Friedreich’s ataxia: clinical heterogeneity in two sisters

Armani, Mario; Zortea, Michela; Pastorello, Ebe; Lombardi, Stefania; Tonello, Simone; Zuliani, Luigi; Rigoni, Maria Teresa; Trevisan, Carlo P.

doi:10.1007/s10072-006-0617-8

Cited by 7 publications

(3 citation statements)

References 7 publications

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“…Since the sister has lost patellar refl exes, it could be arguable that the brother has FARR variant (with retained deep tendon refl exes), while she has the classic variant of the disease. This only supports the idea that FARR is just a phenotype variability of the same genetic disease (9). It may also be that the sister as the more severely aff ected sibling is harboring larger expansions in spinal cord and other aff ected tissues (10).…”

Section: Discussionmentioning

confidence: 73%

Identical mutation associated with distinct clinical phenotypes of Friedreich’s ataxia: case report

Malenica

Kukuruzović²,

Bitanga³

et al. 2014

Paediatr Croat.

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Section: Discussionmentioning

confidence: 73%

Identical mutation associated with distinct clinical phenotypes of Friedreich’s ataxia: case report

Malenica

Kukuruzović²,

Bitanga³

et al. 2014

Paediatr Croat.

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“…These include the late onset Friedreich ataxia (LOFA) and also Friedreich ataxia with retained reflexes (FARR) 5,6 . Thus, the presence of retained reflexes does not exclude the diagnosis of FA, and a genetic test is recommended despite an atypical ARCA presentation 7 .…”

Section: Discussionmentioning

confidence: 99%

Clinical spectrum of early onset cerebellar ataxia with retained tendon reflexes: an autosomal recessive ataxia not to be missed

Pedroso

Braga‐Neto

Ricarte

et al. 2013

Arq. Neuro-Psiquiatr.

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Autosomal recessive cerebellar ataxias are a heterogeneous group of neurological disorders. In 1981, a neurological entity comprised by early onset progressive cerebellar ataxia, dysarthria, pyramidal weakness of the limbs and retained or increased upper limb reflexes and knee jerks was described. This disorder is known as early onset cerebellar ataxia with retained tendon reflexes. In this article, we aimed to call attention for the diagnosis of early onset cerebellar ataxia with retained tendon reflexes as the second most common cause of autosomal recessive cerebellar ataxias, after Friedreich ataxia, and also to perform a clinical spectrum study of this syndrome. In this data, 12 patients from different families met all clinical features for early onset cerebellar ataxia with retained tendon reflexes. Dysarthria and cerebellar atrophy were the most common features in our sample. It is uncertain, however, whether early onset cerebellar ataxia with retained tendon reflexes is a homogeneous disease or a group of phenotypically similar syndromes represented by different genetic entities. Further molecular studies are required to provide definitive answers to the questions that remain regarding early onset cerebellar ataxia with retained tendon reflexes.

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“…Performance on clinical rating scales such as the Friedreich Ataxia Rating Scale (FARS) is similarly predicted by GAA1 repeat length and age, but R 2 values in such models have values of only 0.3–0.4 ( Lynch et al, 2006 ). In addition, substantially different levels of severity of disease features have been found in sibships in which siblings have similar GAA1 lengths ( Armani et al, 2006 ). Together, such results suggest that additional factors influence the severity of the disorder such as environmental events or other genetic influences.…”

Section: Introductionmentioning

confidence: 99%

A non-synonymous single nucleotide polymorphism in SIRT6 predicts neurological severity in Friedreich ataxia

Rodden

Rummey²,

Dong³

et al. 2022

Front. Mol. Biosci.

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Introduction: Friedreich ataxia (FRDA) is a recessive neurodegenerative disease characterized by progressive ataxia, dyscoordination, and loss of vision. The variable length of the pathogenic GAA triplet repeat expansion in the FXN gene in part explains the interindividual variability in the severity of disease. The GAA repeat expansion leads to epigenetic silencing of FXN; therefore, variability in properties of epigenetic effector proteins could also regulate the severity of FRDA.Methods: In an exploratory analysis, DNA from 88 individuals with FRDA was analyzed to determine if any of five non-synonymous SNPs in HDACs/SIRTs predicted FRDA disease severity. Results suggested the need for a full analysis at the rs352493 locus in SIRT6 (p.Asn46Ser). In a cohort of 569 subjects with FRDA, disease features were compared between subjects homozygous for the common thymine SIRT6 variant (TT) and those with the less common cytosine variant on one allele and thymine on the other (CT). The biochemical properties of both variants of SIRT6 were analyzed and compared.Results: Linear regression in the exploratory cohort suggested that an SNP (rs352493) in SIRT6 correlated with neurological severity in FRDA. The follow-up analysis in a larger cohort agreed with the initial result that the genotype of SIRT6 at the locus rs352493 predicted the severity of disease features of FRDA. Those in the CT SIRT6 group performed better on measures of neurological and visual function over time than those in the more common TT SIRT6 group. The Asn to Ser amino acid change resulting from the SNP in SIRT6 did not alter the expression or enzymatic activity of SIRT6 or frataxin, but iPSC-derived neurons from people with FRDA in the CT SIRT6 group showed whole transcriptome differences compared to those in the TT SIRT6 group.Conclusion: People with FRDA in the CT SIRT6 group have less severe neurological and visual dysfunction than those in the TT SIRT6 group. Biochemical analyses indicate that the benefit conferred by T to C SNP in SIRT6 does not come from altered expression or enzymatic activity of SIRT6 or frataxin but is associated with changes in the transcriptome.

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Friedreich’s ataxia: clinical heterogeneity in two sisters

Cited by 7 publications

References 7 publications

Identical mutation associated with distinct clinical phenotypes of Friedreich’s ataxia: case report

Identical mutation associated with distinct clinical phenotypes of Friedreich’s ataxia: case report

Clinical spectrum of early onset cerebellar ataxia with retained tendon reflexes: an autosomal recessive ataxia not to be missed

A non-synonymous single nucleotide polymorphism in SIRT6 predicts neurological severity in Friedreich ataxia

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