Monogenic Chorea Etiologies in Children: A Study of a Cohort of 85 Patients and a Proposal of a Diagnostic Algorithm

Objectives: Chorea is an involuntary, permanent, irregular, arrhythmic, jerky, and movement disorder involving the limbs and/or the trunk and the face, associated to hypotonia. Even if the acute onset evokes acquired causes, many early-onset choreas have a monogenic etiology. The most frequent genetically determined chorea is the benign hereditary chorea due to NKX2.1 mutations. Next-generation sequencing (NGS) technology has recently allowed us to discover new genes (ADCY5, PDE10A, GNAO1, etc.). The aim of our study is to better define the genetic spectrum of early-onset choreas, especially those for whom treatment is available.

Content: We retrospectively studied a cohort of 93 patients, both children and adults, who had early-onset (childhood or infancy) progressive chorea as main symptom. These patients were referred to our center from 2011 to 2019 for a NKX2.1 gene study (Array–CGH and Sanger's sequencing). Chorea was isolated or associated with neurological or extraneurological (lung and thyroid) symptoms. MRI images were not an inclusion/exclusion criteria. Thirty-one patients harbored NKX2.1 genetic anomalies (33%), including three large deletions identified with Array–CGH analysis of which one proximal to but not encompassing the NKX2.1 gene and that included the MBIP gene. In the 46 patients without NKX2.1 mutations, the genetic analysis has been ongoing using Array–CGH, NGS analysis on our targeted “movement disorder” panel, or exome sequencing. Other genetic etiologies have already been identified: ADCY5 (4), ataxia–telangiectasia (3), GNA01 (3), KMT2B, GRIA3, SLC30A9, and POLR3A. In two patients, the diagnosis has been changed (to the Gilles de la Tourette syndrome and kernicterus). Differential diagnosis between chorea and ataxia, tics, myoclonus, and mobile dystonia can also be difficult.

Conclusion: We found the same NKX2.1 frequency as in Thorwharth's series (27%). The spectrum of other genetic etiologies is extensive: ADCY5, GNAO1 (often associated with paroxysmal exacerbations), and recessive ataxias that are frequently revealed by a movement disorder, and rarer causes. We propose a diagnostic algorithm to guide the clinician confronted with early-onset chorea in children as main symptom.

Publication History

Article published online:
16 March 2022