Expanded Genetic Spectrum and Variable Disease Onset in AOPEP‐Associated Dystonia
2022-05-01

With great interest, we read the publication by Zech et al1 reporting bi-allelic loss-of-function AOPEP variants in 4 index cases manifesting from 9 to 36 years with progressive and mostly isolated dystonia of the limbs and variable craniocervical involvement. After the initial report of the homozygous candidate stop variant (c.1477C>T, p.Arg493*, proband 1) in 20202 we searched an in-house database containing diagnostic grade exome and genome datasets3, 4 from more than 15 000 individuals including 354 cases that were assigned the human phenotype ontology term dystonia (HP:0001332). Stringent filtering for recessive-type variants left 2 dystonia patients carrying different protein-truncating variants in compound heterozygosity with predicted pathogenic missense changes (Fig. 1 and Supplementary Table S1). Both patients were the only ones affected in their families and a previous diagnostic trio-exome analysis3 (for methods details see Supplementary Information and Supplementary Table S2, pedigrees Supplementary Fig. S1) had not revealed any evidence of potentially clinically relevant changes in established dystonia-associated disease genes. Informed written consent for publication was obtained and the study was approved by the ethics committee of the University of Tuebingen (066/2021BO2). Although these observations were in line with the postulated AOPEP gene-disease association, we were initially hesitant to publish our data because of the fact that a homozygous stop variant (c.703C>T, p.(Gln235*)) was detected in a third individual who was reportedly healthy at age 35. Individual 1 (c.[122G>A];[696_697del], p.[(Gly41Glu)];[(Ala234Serfs*5)]) noticed tremor of his left arm at the age of 20 years, followed by torticollis and head tremor. At the age of 38, he showed massive retrocollis, accompanied by strong hypertension of neck and shoulder muscles. Hyperkinetic movements predominantly affected his left hand with an alternating hyperflexion and extension of the wrist and were subtly present in his left leg. An athetotic component was observed as well. Similarly to proband 3 reported by Zech et al,1 carrying the identical p.Ala234Serfs*5 change in a homozygous state, he reported that dystonia improved when he had time to relax with symptoms completely subsiding. By sitting with the back against the wall, the retrocollis could be antagonized. Therapies with propranolol and levodopa (l-dopa) were ineffective, whereas some reduction of dystonia and hyperkinesia was achieved by treatment with trihexyphenidyl (6 mg/d). Deep brain stimulation (DBS) has not been conducted. Individual 2 (c.[618C>G];[920T>C], p.[(Tyr206Ter)];[(Leu307Ser)]) noticed first symptoms from the age of 24 years on with cervical dystonia. At age 37, he presented with torticollis and retrocollis accompanied by dystonic tremor. Hyperkinesia with choreatic movements involved head, neck, and upper limbs, but not his legs. He suffered from several bone fractures because of severe dystonia and hyperkinesia and developed a chronic pain syndrome. Treatment with l-dopa and botulinum toxin was ineffective and trihexyphenidyl (up to 30 mg/d) brought only little relief. Pallidal DBS at the age of 39 years resulted in a marked improvement of symptoms. Individual 3 (c.[703C>T];[703C>T], p.[(Gln235*)];[(Gln235*)]) was age 35 years when investigated by trio-exome-sequencing for a child's developmental delay. This proband was reportedly healthy but was lost to follow-up, and no in-depth neurological examination could be performed. Clinical and genetic findings including messenger RNA (mRNA) expression levels are provided in Supplementary Table S3 and Supplementary Figure S2. In summary, our report on 2 index patients with adult-onset cervical dystonia, tremor, and hyperkinesia provide additional evidence of AOPEP variants causing recessive dystonia, possibly responsive to DBS. The identification of potentially clinically relevant missense variants and a novel homozygous stop variant further expands the genetic spectrum and points toward a highly variable age of onset or reduced penetrance, possibly because of genetic or environmental modifiers. To address these issues, larger patient cohorts and functional readouts for variants of uncertain significance and modifying factors are needed. We thank the patients for their cooperation and consent to the publication. Open Access funding enabled and organized by Projekt DEAL. T.B.H. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under the project number 418081722. (1) Letter: A. Conception, B. Organization; (2) Genetic Analysis and Patient Phenotyping: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. B.M.: 1A, 1B, 2B, 3A A.G.: 2B, 3B G.W.: 2B, 3B T.B.H.: 1A, 1B, 2B, 3A The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Appendix S1. Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.