). This study sought to examine lower limb spasticity in FRDA in order to offer new insight as to the best approach and timing of spasticity management. Gastrocnemius and soleus spasticity and muscle length were measured by the Modified Tardieu Scale (MTS) in 31 participants with typical and late-onset FRDA. Relationships between the MTS and the Friedreich Ataxia Rating Scale (FARS), Functional Independence Measure (FIM), and disease duration were analysed. Differences between ambulant (n = 18) and non-ambulant (n = 13) participants were also examined. All participants had spasticity in at least one muscle, and 38.9% of ambulant and 69.2% of non-ambulant participants had contracture in one or both of their gastrocnemius muscles. Significant negative correlations were found between both gastrocnemius and soleus angle of catch and the FARS score. The FIM score also demonstrated significant correlations with gastrocnemius muscle length and angle of catch. Gastrocnemius and soleus spasticity and contracture is apparent in people with FRDA. Spasticity is evident early in the disease and in ambulant participants. Management of spasticity and reduced muscle length should be considered in people with FRDA at disease onset to optimise function. [ABSTRACT FROM AUTHOR]

Summary: Carrier screening for cystic fibrosis (CF) has been available since the early 1990s, yet there are few programs, and none funded as part of a national health care strategy. The aim of this paper is to provide a description of carrier screening for CF and examine the progress that has been made towards the establishment of universal population-based carrier screening programs. This is an evidence based commentary on population-based carrier screening for CF. Peak body recommendations were examined and existing programs for CF carrier screening are reviewed. The attitudes from the non-CF community, CF healthcare professionals and people with CF were studied. Data from health economic assessments is examined. The future of carrier screening for CF in the context of advancing genetic technologies and potentially curative therapies is considered. [Copyright &y& Elsevier]

Abstract: Milne SC, Campagna EJ, Corben LA, Delatycki MB, Teo K, Churchyard AJ, Haines TP. Retrospective study of the effects of inpatient rehabilitation on improving and maintaining functional independence in people with Friedreich ataxia. Objectives: To determine the effects of inpatient intervention for people with Friedreich ataxia (FRDA), and to identify whether improvements gained were sustained postdischarge. Design: This retrospective observational cohort study comprised people with FRDA admitted to inpatient rehabilitation. Setting: All participants in the study were referred by a specialist multidisciplinary FRDA clinic to inpatient rehabilitation. Participants: From 2003 until 2010, people (N=29; men, n=17; women, n=12) with FRDA were admitted to rehabilitation, representing 42 admissions. On admission, 9 participants were ambulant and 33 participants were nonambulant. Interventions: Each participant was prescribed goal-related therapy on an individual basis by the multidisciplinary team, and this consisted of a range of treatment approaches. Main Outcome Measure: The FIM was used to determine the efficacy of inpatient rehabilitation. Results: Consistent with the progressive nature of the condition, FIM scores, as measured on an annual basis preintervention, declined over time. However, FIM scores increased by a mean of 8.5 points during periods of inpatient rehabilitation and continued to increase by a mean of 2.0 points during the period immediately after rehabilitation. Results demonstrate these increases during and immediately after inpatient rehabilitation were significant (P<.001). Conclusions: To the best of our knowledge, this study provides the first evidence that a period of inpatient rehabilitation reverses or halts the downward decline in function for people with FRDA. The benefits from this intervention continued during the period immediately after inpatient rehabilitation, indicating that these gains are more than just short-term achievements. Further exploration of intensity, type, and length of rehabilitation is required to ensure that the most appropriate rehabilitation is provided. [Copyright &y& Elsevier]

Objective: The evidence for an association between mutations in the HFE (hemochromatosis) gene and the risk of hip or knee osteoarthritis is inconsistent. Total joint replacement is considered a surrogate measure for symptomatic end-stage osteoarthritis. We examined the relationship between HFE gene mutations and risk of total hip and knee replacement using a prospective cohort study. Methods: The Melbourne Collaborative Cohort Study recruited participants between 1990 and 1994. Participants born in Australia, New Zealand, the United Kingdom, or Ireland (n = 27,848) were genotyped for the HFE C282Y mutation. Total hip and knee replacements for osteoarthritis during 2001 to 2009 were ascertained from the Australian Orthopaedic Association National Joint Replacement Registry. Hazard ratios (HR)/odds ratios (OR) and confidence intervals (CI) were obtained from Cox regression or logistic regression. Results: Compared with those with no C282Y mutation, C282Y homozygotes had an increased risk of single total hip replacement (HR 1.94, 95% CI 1.04-3.62) and bilateral total hip replacement (OR 5.86, 95% CI 2.36-14.57) for osteoarthritis, adjusting for age, sex, body mass index, and educational level. Only 3 C282Y homozygotes had single total knee replacement; the HR was 0.51 (95% CI 0.16-1.57). C282Y/H63D compound heterozygosity was not related to the risk of total hip or knee replacement. Conclusions: HFE C282Y homozygosity was associated with an increased risk of both single and bilateral total hip replacement for osteoarthritis. [Copyright &y& Elsevier]

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]

Background & Aims: There are few longitudinal studies of serum ferritin (SF) and transferrin saturation (TS) levels in individuals homozygous for the C282Y mutation. We characterized the development of elevated iron measures in C282Y homozygotes followed for 12 years. Methods: From 31,192 people aged 40–69 years at baseline, we identified 203 C282Y homozygotes (95 males), of whom 116 had SF and fasting TS levels measured at baseline (mean age, 55 years) and 86 were untreated and had iron measures at follow-up (mean, 12 years later). The probabilities of SF at follow-up exceeding clinical thresholds were predicted from baseline SF and TS under a multivariate normal model. Results: For C282Y homozygotes, at baseline, 84% of males and 65% of females had elevated SF and 37% of males and 3% of females had SF >1000 μg/L. For males with SF 300–1000 μg/L at baseline, the predicted probability of progressing to SF >1000 μg/L at follow-up was between 13% and 35% and, for females, between 16% and 22%. For C282Y homozygotes with normal baseline SF, <15% were predicted to develop SF >1000 μg/L if left untreated. Conclusions: The majority of C282Y homozygotes who are likely to develop SF levels sufficient to place them at risk of iron overload-related disease will have done so by mean age 55 years. TS >95% at mean age 55 years in males increases the likelihood that SF levels will be elevated at mean age 65 years, but this effect is absent in females, most likely because of physiologic blood loss associated with menstruation. [Copyright &y& Elsevier]

Objectives: To assess the opinions of individuals with mucopolysaccharidoses (MPS) and their parents regarding the use of enzyme replacement therapy (ERT). Study design: A validated questionnaire, including hypothetical clinical scenarios about ERT for MPS, was distributed to members of MPS support groups in the United States and Australia. Results: The questionnaire was completed by 249 MPS support group members. Overall, 92% were in favor of ERT where MPS causes severe physical problems but does not affect intellect, and 69% were in favor of ERT where the physical limitations are mild and intellect is spared. Only 47% were in favor of ERT where severe physical and intellectual problems are well established; however, 77% were in favor of ERT in this situation if treatment begun early prolongs life and improves quality of life. Conclusion: Most respondents were in favor of ERT for MPS, even where it would not alter the intellectual deterioration. The medical community has a responsibility to advocate for their patients in situations where ERT is appropriate and recognize the economic burden and “family function burden” ERT can incur. [Copyright &y& Elsevier]

Summary Background Friedreich Ataxia (FRDA) is the most common hereditary ataxia, with dysarthria as one of its key clinical signs. Objective To describe the voice profile of individuals with FRDA to inform outcome marker development and goals of speech therapy. Methods Thirty-six individuals with FRDA and 30 age-matched controls provided sustained vowel and connected speech samples. Speech and voice samples were analyzed acoustically using the Analysis of Dysphonia in Speech and Voice program and perceptually using the Consensus Auditory-Perceptual Evaluation of Voice form. Correlations between dysphonia and overall dysarthria severity, demographic, clinical, and genetic information were explored. Results Individuals with FRDA presented with mild dysphonia characterized by hoarseness (combined roughness and breathiness), increased strain, and altered pitch variability (increased in vowel productions; slightly decreased on reading samples). Acoustically, individuals with FRDA had significantly higher scores on the Cepstral Spectral Index of Dysphonia during vowel production. A combination of perceptual and acoustic measures of dysphonia used in this study was quite effective in categorizing the FRDA versus control participants, with >80% overall accuracy. Conclusions Although dysphonia severity in FRDA did not correlate significantly with overall disease severity, speaking rate and syllabic duration significantly correlated with age at disease onset and disease duration, and also have an effect on listener perception of dysphonia. The relationship between dysphonia and dysarthria in FRDA suggests that reducing overall dysphonia severity via therapeutic techniques that improve phonatory stability and increase speaking rate is a viable target for speech therapy. [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]

Abstract: Objectives: Cystic fibrosis (CF) is an inherited disease that requires more intensive treatments as the disease progresses. Recent medical advancements have improved survival but have also increased costs. Our lack of understanding on the relationship between disease severity and lifetime health care costs is a major impediment to the timely economic assessment of new treatments. Methods: Using data from three waves of the Australian Cystic Fibrosis Australia Data Registry, we estimate the annual costs of CF care by age and health state. We define health states on the basis of annual lung-function scores and patient’s organ transplant status. We exploit the longitudinal nature of the data to model disease progression, and we use this to estimate lifetime health care costs. Results: The mean annual health care cost for treating CF is US $15,571. Costs for patients with mild, moderate, and severe disease are US $10,151, US $25,647, and US $33,691, respectively. Lifetime health care costs are approximately US $306,332 (3.5% discount rate). The majority of costs are accounted for by hospital inpatients (58%), followed by pharmaceuticals (29%), medical services (10%), complications (2%), and diagnostic tests (1%). Conclusions: Our study is the first of its kind using the Australian Cystic Fibrosis Data Registry, and demonstrates the utility of longitudinal registry data for the purpose of economic analysis. Our results can be used as an input to future economic evaluations by providing analysts with a better understanding of the long-term cost impact when new treatments are developed. [Copyright &y& Elsevier]

Cerebellar ataxia often results in impairment in ambulation secondary to gait pattern dysfunction and compensatory gait adjustments. Pharmaceutical and therapy-based interventions with potential benefit for gait in ataxia are starting to emerge, however evaluation of such interventions is hampered by the lack of outcome measures that are responsive, valid and reliable for measurement of gait decline in cerebellar ataxia. This systematic review aimed for the first time to evaluate the psychometric properties of gait and walking outcomes applicable to individuals with cerebellar ataxia. Only studies evaluating straight walking were included. A comprehensive search of three databases (MEDLINE, CINAHL and EMBASE) identified 53 studies meeting inclusion criteria. Forty-nine were rated as 'poor' as assessed by the COnsensus-based Standards for the selection of health Measurement INstruments checklist. The primary objective of most studies was to explore changes in gait related to ataxia, rather than to examine psychometric properties of outcomes. This resulted in methodologies not specific for psychometric assessment. Thirty-nine studies examined validity, 11 examined responsiveness and 12 measured reliability. Review of the data identified double and single support and swing percentage of the gait cycle, velocity, step length and the Scale for Assessment and Rating of Ataxia (SARA) gait item as the most valid and responsive measures of gait in cerebellar ataxia. However, further evaluation to establish their reliability and applicability for use in clinical trials is clearly warranted. We recommend that inter-session reliability of gait outcomes should be evaluated to ensure changes are reflective of intervention effectiveness in cerebellar ataxia. [ABSTRACT FROM AUTHOR]

Background Quality of life in Friedreich ataxia (FRDA) has been explored using various generic health status measurement tools, most commonly the Short Form Health Survey Version 2 (SF-36v2). The tool did not address many specific issues related to disease impact in people with FRDA. The Friedreich Ataxia Impact Scale (FAIS) was developed to examine clinically relevant areas in FRDA. The aims of the current study were to assess the relationship between the FAIS and clinical characteristics of FRDA, as well as to determine the responsiveness of the FAIS to change over one and two years. Methods One hundred and four individuals with FRDA, homozygous for the GAA expansion in intron 1 of FXN , completed the FAIS at baseline. Seventy individuals completed the FAIS again 12 months later and 49 completed the FAIS at 24 months. Clinical parameters and neurologic scales (Friedreich Ataxia Rating Scale (FARS)) were also recorded. Results The total FARS score, onset age and disease duration correlated significantly with FAIS subscales measuring symptoms and physical functioning. The physical and mental summary measures of the SF-36 V2 also correlated well with the FAIS subscales. Speech was the only subscale that demonstrated significant change over one and two years. Conclusions The FAIS provides valuable insight into the perspective of individuals with FRDA on their health status, and is an important measure of morbidity. It has, however, limited responsiveness to change and its use in intervention studies is questionable. [ABSTRACT FROM AUTHOR]

The dentate nucleus (DN) is the major relay station for neural connection between the cerebellum and cerebrum via the thalamus, and is a significant component of the neuropathological profile of Friedreich ataxia (FRDA). We have previously shown that the size of the superior cerebellar peduncle (SCP), which links the DN to cortical and subcortical structures via the thalamus, is significantly reduced in individuals with FRDA compared to control participants. This study used magnetization transfer imaging (MTI) to examine and contrast the integrity of white matter (WM) in the SCP and the corpus callosum (CC) (control region) in ten individuals with FRDA and ten controls. Individuals with FRDA demonstrated a significant reduction in the magnetization transfer ratio (MTR) in the SCP compared to control participants. However, there was no significant difference between groups in MTR in the CC. When comparing regions within groups, there was a significant reduction in MTR in the SCP compared to CC in participants with FRDA only. We suggest that the reduction in MTR in the SCP may be indicative of lack of myelin secondary to axonal loss and oligodendroglial dysfunction in WM tracts in individuals with FRDA. [ABSTRACT FROM AUTHOR]

Highlights: [•] Up-to-date overview of the epigenetic changes in trinucleotide repeat (TNR) disease. [•] Understanding the link between TNR disease epigenetic profile and clinical outcome. [•] Discuss the future potential of epigenetic biomarkers and therapies for TNR disease. [Copyright &y& Elsevier]

Objective: To investigate the potential role of PArkin co-regulated gene (PACRG) in human male infertility. Design: Case-control study. Setting: Academic reproductive biology department. Patient(s): Blood samples were obtained from 610 patients and 156 normal control subjects. Intervention(s): Genomic DNA was used as template for polymerase chain reaction amplification of the PACRG promoter and coding exons. The amplified fragments were tested for DNA sequence variations by direct sequencing and restriction enzyme analysis. Main Outcome Measure(s): Gene structure and sequence alterations of PACRG in infertile male patients. Result(s): The structure of PACRG was determined to comprise 5 coding exons, generating a single transcript in the testis which encoded a predicted protein of 257 amino acids. No pathogenic mutations were identified; however, a variant in the promoter of PACRG was shown to be significantly associated with azoospermia, but not oligospermia, in the case-control cohort. Conclusion(s): Mutation of PACRG was not identified as a cause of male infertility, but variation in the promoter was demonstrated to be a risk factor associated with azoospermia. [Copyright &y& Elsevier]

Abstract: Parkin Co-Regulated Gene (PACRG) is a gene that shares a bi-directional promoter with the Parkinson''s disease associated gene parkin. The functional role of PACRG is not well understood, although the gene has been associated with parkinsonian syndromes and more recently with eukaryotic cilia and flagella. We investigated the expression of Pacrg in the mouse brain by in situ hybridization and observed robust expression of Pacrg in the cells associated with the lateral, third and fourth ventricle, in addition to the aqueduct of Sylvius and choroid plexus. For all regions of Pacrg expression identified, strong expression was observed in the newborn period and this was maintained into adulthood. Immunohistochemical analysis showed that Pacrg was a component of the ependymal cells and cilia lining the ventricles. Based on our results and the previous association of PACRG homologues with cilia and flagella, we propose that Pacrg is a component of the ependymal cilia and may play an important role in motile cilia development and/or function in the CNS. [Copyright &y& Elsevier]

Abstract: PArkin Co-Regulated Gene (PACRG) is a novel gene which is transcriptionally co-regulated with the parkin gene (PRKN) by a shared bi-directional promoter. To determine whether mutations in PACRG are associated with early-onset Parkinson''s disease (EO-PD), we performed sequence and dosage analysis of 76 EO-PD patients from a Taiwanese–Ethnic Chinese cohort. This analysis identified two novel nucleotide variants in the non-coding region of PACRG. One patient had an IVS2+247851T>C heterozygous change and two patients had an IVS4+78A>G heterozygous alteration. Neither of these variants was present in the 91 controls tested. A third intronic polymorphism (IVS1+85744insC) was present in cases and controls at an equivalent frequency (∼0.25). To facilitate gene dosage analysis, we identified cell lines with a heterozygous deletion or duplication of the entire PACRG locus. Three patients with heterozygous dosage alterations were identified, including two patients with an exon 2 duplication and one patient with an exon 3 deletion of PACRG. No dosage alterations were observed in the 91 controls analyzed (χ 2 =3.66, P =0.056). Our results suggest that point mutations in PACRG are not a common cause of EO-PD but haploinsufficiency for PACRG may be associated with disease. [Copyright &y& Elsevier]

Abstract: Mutations in parkin are a common cause of early-onset autosomal recessive Parkinson''s disease (PD). A single nucleotide polymorphism in the parkin promoter (rs9347683, −258T/G) has been reported to be associated with PD and shown to functionally affect gene transcription in luciferase reporter assays. In addition, homozygosity for the minor allele of rs9347683 may significantly reduce the age of onset of PD. We investigated the polymorphism in a cohort of cases with early-onset PD previously excluded for mutations in PD associated loci. We did not observe any differences in allele or genotype frequencies between the cases and the controls and there was no evidence for an effect on age of disease onset. Our results do not support a role for this variant in early-onset PD. [Copyright &y& Elsevier]

Abstract: Parkin Co-Regulated Gene (PACRG) is a novel gene that is oriented in a head-to-head array with parkin, and expression of the two genes is regulated by a shared bi-directional promoter. Mutations in parkin are the most common cause of early-onset autosomal recessive Parkinson''s disease, however the function of PACRG and potential role in the pathogenesis of Parkinson''s disease are unclear. We generated polyclonal anti-PACRG antisera and performed immunohistochemical analysis of the regional and temporal distribution of Pacrg in the mouse brain. The protein was heterogeneously expressed in neurons throughout the mouse brain, with highest levels observed in the rhombencephalon and mesencephalon. Expression was detectable at 1 week of age, increased to maximal levels by 4 weeks and subsequently declined after 3 months. Comparison of parkin and Pacrg immunohistochemistry demonstrated a correlation of both staining distribution and intensity for the two proteins. These results suggest that the transcriptional co-regulation of Pacrg and parkin leads to a similar regional protein distribution in mouse brain, which may have functional significance for the two proteins. [Copyright &y& Elsevier]

Abstract: There is limited documentation regarding cognitive function in individuals with Friedreich ataxia (FRDA), possibly because FRDA is widely held to predominantly affect the spinal cord, peripheral sensory nerves and cerebellum and not to affect cognition. Traditionally, the cerebellum has been thought to coordinate voluntary movement and motor tone, posture and gait. However, recent studies have implicated the cerebellum in a range of cognitive functions including executive function, visuospatial organisation and memory. We review the available data on cognitive function and neuroimaging in FRDA and the role of the cerebellum in cognitive function. We conclude with recommendations for future research including correlating cognitive function in individuals with FRDA with possible determinants of disease severity, such as age of onset and the causative genetic mutation. [Copyright &y& Elsevier]

Reproductive genetic carrier screening identifies couples with an increased chance of having children with autosomal and X-linked recessive conditions. Initially only offered for single conditions to people with a high priori risk, carrier screening is becoming increasingly offered to individuals/couples in the general population for a wider range of genetic conditions. Despite advances in genomic testing technology and greater availability of carrier screening panels, there is no consensus around which types of conditions to include in carrier screening panels. This study sought to identify which types of conditions parents of children with a genetic condition believe should be included in carrier screening. Participants (n = 150) were recruited through Royal Children's Hospital (RCH) Melbourne outpatient clinics, the Genetic Support Network of Victoria (GSNV) and a databank of children with hearing loss (VicCHILD). This study found that the majority of participants support offering carrier screening for: neuromuscular conditions (n = 128/134, 95.5%), early fatal neurodegenerative conditions (n = 130/141, 92.2%), chronic multi-system disorders (n = 124/135, 91.9%), conditions which cause intellectual disability (n = 128/139, 92.1%) and treatable metabolic conditions (n = 120/138, 87.0%). Views towards the inclusion of non-syndromic hearing loss (n = 88/135, 65.2%) and preventable adult-onset conditions (n = 75/135, 55.6%) were more mixed. Most participants indicated that they would use reproductive options to avoid having a child with the more clinically severe conditions, but most would not do so for clinically milder conditions. A recurring association was observed between participants' views towards carrier screening and their lived experience of having a child with a genetic condition. • Most participants support offering carrier screening for clinically severe conditions. • 65% of participants support offering carrier screening for hearing loss. • 56% of participants support offering carrier screening for adult-onset conditions. • Condition severity is important in reproductive decision-making. • Lived experience of genetic disorders underscores views towards carrier screening. [ABSTRACT FROM AUTHOR]

A small heterozygous deletion involving KANK1 was originally reported in 2005 to cause cerebral palsy in one large Israeli family of Jewish Moroccan origin. There were nine affected children over two generations to five unaffected fathers. All of these children had congenital hypotonia that evolved into spastic quadriplegia over the first year of life, along with intellectual impairment and brain atrophy. The subsequent clinical depictions of other individuals with neurological disease harbouring a comparable KANK1 deletion have been extremely variable and most often quite dissimilar to the original family. The reported pathogenicity of these deletions has also been variable, due to an inconsistent nature of reported disease associations and limited data. We therefore sought to perform a review of the significance of small distal interstitial chromosome 9p24.3 deletions principally involving KANK1 , including data from the VCGS cytogenetics laboratory. We found that carrier parents do not appear to display an increased frequency of neurological disease, individuals with a small KANK1 deletion have sometimes been found to have an alternate genetic diagnosis that explained their neurological condition, and small KANK1 deletions can be seen with approximate equal frequency in case and control populations. These data led us to conclude that small deletions involving KANK1 do not cause a highly-penetrant influence of large effect size and they are unlikely to contribute significantly to the aetiology of disease in patients with development delay, intellectual disability, autism or cerebral palsy. We recommend searching for an alternate explanation for disease in individuals with a neurological disorder found to have a small deletion involving KANK1. [ABSTRACT FROM AUTHOR]