Factors Influencing Disease Progression in Autosomal Dominant Cerebellar Ataxia and Spastic Paraplegia

Montcel, Sophie Tezenas du; Charles, Perrine; Goizet, Cyril; Marelli, Cécilia; Ribaı̈, Pascale; Vincitorio, C.; Anheim, Mathieu; Guyant‐Maréchal, Lucie; Bayon, A. Le; Vandenberghe, N.; Tchikviladzé, Maya; Devos, David; Ber, Isabelle Le; Nguyen, Karine; Cazeneuve, Cécile; Tallaksen, Chantal; Brice, Alexis; Dürr, Alexandra

doi:10.1001/archneurol.2011.2713

Cited by 54 publications

(27 citation statements)

References 24 publications

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“…Moreover, in other ARCAs, deambulation is lost after a mean disease duration of 10 years in ataxia telangiectasia, 10-15 years in Friedreich ataxia and about 20 years in AOA2 [1], which contrasts with the 26/31 (83%) ambulatory ARCA2 patients affected for a mean duration of 18.6 years. Moreover, the slow evolution of ARCA2 ataxia is obvious when compared with dominant spinocerebellar ataxias (SCA) due to polyglutamine tract expansion in which the mean SARA score is 14.9 after a disease duration of 11 years (ratio 1.35 point/year) [13]. The mean SARA score of non polyglutamine-related SCAs is however closer to that of ARCA2, with a value of 11 after 16 years for (ratio 0.68 point/year) [13].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the slow evolution of ARCA2 ataxia is obvious when compared with dominant spinocerebellar ataxias (SCA) due to polyglutamine tract expansion in which the mean SARA score is 14.9 after a disease duration of 11 years (ratio 1.35 point/year) [13]. The mean SARA score of non polyglutamine-related SCAs is however closer to that of ARCA2, with a value of 11 after 16 years for (ratio 0.68 point/year) [13]. …”

Section: Discussionmentioning

confidence: 99%

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Phenotypic variability in ARCA2 and identification of a core ataxic phenotype with slow progression

Mignot

Apartis

Dürr

et al. 2013

Orphanet J Rare Dis

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103

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Autosomal recessive cerebellar ataxia 2 (ARCA2) is a recently identified recessive ataxia due to ubiquinone deficiency and biallelic mutations in the ADCK3 gene. The phenotype of the twenty-one patients reported worldwide varies greatly. Thus, it is difficult to decide which ataxic patients are good candidates for ADCK3 screening without evidence of ubiquinone deficiency. We report here the clinical and molecular data of 10 newly diagnosed patients from seven families and update the disease history of four additional patients reported in previous articles to delineate the clinical spectrum of ARCA2 phenotype and to provide a guide to the molecular diagnosis. First signs occurred before adulthood in all 14 patients. Cerebellar atrophy appeared in all instances. The progressivity and severity of ataxia varied greatly, but no patients had the typical inexorable ataxic course that characterizes other childhood-onset recessive ataxias. The ataxia was frequently associated with other neurological signs. Importantly, stroke-like episodes contributed to significant deterioration of the neurological status in two patients. Ubidecarenone therapy markedly improved the movement disorders, including ataxia, in two other patients. The 7 novel ADCK3 mutations found in the 10 new patients were two missense and five truncating mutations. There was no apparent correlation between the genotype and the phenotype. Our series reveals that the clinical spectrum of ARCA2 encompasses a range of ataxic phenotypes. On one end, it may manifest as a pure ataxia with very slow progressivity and, on the other end, as a severe infantile encephalopathy with cerebellar atrophy. The phenotype of most patients, however, lies in between. It is characterized by a very slowly progressive or apparently stable ataxia associated with other signs of central nervous system involvement. We suggest undergoing the molecular analysis of ADCK3 in patients with this phenotype and in those with cerebellar atrophy and a stroke-like episode. The diagnosis of patients with a severe ARCA2 phenotype may also be performed on the basis of biological data, i.e. low ubiquinone level or functional evidence of ubiquinone deficiency. This diagnosis is crucial since the neurological status of some patients may be improved by ubiquinone therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phenotypic variability in ARCA2 and identification of a core ataxic phenotype with slow progression

Mignot

Apartis

Dürr

et al. 2013

Orphanet J Rare Dis

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103

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“…Several recent studies focused on defining appropriate clinical measurements of progression of the neurological deficit in SCA2 [2], [41]–[43]. However, all clinical scales are operator-dependent and have limited sensitivity to disease progression [44].…”

Section: Discussionmentioning

confidence: 99%

“…However, all clinical scales are operator-dependent and have limited sensitivity to disease progression [44]. In particular, based on longitudinal clinical examinations spanning 2.4 years, in serially examined SCA2 patients it was estimated that a minimum sample size of 57 was necessary to demonstrate a 50% reduction in clinical progression using a dedicated neurological scale [43].…”

Section: Discussionmentioning

confidence: 99%

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Progression of Brain Atrophy in Spinocerebellar Ataxia Type 2: A Longitudinal Tensor-Based Morphometry Study

et al. 2014

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Spinocerebellar ataxia type 2 (SCA2) is the second most frequent autosomal dominant inherited ataxia worldwide. We investigated the capability of magnetic resonance imaging (MRI) to track in vivo progression of brain atrophy in SCA2 by examining twice 10 SCA2 patients (mean interval 3.6 years) and 16 age- and gender-matched healthy controls (mean interval 3.3 years) on the same 1.5 T MRI scanner. We used T1-weighted images and tensor-based morphometry (TBM) to investigate volume changes and the Inherited Ataxia Clinical Rating Scale to assess the clinical deficit. With respect to controls, SCA2 patients showed significant higher atrophy rates in the midbrain, including substantia nigra, basis pontis, middle cerebellar peduncles and posterior medulla corresponding to the gracilis and cuneatus tracts and nuclei, cerebellar white matter (WM) and cortical gray matter (GM) in the inferior portions of the cerebellar hemisphers. No differences in WM or GM volume loss were observed in the supratentorial compartment. TBM findings did not correlate with modifications of the neurological deficit. In conclusion, MRI volumetry using TBM is capable of demonstrating the progression of pontocerebellar atrophy in SCA2, supporting a possible role of MRI as biomarker in future trials.

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Survival and severity in dominant cerebellar ataxias

Monin

Montcel

Marelli

et al. 2015

Ann Clin Transl Neurol

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Inherited spinocerebellar ataxias (SCAs) are known to be genetically and clinically heterogeneous. Whether severity and survival are variable, however, is not known. We, therefore, studied survival and severity in 446 cases and 509 relatives with known mutations. Survival was 68 years [95% CI: 65–70] in 223 patients with polyglutamine expansions versus 80 years [73–84] in 23 with other mutations (P < 0.0001). Disability was also more severe in the former: at age 60, 30% were wheelchair users versus 3% with other SCAs (P < 0.001). This has implications for genetic counseling and the design of therapeutic trials.

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Factors Influencing Disease Progression in Autosomal Dominant Cerebellar Ataxia and Spastic Paraplegia

Abstract: To evaluate disease progression and determine validity of clinical tools for therapeutic trials.

Cited by 54 publications

References 24 publications

Phenotypic variability in ARCA2 and identification of a core ataxic phenotype with slow progression

Phenotypic variability in ARCA2 and identification of a core ataxic phenotype with slow progression

Progression of Brain Atrophy in Spinocerebellar Ataxia Type 2: A Longitudinal Tensor-Based Morphometry Study

Survival and severity in dominant cerebellar ataxias

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