Exome sequencing in paediatric patients with movement disorders

Abstract

Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

Dystonia‐Deafness Syndrome Response to Subthalamic Nucleus Stimulation

“…In light of the prelingual deafness and early‐adulthood‐onset dystonia in this case, combined with the family history and negative results of laboratory and imaging tests, the diagnosis of DDS was suspected. To make a differential diagnosis and predict DBS outcome as recommended, 3 WES was conducted, and the ACTB p.Arg183Trp variant was revealed. The ACTB gene encodes cytoplasmic β‐actin, which participates in many basic cellular processes.…”

“…DBS has been widely used for treating dystonia, and therapeutic targets of the global pallidus internus (GPi) and the STN seem to have similar efficacy 6 . Kwong et al 3 concluded that GPi‐DBS responses varied among different monogenic forms of dystonia, and it did benefit a majority of patients. Among the 9 patients with DDS, the 4 who received GPi‐DBS were observed with lasting improvement 7–10 .…”

“…DBS has been widely used for treating dystonia, and therapeutic targets of the global pallidus internus (GPi) and the STN seem to have similar efficacy. 6 Kwong et al 3 concluded that GPi-DBS Video 1. Segments 1, 2, and 3: patient with dystonia-deafness syndrome attributed to a β-actin (ACTB) gene mutation presenting with dystonic gait, cervical dystonia, and scoliosis 5 days before and 7 and 12 months after deep brain stimulation of the bilateral subthalamic nucleus.…”

A Clinical and Integrated Genetic Study of Isolated and Combined Dystonia in Taiwan

“…Genetic causes were also identified from single cases involving heterozygous single allelic substitutions in TOR1A (c.907_909del, p.303_303del), 32,33 TUBB4A (c.38C>A, p.P13Q), THAP1 (c.122G>A, p.R41H), ATP1A3 (c.1825 G>A, p.D609N), ANO3 (c.2053A>G, p.S685G), 34 GNAL (c.2272G>A, p.G758R), KMT2B (c.3043C>T, p.R1015X), SLC6A3 (c.1634C>A, p.P545H), ADCY5 (c.139G>T, p.G47W), C19orf12 (c.273_274insA, p.P92Tfs*9), and SPG11 (c.4462_4463del, p.V1488fs) (Supplemental Table S3). 35 One patient had compound heterozygous variants in exon 1 (c.332 T>A, p.L111Q) and exon 5 (concomitant c.1499A>T, p.N500I) of PANK2, 36 and another patient had the compound heterozygous substitutions c.1072C>T (p.Gln358X) in exon 6 and c.496-497 (p.503-514) deletion in exon 1 of CYP27A1. 37 The clinical characteristics of patients harboring these variants are summarized in Table 3 ½T3 ½T3…”

Dystonia‐Deafness Syndrome: ACTB Pathogenic Variant in an Argentinean Family

“…There are, to date, 10 reported cases in the literature, the first one described in a 2006 study in twins, 4 and the last one in 2021. 6 All of them displayed infant-onset deafness and dystonia starting in adolescence or young adulthood. In contrast with most of the reported cases, our patient has neither developmental delay nor cognitive impairment.…”