Unit of Neurology, San Luca Hospital, Lucca, Italy.
IRCCS Stella Maris Foundation, Calambrone, Pisa, Italy.
J Neurol Sci. 2024 May 15;460:123012. doi: 10.1016/j.jns.2024.123012. Epub 2024 Apr 13.
Essential Tremor (ET) is one of the most common neurological disorders. In most instances ET is inherited as an autosomal dominant trait with age-related penetrance (virtually complete in advanced age); however, ET genetics remains elusive. The current study aims to identify possibly pathogenic genetic variants in a group of well-characterized ET families.
34 individuals from 14 families with dominant ET were clinically evaluated and studied by whole exome sequencing studies (after excluding trinucleotide expansion disorders).
Most patients had pure ET. In 4 families, exome studies could identify a genetic variant potentially able to significantly alter the protein structure (CADD >20, REVEL score > 0.25), shared by all the affected individuals (in CAMTA1, FUS, MYH14, SGCE genes). In another family there were two variants in dominant genes (PCDH9 and SQSTM1). Moreover, an interrupted "intermediate" trinucleotide expansion in ATXN1 ("SCA1") was identified in a further family with pure ET.
Combining our observations together with earlier reports, we can conclude that ET genes confirmed in at least two families to date include CAMTA1 and FUS (reported here), as well as CACNA1G, NOTCH2NLC and TENM4. Most cases of familial ET, inherited with an autosomal dominant inheritance, may result from "mild" variants of many different genes that, when affected by more harmful genetic variants, lead to more severe neurological syndromes (still autosomal dominant). Thus, ET phenotype may be the "mild", incomplete manifestation of many other dominant neurogenetic diseases. These findings further support evidence of genetic heterogeneity for such disease(s). Author's keywords: cerebellar ataxias, movement disorders, neurogenetics, rare neurological disorders, tremor.
特发性震颤（ET）是最常见的神经退行性疾病之一。在大多数情况下，ET 作为常染色体显性遗传疾病，具有年龄相关的外显率（在高龄时几乎完全外显）；然而，ET 的遗传机制仍难以捉摸。本研究旨在鉴定一组特征明确的 ET 家族中可能存在的致病性遗传变异。
对 14 个具有显性 ET 的家族中的 34 名个体进行了临床评估和全外显子组测序研究（排除三核苷酸扩展疾病后）。
大多数患者均为单纯 ET。在 4 个家族中，外显子组研究可以识别出一种遗传变异，该变异可能显著改变蛋白结构（CADD＞20，REVEL 评分＞0.25），且所有受影响的个体均存在该变异（在 CAMTA1、FUS、MYH14、SGCE 基因中）。另一个家族中存在两个显性基因（PCDH9 和 SQSTM1）的变异。此外，在一个具有单纯 ET 的家族中还发现了 ATXN1 基因（“SCA1”）中“中间”三核苷酸扩展的中断。
结合我们的观察结果和早期报告，我们可以得出结论，迄今为止在至少两个家族中证实的 ET 基因包括 CAMTA1 和 FUS（此处报道），以及 CACNA1G、NOTCH2NLC 和 TENM4。大多数常染色体显性遗传的家族性 ET 病例可能是由许多不同基因的“轻度”变异引起的，当这些基因受到更有害的遗传变异影响时，会导致更严重的神经综合征（仍然是常染色体显性遗传）。因此，ET 表型可能是许多其他显性神经遗传疾病的“轻度”、不完全表现。这些发现进一步支持了此类疾病遗传异质性的证据。作者关键词：小脑共济失调，运动障碍，神经遗传学，罕见神经退行性疾病，震颤。
