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Friedreich ataxia (FRDA) is a slowly progressive neurological disease resulting from decreased levels of the protein frataxin, a small mitochondrial protein that facilitates the synthesis of iron-sulfur clusters in the mitochondrion. It is caused by GAA (guanine-adenine-adenine) repeat expansions in the FXN gene in 96% of patients, with 4% of patients carrying other mutations (missense, nonsense, deletion) in the FXN gene. Compound heterozygote patients with one expanded GAA allele and a non-GAA repeat mutation can have subtle differences in phenotype from typical FRDA, including, in patients with selected missense mutations, both more severe features and less severe features in the same patient. In this review, we propose explanations for such phenotypes based on the potential for activities of frataxin other than enhancement of iron-sulfur cluster synthesis, as well as crucial future experiments for fully understanding the role of frataxin in cells.

Myotonic dystrophy type 1 (DM1) is a dominantly inherited multi-system disease caused by expanded CTG repeats in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Similar to other repeat disorders, the expanded trinucleotide repeat is unstable and demonstrates a tendency to increase repeat size with age in affected tissues. DNA mismatch repair system is implicated in somatic instability. It has been demonstrated that DM1 patient-derived induced pluripotent stem cells (DM1-iPSCs) show repeat instability, in which involvement of mismatch repair proteins has been suggested. Here we identified ZNF850 as a novel CTG repeat expansion-related molecule in DM1-iPSCs. ZNF850 was downregulated in a DM1-iPSC clone whose CTG repeat is exceptionally stable. We found that RNAi-mediated ZNF850 downregulation in DM1-iPSCs significantly reduced the repeat expansion and resulting instability. In adult skeletal muscle tissue of DM1 patients, ZNF850 expression levels were positively correlated with the repeat size. Furthermore, we found that ZNF850 protein can bind to the expanded CTG repeat sequence, and is located in proximity to MutSβ components. These results suggest that ZNF850 might play a role in repeat instability in DM1 by recruiting MutSβ to the repeat sequence., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Friedreich ataxia (FRDA) is a multisystem disorder affecting 1 in 50,000– 100,000 person in the United States. Traditionally viewed as a neurodegenerative disease, FRDA patients also develop cardiomyopathy, scoliosis, diabetes and other manifestation. Although it usually presents in childhood, it continues throughout life, thus requiring expertise from both pediatric and adult subspecialist in order to provide optimal management. The phenotype of FRDA is unique, giving rise to specific loss of neuronal pathways, a unique form of cardiomyopathy with early hypertrophy and later fibrosis, and diabetes incorporating components of both type I and type II disease. Vision loss, hearing loss, urinary dysfunction and depression also occur in FRDA. Many agents are reaching Phase III trials; if successful, these will provide a variety of new treatments for FRDA that will require many specialists who are not familiar with FRDA to provide clinical therapy. This review provides a summary of the diverse manifestation of FRDA, existing symptomatic therapies, and approaches for integrative care for future therapy in FRDA. [ABSTRACT FROM AUTHOR]

Recent technological advancements in genetic analysis have allowed for the consecutive discovery and elucidation of repeat expansion disorders: diseases caused by the abnormal expansion of repeat sequences in the genome. Many of these repeat expansion disorders are neurodegenerative movement disorders. Radical cures for these disorders have yet to be established. Although conventional treatments for repeat expansion disorders have mainly targeted the abnormal mRNA and proteins encoded by the affected genes, therapeutic approaches targeting repeat DNA, the root cause of repeat disorders, is also being explored in current research. In particular, a small molecule has been found that binds to abnormally expanded CAG repeats, the cause of Huntington's disease, and shortens them. Such small molecules targeting nucleic acids are expected to be developed into groundbreaking therapeutic drugs capable of ameliorating the symptoms of repeat expansion disorders and preventing their onset. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 8 (SCA8) is a rare autosomal dominant neurodegenerative disease caused by expanded CTA/CTG repeats in the ATXN8OS gene. Many patients had pure cerebellar ataxia, while some had parkinsonism, both without causal explanation. We analyzed the ATXN8OS gene in 150 Japanese patients with ataxia and 76 patients with Parkinson's disease or related disorders. We systematically reassessed 123 patients with SCA8, both our patients and those reported in other studies. Two patients with progressive supranuclear palsy (PSP) had mutations in the ATXN8OS gene. Systematic analyses revealed that patients with parkinsonism had significantly shorter CTA/CTG repeat expansions and older age at onset than those with predominant ataxia. We show the imaging results of patients with and without parkinsonism. We also found a significant inverse relationship between repeat sizes and age at onset in all patients, which has not been detected previously. Our results may be useful to genetic counseling, improve understanding of the pathomechanism, and extend the clinical phenotype of SCA8. [ABSTRACT FROM AUTHOR]

Spinal and bulbar muscular atrophy (SBMA) is an X-linked disorder that affects males who inherit the androgen receptor (AR) gene with an abnormal CAG triplet repeat expansion. The resulting protein contains an elongated polyglutamine (polyQ) tract and causes motor neuron degeneration in an androgen-dependent manner. The precise molecular sequelae of SBMA are unclear. To assist with its investigation and the identification of therapeutic options, we report here a new model of SBMA in Drosophila melanogaster. We generated transgenic flies that express the full-length, human AR with a wild-type or pathogenic polyQ repeat. Each transgene is inserted into the same safe harbor site on the third chromosome of the fly as a single copy and in the same orientation. Expression of pathogenic AR, but not of its wild-type variant, in neurons or muscles leads to consistent, progressive defects in longevity and motility that are concomitant with polyQ-expanded AR protein aggregation and reduced complexity in neuromuscular junctions. Additional assays show adult fly eye abnormalities associated with the pathogenic AR species. The detrimental effects of pathogenic AR are accentuated by feeding flies the androgen, dihydrotestosterone. This new, robust SBMA model can be a valuable tool toward future investigations of this incurable disease., (© 2023 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Antisense oligonucleotide (ASO) therapies for myotonic dystrophy type 1 (DM1) are based on elimination of transcripts containing an expanded repeat or inhibition of sequestration of RNA-binding proteins. This activity is achievable by both degradation of expanded transcripts and steric hindrance, although it is unknown which approach is superior. We compared blocking ASOs with RNase H-recruiting gapmers of equivalent chemistries. Two DMPK target sequences were selected: the triplet repeat and a unique sequence upstream thereof. We assessed ASO effects on transcript levels, ribonucleoprotein foci and disease-associated missplicing, and performed RNA sequencing to investigate on- and off-target effects. Both gapmers and the repeat blocker led to significant DMPK knockdown and a reduction in (CUG) exp foci. However, the repeat blocker was more effective in MBNL1 protein displacement and had superior efficiency in splicing correction at the tested dose of 100 nM. By comparison, on a transcriptome level, the blocking ASO had the fewest off-target effects. In particular, the off-target profile of the repeat gapmer asks for cautious consideration in further therapeutic development. Altogether, our study demonstrates the importance of evaluating both on-target and downstream effects of ASOs in a DM1 context, and provides guiding principles for safe and effective targeting of toxic transcripts., Competing Interests: D.G.W. is inventor on patents related to ASOs for treatment of myotonic dystrophy type 1., (© 2023 The Author(s).)

The term "junk DNA" has been reconsidered following the delineation of the functional significance of repetitive DNA regions. Typically associated with centromeres and telomeres, DNA repeats are found in nearly all organisms throughout their genomes. Repetitive regions are frequently heterochromatinized resulting in silencing of intrinsic and nearby genes. However, this is not a uniform rule, with several genes known to require such an environment to permit transcription. Repetitive regions frequently exist as dinucleotide, trinucleotide, and tetranucleotide repeats. The association between repetitive regions and disease was emphasized following the discovery of abnormal trinucleotide repeats underlying spinal and bulbar muscular atrophy (Kennedy's disease) and fragile X syndrome of mental retardation (FRAXA) in 1991. In this review, we provide a brief overview of epigenetic mechanisms and then focus on several diseases caused by DNA triplet-repeat expansions, which exhibit diverse epigenetic effects. It is clear that the emerging field of epigenetics is already generating novel potential therapeutic avenues for this group of largely incurable diseases. [ABSTRACT FROM AUTHOR]

The structure of the decadeoxyribonucleotide d(GCATGCATGC) is presented at a resolution of 1.8 Å. The decamer adopts a novel double-folded structure in which the direction of progression of the backbone changes at the two thymine residues. Intra-strand stacking interactions (including an interaction between the endocylic O atom of a ribose moiety and the adjacent purine base), hydrogen bonds and cobalt-ion interactions stabilize the double-folded structure of the single strand. Two such double-folded strands come together in the crystal to form a dimer. Inter-strand Watson-Crick hydrogen bonds form four base pairs. This portion of the decamer structure is similar to that observed in other previously reported oligonucleotide structures and has been dubbed a `bi-loop'. Both the double-folded single-strand structure, as well as the dimeric bi-loop structure, serve as starting points to construct models for triplet-repeat DNA sequences, which have been implicated in many human diseases. [ABSTRACT FROM AUTHOR]

Previously we provided evidence that the anticipation observed in bipolar (BP) disorder may be explained by expanded CAG/CTG triplet repeats. Data were generated with the repeat expansion detection (RED) method in a BP case–control sample showing a significant association of BP disorder with expanded CAG/CTG repeats (RED products of 120 bp). In this study we demonstrated that 86% of the RED expansions could be accounted for by the ERDA1 and CTG18.1 CAG/CTG repeats located respectively on chromosomes 17 and 18. Further, significantly different allele distributions were observed for ERDA1, with a larger proportion of BP patients (34.7%) carrying one or two expanded ERDA1 alleles (CAG/CTG repeats >40) than controls (19.2%) (P=0.032). Also, a negative correlation was observed for ERDA1 between CAG/CTG length and age at onset in affected offspring of eight BP families. Although interesting, these data should be interpreted with caution since the ERDA1 association did not remain significant after correcting for multiple testing. Also, no linkage was observed between BP disorder and expanded ERDA1 alleles in the families.

Abstract: Objectives: To evaluate the relationship between disease features in Friedreich ataxia and aberrant glucose metabolism. Methods: Fasting glucose, fasting insulin and random HbA1C were obtained in 158 patients with Friedreich ataxia. Regression analysis evaluated glucose, insulin, and homeostatic model assessment (HOMA) of insulin resistance (IR) and beta-cell function (ß) in relation to age, BMI, sex, and genetic severity. Categorical glucose values were analyzed in relation to other FRDA-associated disease characteristics. Results: In the FRDA cohort, age and GAA repeat length predicted fasting glucose and HbA1c levels (accounting for sex and BMI), while insulin and HOMA-IR were not predicted by these parameters. Within the cohort, average BMI was consistently lower than the national average by age and was marginally associated with insulin levels and HOMA-IR. Within juvenile subjects, insulin and HOMA-IR were predicted by age. Controlling for age and genetic severity, diabetes-related measures were not independent predictors of any quantitative measure of disease severity in FRDA. Glucose handling properties were also predicted by the presence of a point mutation, with 40% of individuals heterozygous for point mutations having diabetes, compared to 4.3% of subjects who carried two expanded GAA repeats. Interpretation: In FRDA, aberrant glucose metabolism is linked to increasing age, longer GAA repeat length on the shorter allele, frataxin point mutations, and increasing BMI. The effect of age to some degree may be mediated through changes in BMI, with increasing age associated with increases in BMI, and with HOMA-IR and insulin increases in children. [Copyright &y& Elsevier]

We delineate a complication of hypoalbuminemia in dentatorubral−pallidoluysian atrophy (DRPLA), which we have found to be common in this disorder. In addition, we explored the pathogenesis of this phenomenon through clinical and histological examinations. Clinical course and laboratory findings of nine patients with childhood-onset DRPLA (aged 6-49 years; CAG repeat length 62-93) were retrospectively reviewed. Autopsied specimens from three patients were examined by histopathological and immunohistochemical analyses. Eight DRPLA patients showed hypoalbuminemia <3.5 g/dl in the initial stages of the disease (age, 2-32 years), which correlated with the CAG repeat length in each patient. Disease worsened in six patients, often triggered by febrile infections and accompanied by increased urinary protein excretion. One patient showed increased fecal α1-antitripsin while another showed accumulation of radioactive albumin in the urinary and gastrointestinal tracts after intravenous infusion. Immunohistochemistry revealed albumin-containing monocytes and astrocytes in the perivascular areas of the cerebral white matter. Fluid collection in the glomerular capillaries was noted. Immunolabeling using antibodies against the expanded polyglutamine (polyQ) polypeptide was positive in cerebral cortical neurons, hepatocytes, renal collecting ducts, and glomerular podocytes, which act as filtration barrier against serum proteins. Serum albumin appears to easily leak from blood vessels in certain visceral organs in DRPLA during later stages of the illness, particularly in the kidneys of patients with largely expanded CAG repeats. We hypothesize that the accumulation of the DRPLA gene product with expanded polyQ sequences in the podocytes results in the dysfunction of the glomerular filtration barrier. [ABSTRACT FROM AUTHOR]

We recently reported elevated symptoms associated with attention-deficit hyperactivity disorder (ADHD) among adult female carriers of the FMR1 premutation. To gain insight into the contribution of this mutation in the context of polygenes, we examined the proportion of variation in these symptoms due to residual genetic factors after adjustment for the effect of the premutation. To accomplish this, we performed a familial aggregation analysis of ADHD symptoms among 231 females from 82 pedigrees using scores from the Connors Adult ADHD Rating Scales. Results indicate that after accounting for the effect of FMR1, there are significant residual polygenic effects on self-reported symptoms of ADHD, as measured by the ADHD Index ( p = 0.0117) and problems with self-concept ( p = 0.0110), one specific symptom domain associated with ADHD. For both measures, FMR1 accounts for ~5% of the variance while polygenes account for ~50% of the residual variance, suggesting that the premutation acts in concert with additional genetic loci to influence the severity of ADHD symptoms. [ABSTRACT FROM AUTHOR]

Microsatellite repeats are genetically unstable and subject to expansion and shrinkage. A subset of them, triplet repeats, can occur within the coding region and specify homomeric tracts of amino acids. Polyglutamine (polyQ) tracts are enriched in eukaryotic regulatory proteins, notably transcription factors, and we had shown before that they can contribute to transcriptional activation in mammalian cells. Here we generalize this finding by also including evolutionarily divergent organisms, namely, Drosophila and baker's yeast. In all three systems, Gal4-based model transcription factors were more active if they harbored a polyQ tract, and the activity depended on the length of the tract. By contrast, a polyserine tract was inactive. PolyQs acted from either an internal or a C-terminal position, thus ruling out a merely structural 'linker' effect. Finally, a two-hybrid assay in mammalian cells showed that polyQ tracts can interact with each other, supporting the concept that a polyQ-containing transcription factor can recruit other factors with polyQ tracts or glutamine-rich activation domains. The widespread occurrence of polyQ repeats in regu­latory proteins suggests a beneficial role; in addition to the contribution to transcriptional activity, their genetic instability might help a species to adapt to changing environmental conditions in a potentially reversible manner. [ABSTRACT FROM AUTHOR]

Abstract: Evaluation of therapeutic agents for Friedreich Ataxia (FA) has been limited by a lack of adequate markers of disease progression. We assessed the capacity of health related quality of life (HRQOL) questionnaires to reflect disease status in FA. The SF-36 and several symptom-specific scales were administered to an FA cohort. Scores were compared with norms for the United States population, and to a disease-free control group of similar age and gender. FA patients had significantly lower SF-36 Physical Component Summary scores (PCS) and Physical Functioning Subscale (PFS) scores, and both PCS and PFS scores correlated significantly with disease duration and disability status. Mental Component Summary scores (MCS) did not differ between FA patients and controls. Among symptom-specific scales, scores for the Pain Effects, Bladder Control, and Modified Fatigue Impact scales were significantly worse among FA patients than controls, and generally correlated with markers of disease progression. Findings of this study are consistent with the phenotypic characteristics of FA, and suggest that HRQOL measures are potentially useful as clinical markers of disease status in FA. [Copyright &y& Elsevier]

Abstract: Pathological expansions of GAA repeats in the first intron of the frataxin gene cause most cases of Friedreich ataxia, a progressively debilitating neurodegenerative disease. The disease is inherited in an autosomal recessive manner and the GAA repeats are suspected to form unusual non B-DNA conformations that decrease transcription and subsequently reduce levels of the encoded protein, frataxin. Recent work has shown that GAA repeats induce heterochromatin formation and silencing of the frataxin gene locus. Frataxin plays a crucial role in iron metabolism and detoxification and interacts with electron transport chain proteins. Clinical trials are currently underway to examine the efficacy of antioxidants in the treatment of Friedreich ataxia, but therapeutics designed to increase frataxin message levels are still in the developmental stages. This review will focus on the progress of potential treatment strategies for Friedreich ataxia that target the GAA expanded gene and seek to increase the level of frataxin message and protein. [Copyright &y& Elsevier]

Abstract: Background: Expansions of triplet repeats are found in a number of neurodegenerative conditions, and different tissues in the same person can have varying repeat lengths. In Kennedy disease, motor neuron loss is due to expansion of the CAG repeat length in the androgen receptor gene (AR). We hypothesised that patients with other sporadic motor neuron diseases could have AR expansions that were restricted to CNS tissue. Methods: We measured the AR triplet repeat length in DNA extracted from the brains of 23 patients with sporadic amyotrophic lateral sclerosis (SALS) and 3 with sporadic progressive muscular atrophy (SPMA). Paired blood samples were available in 15 patients to look for blood–brain differences in CAG repeat length. Results: No CAG expansions in the Kennedy disease range were found in the SALS or SPMA brains. Furthermore, no brain–blood differences were found in the lengths of AR triplet repeats. Brain AR repeat length was not associated with the duration, or age or site of onset, of disease. Conclusions: The findings indicate that a brain-specific expansion of AR triplet repeats is unlikely to underlie motor neuron loss in SALS or SPMA. [Copyright &y& Elsevier]

Friedreich ataxia is an autosomal recessive trinucleotide-repeat disease caused by expanded GAA repeats in the first intron of the FRDA gene. These GAA repeats are suspected to form unusual non-B DNA conformations that decrease transcription and subsequently reduce levels of the encoded protein, frataxin. GAA repeats also induce heterochromatin formation and silencing of the frataxin gene locus. Frataxin plays a crucial role in iron metabolism and detoxification and interacts with electron transport chain proteins. There is no effective therapy for Friedreich ataxia, but antioxidant therapy has shown promise and is currently in clinical trials. In this review we focus on the mechanisms by which expanded GAA repeats reduce transcription and discuss how these findings have lead to gene-based approaches that may be effective in treating Friedreich ataxia. [ABSTRACT FROM AUTHOR]