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Results for “Friedreich Ataxia”

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At least 19 recordsLinked to original sources
PubMed2025

Type and position of repeat interruptions as determinants of disease severity and expansion size in Friedreich ataxia.

PURPOSE: In Friedreich ataxia (FRDA) the size of the smaller GAA expansion is a major determinant of disease severity; interruption motifs were identified after the discovery of the pathogenic expansions; however, their impact is only recently investigated. METHODS: 164 patients with FRDA with biallelic expansions and 15 patients without FRDA were analyzed for interruption(s) number, position, and motif. Expansion size and age at onset of ataxia (AAO) were determined for patients with FRDA. RESULTS: Three groups of patients with FRDA were identified by the simultaneous analysis of the precise distance ("depth") between the interruptions (mostly nontriplet) and the 3' end of the expansion (P < .001), the smaller expansion size (P < .001), and AAO (P < .001). Classical FRDA corresponds to absence of interruption or interruption depth < 8 repeats, with AAO often <15 years (area under the curve [AUC] = 0.90; 95% CI, 0.84-0.96); LOFA to interruption depth of 8 to 18 repeats (AUC = 0.97; 95% CI, 0.94-1), with AAO 15 to 34 years (AUC = 1; 95% CI, 1-1); and vLOFA to interruption depth > 18 (AUC = 0.97; 95% CI, 0.92-1), with AAO > 34 years. Multiple (>5) triplet interruptions hamper further expansion. CONCLUSION: This study provides the molecular basis for a novel classification of FRDA that should be recommended for correct diagnosis.

Humans↗
PubMed2026

Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia iPSC model.

Friedreich ataxia (FRDA) is a progressive neuromuscular degenerative disorder caused by GAA repeat expansions in the FXN gene, leading to frataxin deficiency and multisystem pathology. Cardiomyopathy is the leading cause of mortality in individuals with FRDA. To investigate the cellular and molecular mechanisms underlying FRDA-associated cardiac dysfunction, we employed induced pluripotent stem cell (iPSC) lines derived from three individuals with FRDA, each paired with an isogenic control line generated through CRISPR/Cas9-mediated excision of the pathogenic GAA repeat expansion. Correction of the mutation restored FXN expression to levels comparable to healthy donor iPSCs, and all lines differentiated efficiently into cardiomyocytes. Functional analysis revealed significant contractile abnormalities in FRDA cardiomyocytes and multicellular cardiac microtissues, including prolonged contraction and relaxation times and faster beating rates, consistent with clinical observations of cardiac contractile dysfunction. FRDA cardiomyocytes also exhibited pathological features such as increased cell size, irregular calcium transients, elevated mitochondrial reactive oxygen species levels, increased mitochondrial fission and increased cell death. These phenotypes were exacerbated by pathological levels of iron supplementation in culture media, highlighting the heightened sensitivity of frataxin-deficient cardiomyocytes to iron-induced metabolic stress. RNA sequencing revealed a distinct transcriptional profile associated with frataxin deficiency. MEG3 and PCDHGA10 were consistently dysregulated across all three FRDA-iPSC lines and may represent early molecular markers of FRDA cardiomyopathy. Functional interrogation of these candidates demonstrated that targeted silencing of MEG3 or PCDHGA10 in FRDA cardiomyocytes significantly reduced disease&#x2011;associated cell death without affecting FXN expression. Notably, PCDHGA10 silencing also normalized elevated mitochondrial reactive oxygen species, whereas MEG3 silencing did not, highlighting gene&#x2011;specific contributions to FRDA cardiomyocyte survival. Collectively, these findings identify MEG3 and PCDHGA10 as functionally relevant regulators of FRDA cardiomyocyte pathology.

Friedreich Ataxia↗
PubMed1979

Jaw reflex in Friedreich ataxia.

Twenty-one patients with Friedreich ataxia were examined and found to have a brisk jaw reflex. This previously unreported clinical finding contrasts with the impairment of tendon reflexes in the limbs and should not rule out the diagnosis of Friedreich ataxia.

Adolescent↗
PubMed1979

Regulation of respiration in Friedreich's ataxia.

Friedreich's Ataxia (F.A.) is a degenerative disease which commonly leads to premature death of cardiorespiratory origin. To explain the early death of these patients, previous investigations have established the existence of 1) a cardiomyopathy in nearly 100% of cases, 2) a restrictive pulmonary syndrome of scoliotic origin and 3) a mild hypoxemia associated with slight respiratory alkalosis and a normal oxyhemoglobin dissociation curve. To further assess the cause of early death in patients with such neuromyopathy, we evaluated, in eleven F.A. patients, the sensitivity of the respiratory centers to hypercapnia, hypoxia, and hyperoxia. Ventilatory (VE, VT, F, VT/Ti) and occlusion pressure (P0.1) responses were taken as indices of the respiratory centers output during progressive hypercapnia (Read's method) and isocarbic hypoxia (Weil's method). We studied 11 Friedreich's Ataxia patients and 11 age, sex, and armspan matched controls. The responses of patients to hypercapnia were significantly greater than controls but their responses to hypoxia were similar to controls. Our study establishes that the respiratory centers are functioning adequately in early Friedreich's Ataxia and do not contribute to cardio-respiratory insufficiency in such neuromyopathy.

Adolescent↗
PubMed1979

Friedreich ataxia. II. Normal kinetics of lipoamide dehydrogenase.

Lipoamide dehydrogenase (LAD) kinetic values, Km and Vmax, were normal in 11 patients with Friedreich ataxia. Fibroblast activities of the pyruvate and alpha-ketoglutarate dehydrogenase complex, and LAD activities, were also normal. There was no reduction in oxidative decarboxylation of pyruvate, alpha-ketoglutarate, or several other substrates in intact fibroblasts. Methodologic differences may account for differences of opinion about putative abnormalities of the alpha-ketoacid dehydrogenase complexes.

Adolescent↗
PubMed1978

Cardiac pharmacology and cardiomyopathy in Friedreich's ataxia.

Friedreich's ataxia is almost always associated with a cardiomyopathy. The cardiomyopathy and its attendant cardiopulmonary sequelae is the usual cause of death in this disease. The author reviews the known pharmacology of the heart, particularly as it applies to hypertrophic cardiomyopathy. The important role played by calcium and the possible role of taurine is stressed. Therapeutic possibilities are mentioned.

Adrenergic beta-Agonists↗
PubMed1976

Vectorcardiographic findings in Friedreich's ataxia.

Cardiac manifestations in Friedreich's ataxia occur frequently. We have studied 17 cases of Friedreich's ataxia, of which 94% showed a disturbance of the repolarization in the scalar ECG, 29% showed evidence of left ventricular hypertrophy. These changes are not specific but typical of Friedreich's ataxia. Vectorcardiograms were taken with the Frank-system. The vectorcardiographic findings showed not only the same changes as seen in the sclar ECG, but furthermore an atypical configuration of the QRS-loop was evident, which was not recognized in the scalar ECG. According to our experience compared with the scalar ECT, the vectorcardiographic investigations can be considered a more useful method in the diagnosis of Friedreich's ataxia.

Adult↗
PubMedDate not supplied

Heart in Friedreich's ataxia.

Most articles on Friedreich's ataxia report that cardiac complications are almost universal in patients with this disease. However, the present study of 30 cases, observed for two to ten years, seems to belie the experience of other writers in the field. Only six (20 per cent) of these patients showed electrocardiographic abnormalities. Only one patient had cardiac enlargement and congestive heart failure. One other patient had paroxysmal tachycardia. Seventy-four family members were also studied and the results were similar. It is suggested that this impressive difference may be a racial one and indeed very few reports on Friedreich's ataxia have come from India. Further study of this group of patients is in progress. The author also includes a review of the literature of neuromyopathic diseases and their relationship to myocardial involvement.

Adolescent↗
PubMed1976

Low activities of the pyruvate and oxoglutarate dehydrogenase complexes in five patients with Friedreich's ataxia.

Since patients with Friedreich's ataxia appear to oxidize pyruvate slowly, we measured the activity of the pyruvate dehydrogenase complex in disrupted fibroblasts from four patients with this syndrome and one patient with a clinical variant. The activity was 43 +/- 4 per cent of that in 16 controls (mean +/- S.E.M., P less than 0.001). The activity of the 2-oxoglutarate dehydrogenase complex was also lower in the patients' cells than in those of controls (50 +/- 2 per cent, P less than 0.001). However, the activity of cytochrome-c oxidase was normal (126 +/- 43 per cent of controls). Mixing experiments gave no evidence of soluble enzyme inhibitors or activators, and the addition of excess substrate or cofactor did not ameliorate the deficiencies. White blood cells from one of the patients had low activities of both complexes. Mutations of these dehydrogenase complexes occur in some patients with Friedreich's ataxia and lead to abnormally low activity of an enzyme of the tricarboxylic acid cycle.

Adolescent↗
PubMed1978

Familial myoclonic epilepsy with ataxia and neuropathy with additional features of Friedreich's ataxia and peroneal muscular atrophy.

A family is described in which a mother and three of her five children showed myoclonic epilepsy. The mother and one son were also ataxic; one other son had additional features of Friedreich's ataxia, and a daughter had peroneal muscular atrophy as well as myoclonic epilepsy and ataxia. Although some of these disorders have been associated in previously reported families, the occurrence of all three disorders in members of one family seems to be unique. It is concluded that this family shows the manifestations of one, probably dominant, gene. The differences in age of onset and manifestations may be explained by the action of one or more subsidiary genes.

Adult↗
PubMed1975

Friedreich's ataxia.

The clinical and pathologic findings in Friedreich's ataxia were discussed and recent literature was reviewed with respect to associated heart disease, diabetes mellitus, peripheral nerve involvement, and EEG changes. Recent research aimed toward discovering an enzyme defect or defects was reviewed and, when available, our conclusions were stated. Friedreich's ataxia remains an unexplained spinocerebellar degeneration occurring in early life, inherited in a predominantly autosomal recessive fashion, and associated with cardiac dysfunction, diabetes mellitus, and peripheral sensory nerve involvement.

Amino Acids↗
PubMed1978

[Audiovestibular study in Friedreich's ataxia].

A preliminary report is presented of the audiovestibular findings in 16 cases of typical Friedreich ataxia. Many ENG abnormalities of the central type were found, the most frequent being square waves, ocular dysmetria, and disorganized pursuit of the pendulum. The other abnormal findings were less frequent or less specific. Peripheral vestibular and auditory impairment were not the rule. Eventually, the electronystagmogram could become an early paraclinical screening test of Friedreich's disease.

Adolescent↗
PubMed1978

Square wave jerks in Friedreich's ataxia.

We observed a brother and sister with Friedreich's ataxia during steady fixation. They both had abnormal eye movements consisting of randomly occurring, small amplitude, conjugate horizontal saccades away from the fixation target. The saccades were followed by maintenance of this eccentric position for a brief period, and finally, a corrective saccade back to the original position. Electro-oculographic recordings showed these eye movements to be square wave jerks. They had an amplitude ranging from 1.5 to 10.7 degrees and a duration averaging less than 200 msec. Square wave jerks were also superimposed on pursuit movements in both patients. Square wave jerks are an additional ocular finding that may signify chronic cerebellar dysfunction. More specifically, they are an additional neuro-ophthalmological finding that may be observed in Friedreich's ataxia.

Adolescent↗
PubMed1978

[Cardiac changes in familial Friedreich's ataxia (clinico-morphologic study)].

In familial Friedreich's ataxia besides lesions of the nervous system there is also cardiac pathology, which frequently may be the reason of a lethal outcome. As a result of a clinico-morphological study of the heart of a deceased patient, it was demonstrated that the character of morphological changes points to severe dystrophical changes of the myocardium of the "idiopathical" cardiomyopathy type.

Adult↗