ADCY5 mutations are another cause of benign hereditary chorea

TY - JOUR

T1 - ADCY5 mutations are another cause of benign hereditary chorea

AU - Mencacci, Niccolo E

AU - Erro, Roberto

AU - Wiethoff, Sarah

AU - Hersheson, Joshua

AU - Ryten, Mina

AU - Balint, Bettina

AU - Ganos, Christos

AU - Stamelou, Maria

AU - Quinn, Niall

AU - Houlden, Henry

AU - Wood, Nicholas W

AU - Bhatia, Kailash P

N1 - © 2015 American Academy of Neurology.

PY - 2015/7/7

Y1 - 2015/7/7

N2 - 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.

AB - 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.

KW - Adenylyl Cyclases

KW - Adult

KW - Chorea

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Pedigree

KW - Young Adult

U2 - 10.1212/WNL.0000000000001720

DO - 10.1212/WNL.0000000000001720

M3 - SCORING: Journal article

C2 - 26085604

VL - 85

SP - 80

EP - 88

JO - NEUROLOGY

JF - NEUROLOGY

SN - 0028-3878

IS - 1

ER -