Adult‐Onset Dystonia and Hypertrophic Cardiomyopathy in Patient with a De Novo 16q12.2q21 Deletion

Here, we report an unusual case of a 21-year-old male with adult-onset focal hand dystonia combined with hypertrophic cardiomyopathy. Whole-exome sequencing revealed a 3.08 Mb de novo deletion in the 16q12.2q21 region (chr16:55686758-58768147, GRCh37/hg19) encompassing the GNAO1 gene and a pathogenic heterozygous variation in MYBPC3, c.1000G>A (p.E334K) in exon 12. A 21-year-old male presented a history of abnormal posture in his left upper limb while walking and tremors in his right hand for almost 1 year. The patient was born by a full-term cesarean section and was denied the occurrence of ischemia or hypoxia during delivery. Focal hand dystonia in the left upper limb when walking (Video 1A) and action tremor can be clearly observed when drawing Archimedean spirals with his right hand (Video 1B). Physical examination revealed dysmorphic features including microcephaly (head circumference, 53 cm), small eye clefts, and upturned lips. Neurological examination revealed focal hand dystonia in the left upper limb and postural tremor in the right upper limb. Brain magnetic resonance imaging showed no abnormalities (Fig. 1A,B). Cognitive assessments showed a Mini-Mental State Examination score of 21 (college-educated) and a Montreal Cognitive Assessment score of 17. The Burke-Fahn-Marsden Dystonia Rating Scale score was 42.5/6 (motor/disability). Tremor analysis revealed tremors in the right upper limb with a frequency of 6 to 7 Hz and co-contraction of antagonistic muscles. Echocardiography revealed a ventricular septum thickness of 14 mm that led to the diagnosis of hypertrophic cardiomyopathy. However, the patient remained asymptomatic with little to no cardiac-related discomfort. On admission, the patient received symptomatic treatments including trihexyphenidyl (1 mg), levodopa (62.5 mg), and baclofen (10 mg) three times daily. Fortunately, dystonia symptoms and action tremor significantly improved after treatment. Patients with a 16q12.2q21 deletion are rare, with only two complete cases reported to date.1, 2 The deleted region in this patient differs from previous cases. As reported, dystonia may be related to GNAO1 haploinsufficiency.3 Up to date, point mutations and small indels in GNAO1 have been found in over 100 patients.4 Clinical manifestations typically appear in childhood. Interestingly, this adult patient exhibited mild non-motor symptoms without severe developmental delay and presented motor symptoms limited to focal dystonia and action tremor. Notably, previous reports on GNAO1 deletions indicated a limited occurrence of heart disease among such patients. Specifically, there were only three individuals with left ventricular hypertrophy5 and five with arrhythmia,6 and no documented cases of hypertrophic cardiomyopathy. Therefore, hypertrophic cardiomyopathy in this patient is considered to be primarily because of a pathogenic variant in MYBPC3. Most notably, the possibility of GNAO1-related diseases should continue to be considered in patients with focal hand dystonia, even if their motor or non-motor symptoms are mild. A previous study demonstrated the favorable efficacy of deep brain stimulation (DBS) in such patients.2 It was appropriate to consider DBS if our patient subsequently developed generalized dystonia. This case prompts movement disorder specialists to consider the possibility of GNAO1-related diseases in patients with adult-onset focal dystonia, even if they do not have severe non-motor symptoms. We thank our patient and his family for their generous participation and permission to publish this case. Y.W. undertakes two projects funded by the National Natural Science Foundation of China, with project numbers 82371248 and 82171239. S.Q. undertakes the provincial and ministerial-level research project with the project number XGZX202117. Yifeng Li and Yanjing Li are currently not involved in any fund-supported projects. The funds mentioned above have no conflict of interest with this manuscript, and the objectivity of this submission has not been influenced by any external factors. (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. Yiwen Wu was responsible for the overall project design, as well as supervision and guidance. Shaochen Qin and Yifeng Li were responsible for execution, data analysis, and writing. They contributed equally as first authors. Yanjing Li was responsible for proofreading, editing the manuscript, and submitting it for publication. The data that support the findings of this study are available from the corresponding author upon reasonable request.