Tremor-associated short tandem repeat intermediate and pathogenic expansions in familial essential tremor

Abstract

There is an obvious clinical-pathological overlap between essential tremor and some known tremor-associated short tandem repeat expansion disorders. The aim is to analyse whether these short tandem repeat genes, including ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, ATXN8OS, ATXN10, PPP2R2B, TBP, BEAN1, NOP56, DAB1, ATN1, SADM12 and FMR1, are associated with familial essential tremor patients. Genetic analysis of repeat sizes in tremor-associated short tandem repeat expansions was performed in a large cohort of 515 familial essential tremor probands and 300 controls. The demographic and clinical features among carriers of pathogenic expansions, intermediate repeats and non-carriers were compared. A total of 18 out of 515 (18/515, 3.7%) patients were found to have repeats expansions, including 12 cases (12/515, 2.5%) with intermediate repeat expansions (one ATXN1, eight TBP, two FMR1, one ATN1), and six cases (6/515, 1.2%) with pathogenic expansions (one ATXN1, one ATXN2, one ATXN8OS, one PPP2R2B, one FMR1, one SAMD12). There were no statistically significant differences in intermediate repeats compared to healthy controls. Furthermore, there were no significant differences in demographics and clinical features among individuals with pathogenic expansions, intermediate repeat expansions carriers and non-carriers. Our study indicates that the intermediate repeat expansion in tremor-associated short tandem repeat expansions does not pose an increased risk for essential tremor, and rare pathogenic expansion carriers have been found in the familial essential tremor cohort. The diagnosis of essential tremor based solely on clinical symptoms remains a challenge in distinguishing it from known short tandem repeat expansions diseases with overlapping clinical-pathological features.

Keywords: essential tremor; intermediate repeats; pathogenic expansion; short tandem repeat.

Graphical Abstract

Figure 1

The screening results of tremor-associated STRs. (A) The frequencies of known tremor-associated STRs expansions in 515 familial ET probands. (B) Results of known STRs size detection in 515 familial ET probands [BEAN1 (SCA31), DAB1 (SCA37) and SAMD12 (FCMTE1) are not shown since the disease is caused by alternative pathogenic repeat insertions]. STRs, short tandem repeats; SCA, spinocerebellar ataxia; DRPLA, Dentatorubral-pallidoluysian atrophy; FXTAS, fragile X tremor/ataxia syndrome; FMCTE, familial cortical myoclonic tremor and epilepsy.

Figure 2

MRI and electropherograms of pathogenic expansion carriers. (A) The brain MRI of patients carried six patients with pathological expansions. (B) Electropherograms of patients with repeat expansions of tremor-associated STRs. STRs, short tandem repeats.