Variable Age at Onset in AOPEP ‐Associated Dystonia

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With great interest, we read the letter of Menden et al1 reporting their findings on bi-allelic loss-of-function AOPEP variants. Following a statement of hesitance to publish their data because of a homozygous stop variant (c.703C > T, p.(Gln235*)) in a reported healthy 35-year-old male, we present a patient carrying the identical homozygous variant with severe symptoms matching AOPEP-associated dystonia. The male patient noticed twitching in his abdominal muscles during weight training at age 29 and developed severe retrocollis 1-year later with intermittent and irregular dystonic tremor leading to dysphagia and neck pain. Within months, he also developed a gait disturbance with circumduction of the right leg and reduced ipsilateral arm swing. The patient was diagnosed with generalized dystonia (Fahn-Marsden dystonia scales, movement: 25/120, disability: 5/30). He experienced relief of the retrocollis by placing his hand lightly on the back of his head (geste antagoniste). Medication with levodopa and trihexyphenidyl showed no benefit, but he responded well to botulinum toxin injections with the cessation of dystonic tremor and dysphagia after 400 units of incobotulinumtoxin into the cervical and shoulder muscles (every 3 months). The consanguineous parents (second-degree cousins of Turkish origin) and the four younger sisters of the patient had no neurological complaints and received no genetic testing. Laboratory testing, including electrolytes, liver enzymes, thyroid hormones, iron, ferritin, transferrin, copper (serum and urine), ceruloplasmin, cardiolipin, and rheumatological antibodies, provided normal results. Brain magnetic resonance imaging and dopamine transporter single photon emission computed tomography were normal as well. A next-generation sequencing-based whole-exome analysis revealed the above-mentioned homozygous nonsense variant of the AOPEP gene (NM_001193329.3:c.703C > T, NP_001180258.1:p.(Gln235*)). The genes ANO3, ATP1A3, GCH1, GNAL, HPCA, PRKRA, SGCE, SPR, TH, THAP1, TOR1A, and VPS13A had no abnormal findings. Our patient and the AOPEP-associated dystonia patients reported by Zech et al2 with similar symptoms and progression, support that the detected homozygous AOPEP variant is pathogenically relevant. Further evidence is provided by an additional Turkish-born patient (age, 30–39 years) with AOPEP-associated dystonia carrying the same homozygous AOPEP variant that was recently listed in the genetic variation interpretation database ClinVar (IDs: 2498245, SCV003915775.1).3 Because the healthy subject, ethnic background not mentioned, presented by Menden et al1 carries the same variant and was (still) asymptomatic at age 35, this might reflect either reduced penetrance or increased variability regarding age at disease-onset because of the gene variant. Currently, the highest reported age at onset in AOPEP-associated dystonia is 37 years of age.4 Follow-up with this subject might not only be relevant for counseling the patient and his family, might also provide insight into the variability of age at onset in this rare disorder. Differences regarding age at onset were also observed in two previously reported pairs of siblings in which each pair had the same genetic mutation, but had a different site2 and age at onset2, 5 (difference at onset of 2 and 5 years, respectively). The variability of age at disease-onset should be considered when counseling patients with AOPEP-associated dystonia, asymptomatic mutation carriers, and their families. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. M.M.: design, data acquisition, writing, editing of final version of the manuscript. B.L.: data analysis and interpretation, writing, editing of final version of the manuscript. A.R.: writing the first draft, editing of final version of the manuscript. T.K.: data acquisition, editing of final version of the manuscript. J.I.L.: data acquisition, editing of final version of the manuscript. C.B.: data analysis and interpretation, editing of final version of the manuscript. A.S.: design, editing of final version of the manuscript. M.M. was supported by the Deutsche Forschungsgemeinschaft (MI 709/2–1) and by the German Heredo Ataxia Society (DHAG) unrelated to this research. J.I.L. has received honoraria for speaking/consultation from Allergan, AbbVie, Ipsen, and received honoraria for Ipsen advisory board participation as well as travel grants from Merz, Allergan, AbbVie, and Ipsen outside the submitted work. He gave a lecture for Pfizer outside the submitted work. T.K. has received travel grants from Merz, AbbVie, and Ipsen outside the submitted work. A.S. was supported by the Deutsche Forschungsgemeinschaft (TRR 295) unrelated to this research. He received, unrelated to this research, consulting fees from Abbott, Zambon, and AbbVie. He received, unrelated to this research, speaker honoraria from bsh medical communication, Abbott, Kyowa Kirin, Novartis, AbbVie, and Alexion. B.L., A.R., and C.B. have nothing to disclose. MM: Conception, organization, execution, writing of the first draft, review and critique. BL: Conception, execution, writing of the first draft, review and critique. AR: Execution, writing of the first draft, review and critique. TK: Execution, review and critique. JIL: Execution, review and critique. CB: Execution, writing of the first draft, review and critique. AS: Conception, review and critique. Open Access funding enabled and organized by Projekt DEAL. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.