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.

Facial twitches in ADCY5 -associated disease - Myokymia or myoclonus? An electromyography study

“…In line with the descriptions of Chang et al [1] and Mencacci et al [6], who did not find myokymia during EMG recordings, we also could not demonstrate discharge patterns typical for myokymia.…”

“…However, a subsequent EMG study in the same individuals did not show fibrillations, fasciculations, myokymia, or myotonia in different muscles [3]. These findings were supported by other studies where EMG in ADCY5 mutation carriers failed to show myokymia [1,4,6]. Myokymia typically but not exclusively occurs in peripheral nerve damage and is defined as an EMG pattern with repetitive discharges of doublets, triplets and groups of monomorphic motor unit potential discharges [7].…”

ADCY5-related dyskinesia presenting as familial myoclonus-dystonia

“…A726T2.5–19 years+++Dilated cardiomyopathyChen et al [2]2 Sporadic(1 Mosaic)2c.1252C>Tp. R418W19 months to 5 years+++++++++Resting tremorDisturbed sleepCamptocormiaCarapito et al [3]1 Family2c.2088 + 1G>A6 months to 4 years+++++Right leg muscular atrophyHypotonia (unspecified)Mencacci et al [4]1 Family(1 Mosaic)1 Sporadic3c.1252C>Tp. R418W1–2 years++++++Ocular impersistenceAbnormal saccadesImpaired tandem walkChen et al [5]1 Family(1 Mosaic)8 Sporadic(3 Mosaic)16c.1252C>Tp.…”

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…Other nonconservative mutations in the ADCY5 gene (R418G and R418Q) are associated with dystonia, myoclonus, and choreoathetosis, too (Chen et al, 2015b;Chang et al, 2016). In line with these data, the R418W mutation may cause benign hereditary chorea (Mencacci et al, 2015). The R418W and A726T mutants may also be associated with chronic heart failure (Chen et al, 2012c).…”