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.

Figure 1. Pedigree and genetic results of families 1 (A) and 2 (B) with ADCY5 pathogenic mutations

Affected individuals in the pedigree are indicated by filled symbols. On the left is the visual output of the whole-exome sequencing data and Sanger sequencing results in the 3 affected individuals carrying the c.1252C>T; p.R418W mutation. In the top section of each box, the read depth of the exonic portion of ADCY5 involved by the mutation is shown. In the bottom part of each box, samples of the reads carrying the mismatching allele are displayed. The mutant T replacing a C is highlighted in red. Sanger sequencing failed to show the mutation in individual II-1 of family 1. Of note, whole-exome sequencing showed that approximately 8% of reads (9/110) carried the mutated allele in individual II-1 of family 1, indicating parental low-level somatic mosaicism. M = mutated; WT = wild-type.

Figure 2. Graphical summary of brain expression data

(A, B) Boxplots of ADCY5 and NKX2-1 messenger RNA (mRNA) expression levels in 10 adult brain regions. The expression levels are based on exon array experiments and are plotted on a log₂ scale (y-axis). This plot shows significant variation in ADCY5 and NKX2-1 transcript expression across the 10 CNS regions analyzed: putamen (PUTM), frontal cortex (FCTX), temporal cortex (TCTX), occipital cortex (OCTX), hippocampus (HIPP), substantia nigra (SNIG), medulla (specifically inferior olivary nucleus, MEDU), intralobular white matter (WHMT), thalamus (THAL), and cerebellar cortex (CRBL). ADCY5 and NKX2-1 mRNA expression is higher in the putamen than in all other brain regions and ADCY5 expression in the putamen is significantly higher than NKX2-1. (C, D) Graphs to show ADCY5 and NKX2-1 longitudinal mRNA expression in 6 brain regions during the course of human brain development. The expression levels are based on exon array experiments and are plotted on a log₂ scale (y-axis). The brain regions analyzed are the striatum (STR), amygdala (AMY), neocortex (NCX), hippocampus (HIP), mediodorsal nucleus of the thalamus (MD), and cerebellar cortex (CBC). The plots show increasing expression of ADCY5 mRNA during human brain development, particularly in the striatum, from 50 to 500 days postconceptualization and an opposite trend for NKX2-1.