Very late-onset Friedreich’s ataxia with rapid course mimicking as possible multiple system atrophy cerebellar type

2021 ◽  
Vol 14 (7) ◽  
pp. e242073
Author(s):  
Tushar Ashok Vidhale ◽  
Hemant R Gupta ◽  
Rohan PJ ◽  
Charmi Gandhi
Keyword(s):  
Late Onset ◽  
Cerebellar Atrophy ◽  
Friedreich’S Ataxia ◽  
Left Ventricular ◽  
Friedreich's Ataxia ◽  
Lower Limbs ◽  
Compound Heterozygous ◽  
Truncal Ataxia ◽  
Gaa Repeats ◽  
Whole Spine

This 55-year-old man was admitted to the hospital with an insidious onset, progressive backward fall (due to severe truncal ataxia), dysarthria, stiffness in extremities, distal dominant muscle wasting along with behavioural changes and urinary incontinence. Clinical assessment indicated mild cognitive decline (Mini-Mental State Examination 22/27) with cerebellar, pyramidal and peripheral nerves involvement. On investigations, nerve conduction studies revealed symmetrical, sensorimotor peripheral neuropathy affecting both lower limbs. Brain and whole spine MRI revealed widespread cerebral and mild cerebellar atrophy, pons and medulla volume loss, and a normal spinal cord. Transthoracic echocardiography revealed concentric left ventricular hypertrophy. His gene analysis revealed eight GAA repeats on allele 1, and 37 GAA repeats on allele 2 in the first intron of the frataxin gene. Considering his clinical profile and genetic analysis, he was diagnosed as a case of very late-onset Friedreich’s ataxia with likely compound heterozygous genotype.

scholarly journals Echocardiographic Findings in Friedreich's Ataxia

1976 ◽  
Vol 3 (4) ◽  
pp. 329-332 ◽  
Author(s):  
H.F. Gattiker ◽  
A. Davignon ◽  
A. Bozio ◽  
J. Batlle-Diaz ◽  
G. Geoffroy ◽  
...  
Keyword(s):  
Friedreich’S Ataxia ◽  
Left Ventricular ◽  
Friedreich's Ataxia ◽  
Ventricular Free Wall ◽  
Slight Reduction ◽  
Free Wall ◽  
Left Ventricular Free Wall ◽  
Echocardiographic Examination ◽  
Septal Hypertrophy ◽  
Echocardiographic Findings

SUMMARY:Echocardiographic examination of 21 patients with Friedreich's ataxia (age 7 to 28 years) showed cardiac abnormalities in 90% of the cases. They were characterized by varying degrees of septal hypertrophy in 81%, left ventricular free wall hypertrophy in 61%, and a slight reduction of left ventricular internal dimension in 57% of the cases. Asymmetric septal hypertrophy (ASH) with a septal/left ventricular free wall ratio of over 1.3 was found in 29% of the cases, and systolic anterior motion (SAM) of the mitral valve in three patients. Two other patients showed evidence of a different type of cardiomyopathy with marked symmetric left ventricular hypertrophy and marked left ventricular enlargement.

Structural properties of Friedreich’s ataxia d(GAA) repeats

1999 ◽  
Vol 1444 (1) ◽  
pp. 14-24 ◽  
Author(s):  
Iang-Shan Suen ◽  
Jamie N. Rhodes ◽  
Mellisa Christy ◽  
Brian McEwen ◽  
Donald M. Gray ◽  
...  
Keyword(s):  
Structural Properties ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Gaa Repeats

Abstract 17263: Pre-Clinical Left Ventricular Myocardial Remodeling in Patients With Friedreich’s Ataxia: A Cardiac MRI Study

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Karen A Takazaki1 ◽  
Thiago Quinaglia A. C. Silva ◽  
Alberto Martinez ◽  
Tomas Neilan ◽  
Ravi SHAH ◽  
...  
Keyword(s):  
Heart Failure ◽  
Volume Fraction ◽  
Extracellular Volume ◽  
Extracellular Volume Fraction ◽  
Friedreich’S Ataxia ◽  
Left Ventricular ◽  
Friedreich's Ataxia ◽  
Intracellular Water ◽  
Lv Mass ◽  
Burn Out

Background: Heart Failure (HF) is the most common cause of death in Friedreich’s ataxia (FRDA), an inherited mitochondrial disease. Myocardial fibrosis is a well-documented histopathological feature among FRDA patients with HF. Objectives: In this study we will investigate the myocardial extracellular volume fraction (ECV) and intracellular water lifetime (τ ic ), using T1-weighted CMR imaging, in a cohort of patients with FRDA without signs of heart failure. We will also investigate whether myocardial tissue phenotyping by CMR can highlight particular characteristics of LV remodeling in FRDA’s cardiomyopathy, beyond those currently assessed with imaging-based classification of disease severity. Methods: Twenty-six FRDA’s patients (age 26.6±9.3 years, 15 women) without signs of HF, and 10 healthy controls (32.6±7.3 years, 5 women) underwent cardiac magnetic resonance (CMR) studies for assessment of left ventricular (LV) function, myocardial T1, late gadolinium enhancement (LGE), extracellular volume fraction (ECV), and intracellular water-lifetime (τ ic ) as marker of cardiomyocyte size. Neurological decline was determined using the FRDA rating scale (FARS 3). Results: FRDA patients had normal LV ejection fraction (LVEF: 67.66±11.4 vs. 63.9±9.0, P=0.311), larger LV mass index (LVMASSi: 61.03±22.1 vs. 45±4.2g/m 2 , P<0.001), and decreased LV end-diastolic volume index (LVEDVi 53.42±12 vs. 75.7±16.1, P=0.002), compared with controls. ECV and τ ic , were increased in FRDA patients (ECV: 0.36±0.05 vs. 0.25±0.02, P<0.0001; τ ic : 0.13±0.07 vs. 0.06±0.03, P=0.001). ECV was positively associated with LV mass-to-volume ratio (r=0.628, P<0.001). FARS 3 correlated positively with disease duration (r=0.669, P<0.001), and negatively with τ ic , (r=0.478, P=0.039). LVMASSi and cardiomyocyte mass-index [(1–ECV)LVMASSi] declined with age, indicating that LV hypertrophy may transition to a “burn-out” phase with LV atrophy. Conclusions: LV hypertrophy in FRDA reflects an expansion of the myocardial interstitium and an increase in cardiomyocyte size. In contrast, the neurological decline was more likely with decreasing cardiomyocyte size, possibly an early sign of myocardial “burn-out” in FRDA.

scholarly journals Friedreich's Ataxia Frequency in a Large Cohort of Genetically Undetermined Ataxia Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexander F. Brown ◽  
Michael H. Parkinson ◽  
Hector Garcia-Moreno ◽  
Ese Mudanohwo ◽  
Robyn Labrum ◽  
...  
Keyword(s):  
Late Onset ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Diagnostic Process ◽  
Spinocerebellar Ataxias ◽  
Screening Process ◽  
Group A ◽  
Improve Patient Management ◽  
Group B ◽  
Testing Group

Background: Patients with suspected genetic ataxia are often tested for Friedreich's ataxia (FRDA) and/or a variety of spinocerebellar ataxias (SCAs). FRDA can present with atypical, late-onset forms and so may be missed in the diagnostic process. We aimed to determine FRDA-positive subjects among two cohorts of patients referred to a specialist ataxia centre either for FRDA or SCA testing to determine the proportion of FRDA cases missed in the diagnostic screening process.Methods: 2000 SCA-negative ataxia patients, not previously referred for FRDA testing (group A), were tested for FRDA expansions and mutations. This group was compared with 1768 ataxia patients who had been previously referred for FRDA testing (group B) and were therefore more likely to have a typical presentation. The phenotypes of positive cases were assessed through review of the clinical case notes.Results: Three patients (0.2%) in group A had the FRDA expansion on both alleles, compared with 207 patients (11.7%) in group B. The heterozygous carrier rate across both cohorts was of 41 out of 3,768 cases (1.1%). The size of the expansions in the three FRDA-positive cases in group A was small, and their presentation atypical with late-onset.Conclusions: This study demonstrates that FRDA is very rare among patients who were referred purely for SCA testing without the clinical suspicion of FRDA. Such cases should be referred to specialist ataxia centres for more extensive testing to improve patient management and outcomes.

scholarly journals Effects of Friedreich's ataxia GAA repeats on DNA replication in mammalian cells

2012 ◽  
Vol 40 (9) ◽  
pp. 3964-3974 ◽  
Author(s):  
Gurangad S. Chandok ◽  
Mayank P. Patel ◽  
Sergei M. Mirkin ◽  
Maria M. Krasilnikova
Keyword(s):  
Dna Replication ◽  
Mammalian Cells ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Gaa Repeats

FRIEDREICH'S ATAXIA

PEDIATRICS ◽  
1982 ◽  
Vol 69 (6) ◽  
pp. 767-767
Author(s):  
Stephen C. Copps
Keyword(s):  
Optic Atrophy ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Pes Cavus ◽  
Truncal Ataxia ◽  
Main Gene ◽  
Oral Hypoglycaemic Drugs ◽  
Neurological Features ◽  
The Mean ◽  
Index Cases

The clinical features of 115 patients from 90 families with Friedreich's ataxia are described. Onset of symptoms was before the age of 25 (mean 10.52) years in all the index cases. An analysis of early cases suggested that limb and truncal ataxia and absent tendon reflexes in the legs were the only consistent diagnostic criteria within five years of presentation. Dysarthria, signs of pyramidal tract dysfunction in the legs and loss of joint position and vibration sense are not necessarily present during the first five years of symptoms, but appear to develop eventually in all cases. Scoliosis and ECG evidence of cardiomyopathy were found in over two-thirds of the patients studied; pes cavus, distal amyotrophy, optic atrophy, nystagmus and deafness were all less frequent. The disorder was gradually progressive in all cases. The mean age of losing the ability to walk was 25 years; 95 per cent were chair-bound by the age of 44 years. About 10 per cent of the patients had diabetes mellitus which was controlled by oral hypoglycaemic drugs in one quarter. Diabetes appeared to be associated with a higher incidence of optic atrophy and deafness. Diabetes also clustered within sibships; the risk of an individual with Friedreich's ataxia developing diabetes if an affected sib has it is over 40 per cent. Similarly, cardiomyopathy ran true within affected members of the same sibship, but there were instances of discordance which suggest that the development of the non-neurological features of Friedreich's ataxia may be controlled by modifying genes rather than heterogeneity of the main gene.

scholarly journals SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich's Ataxia

2019 ◽  
Vol 47 (20) ◽  
pp. 10728-10743 ◽  
Author(s):  
Carlotta Bon ◽  
Riccardo Luffarelli ◽  
Roberta Russo ◽  
Silvia Fortuni ◽  
Bianca Pierattini ◽  
...  
Keyword(s):  
Genetic Defect ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Monogenic Disease ◽  
Transcriptional Level ◽  
Gene Encoding ◽  
Mitochondrial Aconitase ◽  
Non Coding Rnas ◽  
Gaa Repeats

Abstract Friedreich's ataxia (FRDA) is an untreatable disorder with neuro- and cardio-degenerative progression. This monogenic disease is caused by the hyper-expansion of naturally occurring GAA repeats in the first intron of the FXN gene, encoding for frataxin, a protein implicated in the biogenesis of iron-sulfur clusters. As the genetic defect interferes with FXN transcription, FRDA patients express a normal frataxin protein but at insufficient levels. Thus, current therapeutic strategies are mostly aimed to restore physiological FXN expression. We have previously described SINEUPs, natural and synthetic antisense long non-coding RNAs, which promote translation of partially overlapping mRNAs through the activity of an embedded SINEB2 domain. Here, by in vitro screening, we have identified a number of SINEUPs targeting human FXN mRNA and capable to up-regulate frataxin protein to physiological amounts acting at the post-transcriptional level. Furthermore, FXN-specific SINEUPs promote the recovery of disease-associated mitochondrial aconitase defects in FRDA-derived cells. In summary, we provide evidence that SINEUPs may be the first gene-specific therapeutic approach to activate FXN translation in FRDA and, more broadly, a novel scalable platform to develop new RNA-based therapies for haploinsufficient diseases.

scholarly journals Peripheral Nervous System Involvement in Late-Onset Cobalamin C Disease?

2020 ◽  
Vol 11 ◽  
Author(s):  
Xujun Chu ◽  
Lingchao Meng ◽  
Wei Zhang ◽  
Jinjun Luo ◽  
Zhaoxia Wang ◽  
...  
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Methylenetetrahydrofolate Reductase ◽  
Late Onset ◽  
Hot Spot ◽  
Axonal Neuropathy ◽  
Methylmalonic Aciduria ◽  
Lower Limbs ◽  
Compound Heterozygous ◽  
Limb Weakness

Background: Cobalamin C (cblC) has a fundamental role in both central and peripheral nervous system function at any age. Neurologic manifestations may be the earliest and often the only manifestation of hereditary or acquired cblC defect. Peripheral neuropathy remains a classical but underdiagnosed complication of cblC defect, especially in late-onset cblC disease caused by mutations in the methylmalonic aciduria type C and homocysteinemia (MMACHC) gene. So the clinical, electrophysiological, and pathological characteristics of late-onset cblC disease are not well-known.Methods: A retrospective study of patients with late-onset cblC disease was conducted at our hospital on a 3-year period. The neuropathy was confirmed by the nerve conduction study. Sural biopsies were performed in 2 patients.Results: Eight patients were identified, with a mean onset age of 16.25 ± 6.07 years. All patients had methylmalonic aciduria, homocysteinemia, compound heterozygous MMACHC gene mutations were detected in all patients, and 7/8 patients with c.482G&gt;A mutation. One patient concomitant with homozygote c.665C&gt;T mutation in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. All patients showed limb weakness and cognitive impairment. Five patients had possible sensorimotor axonal polyneuropathy predominantly in the distal lower limbs. Sural biopsies showed loss of myelinated and unmyelinated fibers. Electro microscopy revealed crystalline-like inclusions bodies in Schwann cells and axonal degeneration.Conclusion: Late-onset cblC disease had possible heterogeneous group of distal axonal neuropathy. c.482G&gt;A mutation is a hot spot mutation in late-onset cblC disease.

Predictors of Left Ventricular Dysfunction in Friedreich’s Ataxia in a 16-Year Observational Study

2019 ◽  
Vol 20 (2) ◽  
pp. 209-216 ◽  
Author(s):  
Lise Legrand ◽  
Abdourahmane Diallo ◽  
Marie-Lorraine Monin ◽  
Claire Ewenczyk ◽  
Perrine Charles ◽  
...  
Keyword(s):  
Observational Study ◽  
Left Ventricular Dysfunction ◽  
Ventricular Dysfunction ◽  
Friedreich’S Ataxia ◽  
Left Ventricular ◽  
Friedreich's Ataxia

scholarly journals Molecular Analysis of Friedreich's Ataxia in Macedonian Patients

2008 ◽  
Vol 11 (1) ◽  
pp. 61-64 ◽  
Author(s):  
S Kocheva ◽  
S Trivodalieva ◽  
S Vlaski-Jekic ◽  
M Kuturec ◽  
G Efremov
Keyword(s):  
Molecular Analysis ◽  
Early Onset ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Autosomal Recessive Inheritance ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
The Republic ◽  
Gaa Repeats ◽  
Frataxin Gene

Molecular Analysis of Friedreich's Ataxia in Macedonian PatientsFriedreich's ataxia (FRDA) is rare a progressive neurodegenerative disorder of autosomal recessive inheritance, which is associated with an unstable expansion of a GAA trinucleotide repeat in the first intron of the frataxin gene on chromosome 9q13. We have performed molecular analyses of the frataxin gene of 40 patients with spinocerebellar ataxia from the Republic of Macedonia. Fifteen had early onset of progressive ataxia (before the age of 25), while the remainder were over 25 years old at the time of diagnosis. Only 14 patients had a mutation in the frataxin gene and all of these had early onset ataxia. The number of GAA repeats was in the normal range in 50 healthy individuals.

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