ADCY5 mutations are another cause of benign hereditary chorea

Abstract

Objective: To determine the contribution of ADCY5 mutations in cases with genetically undefined benign hereditary chorea (BHC). Methods:We studied 18 unrelated cases with BHC (7 familial, 11 sporadic) who were negative for NKX2-1 mutations. The diagnosis of BHC was based on the presence of a childhood-onset movement disorder, predominantly characterized by chorea and no other major neurologic features. ADCY5 analysis was performed by whole-exome sequencing or Sanger sequencing. ADCY5 and NKX2-1 expression during brain development and in the adult human brain was assessed using microarray analysis of postmortem brain tissue.Results: The c.1252C.T; p.R418W mutation was identified in 2 cases (1 familial, 1 sporadic).The familial case inherited the mutation from the affected father, who had a much milder presentation, likely due to low-grade somatic mosaicism. The mutation was de novo in the sporadic case. The clinical presentation of these cases featured nonparoxysmal generalized chorea, as well as dystonia in the most severely affected, but no facial myokymia. We observed significant progression of symptoms in ADCY5 mutation carriers, in contrast to BHC secondary to NKX2-1 mutations. The difference in the clinical course is mirrored by the brain expression data, showing increasing ADCY5 expression in the striatum during brain development, whereas NKX2-1 shows an opposite trend.Conclusions: Our study identifies mutations in ADCY5, the gene previously linked to familial dyskinesia with facial myokymia, as a cause of familial and sporadic BHC. ADCY5 genetic analysis should be performed in cases with a benign choreiform movement disorder even in the absence of facial myokymia. Benign hereditary chorea (BHC) (OMIM 118700) is a rare and poorly delineated syndrome, clinically characterized by onset of symptoms in infancy or early childhood, relatively little clinical progression, and absence of other major neurologic deficits, in particular prominent cognitive decline.

Pediatric Paroxysmal Exercise-Induced Neurological Symptoms: Clinical Spectrum and Diagnostic Algorithm

“…Mutations in ADCY5, which encodes for adenylate cyclase type 5 (AC5), a membrane-bound enzyme highly expressed in striatal neurons, were first described in a large dominant kindred with affected cases presenting with an early-onset hyperkinetic movement disorder defined Familial Dyskinesia with Facial Myokymia (18). The spectrum of ADCY5-related movement disorder have been gradually expanded to include NKX2-1 negative patients with benign hereditary chorea (19), childhood-onset dystonia, chorea and myoclonus and patients diagnosed with dyskinetic cerebral palsy. The hallmarks of the disease are episodic exacerbations of baseline movement during sleep and when awake (20,21).…”

Recent advances in genetics of chorea

“…NKX2-1 mutations lead to a complex multi-systemic disease, featuring not only chorea, but also thyroid and pulmonary defects ( brain-lung-thyroid syndrome) in ~80% of cases [54, 56]. It was recently proposed to abandon the term BHC [57] given that (i) 60% of the identified NKX2-1 mutations are de novo (hence, the disease is not hereditary)[54]; (ii) NKX2-1 -mutated cases commonly present with a variety of neurological symptoms other than chorea (i.e. hypotonia, neurodevelopmental delay, dystonia, myoclonus, tics and ataxia) [54, 58–61]; (iii) patients with NKX2-1 mutations may present various degrees of non-progressive intellectual disability, as well as behavioural and psychiatric symptoms (recently reviewed in [62]).…”