A <i>de novo</i><i>ADCY5</i> mutation causes early‐onset autosomal dominant chorea and dystonia

Carapito, Raphaël; Paul, Nicodéme; Untrau, Meiggie; Gentil, Marion Le; Ott, Louise; Alsaleh, Ghada; Jochem, Pierre; Radosavljevic, Mirjana; Caignec, Cédric Le; David, Albert; Damier, Philippe; Isidor, Bertrand; Bahram, Seiamak

doi:10.1002/mds.26115

Cited by 71 publications

(80 citation statements)

References 12 publications

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“…With the caveat that pathogenicity of the 2 novel variants requires corroboration, with 18 families described herein and 3 other published families, 27,29 it appears this disorder is less rare than initially thought. As additional families are found, the full spectrum of mutations and their relationship to phenotype will be elucidated.…”

Section: Id027 (Pr418w Mosaic)mentioning

confidence: 58%

“…Recently, however, a splice site mutation in ADCY5 was identified in a father and son with chorea and dystonia. 27 It is difficult to reconcile the similar manifestations caused by this lossof-function mutation and the possible gain-of-function missense mutations in our patients. The missense mutations may have a different effect in vivo than what we observed in vitro.…”

Section: Id027 (Pr418w Mosaic)mentioning

confidence: 79%

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ADCY5 -related dyskinesia

et al. 2015

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Objective: To investigate the clinical spectrum and distinguishing features of adenylate cyclase 5 (ADCY5)-related dyskinesia and genotype-phenotype relationship. Methods:We analyzed ADCY5 in patients with choreiform or dystonic movements by exome or targeted sequencing. Suspected mosaicism was confirmed by allele-specific amplification. We evaluated clinical features in our 50 new and previously reported cases.Results: We identified 3 new families and 12 new sporadic cases with ADCY5 mutations. These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea, and myoclonus, often with facial involvement. The movements are sometimes painful and show episodic worsening on a fluctuating background. Many patients have axial hypotonia. In 2 unrelated families, a p.A726T mutation in the first cytoplasmic domain (C1) causes a relatively mild disorder of prominent facial and hand dystonia and chorea. Mutations p.R418W or p.R418Q in C1, de novo in 13 individuals and inherited in 1, produce a moderate to severe disorder with axial hypotonia, limb hypertonia, paroxysmal nocturnal or diurnal dyskinesia, chorea, myoclonus, and intermittent facial dyskinesia. Somatic mosaicism is usually associated with a less severe phenotype. In one family, a p.M1029K mutation in the C2 domain causes severe dystonia, hypotonia, and chorea. The progenitor, whose childhood-onset episodic movement disorder almost disappeared in adulthood, was mosaic for the mutation.Conclusions: ADCY5-related dyskinesia is a childhood-onset disorder with a wide range of hyperkinetic abnormal movements. Genotype-specific correlations and mosaicism play important roles in the phenotypic variability. Recurrent mutations suggest particular functional importance of residues 418 and 726 in disease pathogenesis. Neurology ® 2015;85:2026-2035 GLOSSARY ADCY5 5 adenylate cyclase 5; ATP 5 adenosine-59-triphosphate; cAMP 5 39,59-cyclic adenosine monophosphate; ChDys 5 chorea-dystonia; EHC 5 essential hereditary chorea; FDFM 5 familial dyskinesia with facial myokymia; MIP 5 molecular inversion probe; SNP 5 single nucleotide polymorphism; STRP 5 short tandem repeat marker.

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Section: Id027 (Pr418w Mosaic)mentioning

confidence: 58%

Section: Id027 (Pr418w Mosaic)mentioning

confidence: 79%

ADCY5 -related dyskinesia

et al. 2015

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“…More recently, a splice-site mutation in ADCY5 was identified in a family with autosomal dominant earlyonset chorea, dystonia, and pyramidal signs. 20 We report here the results of the ADCY5 mutational analysis in a cohort of NKX2-1-negative sporadic and familial cases with a BHC-like presentation. These cases had previously been extensively investigated for genetic and acquired causes of chorea, without reaching a conclusive diagnosis.…”

Section: Clinical Presentations Of Cases With Pathogenic Adcy5mentioning

confidence: 98%

ADCY5 mutations are another cause of benign hereditary chorea

Morgan

Mencacci²,

Kurek

et al. 2016

Neurology

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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.

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“…2 Subsequently, several other affected families and sporadic cases with various mutations of the same gene, and some variation in the phenotype, have been identified recently. [3][4][5] Inheritance is autosomal dominant, but new cases can appear due to de novo mutations 3 or mosaicism. 5 This syndrome is characterized as chorea of childhood onset, often with episodic worsening, particularly at night.…”

Section: Adcy5-related Dyskinesiamentioning

confidence: 99%

“…Despite the hypotonia, hyperreflexia is typical. 3,4 Cognitive function can be mild to moderately impaired or normal, but does not appear to deteriorate with time. The abnormal involuntary movements may worsen over the initial few years, but then are typically stable.…”

Section: Adcy5-related Dyskinesiamentioning

confidence: 99%

The non–Huntington disease choreas

Walker

2016

Neur Clin Pract

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A de novoADCY5 mutation causes early‐onset autosomal dominant chorea and dystonia

Cited by 71 publications

References 12 publications

ADCY5 -related dyskinesia

ADCY5 -related dyskinesia

ADCY5 mutations are another cause of benign hereditary chorea

The non–Huntington disease choreas

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