Adcy5 Dyskinesia
Summary
Clinical characteristics.
ADCY5 dyskinesia is a hyperkinetic movement disorder (more prominent in the face and arms than the legs) characterized by infantile to late-adolescent onset of chorea, athetosis, dystonia, myoclonus, or a combination of these. To date, affected individuals have had overlapping (but not identical) manifestations with wide-ranging severity. The facial movements are typically periorbital and perioral. The dyskinesia is prone to episodic or paroxysmal exacerbation lasting minutes to hours, and may occur during sleep. Precipitating factors in some persons have included emotional stress, intercurrent illness, sneezing, or caffeine; in others, no precipitating factors have been identified. In some children, severe infantile axial hypotonia results in gross motor delays accompanied by chorea, sometimes with language delays. The overall tendency is for the abnormal movements to stabilize in early middle age, at which point they may improve in some individuals; less commonly, the abnormal movements are slowly progressive, increasing in severity and frequency.
Diagnosis/testing.
The diagnosis of ADCY5 dyskinesia is established in a proband with a hyperkinetic movement disorder (in the absence of structural brain abnormalities) and a heterozygous pathogenic variant (or, rarely, biallelic pathogenic variants) in ADCY5 identified by molecular genetic testing.
Management.
Treatment of manifestations: Management by multidisciplinary specialists, including a neurologist or neurogeneticist, cardiologist, physical therapist, social worker, speech and language pathologist, and other specialists is recommended as needed. Anecdotally, medications have had variable effect in suppressing debilitating symptoms. Treatment should be determined by the individual's physician, taking into account potential risk/benefit, other medical conditions, allergies, and potential drug-drug interactions. Response to medication is difficult to evaluate because some individuals have long periods (weeks) of remission of the dyskinesia. Physical and occupational therapy may help maintain mobility and function. Speech and language therapy for dysarthria may include alternative communication methods. Cognitive impairment and psychiatric manifestations are managed per standard practice.
Surveillance: Routine follow up of neurologic involvement, dysarthria, oculomotor involvement, musculoskeletal involvement, activities of daily living, cognitive impairment, and psychiatric manifestations.
Pregnancy management: Potential teratogenic effects of medications given for treatment of ADCY5 dyskinesia should be discussed with affected women of childbearing age, ideally prior to conception.
Genetic counseling.
ADCY5 dyskinesia is typically inherited in an autosomal dominant (AD) manner. Autosomal recessive (AR) inheritance has been reported in two families.
AD inheritance: The majority of individuals diagnosed with ADCY5 dyskinesia represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a de novo pathogenic variant. Each child of an individual with ADCY5 dyskinesia has a 50% chance of inheriting the pathogenic variant.
Both AD and AR inheritance: Once the ADCY5 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for ADCY5 dyskinesia are possible.
Diagnosis
No consensus diagnostic guidelines for ADCY5 dyskinesia have been published.
Suggestive Findings
Diagnosis of ADCY5 dyskinesia should be suspected in individuals with the following clinical findings, neuroimaging, and family history.
Clinical findings
- Infantile to late-adolescent onset of choreiform, myoclonic, and/or dystonic movements that involve the limbs, neck, and/or face
- Familial benign chorea
- Alternating hemiplegia in childhood
- Myoclonus-dystonia
- Focal dystonia and tremor
- Spasticity and dystonia
- Sleep-related motor and behavior disorder
Neuroimaging. Brain MRI shows no evidence of structural abnormalities.
Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) or, rarely, autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
Establishing the Diagnosis
The diagnosis of ADCY5 dyskinesia is established in a proband with a hyperkinetic movement disorder (in the absence of structural brain abnormalities) and a heterozygous pathogenic variant (or, rarely, biallelic pathogenic variants) in ADCY5 identified by molecular genetic testing (see Table 1).
Note: Identification of a heterozygous ADCY5 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of ADCY5 dyskinesia has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
Single-gene testing. Sequence analysis of ADCY5 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected.
If no variant is detected by the sequencing method used, the next step typically is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; however, because ADCY5 dyskinesia occurs through a gain-of-pathogenic-function mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
Mosaicism of pathogenic variants has been reported.
A movement disorder multigene panel that includes ADCY5 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in ADCY5 Dyskinesia
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| ADCY5 | Sequence analysis 3 | 100% 4, 5 |
| Gene-targeted deletion/duplication analysis 6 | None reported 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Chen et al [2012], Chen et al [2014], Chen et al [2015], Zech et al [2017], and data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]
- 5.
In a simplex case (i.e., a single occurrence in a family), germline mosaicism for the pathogenic variant may complicate interpretation of sequencing results.
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
Because ADCY5 dyskinesia occurs through a gain-of-pathogenic-function mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease causing variant.
Clinical Characteristics
Clinical Description
The hallmark of ADCY5 dyskinesia is infantile to late-adolescent onset of a hyperkinetic movement disorder characterized by chorea, athetosis, dystonia, myoclonus, or a combination which tends to be more prominent in the face and arms than the legs [Chen et al 2015]. Affected individuals identified to date have overlapping but not identical clinical manifestations with wide-ranging clinical severity. The facial movements are typically periorbital and perioral. The dyskinesia is prone to episodic or paroxysmal bouts of exacerbation lasting minutes to hours, and may occur during sleep. Precipitating factors have included emotional stress, intercurrent illness, sneezing, or caffeine [Vijiaratnam et al 2019]. In other affected individuals, no precipitating factors have been identified. In some children, severe infantile axial hypotonia results in gross motor delays accompanied by chorea, sometimes with language delays [Carecchio et al 2017]. The phenotypic spectrum of this disorder is still being elucidated.
ADCY dyskinesia was first identified in a single multigenerational family [Chen et al 2012]. Following that publication, more than 40 individuals representing simplex cases (i.e., a single occurrence in a family) and members of more than ten families with ADCY5 dyskinesia have been reported [Chen et al 2015, Vijiaratnam et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
ADCY5 Dyskinesia: Frequency of Select Features
| Feature | Frequency | Comment | ||
|---|---|---|---|---|
| Nearly all | Common | Infrequent | ||
| Dyskinesia | ● | |||
| Axial hypotonia | ● | In children presenting in infancy | ||
| Spasticity | ● | |||
| Intellectual disability | ● | |||
| Epilepsy | ● | |||
| Psychiatric disease | ● | |||
| Cardiomyopathy | ● | |||
Neurologic Manifestations
All affected individuals reported to date have had episodes of choreiform, myoclonic, and/or dystonic movements that primarily affect the limbs, face, and/or neck. Typically the abnormal movements first appear during infancy, childhood, or early adolescence (range: neonatal period to age 19 years) [Chen et al 2015].
In those with milder manifestations, the abnormal movements involve the face and distal limbs (although minimally affecting function) and are socially debilitating. Some affected individuals may be described as "excessively clumsy."
In more severely affected infants, the earliest manifestations can include severe axial hypotonia resulting in developmental delays that lead to impairment in the ability to ambulate, requiring use of wheelchairs.
The abnormal movements are continual during waking hours, and have been noted to persist during sleep, particularly in infancy. Several affected individuals have noted severe, sleep-disrupting movements [Chen et al 2014, Chen et al 2015] that occurred during stages N2 and N3 of sleep, and were not associated with epileptiform discharges in one individual [Chen et al 2014].
A curious feature observed in some individuals is the occurrence of long periods (days to weeks) of remission.
The movements are often exacerbated by anxiety or stress and with drowsiness or sleep (although not by startle or alcohol). Less common triggers include intercurrent illness, fatigue, excitement, or caffeine, although one individual showed improvement with caffeine and other individuals have reported benefit [J Friedman, personal observation]. One woman reported that her choreiform movements were precipitated by enforced inactivity (e.g., as during a road trip), and could often be alleviated by voluntary movement.
Facial "twitches" (previously thought to be myokymia) involving the periorbital and/or perioral muscles may also be present. Twitches were also documented in limb muscles in one individual [Fernandez et al 2001].
Dysarthria and hypotonia have been reported in some affected individuals [Chen et al 2014, Chen et al 2015, Mencacci et al 2015].
Intellect and life span are usually normal. In severely affected individuals with onset in early childhood, intellectual disability may be present.
Neurologic examination can vary widely between individuals and in the same individual over time. Examination may reveal:
- A mixed movement disorder that may include prominent choreiform movements usually affecting the hands and/or feet, often characterized as piano playing movements [Vijiaratnam et al 2019];
- Myoclonic and dystonic movements [Friedman et al 2016];
- Non-myokymic facial twitching, hyperreflexia of the lower limbs, and intermittent head or limb tremors [Chen et al 2014];
- Axial hypotonia with limb and axial weakness including severe neck weakness [Chen et al 2014, Chen et al 2015];
- Alternating hemiplegia of childhood [Westenberger et al 2017];
- Progressive spasticity and dystonia with hyperreflexia [Dean et al 2019, Waalkens et al 2018].
Somatic mosaicism has been demonstrated in 43% of individuals with a de novo pathogenic variant [Raskind et al 2017] and in the founders of two multigenerational families, including one individual shown to be mosaic for the p.Met1029Lys variant who demonstrated considerable improvement during adulthood [Chen et al 2015].
Another individual, thought to be mosaic for p.Arg418Trp, exhibited significantly milder phenotypic features: fewer facial twitches, milder chorea, and no dysarthria [Mencacci et al 2015].
The natural history varies. In most, the abnormal movements are static or slowly progressive with increased severity and frequency. In some instances, choreiform movements have been more constant, and less paroxysmal, from the onset [Mencacci et al 2015]. The overall tendency is for the abnormal movements to stabilize in early middle age, at which point they may improve in some individuals.
Cardiac Complications
Chen et al [2011] reported that five individuals in a family with ADCY5 dyskinesia also had congestive heart failure. Because ADCY5 encodes a specific adenylyl cyclase that is highly expressed in both striatum and myocardium [Ho et al 2010], these observations suggest that pathogenic variants in ADCY5 could contribute to cardiac pathology; further study is required.
Studies
Needle electromyogram (EMG) studies in two individuals with facial muscle twitching suggested centrally driven irregular muscle movements that were also observed in other muscles, including the orbicularis oculi, tongue, frontalis, and dorsal interosseous muscles. No fibrillations, fasciculations, myokymia, or myotonia were noted on EMG.
Brain imaging (MRI, CT) is normal.
Neuropathology. Gross pathology is normal. Detailed immunohistochemical analysis in one individual with molecularly confirmed ADCY5 dyskinesia revealed increased immunoreactivity for ADCY5 in multiple brain regions as well as tau deposits in deep cortical sulci, the midbrain and hippocampus. Lewy bodies and amyloid pathology were absent [Chen et al 2019].
Genotype-Phenotype Correlations
In general, the number of individuals and families tested to date is too small to make reliable predictions of phenotypic features based on genotype; however, one missense variant, p.Ala726Thr, has been associated with a milder phenotype [Vijiaratnam et al 2019] (see Table 7).
Penetrance
In molecularly confirmed ADCY5 dyskinesia, penetrance has been 100% in both men and women.
Nomenclature
ADCY5 dyskinesia has been previously described as:
- A variant of familial essential ("benign") chorea. Although the term "benign" was used to distinguish the movement disorder from progressive, neurodegenerative forms of chorea such as Huntington disease, ADCY5 dyskinesia can be disabling and in some instances progressive, and, thus, use of the term "benign hereditary chorea" should be avoided.
- "Familial dyskinesia facial myokymia" because the prominent facial twitching was originally thought to be myokymia (see Clinical Description); however, more recently EMG studies of affected individuals have revealed that these twitches are not myokymia.
DYT-ADCY5 may be an appropriate designation because dystonia is often a prominent feature [Marras et al 2012].
Prevalence
No data are available for the prevalence of ADCY5 dyskinesia. It is likely underdiagnosed because of the variability in the clinical presentation and age of onset, and because of the high rate of de novo variants resulting in simplex cases (i.e., a single occurrence in a family) [Vijiaratnam et al 2019].
Differential Diagnosis
Hereditary Disorders
Table 3.
Genes of Interest in the Differential Diagnosis of ADCY5 Dyskinesia
| Gene(s) | Disorder | MOI | Clinical Characteristics of Differential Diagnosis | |
|---|---|---|---|---|
| Overlapping w/ADCY5 Dyskinesia | Distinguishing from ADCY5 Dyskinesia | |||
| ANO3 | DYT-ANO3 (See Hereditary Dystonia Overview.) | AD | Focal dystonia & tremor | Affects neck, laryngeal muscles, and arms |
| ATP1A3 | Alternating hemiplegia of childhood (See ATP1A3 Neurologic Disorders.) | AD | Alternating hemiplegia | Episodic hemiplegia assoc w/movement disorder |
| CHRNA2 CHRNA4 CHRNB2 CRH DEPDC5 KCNT1 | AD nocturnal frontal lobe epilepsy | AD | Sleep-related motor & behavioral disorders | On video-EEG: focal interictal epileptiform discharges arising from the frontal lobe; seizures recorded |
| GCH1 | GTP cyclohydrolase 1-deficient dopa-responsive dystonia | AD | Dystonia | Dramatic response to treatment w/L-dopa |
| HTT | Huntington disease | AD | Chorea |
|
| NKX2-1 | Benign hereditary chorea (See NKX2-1 Disorders.) | AD | Presents before age 5 yrs |
|
| PDE10A | Infantile-onset limb & orofacial dyskinesia (OMIM 616921) | AR | Childhood onset chorea |
|
| PDE2A | PDE10A childhood-onset chorea 1 | Childhood onset chorea | Striatal lesions on brain MRI | |
| PNKD | Familial paroxysmal nonkinesigenic dyskinesia | AD |
| Consumption of alcohol or caffeine may precipitate attacks |
| PRRT2 | Paroxysmal kinesigenic dyskinesia (PKD) (See PRRT2 Paroxysmal Movement Disorders.) | AD |
| PKD is more common in men & is precipitated by voluntary movement. |
| SGCE | SGCE myoclonus-dystonia | AD | Myoclonus-dystonia | Improves w/alcohol consumption; psychiatric manifestations are more common. |
| SLC2A1 | Paroxysmal choreoathetosis w/spasticity (See Glucose Transporter Type 1 Deficiency Syndrome.) | AD (AR) | Presents w/dystonic paroxysms affecting toes, legs, & arms; dysarthria; & changes in perioral sensation | No distinguishing clinical characteristics |
AD = autosomal dominant; AR = autosomal recessive; DYT = dystonia; MOI = mode of inheritance
- 1.
Mencacci et al [2016]
Mitochondrial disorders can present with dystonia or other abnormal movements.
Drug-Induced and Acquired Disorders
Tardive dyskinesia, a hyperkinetic movement disorder associated with long-term use of specific dopamine receptor blocking agents (including neuroleptics and certain antiemetics) [Aquino & Lang 2014], is often precipitated by a recent dose reduction or a change to a less potent drug.
Sydenham chorea, a manifestation of acute rheumatic fever, is the most common cause of acquired chorea in childhood, and typically presents between ages five and 12 years. Although carditis and arthritis are other manifestations of rheumatic fever, chorea may be the only clinical sign. Antistreptolysin O (ASO) titers are elevated in a significant proportion of affected individuals.
Multiple sclerosis can cause continuous facial myokymia in individuals with lesions impinging on the facial nerve as it courses in the dorsolateral pontine tegmentum. Other features – particularly abnormalities on brain MRI, which are disseminated in space and time – should assist in making the correct diagnosis.
Note: The hyperkinetic movements of ADCY5 dyskinesia may be mistakenly thought to be epileptiform; however, normal EEGs, lack of impaired consciousness, and/or lack of response to antiepileptic medication distinguish epilepsy from ADCY5 dyskinesia.
Management
Consensus clinical management recommendations for ADCY5 dyskinesia have not been published.
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with ADCY5 dyskinesia, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with ADCY5 Dyskinesia
| System/Concern | Evaluation | Comment |
|---|---|---|
| Neurologic involvement | By a neurologist | Assess:
|
| Oculomotor involvement | Complete ophthalmologic examination | Assess best corrected visual acuity; nystagmus, saccades & smooth pursuit; vertical & horizontal gaze limitation; ptosis. |
| Musculoskeletal | Orthopedics / physical medicine & rehabilitation / PT/OT evaluation | To incl assessment of:
|
| DD / Cognitive impairment | Developmental behavioral pediatrician, neurologist, or geneticist | Children |