Niccolo E Mencacci1, Roberto Erro2, Sarah Wiethoff1, Joshua Hersheson1, Mina Ryten1, Bettina Balint1, Christos Ganos1, Maria Stamelou1, Niall Quinn1, Henry Houlden1, Nicholas W Wood1, Kailash P Bhatia1. 1. From the Department of Molecular Neuroscience (N.E.M., S.W., J.H., M.R., H.H., N.W.W.) and Sobell Department of Motor Neuroscience and Movement Disorders (R.E., B.B., C.G., M.S., N.Q., K.P.B.), UCL Institute of Neurology, London, UK; IRCCS Istituto Auxologico Italiano (N.E.M.), Department of Neurology and Laboratory of Neuroscience-Department of Pathophysiology and Transplantation, "Dino Ferrari" Centre, Università degli Studi di Milano; Dipartimento di Scienze Neurologiche e del Movimento (R.E.), Università di Verona, Italy; Department of Neurology (B.B.), University Hospital Heidelberg; Department of Neurology (C.G.), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; Neurology Clinic (M.S.), Attiko Hospital, University of Athens; and Movement Disorders Department (M.S.), Hygeia Hospital, Athens, Greece. 2. From the Department of Molecular Neuroscience (N.E.M., S.W., J.H., M.R., H.H., N.W.W.) and Sobell Department of Motor Neuroscience and Movement Disorders (R.E., B.B., C.G., M.S., N.Q., K.P.B.), UCL Institute of Neurology, London, UK; IRCCS Istituto Auxologico Italiano (N.E.M.), Department of Neurology and Laboratory of Neuroscience-Department of Pathophysiology and Transplantation, "Dino Ferrari" Centre, Università degli Studi di Milano; Dipartimento di Scienze Neurologiche e del Movimento (R.E.), Università di Verona, Italy; Department of Neurology (B.B.), University Hospital Heidelberg; Department of Neurology (C.G.), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; Neurology Clinic (M.S.), Attiko Hospital, University of Athens; and Movement Disorders Department (M.S.), Hygeia Hospital, Athens, Greece. r.erro@ucl.ac.uk.
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.
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.
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