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ADCY5-Related Dyskinesia

, BS, , MD, , MD, and , MD.

Author Information

Initial Posting: ; Last Revision: December 17, 2015.

Summary

Clinical characteristics.

ADCY5-related dyskinesia is characterized by infantile to late-adolescent onset of paroxysmal choreiform, myoclonic, and/or dystonic movements that involve the limbs, neck, and/or face. Dyskinesias are often exacerbated by anxiety (although not by startle, caffeine, or alcohol). Facial "twitches" (previously thought to be myokymia) involving the periorbital and/or perioral muscles may also be present. Hypotonia and delayed motor milestones may be present in more severely affected infants. The movement disorder can be static or slowly progressive, with a tendency to stabilize in early middle age. Intellect and life span are normal.

Diagnosis/testing.

The diagnosis is established in a proband with a hyperkinetic movement disorder in the absence of structural brain abnormalities and confirmed by the detection of a pathogenic variant in ADCY5.

Management.

Treatment of manifestations: Anecdotally, medications have had variable effect in suppressing debilitating symptoms. Treatment trials 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 patients have long periods (weeks) of remission of the dyskinesia.

Prevention of secondary complications: Physical and occupational therapy may help maintain mobility and function.

Surveillance: Most affected individuals are reevaluated annually (or more frequently if medication trials are undertaken) to document disease progression and determine if other interventions are necessary.

Agents/circumstances to avoid: Known triggers (anxiety and stress) and possible triggers (intercurrent illness, prolonged inactivity, fatigue, and excitement).

Pregnancy management: Potential teratogenic effects of medications given for treatment of dyskinesias should be discussed with affected women of childbearing age, ideally prior to conception.

Genetic counseling.

ADCY5-related dyskinesia is inherited in an autosomal dominant manner. De novo mutation has been reported. Each child of an affected individual has a 50% chance of inheriting the ADCY5 pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the ADCY5 pathogenic variant has been identified in an affected family member.

GeneReview Scope

ADCY5-Related Dyskinesia: Included Phenotypes 1
  • Familial dyskinesia with facial myokymia (FDFM)
  • Familial benign chorea

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes, see Differential Diagnosis.

Diagnosis

There are no current published guidelines for the diagnosis of ADCY5-related dyskinesia.

Suggestive Findings

Diagnosis of ADCY5-related dyskinesia should be suspected in individuals with:

  • Infantile to late-adolescent onset of paroxysmal choreiform, myoclonic, and/or dystonic movements that involve the limbs, neck, and/or face;
  • No evidence of structural abnormalities on brain MRI.

Establishing the Diagnosis

The diagnosis of ADCY5-related dyskinesia is established in a proband with a hyperkinetic movement disorder in the absence of structural brain abnormalities and confirmed by the detection of a pathogenic variant in ADCY5 (see Table 1).

Approaches to molecular genetic testing are the following:

  • Sequence analysis of ADCY5. No deletions or duplications in ADCY5 associated with dyskinesia have been reported thus far. To date, only 15 persons representing simplex (i.e., a single occurrence in a family) cases and members of five families have been proven to have ADCY5-related dyskinesia (see Table 2).
  • Use of a multigene panel that includes ADCY5 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multigene panels vary by laboratory and over time.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in ADCY5-Related Dyskinesia

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
ADCY5Sequence analysis 27/7 3
Deletion/duplication analysis 4None reported
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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.

3.
4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Clinical Characteristics

Clinical Description

Thus far, only 15 individuals representing simplex (i.e., a single occurrence in a family) cases and members of seven families with ADCY5-related dyskinesia have been reported [Chen et al 2011; Chen et al 2014; YZ Chen, personal observation]. Therefore, the phenotypic spectrum of this disorder is still being elucidated. Affected individuals identified to date have overlapping but not identical clinical manifestations with wide-ranging clinical severity.

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) [Fernandez et al 2001].

In those with milder manifestations, the abnormal movements involve the face and distal limbs and (although minimally affecting function) are socially debilitating. Some affected individuals may be described as "excessively clumsy."

In those with more severe manifestations, the hypotonia or movement disorder can interfere with activities of daily living. For example, proximal adventitious movements and/or weakness and hypotonia may affect the ability to ambulate, requiring the 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; YZ Chen, personal observation], which 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 (although not by startle, caffeine, or alcohol). Some report that episodes are more frequent in the morning or when tired. 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].

Hypotonia and delayed motor milestones may be present in more severely affected infants.

Dysarthria and hypotonia have been reported in some affected individuals [Chen et al 2014, Chen et al 2015, Mencacci et al 2015].

Neurologic examination can vary widely between individuals and in the same individual over time. Examination may reveal:

  • A mixed movement disorder that may include prominent choreiform movements usually affecting the hands and/or feet, often characterized as piano playing movements;
  • Myoclonic and dystonic movements;
  • Non-myokymic facial twitching, hyperreflexia of the lower limbs, and intermittent head or limb tremors [Chen et al 2014];
  • Axial hypotonia with limb and axial weakness including severe neck weakness [Chen et al 2014; Chen et al 2015; YZ Chen, personal observation].

The natural history varies. In most, the abnormal movements are static or slowly progressive with increased severity and frequency. In some cases, choreiform movements have been more constant, and less paroxysmal, from 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.

Intellect and life span are normal in individuals with ADCY5-related dyskinesia.

Cardiac complications. Chen et al [2011] reported that five individuals in a family with ADCY5-related dyskinesia also had congestive heart failure. Because ADCY5 encodes a specific adenylyl cyclase that is highly expressed in both striatum and myocardium [Matsuoka et al 1997], these observations suggest that mutation of ADCY5 could contribute to cardiac pathology; further study is required.

Studies

  • Needle electromyogram (EMG) in two individuals with facial muscle twitching initially revealed what was thought to be myokymia (see Note) [Fernandez et al 2001]; however, subsequent EMG studies in the same individuals suggested centrally driven irregular muscle movements that were also observed in other muscles, including the orbicularis oculi, tongue, frontalis, and dorsal interosseus muscles. No fibrillations, fasciculations, myokymia, or myotonia were noted on EMG.
    Note: Myokymia is clinically characterized by a localized, fine, rippling motion of muscles under the skin; it can be differentiated from other causes of involuntary muscle movements more precisely by EMG.
  • Neuroimaging. Brain MRI in all reported affected individuals has been normal.
    SPECT imaging in one patient showed nonspecific slight hypo-perfusion in the temporal lobes, right-sided basal ganglia, and right cerebellar hemisphere [Chen et al 2014].

Pathophysiology

The mechanism underlying neurologic dysfunction and dyskinesias has not been clearly delineated yet. In ADCY5-related dyskinesia, the changes seen in adenylyl cyclase V have been shown to increase intracellular cAMP, which could exert a myriad of effects at the cellular level [Chen et al 2014].

Genotype-Phenotype Correlations

Currently, the number of patients and families tested is too small to make reliable predictions of phenotypic features based on genotype (Table 2).

Table 2.

Confirmed Familial and Simplex Cases of ADCY5-Related Dyskinesia

Familial or Simplex CaseClinical FeaturesADCY5 VariantCitation
DyskinesiaFacial TwitchingHypotonia
FamilialXXp.Ala726ThrChen et al [2011]
Simplex 1XXp.Arg418TrpChen et al [2014]
Simplex 1XXp.Arg418TrpChen et al [2014]
FamilialXXp.Ala726ThrChen et al [2015]
FamilialXXp.Met1029LysChen et al [2015]
FamilialXXp.Arg418TrpMencacci et al [2015]
SimplexXXp.Arg418TrpMencacci et al [2015]
1.

In the two individuals who represent simplex cases, mutation of ADCY5 occurred de novo.

Additional cases with confirmed ADCY5 pathogenic variants are reported in Chen et al [2015].

Of note, the two simplex cases with documented de novo pathogenic variants had more severe phenotypes than those with inherited pathogenic variants [Chen et al 2014].

One person who improved considerably during adulthood was shown to be mosaic for the variant p.Met1029Lys [Chen et al 2015]. A second individual, thought to be mosaic for p.Arg418Trp, exhibited significantly milder phenotypic features: with fewer facial twitches, milder chorea, and no dysarthria [Mencacci et al 2015].

Penetrance

In the few documented cases of ADCY5 dyskinesia, penetrance has been 100% in both men and women.

Nomenclature

ADCY5-related dyskinesia has been previously described as:

  • A variant of familial essential ("benign") chorea [Bird et al 1976, Bird & Hall 1978]. Although the term "benign" was used to distinguish the movement disorder from progressive, neurodegenerative forms of chorea such as Huntington disease, ADCY5-related 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

There are no data available for the prevalence of ADCY5-related dyskinesia.

To date, ADCY5 pathogenic variants have been found to segregate with the disease in three unrelated families, each with affected individuals in three or more generations (18 in 1 family, 11 in the 2nd family, and 4 in the 3rd family) and in four additional smaller families. ADCY5 pathogenic variants have been identified in two simplex cases (i.e., a single occurrence in a family) [Bird et al 1976, Fernandez et al 2001, Chen et al 2014, Chen et al 2015].

ADCY5-related dyskinesia is probably underrecognized.

Differential Diagnosis

See Dystonia Overview.

Huntington disease, a progressive, neurodegenerative, fatal disorder characterized by motor, cognitive, and psychiatric disturbances, can be differentiated from ADCY5-related dyskinesia by: mean age of onset of Huntington disease (35 to 44 years); and presence of choreiform movements that become constant over time.

Benign hereditary chorea (BHC) (OMIM 118700) is a relatively rare autosomal dominant condition caused by mutation of NKX2-1. BHC presents before age five years; however, in contrast to ADCY5-related dyskinesia, symptoms often improve by late adolescence [Bird & Hall 1978]. Non-neurologic manifestations have been seen in both disorders; mutation of NKX2-1 has been associated with pulmonary symptoms and endocrine abnormalities, most commonly hypothyroidism, while ADCY5 pathogenic variants have rarely coincided with cardiac dysfunction [Inzelberg et al 2011].

Familial paroxysmal kinesigenic dyskinesia (PKD) is characterized by unilateral or bilateral involuntary movements precipitated by other sudden movements such as standing up from a sitting position, being startled, or changes in velocity; attacks include combinations of dystonia, choreoathetosis, and ballism; are sometimes preceded by an aura; and do not involve loss of consciousness. Unlike ADCY5-related dyskinesia, PKD is more common in men and is precipitated by voluntary movement. PKD is caused by mutation of PRRT2, encoding proline-rich transmembrane protein 2 [Chen et al 2011, Wang et al 2011].

Familial paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by unilateral or bilateral involuntary movements; attacks are spontaneous or precipitated by alcohol, chocolate, coffee or tea, excitement, stress, or fatigue. Attacks involve dystonic posturing with choreic and ballistic movements, may be accompanied by a preceding aura, occur while the individual is awake, and are not associated with seizures. Unlike the episodes in ADCY5-related dyskinesia, these episodes may be precipitated by consumption of alcohol or caffeine. In some families, PNKD is caused by mutation of PNKD, encoding probable hydrolase PNKD [Rainier et al 2004].

Paroxysmal choreoathetosis/spasticity (DYT9) presents with dystonic paroxysms affecting the toes, legs, and arms; dysarthria; and changes in perioral sensation, sometimes accompanied by headache. This disorder is caused by mutation of SLC2A1 leading to a defect in GLUT1 (also known as glucose transporter type 1 deficiency syndrome) [Weber et al 2011].

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.

Mitochondrial disorders can present with dystonia or other abnormal movements.

Neurotransmitter disorders include GTP cyclohydolase deficiency, which results in an autosomal dominant dystonia with a dramatic response to treatment with L-dopa.

The hyperkinetic movements of ADCY5-related 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-related dyskinesia.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ADCY5-related dyskinesia, the following are recommended:

  • Neurologic consultation with particular attention to documenting the findings on neurologic examination, and response or lack of response to medications
  • Consideration of cardiac evaluation, as cardiomyopathy may be a manifestation of ADCY5-related dyskinesia [Chen et al 2011]
  • Social services consultation (depending on the severity of the paroxysms), as disease severity may qualify some patients for disability or social security benefits
  • Clinical genetics consultation

Treatment of Manifestations

Medication has been variably effective in suppressing debilitating symptoms. Treatment trials 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 patients have long periods (weeks) of remission of the dyskinesia.

  • Acetazolamide, which induces a mild alkalosis, has been shown previously to improve the dyskinesia [Chen et al 2015]. In one individual 15 mg/kg/day completely alleviated episodes of dyskinesia for an extended, but non-sustained, period of time [Fernandez et al 2001].
  • Propanolol, which has suppressed dyskinesia in other disorders (including essential tremor, paroxysmal kinesigenic dyskinesia, and episodic ataxia type 1), has had variable success in ADCY5-related dyskinesia.
  • Levetiracetam, an anti-convulsant, helped decrease the severity of adventitious movements in one patient [T Bird, personal observation; J Friedman, personal observation].
  • Tetrabenazine, which has been used as a symptomatic treatment for other hyperkinetic disorders, resulted in subjective symptom improvement in two patients [Mencacci et al 2015; FM Hisama, personal observation].
  • Benzodiazepines, which have been used in symptomatic treatment for other hyperkinetic disorders, have been associated with variable improvement in ADCY5-related dyskinesia [J Friedman, personal observation].
  • Trihexylphenidyl, an antimuscarinic compound used in treating Parkinson disease, was observed to decrease the intensity and frequency of episodes of dyskinesia in one patient, when paired with tetrabenazine [Mencacci et al 2015].

Of note, little to no improvement was observed after administration of primidone, chlordiazepoxide, amitriptyline, trifluoperazine, trihexylphenidyl, vitamin C, coenzyme Q10, carbamazepine, and valproic acid.

Stress management. 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.

Prevention of Secondary Complications

Physical and occupational therapy may assist patients in maintaining mobility and function.

Surveillance

There are no published guidelines for surveillance. Most affected individuals are reevaluated in neurology clinics and/ or clinical genetics clinics annually (or more frequently if medication trials are undertaken) to document disease progression and determine if other interventions are necessary.

Agents/Circumstances to Avoid

All patients have reported that anxiety and stress worsen disease manifestations.

Less commonly reported triggers include intercurrent illness, prolonged inactivity, fatigue, and excitement.

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-related dyskinesia should be discussed with affected women of childbearing age, ideally prior to conception.

Therapies Under Investigation

Search ClinicalTrials.gov 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-related dyskinesia is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with ADCY5-related dyskinesia have an affected parent.
  • A proband with ADCY5-related dyskinesia may have the disorder as the result of a de novo pathogenic variant [Chen et al 2014]. The proportion of ADCY5-related dyskinesia caused by a de novo pathogenic variant is currently unknown, as molecular genetic data are insufficient. When neither parent of a proband with an autosomal dominant condition has the ADCY5 pathogenic variant or clinical evidence of the disorder, the pathogenic variant is likely de novo.
  • If the ADCY5 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent and a de novo pathogenic variant in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include a detailed clinical and family history with molecular genetic testing of both parents if the pathogenic variant has been identified in the proband.
  • The family history of some individuals diagnosed with ADCY5-related dyskinesia may appear to be negative because of failure to recognize the disorder in family members, or mild/late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., sequence analysis) have been performed on the parents of the proband.
    Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.

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 or has the ADCY5 pathogenic variant, the risk to the sibs of the proband is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the ADCY5 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism in a parent resulting in more than one affected child.

Offspring of a proband. Each child of an individual with ADCY5-related 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 is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variant in the family.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the ADCY5 pathogenic variant or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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 Diagnosis

Once the ADCY5 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for ADCY5-related dyskinesia are possible.

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.

  • 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-Related 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-Related Dyskinesia (View All in OMIM)

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

Gene structure. ADCY5 consists of 21 exons spanning 173.25 kb. Transcript NM_183357.2 is 6098 bp in length and encodes the isoform NP_899200.1. A shorter alternative transcript NM_001199642.1 has a different 5' untranslated region and is missing a portion of the 5' coding region. A functional difference has not been assigned to this structural change or to the shorter isoform that it encodes. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. No benign variants of clinical significance have been documented in the coding region of ADCY5.

Pathogenic variants. The variant c.2176G>A (p.Ala726Thr) was identified as an inherited change in a large German American family [Chen et al 2012] and later detected in another multigenerational family of English American ancestry [Chen et al 2015]. The variant c.1252C>T (p.Arg418Trp) was identified as a de novo change in two separate families [Chen et al 2014] and more recently shown to be a recurrent do novo pathogenic variant in ADCY5-related dyskinesia [Chen et al 2015]. A different missense variant, c.1253G>A (Arg418Gln), has also been repeatedly found in de novo cases [Chen et al 2015]. The pathogenic variant p.Met1029Lys has been identified in a single three-generation family [Chen et al 2015]. A French father and son with chorea and dystonia and a c.2088+1G>A variant affecting a donor splice site was recently reported [Carapito et al 2015]. No RNA was detected from the mutated allele, and ADCY5 RNA concentration was half that in normal controls. The authors postulated ADCY5 haploinsuffiency as the mechanism, in contrast to the gain-of-function mechanism demonstrated for missense variants [Chen et al 2014]. This finding is not consistent with heterozygous Adcy5-knockout mice, which have normal motor function [Iwamoto et al 2003]. The effect of pathogenic variants on signaling in the striatum of humans remains unclear.

Table 3.

ADCY5 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1252C>Tp.Arg418TrpNM_183357​.2
NP_899200​.1
c.2176G>Ap.Ala726Thr
c.3086T>Ap.Met1029Lys
c.1253G>Ap.Arg418Gln
c.2088+1G>A

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

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

Normal gene product. The normal product of ADCY5 is the adenylyl cyclase type V protein (ADCY5). The longest isoform of ADCY5 (NP_899200.1) consists of 1261 amino acid residues, which are organized into four domains: two 6-helical section transmembrane regions and two cytosolic catalytic regions [Chen et al 2014].

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 [Buck et al 1999]. ADCY5 is one of nine different membrane-bound adenylyl cyclases, and converts adenosine triphosphate (ATP) to cyclic adenosine-3',5'-monophosphate (cAMP). It is highly expressed in myocardium and striatum [Matsuoka et al 1997]. ADCY5 is especially prevalent in the nucleus accumbens, accounting for 80% of adenylate cyclase activation [Chen et al 2011]. 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 [Whisnant et al 1996].

Abnormal gene product. The c.2176G>A pathogenic variant occurs in the region of the gene encoding the S6 domain of the transmembrane domain (M1) and the c.1252C>T pathogenic variant occurs in the first catalytic domain (C1b) [Chen et al 2014]. These two pathogenic variants are gain-of-function variants which are hypothesized to increase ADCY5 activity by affecting either the signal transduction pathway following β-adrenergic stimulation or the interaction of the protein with other regulatory molecules. The expression of the c.1252C>T variant has been shown to progressively increase during the first 500 days post conception in striatal tissue [Mencacci et al 2015].

References

Literature Cited

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