A hyperkinetic disorder
Familial dyskinesia with facial myokymia (also known as ADCY5-related dyskinesia) is an autosomal dominant mixed hyperkinetic disorder characterized by paroxysmal choreiform, myoclonic, and/or dystonic movements of the limbs and neck with frequent facial involvement. Onset is typically from infancy to late adolescence. The severity is variable, sometimes resulting in difficulty walking and talking. The disorder has been intially reported by Bird and Hall in 1978 as a possible variant of familial essential chorea, but the finding of myokymia-like twitches led to exclude this possibility. Dyskinetic movements are often aggravated by stress and anxiety.
In more severe patients axial hypotonia, limb hypertonia, paroxysmal nocturnal or diurnal dyskynesia and delayed motor development may also appear. The movement disorder can be static or slowly progressive, but tends to stabilize in early middle age. Mental retardation is not a feature of ADCY5-related dyskinesia and life expectancy is normal. The diagnosis of the condition is both clinical and genetic, since the confirmation through the detection of an ADYC5 mutation is necessary.
ADCY5 mutational spectrum & testing method
It is thought that the disorder, like many other autosomal dominant genetic diseases, is caused by gain-of-function mutations (PMID: 24700542). Adenylate (adenylyl) cyclase 5 and adenylyl cyclase 6 (ADCY5 and ADCY6) are strongly expressed in cerebellar granular neuron precursors and their overexpression may repress the hedgehog pathway in these cells and in the embryonic neural tube (PMID: 26092933). Of note, ADCY6 gene mutations are thought to cause a lethal form of arthrogryposis multiplex congenita (lethal congenital contracture syndrome-8 – LCCS8).
Particular importance seems to be attributable to the codons 418 and 726, where mutations are recurrent. So far, at least the following four pathogenic missense mutations have been detected in the ADCY5 gene: p.Arg418Trp, p.Arg418Gln, p.Ala726Thr, and p.Met1029Lys (reference transcript: NM_183357.2 reference protein sequence: NP_899200.1)
No large deletions/duplications not detectable by sequencing have been reported thus far to cause familial dyskynesia, although the ADCY5 gene falls surrounded by several other morbid genes in a region of which copy number variations (CNV) have been found in patients with complex polysyndromic disorders (see the DECIPHER database – query “ADCY5”).
How to analyze ADCY5
The ADCY5 gene canbe analyzed by sequencing of the entire coding region (Sanger, targeted NGS, exome sequencing). Of note, a significant number of studies on the ADCY5 gene have been conducted by exome sequencing. Large deletion/duplication testing (MLPA, qPCR) is not needed nor recommended.
Genotype-specific correlations and mosaicism have been found to play important roles in the phenotypic variability. The four common mutations can be placed on the spectrum of clinical variability with the p.A726T mutation staying at the mildest end, mutations p.R418W or p.R418Q staying in the middle-severe phenotypic range and the p.M1029K mutation staying at the most severe end. As expected, somatic mosaicism is usually associated with a less severe phenotype (PMID: 26537056).
Benign hereditary chorea: ADCY5 mutations may also cause benign hereditary chorea, as reported by Menacci et al (2015). The authors found that ADCY5 mutations may be present also in some patients with no facial myokymia and genetically undefined benign hereditary chorea (BHC). They observed, though, a significant progression of symptoms in ADCY5 mutation carriers, in contrast to BHC secondary to NKX2-1 mutations. They stated that ADCY5 genetic analysis should be performed in cases with a benign choreiform movement disorder even in the absence of facial myokymia.
Epiplepsia is often considered as an alternative diagnosis at first, but the lack of EEGs stigmata and response to antiepileptic drug helps redirecting the diagnosis. Facial myokymia may also evoke multiple sclerosis. Genetically determined conditions which can be included in the differential diagnosis are:
– Benign hereditary chorea (BHC), which is also autosomal dominantly inherited and caused by mutation in the NKX2-1 gene (given, however, that BHC is also allelic to ADCY5-related dyskinesia, since ADCY5 mutations can be found also in BHC – see above).
– Familial paroxysmal kinesigenic dyskinesia (PKD), caused by mutation of PRRT2.
– Familial paroxysmal nonkinesigenic dyskinesia (PNKD), caused by mutation of PNKD.
– Paroxysmal choreoathetosis/spasticity (DYT9), caused by mutation of SLC2A1.
Recommended testing workflow
Recommended panel testing at Breda Genetics for this condition (EXOME PANEL):
ADCY5-Related Dyskinesia. Shaw C, Hisama F, Friedman J, Bird TD. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2014 Dec 18 [updated 2015 Dec 17]. PMID: 25521004
ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations. Chen DH, Méneret A, Friedman JR, Korvatska O, Gad A, Bonkowski ES, Stessman HA, Doummar D, Mignot C, Anheim M, Bernes S, Davis MY, Damon-Perrière N, Degos B, Grabli D, Gras D, Hisama FM, Mackenzie KM, Swanson PD, Tranchant C, Vidailhet M, Winesett S, Trouillard O, Amendola LM, Dorschner MO, Weiss M, Eichler EE, Torkamani A, Roze E, Bird TD, Raskind WH. Neurology. 2015 Dec 8;85(23):2026-35. PMID: 26537056
ADCY5 mutations are another cause of benign hereditary chorea. Mencacci NE, Erro R, Wiethoff S, Hersheson J, Ryten M, Balint B, Ganos C, Stamelou M, Quinn N, Houlden H, Wood NW, Bhatia KP. Neurology. 2015 Jul 7;85(1):80-8. PMID: 26085604
Ciliary adenylyl cyclases control the Hedgehog pathway. Vuolo L, Herrera A, Torroba B, Menendez A, Pons S. J Cell Sci. 2015 Aug 1;128(15):2928-37. PMID: 26092933
Additional resources for patients and professionals: www.adcy5.org