Alternative titles; symbols
ORPHA: 324588;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q21.1 | Dyskinesia with orofacial involvement, autosomal dominant | 606703 | Autosomal dominant | 3 | ADCY5 | 600293 |
A number sign (#) is used with this entry because of evidence that autosomal dominant dyskinesia with orofacial involvement (DSKOD) is caused by heterozygous mutation in the ADCY5 gene (600293) on chromosome 3q21.
Biallelic mutation in the ADCY5 gene can also cause similar recessive movement disorders: see DSKOR (619647) and the more severe NEDHYM (619651).
Autosomal dominant dyskinesia with orofacial involvement (DSKOD) is a complex neurologic disorder characterized by onset of involuntary choreiform, myoclonic, and dystonic movements involving the neck, limb, and facial muscles in the first decade of life. The manifestations and severity are variable; the disorder can also include episodic weakness and spasticity, resulting in difficulty walking and talking. It is generally nonprogressive, especially in adulthood, and dementia is not observed, although some individuals may have difficulties in school or behavioral abnormalities, such as social isolation (summary by Chen et al., 2014; Carapito et al., 2015; Dean et al., 2019; Vijiaratnam et al., 2019).
Vijiaratnam et al. (2019) provided a review of ADCY5-related dyskinesia, noting that the phenotypic features, manifestations, and severity are broad and variable. There are also variable molecular findings, including de novo mutations and mosaicism, the latter of which can influence expressivity.
Bird et al. (1976) and Fernandez et al. (2001) reported a large multigenerational American family of English ancestry (family EHC) with an autosomal dominant hereditary movement disorder. Affected individuals presented in childhood with rapid jerky choreic movements involving the extremities, head, and face. The abnormal movements increased until early adolescence, when progression ceased. Although the disorder was not associated with dementia, some patients had learning difficulties or behavioral abnormalities, possibly associated with social isolation. Bird et al. (1976) noted that the disorder can be a socially embarrassing condition and, perhaps for that reason, may be associated with behavioral problems and learning difficulties. For purposes of genetic counseling and prognostication, it is important to distinguish it from Huntington disease (HD; 143100).
Fernandez et al. (2001) reported a 5-generation German family segregating an autosomal dominant syndrome of familial dyskinesia and what they termed 'facial myokymia' (FDFM). The disorder was characterized by adventitious movements that sometimes appeared to be choreiform and were associated with perioral and periorbital movements interpreted as myokymia. The same family had been reported by Bird and Hall (1978) as a possible variant of familial essential chorea (118700) before the recognition of myokymia as a feature. Eighteen members of the family, including 10 males and 8 females, were affected, and all had onset in early childhood or adolescence. The involuntary movements were paroxysmal at early ages, increased in frequency and severity, and in some became constant in the third decade. Thereafter, there was no further deterioration. The adventitious movements were worsened by anxiety but not by voluntary movement, startle, caffeine, or alcohol. The disease was socially disabling, but had no effect on intellect or life span.
Chen et al. (2012) provided follow-up of the family reported by Fernandez et al. (2001). The age at onset ranged from 2.5 to 19 years. Reexamination of 1 affected individual at age 50 years showed some improvement of the neurologic manifestations. However, he had developed severe dilated cardiomyopathy at age 46 years, and family history revealed that 4 neurologically affected individuals also developed congestive heart failure. Chen et al. (2012) suggested that heart disease may be a component of FDFM.
Chen et al. (2014) reported 2 unrelated teenaged girls of European descent with a movement disorder since childhood. A 15-year-old girl presented with axial hypotonia and weakness, limb hypertonia, hyperreflexia, intermittent tremors and paroxysmal dyskinesia, dystonia, and myoclonus both at rest and with activity. She had poor neck support, extreme difficulty walking, dysarthria, and subtle signs of perioral and periorbital dyskinesia. The abnormal movements also caused significant sleep disruption. The patient had had mildly delayed motor development in infancy, with the first appearance of paroxysmal choreic movements at age 19 months. An 18-year-old girl was less severely affected. She had onset of choreiform movements at age 5 years. Choreoathetosis and dystonia were most prominent at rest and were alleviated by physical activity. The abnormal movements progressed to include facial twitches and mild dysarthria, but frank myokymia was not present. Treatments were ineffective.
Carapito et al. (2015) reported a French father and son with onset of dystonia and chorea in early childhood. They had mild motor delay with walking on tiptoes and frequent falls, but no ataxia. Involuntary choreic movements in the fingers, toes, and face were also observed, although myokymia was not present. The patients were diagnosed clinically with dystonia affecting all four limbs and the neck. Hyperreflexia and extensor plantar responses indicated pyramidal involvement. Oculomotor function and cognition were normal. The report expanded the phenotype associated with ADCY5 mutations.
Westenberger et al. (2017) reported 2 unrelated boys, 14 and 9 years of age, with onset of a hyperkinetic movement disorder in early childhood. They had delayed walking and speech delay, axial hypotonia, choreic movements, orofacial dystonia and chorea, perioral dyskinesia, dysarthria or drooling, paroxysmal dystonia, retrocollis, and limb jerks. Both patients also had episodic weakness and paralysis reminiscent of alternating hemiplegia of childhood. In addition, they had variable developmental delay and ADHD.
Tunc et al. (2017) performed electrophysiologic studies on 5 patients with hyperkinetic movement disorders associated with heterozygous ADCY5 mutations. The findings indicated that the facial and truncal muscle twitches/jerks were consistent with myoclonus and chorea rather than myokymia. The authors concluded that the term 'myokymia' is misleading in describing this disorder and suggested the term 'myoclonus-chorea.'
Waalkens et al. (2018) reported 3 unrelated patients with DSKOD. Patient 1 was a 40-year-old woman with a history of delayed walking who presented with progressive weakness of the lower limbs and spastic paraparesis with hyperreflexia, hypertonia, and extensor plantar responses. She had mild dystonic posturing of the foot and writer's cramp. The authors emphasized the expansion of the phenotype to include spastic paraplegia. The other 2 patients had delayed motor milestones, axial hypotonia, dyskinesia, involuntary movements, orofacial involvement, dysarthria or absent speech, myoclonus, dystonia, and chorea. One patient had significant psychiatric features, including tics, coprolalia, obsessive-compulsive disorder, and anxiety with phobias.
Dean et al. (2019) reported a 21-year-old woman with lower limb spasticity, dystonia, and weakness with symptom onset around 5 years of age when she developed an abnormal gait and toe walking. The disorder was progressive and she was unable to stand unassisted at age 21. Other features included slurred speech, leg jerks in the evening, intermittent hand tremor, hyperreflexia with extensor plantar responses, distal sensory impairment of the toes, and leg dystonia. She also had learning difficulties and dropped out of school. Brain imaging showed T2-weighted hyperintensities in the white matter and mild cerebellar vermis atrophy. The report indicated that spastic paraplegia can be a manifestation of this disorder.
Shetty et al. (2020) reported a 32-year-old Indian man with a mosaic missense mutation in the ADCYY5 gene (600293.0002). At the age of 4 years, he started to have paroxysmal involuntary movements during sleep. The movement events, which consisted of generalized nonpatterned choreiform with dystonic movements, lasted about 3 minutes each and occurred 20 to 30 times per night. He did not have movement- or exercise-triggered events.
Meneret et al. (2019) reported an 11-year-old boy from Madagascar who had ADCY5-related dyskinesia since early childhood. He had frequent daily episodes of choreodystonic movements that disrupted his activities. Genetic analysis identified mosaicism for a splice site mutation in the ADCY5 gene (c.2088+1G-A; 600293.0003), which the authors postulated resulted in a gain-of-function effect, although no functional studies of the variant or studies of patient cells were performed. The patient had a remarkable favorable response to caffeinated coffee, which resulted in near complete resolution of the dyskinetic episodes. Meneret et al. (2019) postulated that the caffeine antagonized adenosine A2A receptors, which would inhibit the ADCY5 enzyme. Of note, this mutation had previously been identified by Carapito et al. (2015), who concluded that the splice site mutation resulted in a loss of function and haploinsufficiency.
Shetty et al. (2020) reported a patient with DSKOD and a mosaic missense mutation in the ADCY5 gene (600293.0002) who was treated with caffeine capsules and experienced a 90% reduction in the number of paroxysmal movement events.
The transmission pattern of DSKOD in the family reported by Fernandez et al. (2001) was consistent with autosomal dominant inheritance.
Fernandez et al. (2001) performed a candidate gene and haplotype analysis in 9 affected and 3 unaffected members from 3 generations of a German family segregating dyskinesia with orofacial involvement and excluded linkage to 11 chromosomal regions containing genes associated with chorea and myokymia.
In affected members of a large German family with DSKOD (Bird et al., 1976; Fernandez et al., 2001), Chen et al. (2012) identified a heterozygous missense mutation in the ADCY5 gene (A726T; 600293.0001). Chen et al. (2012) noted that Adcy5-null mice develop a movement disorder that is worsened by stress (Kim et al., 2006), supporting the pathogenicity of the A726T mutation.
In 2 unrelated teenaged girls of European ancestry with DSKOD, Chen et al. (2014) identified a de novo heterozygous mutation in the ADCY5 gene (R418W; 600293.0002). The mutations were found by whole-exome sequencing. In vitro functional expression studies showed that both mutant A726T and R418W ADCY5 caused a significant increase in cAMP production in response to beta-adrenergic stimulation compared to wildtype, consistent with a gain of function. One of the girls with a more severe phenotype also carried a de novo heterozygous N1882S variant in the DOCK3 gene (603123), which may have a role in neuronal activity and could have possibly contributed to the phenotype. In addition, sequence reads suggested that the girl with the less severe phenotype may have been somatic mosaic for the R418W mutation. Chen et al. (2014) postulated that these findings may have played a role in the phenotypic variability observed in the 2 patients.
In affected members of a large 5-generation family (EHC), previously reported by Bird et al. (1976) and Fernandez et al. (2001) as having benign hereditary chorea, Chen et al. (2015) identified a heterozygous A726T mutation in the ADCY5 gene. Functional studies of the variant and studies of patient cells were not performed.
In a French father and son with DSKOD, Carapito et al. (2015) identified a heterozygous splice site mutation in the ADCY5 gene (600293.0003). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells had decreased ADCY5 mRNA levels, consistent with degradation of the mutant transcript, a loss of function, and haploinsufficiency. The findings suggested that haploinsufficiency of ADCY5 is pathogenic, although a gain-of-function effect could not be ruled out.
In 2 unrelated boys with DSKOD and paroxysmal paralysis reminiscent of alternating hemiplegia of childhood, Westenberger et al. (2017) identified heterozygous missense mutations in the ADCY5 gene (D1015E; 600293.0004 and E1025V). Both mutations occurred at conserved residues in the second cytoplasmic domain that forms the catalytic pocket. The mutations, which were found by direct sequencing, were not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
In a woman with DSKOD who presented with spastic paraplegia, Waalkens et al. (2018) identified a heterozygous E908K mutation in the M2 domain of the ADCY5 gene. Two additional unrelated patients with more classic features of the disorder were heterozygous for the R418W (600293.0002) and R418Q missense mutations in the ADCY5 gene, respectively. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to be pathogenic.
In a 21-year-old woman with DSKOD, Dean et al. (2019) identified a de novo heterozygous missense mutation in the ADCY5 gene (Y233H; 600293.0005) affecting a conserved residue in the M1 domain. The mutation, which was found by whole-genome sequencing, was not present in the ExAC or 1000 Genomes Project databases. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to be likely pathogenic according to ACMG criteria. In addition to dyskinesia and dystonia, the patient had spastic paraplegia and mild distal sensory impairment. Dean et al. (2019) noted that the E908K variant identified by Waalkens et al. (2018) in a patient with spastic paraparesis and mild dystonia occurred in the M2 domain.
In an 18-year-old man (INDF10_3) of Indian origin with DSKOD, Kumar et al. (2019) identified a de novo heterozygous missense mutation in the ADCY5 gene (M1029K; 600293.0006). The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing and filtered against control databases. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to be pathogenic according to ACMG criteria. The patient had myoclonic dystonia, congenital encephalopathy, and daily paroxysmal ballismus.
Chen et al. (2015) observed that patients with DSKOD with the A726T mutation had a relatively mild phenotype compared to patients with an R418W or R418Q mutation. In addition to dystonia, myoclonus, chorea, and facial twitching, those with the R418 mutations tended to also have axial hypotonia, paroxysmal episodes, nocturnal movements, and painful movements. A few had mild cognitive or behavioral disturbances.
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