NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

ADCY5 Dyskinesia

, MD, , MD, , MD, PhD, and , MD.

Author Information

Initial Posting: ; Last Update: July 30, 2020.

Estimated reading time: 23 minutes

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 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
ADCY5Sequence analysis 3100% 4, 5
Gene-targeted deletion/duplication analysis 6None reported 7
1.
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

FeatureFrequencyComment
Nearly allCommonInfrequent
Dyskinesia
Axial hypotoniaIn 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:

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)DisorderMOIClinical Characteristics of Differential Diagnosis
Overlapping w/ADCY5 DyskinesiaDistinguishing from ADCY5 Dyskinesia
ANO3DYT-ANO3 (See Hereditary Dystonia Overview.)ADFocal dystonia & tremorAffects neck, laryngeal muscles, and arms
ATP1A3Alternating hemiplegia of childhood (See ATP1A3 Neurologic Disorders.)ADAlternating hemiplegiaEpisodic hemiplegia assoc w/movement disorder
CHRNA2
CHRNA4
CHRNB2
CRH
DEPDC5
KCNT1
AD nocturnal frontal lobe epilepsyADSleep-related motor & behavioral disordersOn video-EEG: focal interictal epileptiform discharges arising from the frontal lobe; seizures recorded
GCH1GTP cyclohydrolase 1-deficient dopa-responsive dystoniaADDystoniaDramatic response to treatment w/L-dopa
HTTHuntington diseaseADChorea
  • Mean onset age: 35-44 yrs
  • Choreiform movements become constant over time.
NKX2-1Benign hereditary chorea (See NKX2-1 Disorders.)ADPresents before age 5 yrs
  • Manifestations often improve by late adolescence.
  • Pulmonary dysfunction & endocrine abnormalities, most commonly hypothyroidism (Note: Non-neurologic manifestations are rare in ADCY5 dyskinesia.)
PDE10AInfantile-onset limb & orofacial dyskinesia (OMIM 616921)ARChildhood onset chorea
  • Diurnal fluctuation
  • Striatal lesions on brain MRI
PDE2APDE10A childhood-onset chorea 1Childhood onset choreaStriatal lesions on brain MRI
PNKDFamilial paroxysmal nonkinesigenic dyskinesiaAD
  • Unilateral or bilateral involuntary movements
  • Attacks are spontaneous or precipitated; involve dystonic posturing w/choreic & ballistic mvmts; may be accompanied by preceding aura; occur while awake; are not assoc w/seizures.
Consumption of alcohol or caffeine may precipitate attacks
PRRT2Paroxysmal kinesigenic dyskinesia (PKD) (See PRRT2 Paroxysmal Movement Disorders.)AD
  • Unilateral or bilateral involuntary mvmts precipitated by other sudden mvmts (e.g., standing up from sitting position; being startled; changes in velocity).
  • Attacks incl combinations of dystonia, choreoathetosis, & ballism; are sometimes preceded by an aura; do not involve loss of consciousness.
PKD is more common in men & is precipitated by voluntary movement.
SGCESGCE myoclonus-dystoniaADMyoclonus-dystoniaImproves w/alcohol consumption; psychiatric manifestations are more common.
SLC2A1Paroxysmal choreoathetosis w/spasticity (See Glucose Transporter Type 1 Deficiency Syndrome.)AD
(AR)
Presents w/dystonic paroxysms affecting toes, legs, & arms; dysarthria; & changes in perioral sensationNo distinguishing clinical characteristics

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/ConcernEvaluationComment
Neurologic
involvement
By a neurologistAssess:
  • Neurologic findings incl spasticity, dystonic posturing, sleep-related movements;
  • Response or lack of response to medications.
Oculomotor
involvement
Complete ophthalmologic examinationAssess best corrected visual acuity; nystagmus, saccades & smooth pursuit; vertical & horizontal gaze limitation; ptosis.
MusculoskeletalOrthopedics / physical medicine & rehabilitation / PT/OT evaluationTo incl assessment of:
  • Gross motor & fine motor skills
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
  • Mobility, self-help skills, activities of daily living, & need for adaptive devices
DD / Cognitive
impairment
Developmental behavioral pediatrician, neurologist, or geneticistChildren: To incl motor, adaptive, cognitive, & speech/language eval; eval for early intervention / special education
Clinical psychologistAdults: Assess for deficits in spatial working & episodic memory
DysarthriaSpeech & language assessmentRelated to abnormal tongue & facial movements
Psychiatric
manifestations
  • Child psychiatrist
  • Clinical psychologist
Depression, psychosis w/delusions & auditory hallucinations, obsessive-compulsive symptoms, autistic-like behavior
Cardiac
involvement
ECG, echocardiogram, cardiology evalDilated cardiomyopathy may be a manifestation.
Genetic counselingBy genetics professionals 1To inform affected persons & their families re nature, MOI, & implications of ADCY5 dyskinesia in order to facilitate medical & personal decision-making
Family support/
resources
Assess:
  • Use of community or online resources such as Parent to Parent;
  • Need for social work involvement for parental support;
  • Need for home nursing referral.
Disease severity may qualify some persons for disability &/or social security benefits.

DD = developmental delay; MOI= mode of inheritance

1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

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.

Medication has been variably effective in suppressing debilitating manifestations. 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 in an individual because some have long periods (weeks) of remission of the dyskinesia [Vijiaratnam et al 2019].

Table 5.

Treatment of Manifestations in Individuals with ADCY5 Dyskinesia

Manifestation/
Concern
TreatmentConsiderations/Other
Chorea &
dyskinesia
AcetazolamideUp to 30 mg/kg/day
Other potentially beneficial medications
  • Trihexyphenidyl
  • Tetrabenazine
  • Clonazepam
  • Propranolol
  • Levocarnitine
  • Levetirracetam
  • Methylphenidate
Medications that may worsen manifestationsAny of the above
Deep brain stimulationImproves movement disorder in some persons refractory to medical treatment 1
Sleep-related
movements
ClonazepamImproves nocturnal dystonia & axial hypotonia in some
Other potentially beneficial medicationsMelatonin
DysarthriaSpeech/language evalConsider alternative communication methods as needed (e.g., writing pads & digital devices).
Oculomotor
involvement
Per treating ophthalmologist
MusculoskeletalOrthopedics / physical medicine & rehabilitation / PT / OT
  • To help maintain mobility & function
  • Walking aids incl canes or walkers when appropriate
  • Durable medical equipment & positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers)
  • Home adaptations for safety & function
  • Consider disability parking placard for care-givers.
Developmental
delay
See Developmental Delay / Intellectual Disability Management Issues.
Cognitive
impairment
  • Developmental eval
  • Individualized education plan
To identify degree of disability & provide resources for learning
Psychiatric
manifestations
  • Cognitive behavioral therapy
  • Medication
  • Mental health professionals
Family support/
resources
Ensure appropriate social work involvement to:
  • Connect families w/local resources, respite, & support;
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
1.

Reported in fewer than five individuals with overall beneficial effects [Dy et al 2016, Meijer et al 2017]

Developmental Disability / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • Individualized education plan (IEP) services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Surveillance

Table 6.

Recommended Surveillance for Individuals with ADCY5 Dyskinesia

System/ConcernEvaluationFrequency
Neurologic involvementAssess for new manifestations incl changes in tone, scoliosis, & movement disorders.Annually
DysarthriaSpeech & language eval incl need for alternative communication methodsAt each visit
Oculomotor involvementPer treating ophthalmologistAs clinically indicated
Musculoskeletal /
Activities of daily living
PT/OT evalAt each visit
Developmental delayMonitor developmental progress & educational needs.
Cognitive impairmentNeuropsychological testing; developmental eval
Psychiatric manifestationsAssess for changes in mood, attention, psychosis, or obsessive-compulsive disorder.
Cardiac involvementECG, echocardiogram, cardiac MRIAs clinically indicated

OT = occupational therapy; PT = physical therapy

Agents/Circumstances to Avoid

The only exacerbating factor that is observed consistently across affected individuals is the presence of anxiety and exposure to typical life stressors. Further investigation is needed to determine whether stress management techniques or limitation of stressful activities may reduce the number and frequency of movements.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

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.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

ADCY5 dyskinesia is typically inherited in an autosomal dominant manner, often as the result of a de novo pathogenic variant. Autosomal recessive inheritance of ADCY5 dyskinesia has been reported in two families [Barrett et al 2017, Bohlega et al 2019].

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

  • If a parent of the proband is affected and/or is known to have the ADCY5 pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. All sibs who inherit an ADCY5 pathogenic variant will most likely have clinical manifestations of the disorder (see Penetrance); however, the range of clinical manifestations may vary widely among heterozygous family members.
  • If the ADCY5 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent (or the parents are clinically unaffected but their genetic status is unknown), the recurrence risk to sibs is greater than that of the general population because of the possibility of parental mosaicism (which has been documented in ADCY5 dyskinesia) [Chen et al 2015, Chen et al 2016].

Offspring of a proband. Each child of an individual with ADCY5 dyskinesia has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, his or her family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

Sibs of a proband

Offspring of a proband. Unless an individual with ADCY5 dyskinesia has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in ADCY5.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ADCY5 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ADCY5 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • ADCY5.ORG
    Phone: 858.882.7280
    Email: info@adcy5.org
  • Dystonia Medical Research Foundation
    One East Wacker Drive
    Suite 1730
    Chicago IL 60601-1905
    Phone: 800-377-3978 (toll-free); 312-755-0198
    Fax: 312-803-0138
    Email: dystonia@dystonia-foundation.org
  • National Library of Medicine Genetics Home Reference

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

ADCY5 Dyskinesia: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
ADCY53q21​.1Adenylate cyclase type 5ADCY5ADCY5

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for ADCY5 Dyskinesia (View All in OMIM)

600293ADENYLATE CYCLASE 5; ADCY5
606703DYSKINESIA, FAMILIAL, WITH FACIAL MYOKYMIA; FDFM

Molecular Pathogenesis

The adenylyl cyclase gene family encodes a number of proteins that convert adenosine triphosphate (ATP) to cyclic adenosine-3',5'-monophosphate (cAMP), a second messenger molecule that exerts a wide variety of effects via a number of intracellular signaling pathways [Halls & Cooper 2017].

ADCY5 encodes adenylyl cyclase type V (ADCY5), one of nine different membrane-bound adenylyl cyclases. ADCY5 converts adenosine triphosphate (ATP) to cyclic adenosine-3',5'-monophosphate (cAMP). Stimulation of ADCY5 by β-adrenergic agonists through a G-protein-coupled receptor induces a conformational change, aligning the two cytoplasmic domains such that they form a catalytic pocket in which ATP can bind [Chen et al 2014].

ADCY5 is highly expressed in striatum and myocardium. ADCY5 is especially prevalent in the nucleus accumbens, accounting for 80% of adenylate cyclase activation [Chen et al 2011].

Mechanism of disease causation. Gain-of-pathogeonic-function missense pathogenic variants in ADCY5 have been shown to increase intracellular cAMP, which could exert a myriad of effects at the cellular level [Chen et al 2014]. Presumably, increased ADCY5 activity affects either the signal transduction pathway following β-adrenergic stimulation or the interaction of the protein with other regulatory molecules [Mencacci et al 2015].

A loss-of-function (c.2088+1G>A) variant has been identified in a single family with hyperkinetic movements [Carapito et al 2015].

The mechanism by which contrasting gain of pathogenic function and haploinsufficiency both result in a similar clinical presentation is currently unknown, but may result from the sum of ADCY effects on both stimulatory and inhibitory cellular pathways.

In mice, overexpression of ADCY5 leads to age-related cardiomyopathy and disruption protects against β-adrenergic-mediated cardiac stress [Ho et al 2010].

Table 7.

Notable ADCY5 Pathogenic Variants

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_183357​.3
NP_899200​.1
c.1252C>Tp.Arg418Trp 1Recurrent de novo pathogenic variants affecting the same residue [Chen et al 2014, Chen et al 2015, Chang et al 2016]
c.1252C>Gp.Arg418Gly
c.1253G>Ap.Arg418Gln
c.1762G>Ap.Asp588AsnAssoc w/autosomal recessive inheritance [Barrett et al 2017, Bohlega et al 2019]
c.2088+1G>AApparent loss-of-function variant w/unclear disease mechanism [Carapito et al 2015]
c.2176G>Ap.Ala726ThrAssoc w/milder phenotype [Vijiaratnam et al 2019]
c.3086T>Ap.Met1029Lys 2Assoc w/somatic mosaicism [Chen et al 2015]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.
2.

See Clinical Description, Neurologic Manifestations.

References

Literature Cited

  • Aquino CC, Lang AE. Tardive dyskinesia syndromes: current concepts. Parkinsonism Relat Disord. 2014;20 Suppl 1:S113–7. [PubMed: 24262160]
  • Barrett MJ, Williams ES, Chambers C, Dhamija R. Autosomal recessive inheritance of ADCY5-related generalized dystonia and myoclonus. Neurol Genet. 2017;3:193. [PMC free article: PMC5612768] [PubMed: 28971144]
  • Bohlega SA, Abou-Al-Shaar HA, AlDakheel A, Alajlan H, Bohlega BS, Meyer BF, Monies D, Cupler EJ, Al-Saif AM. Autosomal recessive ADCY5-Related dystonia and myoclonus: expanding the genetic spectrum of ADCY5-related movement disorders. Parkinsonism Relat Disord. 2019;64:145–9. [PubMed: 30975617]
  • Carapito R, Paul N, Untrau M, Le Gentil M, Ott L, Alsaleh G, Jochem P, Radosavljevic M, Le Caignec C, David A, Darnier P, Isidor B, Bahram S. A de novo ADCY5 mutation causes early-onset autosomal dominant chorea and dystonia. Movement Dis. 2015;30:423–7. [PubMed: 25545163]
  • Carecchio M, Mencacci NE, Iodice A, Pons R, Panteghini C, Zorzi G, Zibordi F, Bonakis A, Dinopoulos A, Jankovic J, Stefanis L, Bhatia KP, Monti V. R'Bibo L, Veneziano L, Garavaglia B, Fusco C, Wood N, Stamelou M, Nardocci N. ADCY5-related movement disorders: Frequency, disease course and phenotypic variability in a cohort of paediatric patients. Parkinsonism Relat Disord. 2017;41:37–43. [PMC free article: PMC5549507] [PubMed: 28511835]
  • Chang FC, Westenberger A, Dale RC, Smith M, Pall HS, Perez-Dueñas B, Grattan-Smith P, Ouvrier RA, Mahant N, Hanna BC, Hunter M, Lawson JA, Max C, Sachdev R, Meyer E, Crimmins D, Pryor D, Morris JG, Münchau A, Grozeva D, Carss KJ, Raymond L, Kurian MA, Klein C, Fung VS. Phenotypic insights into ADCY5-associated disease. Mov Disord. 2016;31:1033–40. [PMC free article: PMC4950003] [PubMed: 27061943]
  • Chen DH, Friedman J, Méneret A, Bonkowski E, Hisama F, Davis M, Swanson P, Bernes S, Vidailhet M, Roze E, Bird T, Raskind W. Likely underrecognized mosaicism in genetic disease: high frequency of mosaic mutations in ADCY5-related dyskinesia. Neurology. 2016;86(16 Suppl):P5.398.
  • Chen DH, Latimer CS, Spencer M, Karna P, Gonzalez-Cuyar LF, Davis MY, Keene CD, Bird TD, Raskind WH. Hyperphosphorylated tau, increased adenylate cyclase 5 (ADCY5) immunoreactivity, but no neuronal loss in ADCY5-dyskinesia. Mov Disord Clin Pract. 2019;7:70–7. [PMC free article: PMC6962666] [PubMed: 31970214]
  • 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, Trouillard O, Amendola LM, Dorschner MO, Weiss M, Eichler EE, Winesett S, Torkamani A, Roze E, Bird TD, Raskind WH. ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations. Neurology. 2015;85:2026–35. [PMC free article: PMC4676753] [PubMed: 26537056]
  • Chen WJ, Lin Y, Xiong ZQ, Wei W, Ni W, Tan GH, Guo SL, He J, Chen YF, Zhang QJ, Li HF, Lin Y, Murong SX, Xu J, Wang N, Wu ZY. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet. 2011;43:1252–5. [PubMed: 22101681]
  • Chen YZ, Friedman JR, Chen DH, Chan GC, Bloss CS, Hisama FM, Topol SE, Carson AR, Pham PH, Bonkowski ES, Scott ER, Lee JK, Zhang G, Oliveira G, Xu J, Scott-Van Zeeland AA, Chen Q, Levy S, Topol EJ, Storm D, Swanson PD, Bird TD, Schork NJ, Raskind WH, Torkamani A. Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia. Ann Neurol. 2014;75:542–9. [PMC free article: PMC4457323] [PubMed: 24700542]
  • Chen YZ, Matsushita MM, Robertson P, Rieder M, Girirajan S, Antonacci F, Lipe H, Eichler EE, Nickerson DA, Bird TD, Raskind WH. Autosomal dominant familial dyskinesia and facial myokymia: single exome sequencing identifies a mutation in adenylyl cyclase 5. Arch Neurol. 2012;69:630–5. [PMC free article: PMC3508680] [PubMed: 22782511]
  • Dean M, Messiaen L, Cooper GM, Amaral MD, Rashid S, Korf BR, Standaert DG. Child Neurology: Spastic paraparesis and dystonia with a novel ADCY5 mutation. Neurology. 2019;93:510–4. [PMC free article: PMC6746208] [PubMed: 31501304]
  • Dy ME, Chang FC, Jesus SD, Anselm I, Mahant N, Zeilman P, Rodan LH, Foote KD, Tan WH, Eskandar E, Sharma N, Okun MS, Fung VS, Waugh JL. Treatment of ADCY5-associated dystonia, chorea, and hyperkinetic disorders with deep brain stimulation: a multicenter case series. J Child Neurol. 2016;31:1027–35. [PubMed: 27052971]
  • Fernandez M, Raskind W, Wolff J, Matsushita M, Yuen E, Graf W, Lipe H, Bird T. Familial dyskinesia and facial myokymia (FDFM): a novel movement disorder. Ann Neurol. 2001;49:486–92. [PubMed: 11310626]
  • Friedman JR, Meneret A, Chen DH, Trouillard O, Vidailhet M, Raskind WH, Roze E. ADCY5 mutation carriers display pleiotropic paroxysmal day and nighttime dyskinesias. Mov Disord. 2016;31:147–8. [PMC free article: PMC4724296] [PubMed: 26686870]
  • Halls ML, Cooper DMF. Adenylyl cyclase signalling complexes - Pharmacological challenges and opportunities. Pharmacol Ther. 2017;172:171–80. [PubMed: 28132906]
  • Ho D, Yan L, Iwatsubo K, Vatner DE, Vatner SF. Modulation of beta-adrenergic receptor signaling in heart failure and longevity: targeting adenylyl cyclase type 5. Heart Fail Rev. 2010;15:495–512. [PMC free article: PMC3655553] [PubMed: 20658186]
  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
  • Marras C, Lohmann K, Lang A, Klein C. Fixing the broken system of genetic locus symbols: Parkinson disease and dystonia as examples. Neurology. 2012;78:1016–24. [PMC free article: PMC3310311] [PubMed: 22454269]
  • Meijer IA, Miravite J, Kopell BH, Lubarr N. Deep brain stimulation in an additional patient with ADCY5-related movement disorder. J Child Neurol. 2017;32:438–9. [PubMed: 27920267]
  • Mencacci NE, Erro R, Wiethoff S, Hersheson J, Ryten M, Balint B, Ganos C, Stamelou M, Quinn N, Houlden H, Wood NW, Bhatia KP. ADCY5 mutations are another cause of benign hereditary chorea. Neurology. 2015;85:80–8. [PMC free article: PMC4501937] [PubMed: 26085604]
  • Mencacci NE, Kamsteeg EJ, Nakashima K. R'Bibo L, Lynch DS, Balint B, Willemsen MA, Adams ME, Wiethoff S, Suzuki K, Davies CH, Ng J, Meyer E, Veneziano L, Giunti P, Hughes D, Raymond FL, Carecchio M, Zorzi G, Nardocci N, Barzaghi C, Garavaglia B, Salpietro V, Hardy J, Pittman AM, Houlden H, Kurian MA, Kimura H, Vissers LE, Wood NW, Bhatia KP. De novo mutations in PDE10A cause childhood-onset chorea with bilateral striatal lesions. Am J Hum Genet. 2016;98:763–71. [PMC free article: PMC4833291] [PubMed: 27058447]
  • Raskind WH, Friedman JR, Roze E, Meneret A, Chen DH, Bird TD. ADCY5-related dysinesia: comments on characteristic manifestations and variant-associated severity. Mov Disord. 2017;32:305–6. [PMC free article: PMC5318268] [PubMed: 27933653]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–77. [PMC free article: PMC5429360] [PubMed: 28349240]
  • Vijiaratnam N, Bhatia KP, Lang AE, Raskind WH, Espay AJ. ADCY5-related dyskinesia: improving clinical detection of an evolving disorder. Mov Disord Clin Pract. 2019;6:512–20. [PMC free article: PMC6749814] [PubMed: 31538084]
  • Waalkens AJE, Vansenne F, van der Hout AH, Zutt R, Mourmans J, Tolosa E, de Koning TJ, Tijssen MAJ. Expanding the ADCY5 phenotype toward spastic paraparesis: a mutation in the M2 domain. Neurol Genet. 2018;4:e214 [PMC free article: PMC5820596] [PubMed: 29473048]
  • Westenberger A, Max C, Brüggemann N, Domingo A, Grütz K, Pawlack H, Weissbach A, Kühn AA, Spiegler J, Lang AE, Sperner J, Fung VSC, Schallner J, Gillessen-Kaesbach G, Münchau A, Klein C. Alternating hemiplegia of childhood as a new presentation of adenylate cyclase 5-mutation-associated disease: a report of two cases. J Pediatr. 2017;181:306–8.e1. [PubMed: 27931826]
  • Zech M, Boesch S, Jochim A, Weber S, Meindl T, Schormair B, Wieland T, Lunetta C, Sansone V, Messner M, Mueller J, Ceballos-Baumann A, Strom TM, Colombo R, Poewe W, Haslinger B, Winkelmann J. Clinical exome sequencing in early-onset generalized dystonia and large-scale resequencing follow-up. Mov Disord. 2017;32:549–59. [PubMed: 27666935]

Chapter Notes

Author History

Thomas D Bird, MD (2014-present)
Jennifer Friedman, MD (2014-present)
Fuki M Hisama, MD (2014-present)
Wendy H Raskind, MD, PhD (2020-present)
Chris Shaw, BS; University of Washington (2014-2020)

Revision History

  • 30 July 2020 (bp) Comprehensive update posted live
  • 17 December 2015 (fh) Revision: addition of data from Chen et al [2015] and Mencacci et al [2015]
  • 18 December 2014 (me) Review posted live
  • 29 August 2014 (fh) Original submission
Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2020 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK263441PMID: 25521004

Views

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...