Clinical Reasoning: A middle-aged man with episodes of gait imbalance and a newly found genetic mutation

Yugrakh, Marianna Shnayderman; Levy, Oren

doi:10.1212/wnl.0b013e31826e9b40

Cited by 2 publications

(1 citation statement)

References 10 publications

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“…Concerning EA2, numerous reports described IEDs [36][37][38][39][40][41][42]. Very few cases reported additional information on EEG findings, which were reported to be normal [43] or with interposed slowing [36,40]. Descriptions of EEG findings during an attack are lacking.…”

Section: Review Of the Literaturementioning

confidence: 99%

The electrophysiological footprint of CACNA1A disorders

et al. 2021

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Objectives CACNA1A variants underlie three neurological disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). EEG is applied to study their episodic manifestations, but findings in the intervals did not gain attention up to date. Methods We analyzed repeated EEG recordings performed between 1994 and 2019 in a large cohort of genetically confirmed CACNA1A patients. EEG findings were compared with those of CACNA1A-negative phenocopies. A review of the related literature was performed. Results 85 EEG recordings from 38 patients (19 EA2, 14 FHM1, 5 SCA6) were analyzed. Baseline EEG was abnormal in 55% of cases (12 EA2, 9 FHM1). The most common finding was a lateralized intermittent slowing, mainly affecting the temporal region. Slowing was more pronounced after a recent attack but was consistently detected in the majority of patients also during the follow-up. Interictal epileptic discharges (IEDs) were detected in eight patients (7 EA2,1 FHM1). EEG abnormalities and especially IEDs were significantly associated with younger age at examination (16 ± 9 vs 43 ± 21 years in those without epileptic changes, p = 0.003) and with earlier onset of disease (1 (1–2) vs 12 (5–45) years, p = 0.0009). EEG findings in CACNA1A-negative phenocopies (n = 15) were largely unremarkable (p = 0.03 in the comparison with CACNA1A patients). Conclusions EEG abnormalities between attacks are highly prevalent in episodic CACNA1A disorders and especially associated with younger age at examination and earlier disease onset. Our findings underpin an age-dependent effect of CACNA1A variants, with a more severe impairment when P/Q channel dysfunction manifests early in life.

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Section: Review Of the Literaturementioning

confidence: 99%

The electrophysiological footprint of CACNA1A disorders

et al. 2021

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Diagnostic Efficacy of Genetic Studies in a Series of Hereditary Cerebellar Ataxias in Eastern Spain

et al. 2022

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Background and ObjectivesTo determine the diagnostic efficacy of clinical exome-targeted sequencing (CES) and spinocerebellar ataxia 36 (SCA36) screening in a real-life cohort of patients with cerebellar ataxia (CA) from Eastern Spain.MethodsA total of 130 unrelated patients with CA, negative for common trinucleotide repeat expansions (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, dentatorubral pallidoluysian atrophy [DRPLA], and Friedreich ataxia), were studied with CES. Bioinformatic and genotype-phenotype analyses were performed to assess the pathogenicity of the variants encountered. Copy number variants were analyzed when appropriate. In undiagnosed dominant and sporadic cases, repeat primed PCR was used to screen for the presence of a repeat expansion in theNOP56gene.ResultsCES identified pathogenic or likely pathogenic variants in 50 families (39%), including 23 novel variants. Overall, there was a high genetic heterogeneity, and the most frequent genetic diagnosis wasSPG7(n = 15), followed bySETX(n = 6),CACNA1A(n = 5),POLR3A(n = 4), andSYNE1(n = 3). In addition, 17 families displayed likely pathogenic/pathogenic variants in 14 different genes:KCND3(n = 2),KIF1C(n = 2),CYP27A1A(n = 2),AFG3L2(n = 1),ANO10(n = 1),CAPN1(n = 1),CWF19L1(n = 1),ITPR1(n = 1),KCNA1(n = 1),OPA1(n = 1),PNPLA6(n = 1),SPG11(n = 1),SPTBN2(n = 1), andTPP1(n = 1). Twenty-two novel variants were characterized. SCA36 was diagnosed in 11 families, all with autosomal dominant (AD) presentation. SCA36 screening increased the total diagnostic rate to 47% (n = 61/130). Ultimately, undiagnosed patients showed delayed age at onset (p< 0.05) and were more frequently sporadic.DiscussionOur study provides insight into the genetic landscape of CA in Eastern Spain. Although CES was an effective approach to capture genetic heterogeneity, most patients remained undiagnosed. SCA36 was found to be a relatively frequent form and, therefore, should be tested prior to CES in familial AD presentations in particular geographical regions.

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Clinical Reasoning: A middle-aged man with episodes of gait imbalance and a newly found genetic mutation

Cited by 2 publications

References 10 publications

The electrophysiological footprint of CACNA1A disorders

The electrophysiological footprint of CACNA1A disorders

Diagnostic Efficacy of Genetic Studies in a Series of Hereditary Cerebellar Ataxias in Eastern Spain

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