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.
Advances in genetics have had a huge impact on reproductive choices. Reproductive carrier screening has transitioned from testing for a small number of conditions, often ethnically specific, to pan ...ethnic large panels. The Australian Reproductive Genetic Carrier Screening Project (Mackenzie’s Mission), funded by the Medical Research Future Fund, studied the acceptability and feasibility of offering such a large panel to couples pre pregnancy or in the early stages of pregnancy. Screening of around 1300 genes was offered by healthcare professionals. Education and consent were largely through an online portal. Genomic testing was conducted on self-collected cheek swabs. The study demonstrated that such screening can be offered at scale and that people use the information to inform reproductive decisions. Another area where genetic advances has played a crucial role in obstetrics is the ability to undertake genomic sequencing to identify the cause for abnormal ultrasound findings. Whereas in the relatively recent past, the only test available to try to identify the cause of add normal ultrasound findings was a banded karyotype on CVS or amniocentesis, now a specific single gene diagnosis can be made in some instances to inform prognosis and better enable couples to make informed reproductive decisions.
Clinical Features of Friedreich Ataxia Delatycki, Martin B.; Corben, Louise A.
Journal of child neurology,
09/2012, Letnik:
27, Številka:
9
Journal Article
Recenzirano
Odprti dostop
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.
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
Although a concentric pattern of left ventricular (LV) geometry appears to be common in Friedreich ataxia (FRDA), there is no accepted method for diagnosing LV abnormalities in FRDA, sex and body ...size have often not been taken into consideration, and it has not been clear whether children and adults should be classified using the same criteria. The aim of this study was to better define the LV geometric changes in FRDA with respect to sex, body size and subject age, and to investigate the relationship of LV changes with genetic severity, as assessed by GAA repeat length within the shorter allele of the FXN gene (GAA1).
Echocardiography was performed in 216 subjects (68 children, 148 adults), measurements were made at end-diastole of LV internal diameter (LVEDID), septal wall thickness (SWT), LV length (LVEDL) and LV volume (LVEDV), and calculations were made of relative wall thickness (RWT), LV mass and LV ejection fraction (LVEF).
The most common LV abnormalities in both adults and children with FRDA were increases in RWT and age-normalized RWT. In adults with a normal LVEF, all LV variables other than RWT were larger in males independent of body surface area (BSA), and all LV variables other than SWT and RWT were positively correlated with BSA. After adjustment for sex and BSA, GAA1 was a positive correlate of SWT and RWT (but not of LV mass), and was an inverse correlate of LVEDID, LVEDL and LVEDV. In children with a normal LVEF, SWT, LV mass and LVEDL were larger in males than females after adjusting for BSA, and in combination with sex, BSA was a positive correlate of all the LV variables except SWT and RWT. In children there were no correlations of GAA1 with any of the LV variables.
In FRDA, increases in RWT and age-normalized RWT are the most frequent LV structural abnormalities, sex and body size are important determinants of most other LV structural variables in both children and adults, and increased genetic severity is associated with a smaller left ventricle and increased LV wall thickness in adults, but not associated with LV size or wall thickness in children.
Correspondence to Professor Martin B Delatycki, Murdoch Childrens Research Institute - Bruce Lefroy Centre for Genetic Health Research, Parkville, VIC 19618, Australia; martin.delatycki@vcgs.org.au ...In this issue of Journal of Medical Ethics, Pugh1 offers a pluralist justice-based argument in support of the spirit, if not the precise letter, of the UK approach to the use of genetic test results (GTRs) to underwrite life insurance. ...despite the competing theories, the United Nations Universal Declaration on the Human Genome and Human Rights (UDHGHR) has already made a clear statement on this issue. There is already extensive international research which demonstrates the deterrent effect of insurance discrimination fears in both clinical and research genetic testing.5–12 In 2018, an Australian Joint Parliamentary Committee recommended an urgent ban on using predictive GTR in life insurance underwriting.13 The government did not respond to the recommendations. ...when individuals are given predictive genetic information about medically actionable risks, they can take steps to reduce that risk, placing both the individual and their life insurer in a better position.22 23 For example, regular colonoscopies in an individual with a predictive GTR that increases their risk of colorectal cancer can detect precancerous lesions.
Repeat expansions cause more than 30 inherited disorders, predominantly neurogenetic. These can present with overlapping clinical phenotypes, making molecular diagnosis challenging. Single-gene or ...small-panel PCR-based methods can help to identify the precise genetic cause, but they can be slow and costly and often yield no result. Researchers are increasingly performing genomic analysis via whole-exome and whole-genome sequencing (WES and WGS) to diagnose genetic disorders. However, until recently, analysis protocols could not identify repeat expansions in these datasets. We developed exSTRa (expanded short tandem repeat algorithm), a method that uses either WES or WGS to identify repeat expansions. Performance of exSTRa was assessed in a simulation study. In addition, four retrospective cohorts of individuals with eleven different known repeat-expansion disorders were analyzed with exSTRa. We assessed results by comparing the findings to known disease status. Performance was also compared to three other analysis methods (ExpansionHunter, STRetch, and TREDPARSE), which were developed specifically for WGS data. Expansions in the assessed STR loci were successfully identified in WES and WGS datasets by all four methods with high specificity and sensitivity. Overall, exSTRa demonstrated more robust and superior performance for WES data than did the other three methods. We demonstrate that exSTRa can be effectively utilized as a screening tool for detecting repeat expansions in WES and WGS data, although the best performance would be produced by consensus calling, wherein at least two out of the four currently available screening methods call an expansion.