scholarly journals A Possible Genetic Pattern of Taurine Urinary Excretion in Friedreich’s Ataxia

1982 ◽  
Vol 9 (2) ◽  
pp. 209-215 ◽  
Author(s):  
A. Barbeau ◽  
F. Patenaude ◽  
G. Nadon ◽  
M. Charbonneau ◽  
T. Cloutier
Keyword(s):  
Urinary Excretion ◽  
Autosomal Recessive ◽  
Genetic Defect ◽  
High Capacity ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Uptake System ◽  
Genetic Pattern ◽  
Before And After ◽  
Normal Controls

SUMMARY:The taurine urinary excretion pattern, before and after an oral load of 250 mg taurine, was studied in normal control subjects and in patients with typical Friedreich’s ataxia. It was demonstrated that in both situations the ataxic patients fell within the sub-types of “intermediate” and “high taurine excretors”, while none were “low taurine excretors”. It was also demonstrated that the excretion of taurine after a load in the obligate heterozygotes parents of the ataxic patients was intermediate between normal controls and patients. It is postulated that patients with Friedreich’s Ataxia lack normal regulation of the high affinity-low capacity uptake system for taurine (the TH system) in the brush border of kidney tubules. The low affinity-high capacity uptake system in the same membranes (the TL system) appears to be normal in Friedreich’s patients. The normal allele could be called THN and the variant THF and this trait would be inherited in an autosomal recessive fashion if it is linked to the Freidreich phenotype. Whether this finding is or is not the basic genetic defect in Friedreich’s Ataxia will require more studies to clarify, but it is of interest to note that a similar pattern appears to be present in the fibroblasts of these patients.

scholarly journals Future Prospects of Gene Therapy for Friedreich’s Ataxia

2021 ◽  
Vol 22 (4) ◽  
pp. 1815 ◽  
Author(s):  
Gabriel Ocana-Santero ◽  
Javier Díaz-Nido ◽  
Saúl Herranz-Martín
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Autosomal Recessive ◽  
State Of The Art ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
First Intron ◽  
Progressive Neurodegeneration ◽  
Feasible Solutions ◽  
Neurogenetic Disease

Friedreich’s ataxia is an autosomal recessive neurogenetic disease that is mainly associated with atrophy of the spinal cord and progressive neurodegeneration in the cerebellum. The disease is caused by a GAA-expansion in the first intron of the frataxin gene leading to a decreased level of frataxin protein, which results in mitochondrial dysfunction. Currently, there is no effective treatment to delay neurodegeneration in Friedreich’s ataxia. A plausible therapeutic approach is gene therapy. Indeed, Friedreich’s ataxia mouse models have been treated with viral vectors en-coding for either FXN or neurotrophins, such as brain-derived neurotrophic factor showing promising results. Thus, gene therapy is increasingly consolidating as one of the most promising therapies. However, several hurdles have to be overcome, including immunotoxicity and pheno-toxicity. We review the state of the art of gene therapy in Friedreich’s ataxia, addressing the main challenges and the most feasible solutions for them.

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 Oral Lecithin and Linoleic Acid in Friedreich’s Ataxia: II. Clinical Results

1982 ◽  
Vol 9 (2) ◽  
pp. 155-164 ◽  
Author(s):  
S.B. Melancon ◽  
M. Vanasse ◽  
G. Geoffroy ◽  
L. Barabe ◽  
A. Proulx ◽  
...  
Keyword(s):  
Linoleic Acid ◽  
Clinical Performance ◽  
Stage Iv ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Safflower Oil ◽  
Therapeutic Trial ◽  
Mean Values ◽  
Significant Difference ◽  
Normal Controls

SUMMARY:Twenty-two patients with Friedreich’s Ataxia and ten normal controls were followed for one year and assessed as to their clinical performance after two successive six-month periods of lecithin or safflower oil. Results demonstrated no significant difference in performance scores according to group assignation, neither in patients nor in controls. According to stages, two patients in stage I and to a lesser degree, one patient in stage IV showed better scores for muscle strength and some motor accuracy and coordination tests with lecithin. Controls as groups maintained positive scores in all tests. Patients as groups showed negative mean values in nine out of eleven tests. Again as groups, patients receiving safflower oil demonstrated a mean 8% less deterioration than patients receiving lecithin. This study demonstrates that objective clinical tests and the participation of normal controls are a must in a therapeutic trial implicating patients with a progressive disorder such as Friedreich’s Ataxia. The possible role of linoleic acid as the active factor from which clinical improvement proceeded in some specific patients and with early functional stages of the disease, has to be considered and reevaluated in the near future.

scholarly journals Amino Acid Changes in the Mouse Mutant Dystonia Musculorum Similar to Those in Friedreich’s Ataxia

1982 ◽  
Vol 9 (2) ◽  
pp. 185-188 ◽  
Author(s):  
A. Messer
Keyword(s):  
Amino Acid ◽  
Experimental Model ◽  
Neurological Disorder ◽  
Autosomal Recessive ◽  
Red Nucleus ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Mouse Mutant ◽  
Sensory Afferents ◽  
Recessive Mutant

SUMMARY:An autosomal recessive mutant strain of mouse with a progressive neurological disorder is described. Histopathology is dramatic in the sensory afferents and in the red nucleus. In the cerebellar vermis the concentrations of glutamate, aspartate, glycine and GABA are significantly reduced, and in the cerebellar hemispheres the taurine/glutamate ratio is elevated. These mice may provide a useful experimental model of Friedreich’s ataxia.

scholarly journals Amino Acid Metabolism in Friedreich's Ataxia

1976 ◽  
Vol 3 (4) ◽  
pp. 373-378 ◽  
Author(s):  
B. Lemieux ◽  
A. Barbeau ◽  
V. Beroniade ◽  
D. Shapcott ◽  
G. Breton ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Aspartic Acid ◽  
Plasma Levels ◽  
Genetic Defect ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Physiological Importance ◽  
And Control ◽  
Csf Concentration

SUMMARY:A study of amino acids determined by sequential Multi-sample Amino Acid Automatic Analyzer in plasma, urine and cerebrospinal fluid (CSF) in patients with Friedreich's ataxia and control subjects has revealed a number of mathematically significant variations from normal. Of practical physiological importance are the following: a high urinary excretion of alanine with slightly elevated plasma levels; a low plasma and CSF concentration of aspartic acid in the resence of normal urinary values and finally a low CSF concentration of taurine accompanied by normal plasma levels, but elevated urinary output and renal clearance rates. We postulate that the modifications in alanine and aspartic acid are less specific and probably secondary, but there could be a genetic defect in the membrane transport of taurine and the other β-amino acids in Friedreich's ataxia.

scholarly journals Studies on the role of taurine in Friedreich's ataxia

1984 ◽  
Vol 11 (S4) ◽  
pp. 610-615 ◽  
Author(s):  
B. Lemieux ◽  
R. Giguère ◽  
D. Shapcott
Keyword(s):  
Urinary Excretion ◽  
Muscle Mass ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Control Groups ◽  
Creatinine Excretion

AbstractNew studies were undertaken to verify the previous findings of increased urinary excretion of taurine, in the basal state and after challenge with a taurine load, in Friedreich's disease. Particular attention was paid to possible causes of error such as weight, muscle mass, creatine and creatinine excretion, variability with time and appropriate control groups. Although the overall findings were confirmed, their interpretation is open to question because of all these factors of error. Many possibilities must still be further explored to account for the apparent taurine retention defect observed in many cases of Friedreich's disease.

scholarly journals Electrophysiological Investigation of the Auditory System in Friedreich’s Ataxia

1982 ◽  
Vol 9 (2) ◽  
pp. 131-135 ◽  
Author(s):  
M.J. Taylor ◽  
J.B. McMenamin ◽  
E. Andermann ◽  
G.V. Watters
Keyword(s):  
Auditory System ◽  
Friedreich’S Ataxia ◽  
Auditory Brainstem ◽  
Friedreich's Ataxia ◽  
The Other ◽  
Auditory Brainstem Responses ◽  
Evoked Responses ◽  
Electrophysiological Investigation ◽  
Auditory Evoked Responses ◽  
Normal Controls

ABSTRACT:Auditory brainstem responses (ABRs) and cortical auditory evoked responses (AERs) were studied in a series of 16 Friedreich’s ataxia patients who varied in age, degree of clinical involvement and duration of the disorder. The ABRs were markedly abnormal in all but the youngest patient, and the abnormalities reflected the severity and duration of the disease. The latencies of the AERs were significantly longer in the Friedreich’s ataxia patients compared to normal controls, suggesting cortical as well as peripheral involvement of the auditory system. These data are discussed in terms of the neuropathology of the disorder and the similarities with the other sensory systems in Friedreich’s ataxia patients.

scholarly journals Electromyography and Nerve Conduction Studies in Friedreich's Ataxia and Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS)

1979 ◽  
Vol 6 (2) ◽  
pp. 185-189 ◽  
Author(s):  
J.P. Bouchard ◽  
A. Barbeau ◽  
R. Bouchard ◽  
R.W. Bouchard
Keyword(s):  
Nerve Conduction ◽  
Autosomal Recessive ◽  
Clinical Signs ◽  
Sensory Nerve ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Nerve Conduction Studies ◽  
Spastic Ataxia ◽  
Group I ◽  
Electrophysiological Studies

SummaryTwenty four ataxie patients were investigated with electromyography and nerve conduction studies. They were divided in two groups according to the area they came from, the evolution of the disease, and the clinical signs. Group I patients from the Rimouski area displayed all the clinical and electrophysiological signs of Friedreich's ataxia. Group II comprised patients who presented with a new syndrome known as the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Although the clinical evolution was better in the latter, there were more electromyographic signs of denervation and the motor conduction velocities were slower. Both groups showed identical and important abnormalities in sensory nerve conduction.The results of electrophysiological studies in spastic ataxia have not been reported to our knowledge. They underline the place of spastic ataxia as distinct f rom Friedreich's ataxia, spastic paraplegia, and the known familial neuropathies.

scholarly journals Lipoamide Dehydrogenase in Friedreich's Ataxia Fibroblasts

1978 ◽  
Vol 5 (1) ◽  
pp. 115-118 ◽  
Author(s):  
S. B. Melançon ◽  
M. Potier ◽  
L. Dallaire ◽  
G. Fontaine ◽  
B. Grenier ◽  
...  
Keyword(s):  
Subcellular Distribution ◽  
Specific Activity ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Skin Fibroblasts ◽  
Lipoamide Dehydrogenase ◽  
Normal Controls

SUMMARY:Lipoamide dehydrogenase was measued in cultivated skin fibroblasts from twelve patients with Friedreich's ataxia and nine normal controls. No difference in specific activity, subcellular distribution and Vmax or Km was observed between patients and controls.

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