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Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

ADCY5 Dyskinesia

, MD
Division of Medical Genetics
Department of Medicine
University of Washington
Seattle, Washington
, MD
Departments of Neuroscience and Pediatrics
University of California San Diego;
Rady Children’s Hospital and Rady Children’s Institute for Genomic Medicine
San Diego, California
, MD, PhD
Division of Medical Genetics
Department of Medicine
University of Washington
Seattle, Washington
, MD
Seattle VA Medical Center;
Departments of Neurology and Medicine
University of Washington
Seattle, Washington

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

Estimated reading time: 25 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 or likely pathogenic variant (or, rarely, biallelic pathogenic or likely 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 or likely pathogenic variant (or, rarely, biallelic pathogenic or likely pathogenic variants) in ADCY5 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous ADCY5 variant(s) 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-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 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
ADCY5 Sequence analysis 3100% 4, 5
Gene-targeted deletion/duplication analysis 6None 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 2020]

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 a range of techniques such as 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-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 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:

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)DiffDx DisorderMOIClinical Characteristics of DiffDx Disorder
Overlapping w/ADCY5 dyskinesiaDistinguishing from ADCY5 dyskinesia
ANO3 DYT-ANO3 (See Hereditary Dystonia Overview.)ADFocal dystonia & tremorAffects neck, laryngeal muscles, and arms
ATP1A3 Alternating hemiplegia of childhood (See ATP1A3 Neurologic Disorders.)ADAlternating hemiplegiaEpisodic hemiplegia assoc w/mvmt disorder
CHRNA2
CHRNA4
CHRNB2
CRH
DEPDC5
KCNT1 		AD nocturnal frontal lobe epilepsy ADSleep-related motor & behavioral disordersOn video-EEG: focal interictal epileptiform discharges arising from the frontal lobe; seizures recorded
GCH1 GTP cyclohydrolase 1-deficient dopa-responsive dystonia ADDystoniaDramatic response to treatment w/L-dopa
HTT Huntington disease ADChorea
  • Mean onset age: 35-44 yrs
  • Choreiform mvmts become constant over time.
NKX2-1 Benign 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.)
PDE10A Infantile-onset limb & orofacial dyskinesia (OMIM 616921)ARChildhood onset chorea
  • Diurnal fluctuation
  • Striatal lesions on brain MRI
PDE2A PDE10A childhood-onset chorea 1Childhood onset choreaStriatal lesions on brain MRI
PNKD Familial paroxysmal nonkinesigenic dyskinesia AD
  • Unilateral or bilateral involuntary mvmts
  • 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
PRRT2 Paroxysmal 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 mvmt.
SGCE SGCE myoclonus-dystonia ADMyoclonus-dystoniaImproves 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 sensationNo distinguishing clinical characteristics

AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; DYT = dystonia; MOI = mode of inheritance

1.

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 mvmts;
  • Response or lack of response to medications.
Oculomotor
involvement 		Complete ophthalmologic examAssess best corrected visual acuity; nystagmus, saccades & smooth pursuit; vertical & horizontal gaze limitation; ptosis.
Musculoskeletal Orthopedics / physical medicine & rehab / PT/OT evalTo 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
Dysarthria Speech & language assessmentRelated to abnormal tongue & facial mvmts
Psychiatric
manifestations
  • Child psychiatrist
  • Clinical psychologist
Depression, psychosis w/delusions & auditory hallucinations, obsessive-compulsive symptoms, autistic-like behavior
Cardiac
involvement 		EKG, echocardiogram, cardiology evalDilated cardiomyopathy may be a manifestation.
Genetic counseling By 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; OT = occupational therapy; PT = physical therapy

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 mvmt disorder in some persons refractory to medical treatment 1
Sleep-related
movements 		ClonazepamImproves nocturnal dystonia & axial hypotonia in some
Other potentially beneficial medicationsMelatonin
Dysarthria Speech/language evalConsider alternative communication methods as needed (e.g., writing pads & digital devices).
Oculomotor
involvement 		Per treating ophthalmologist
Musculoskeletal Orthopedics / physical medicine & rehab / 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 5 persons with overall beneficial effects [Dy et al 2016, Meijer et al 2017]

Developmental Delay / 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.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where 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 involvement Assess for new manifestations incl changes in tone, scoliosis, & mvmt disorders.Annually
Dysarthria Speech & language eval incl need for alternative communication methodsAt each visit
Oculomotor involvement Per treating ophthalmologistAs clinically indicated
Musculoskeletal /
Activities of daily living 		PT/OT evalAt each visit
Developmental delay Monitor developmental progress & educational needs.
Cognitive impairment Neuropsychological testing; developmental eval
Psychiatric manifestations Assess for changes in mood, attention, psychosis, or obsessive-compulsive disorder.
Cardiac involvement EKG, 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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise 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

  • 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 [Vijiaratnam et al 2019].
  • Some individuals diagnosed with ADCY5 dyskinesia have the disorder as the result of a pathogenic variant inherited from a parent who may or may not have clinical manifestations of the disorder.
  • Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling.
  • If the pathogenic variant identified in the proband is not identified in either parent several possibilities should be considered:
    • The proband has a de novo pathogenic variant. In a high percentage of individuals with an ADCY5 de novo pathogenic variant, mutation occurred in later stages of embryogenesis resulting in somatic mosaicism for that variant [Vijiaratnam et al 2019] (Note: A pathogenic variant is reported as de novo if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity; if parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015]).
    • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Vijiaratnam et al 2019]. (Note: Testing of parental leukocyte DNA may not detect all instances of parental somatic mosaicism.)
      A parent with somatic and germline mosaicism for an ADCY5 pathogenic variant may be mildly/minimally affected [Chen et al 2015].
  • The family history of some individuals diagnosed with ADCY5 dyskinesia may appear to be negative because of failure to recognize the disorder in family members or mild/late onset of the disease in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has established that neither parent is heterozygous for the pathogenic variant identified in the 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, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one ADCY5 pathogenic variant based on family history).
  • Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for an ADCY5 pathogenic variant and to allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
  • Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive ADCY5 dyskinesia are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for an ADCY5 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive ADCY5 dyskinesia are asymptomatic and are not at risk of developing the disorder.

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.

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.

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
ADCY5 3q21​.1 Adenylate cyclase type 5 ADCY5 ADCY5

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 WITH OROFACIAL INVOLVEMENT, AUTOSOMAL DOMINANT; DSKOD

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-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 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
Change		Predicted
Protein Change		Comment [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]
NM_183357​.3 c.2088+1G>AApparent loss-of-function variant w/unclear disease mechanism [Carapito et al 2015]
NM_183357​.3
NP_899200​.1 		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.

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

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