Clinical characteristics.

ADCY5-related movement disorder (ADCY5-MD) encompasses a broad spectrum of continuous and/or paroxysmal hyperkinetic involuntary movements, the most common of which are generalized chorea, generalized dystonia, and/or generalized or segmental myoclonus. At the mild end of the spectrum, affected individuals may maintain overall motor development and remain ambulatory; however, fine motor skills may be affected by involuntary movements. At the severe end of the spectrum, affected individuals may have early-onset hyperkinetic movements with significant disability and global developmental delay. Intrafamilial variability has also been demonstrated in one multigenerational family in which a mildly affected parent had much more severely affected children with disease onset in early childhood.

Diagnosis/testing.

The diagnosis of ADCY5-MD is established in most probands by identification of a heterozygous pathogenic variant in ADCY5 by molecular genetic testing (autosomal dominant ADCY5-MD); rarely, the diagnosis is established in a proband by identification of biallelic pathogenic variants in ADCY5 by molecular genetic testing (autosomal recessive ADCY5-MD).

Management.

Treatment of manifestations: Multidisciplinary care by specialists in movement disorders for consideration of treatment options; speech-language therapy for dysarthria; occupational therapy, speech-language therapy, and nutritional support for feeding issues; management of manifestations of GI dysmotility (e.g., GERD and constipation) by gastroenterologist; orthopedics, physical medicine and rehabilitation, and physical/occupational therapy to maintain mobility and function; management of neurobehavioral/psychiatric manifestations by mental health professionals.

Surveillance: Routinely scheduled visits with treating clinicians to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Pregnancy management: Potential teratogenic effects of medications given for treatment of ADCY5-MD should be discussed with affected women of childbearing age, ideally prior to conception.

Genetic counseling.

ADCY5-MD is typically inherited in an autosomal dominant manner. Autosomal recessive inheritance of ADCY5-MD has been reported in eight individuals (from five families) to date.

Autosomal dominant inheritance: The majority of individuals have the disorder as the result of a de novo heterozygous constitutional or mosaic (postzygotic) pathogenic variant; some individuals 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. Each child of an individual with a constitutional ADCY5 pathogenic variant has a 50% chance of inheriting the pathogenic variant. Each child of an individual with a mosaic ADCY5 pathogenic variant has up to a 50% chance of inheriting the pathogenic variant (offspring who inherit a pathogenic variant from a proband with mosaic ADCY5-MD will have a constitutional pathogenic variant and consequently may be more severely affected than the proband).

Autosomal recessive inheritance: 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 heterozygous, and a 25% chance of inheriting neither of the familial ADCY5 pathogenic variants. Heterozygous sibs of a proband with autosomal recessive ADCY5-MD are asymptomatic and are not at risk of developing the disorder.

Once the ADCY5 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for ADCY5-MD are possible.

Suggestive Findings

ADCY5-MD should be suspected in individuals with the following clinical and imaging findings and family history.

Clinical findings

• Axial hypotonia and weakness (severe in some individuals)
• Complex and often mixed hyperkinetic movement disorder of variable severity, including generalized chorea, generalized dystonia, and/or segmental or generalized myoclonus with:
  • Paroxysmal exacerbations
  • Persistence of dyskinesia during sleep, with exacerbations during sleep-wake transitions that are highly suggestive of the diagnosis
  • Perioral/facial chorea and myoclonus that may be distinguishing features
• Lower-limb spasticity with pyramidal signs
• Mild-to-moderate dysarthria
• Delayed motor and speech development

Other features (rare)

• Global developmental delay / intellectual disability
• Neurobehavioral/psychiatric manifestations (including anxiety, obsessive-compulsive behavior, depression, and psychosis)
• Dilated cardiomyopathy

Supportive imaging findings

• Normal brain MRI
• Normal EEG

Family history. Because most individuals with ADCY5-MD have the disorder as the result of a de novo heterozygous constitutional or mosaic (postzygotic) pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Less commonly, the family history may suggest autosomal dominant (e.g., affected males and females in multiple generations) or, rarely, autosomal recessive (e.g., affected sibs and/or parental consanguinity) inheritance.

Establishing the Diagnosis

The diagnosis of ADCY5-MD is established in most probands by identification of a heterozygous pathogenic (or likely pathogenic) variant in ADCY5 by molecular genetic testing (autosomal dominant ADCY5-MD); rarely, the diagnosis is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in ADCY5 by molecular genetic testing (autosomal recessive ADCY5-MD) (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not.

Note: (1) Single-gene testing (sequence analysis of ADCY5, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. (2) Some heterozygous ADCY5 variants are mosaic and may therefore escape detection in peripheral blood. Performing high-depth sequencing and/or allele-specific PCR, as well as testing other tissues such as buccal mucosa or skin biopsy, may be needed to establish a molecular diagnosis [Chen et al 2016, Shetty et al 2020, Menon et al 2023] (see GeneReviews Resource Materials, Mosaicism). (3) Use of a multigene panel may be too restrictive given the rarity of ADCY5-MD.

• Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, the majority of ADCY5 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
• A 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 pathogenic variants and variants of uncertain significance 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.

Clinical Description

ADCY5-related movement disorder (ADCY5-MD) covers a broad spectrum of continuous and/or paroxysmal hyperkinetic involuntary movements, the most common of which are generalized chorea, generalized dystonia, and/or generalized or segmental myoclonus. At the mild end of the spectrum, affected individuals may maintain overall motor development and remain ambulatory; however, fine motor skills may be affected by involuntary movements. At the severe end of the spectrum, affected individuals may have early-onset hyperkinetic movements with significant disability and global developmental delay. Intrafamilial variability was noted in one multigenerational family in which a mildly affected parent had children who were much more severely affected with disease onset in early childhood [Chen et al 2015].

ADCY5-MD has been reported in approximately 100 individuals to date [Menon et al 2023] (full text).

Movement disorder. Onset is typically in infancy or early childhood, most commonly presenting as an infantile-onset hyperkinetic movement disorder. The movement disorder is often a continuous background of choreiform and dystonic movements with random involuntary movements present throughout wakefulness and/or paroxysmal with discrete episodic exacerbations that are frequently triggered by voluntary movements, transitions between sleep and wakefulness, emotional stress, excitement, fatigue, gastrointestinal discomfort, and/or intercurrent illness. Exacerbations can last from seconds to hours. The frequency of exacerbations can range from a few to dozens per day.

Chorea or dystonia that affects the face, neck, trunk, or limbs is common, and is typically uncomfortable.

Frequently observed distinctive findings are facial involvement (particularly perioral and periorbital chorea or myoclonus), nocturnal paroxysmal dyskinesias, and dyskinesia that persists during sleep or worsens at sleep-wake transitions that can cause significant sleep disturbance.

Although ADCY5-MD is generally considered non-progressive, the natural history of the movement disorder is not yet fully established. Some individuals experience increased frequency and severity of dyskinesia during childhood or adolescence, followed by stabilization or partial improvement in adulthood.

Axial hypotonia and generalized weakness in severely affected individuals can be prominent early in the disease course, especially in children with onset in infancy. These findings can contribute to delayed gross motor milestones (e.g., delayed head control, sitting, and walking) and often require assistive devices for mobility.

Speech development in severely affected children can be delayed, in part due to oral motor dysfunction and orofacial and lingual dyskinesia. Dysarthria is common and varies in severity. Mildly affected individuals may have only slightly slurred speech, whereas more severely affected individuals can have marked dysarthria that significantly impairs intelligibility.

Epilepsy, reported in a minority of individuals, particularly those with a more severe phenotype, is not a major feature of the disorder.

Oculomotor involvement, a distinctive oculomotor apraxia, has been documented in several adults who have difficulty initiating voluntary eye movements, with marked limitation in gaze. Saccades can be hypometric and smooth pursuit is impaired.

Neurobehavioral/psychiatric issues. Although a range of issues has been observed, it is unclear to what extent these reflect a primary feature of the disorder rather than secondary effects of living with a chronic disabling illness. Anxiety and depression, the most common psychiatric manifestations that often emerge in adolescence or adulthood, are possibly reactions to the social and functional challenges imposed by the movement disorder; however, some evidence suggests that mood disturbances and other psychiatric features might be part of the phenotypic spectrum [Menon et al 2023].

Dilated cardiomyopathy. A case report described members of a multigenerational family who developed congestive heart failure consistent with dilated cardiomyopathy [Chen et al 2015]. While the age of onset was not explicitly reported, the heart failure was presumably identified in adulthood. Except for this family, cardiomyopathy has only been rarely observed among reported individuals.

Mosaic ADCY5-MD. Somatic mosaicism has been demonstrated in 43% of individuals with a de novo pathogenic variant [Raskind et al 2017].

Somatic mosaicism is an important contributor to phenotypic variability, as individuals with somatic mosaicism typically have a milder phenotype [Chen et al 2015]. The following are some examples:

• An individual mosaic for the recurrent p.Arg418Trp variant exhibited only mild chorea with infrequent facial twitches and no dysarthria, whereas non-mosaic heterozygotes for the same variant can have significant dyskinesia and speech impairment [Mencacci et al 2015].
• An individual with somatic mosaicism had predominantly paroxysmal nocturnal dyskinesias (with near-normal daytime motor function) and showed a dramatic therapeutic response to caffeine [Shetty et al 2020].
• In two families, the mosaic parent had at disease onset a mild phenotype in contrast to the more severe phenotype in the heterozygous offspring [Chen et al 2015].

Prognosis. Despite the broad clinical spectrum of ADCY5-MD, individuals usually have a normal life span.

Needle electromyogram (EMG) studies in individuals with ADCY5-MD with facial muscle twitching suggested that these are most consistent with chorea and myoclonus [Tunc et al 2017]. 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-MD revealed increased immunoreactivity for adenylate cyclase type 5 (the enzyme encoded by 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

The following genotype-phenotype correlations for ADCY5-MD have been proposed based on the location of the pathogenic variant within the protein [Menon et al 2023].

• To date, the pathogenic missense variant p.Ala726Thr within the C1b domain has been associated with the mildest phenotype (i.e., often only having episodic [paroxysmal] dyskinesias with little or no permanent neurologic deficits) [Vijiaratnam et al 2019].
• Pathogenic variants in the C1a and C2a domains cause moderate-to-severe disease with infantile- to childhood-onset hyperkinetic movement disorders (chorea, dystonia, myoclonus) and frequent paroxysmal exacerbations.
• Pathogenic variants involving the arginine residue (amino acid position 418) in the C1a domain, and especially the p.Arg418Trp variant, are highly recurrent. Individuals with pathogenic variants at this site have a more severe presentation with early onset, generalized chorea and dystonia, prominent facial twitching, dysarthria, and nocturnal dyskinesias that impair sleep.
• Pathogenic variants in the M1 and M2 domains have been associated with a spastic paraparesis phenotype [Menon et al 2023]. Affected individuals can develop early childhood-onset lower-limb spastic weakness with upper motor neuron signs, variably accompanied by dystonic posturing. This spastic-dystonic phenotype tends to be slowly progressive over time.

Penetrance

To date, penetrance in autosomal dominant ADCY5-MD has been 100% in both males and females. However, it is possible that penetrance is lower due to undetected somatic mosaicism and/or the milder phenotypes seen in individuals with mosaic ADCY5-MD.

Nomenclature

ADCY5-MD has been previously described as the following:

• 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-MD 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 [Fernandez et al 2001]; however, more recent EMG studies of affected individuals have revealed that these twitches are not myokymia.

ADCY5-MD is categorized as a mixed movement disorder (MxMD-ADCY5) in the 2022 update of the Nomenclature of Genetic Movement Disorders [Lange et al 2022].

Prevalence

Prevalence is not known. To date, about 100 individuals have been reported [Menon et al 2023].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ADCY5-MD, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for ADCY5-MD. Management is symptomatic and tailored to each individual. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4a).

Because of the rarity of ADCY5-MD and the broad phenotypic spectrum, systematic trials have been difficult; thus, most treatment effectiveness data are derived from case reports and small series. Medications are variably effective in suppressing debilitating manifestations. Nevertheless, several therapeutic approaches have shown promise.

Interventions for the treatment of chorea, dyskinesia, and sleep-related movements in individuals with ADCY5-MD are listed in Table 4b.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

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

Pregnancy Management

Reduction in manifestations during pregnancy has been reported [Menon et al 2023]

Potential teratogenic effects of medications given for treatment of ADCY5-MD 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

Emerging therapies for ADCY5-MD focus on modulating cyclic AMP signaling, particularly through antagonism of the adenosine A2A receptor that is highly expressed in the striatum. Antagonizing this receptor may counteract the excessive cAMP production associated with pathogenic gain-of-function ADCY5 variants.

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.

Mode of Inheritance

ADCY5-related movement disorder (ADCY5-MD) is typically inherited in an autosomal dominant manner. Autosomal recessive inheritance of ADCY5-MD has been reported in eight individuals (from five families) to date.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• The majority of individuals diagnosed with autosomal dominant ADCY5-MD have the disorder as the result of a de novo heterozygous constitutional or mosaic (postzygotic) pathogenic variant [Vijiaratnam et al 2019].
• Some individuals diagnosed with ADCY5-MD 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.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or mild/late onset of the disease in a parent with an ADCY5 pathogenic variant . De novo occurrence of an ADCY5 pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has a constitutional ADCY5 pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo heterozygous constitutional or mosaic pathogenic variant (somatic mosaicism has been demonstrated in 43% of individuals with a de novo pathogenic variant [Raskind et al 2017]).
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism* [Chen et al 2015, Mencacci et al 2015]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for an ADCY5 pathogenic variant may be mildly/minimally affected [Chen et al 2015] (see Clinical Description, Mosaic ADCY5-MD).

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/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 [Chen et al 2015, Chen et al 2016].

Offspring of a proband

• Each child of an individual with a heterozygous constitutional ADCY5 pathogenic variant has a 50% chance of inheriting the pathogenic variant.
• Each child of an individual with a mosaic ADCY5 pathogenic variant has up to a 50% chance of inheriting the pathogenic variant. Note: Offspring who inherit a pathogenic variant from a proband with mosaic ADCY5-MD will have a constitutional pathogenic variant and consequently may be more severely affected than the proband.

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 a child with biallelic ADCY5 pathogenic variants are presumed to be heterozygous for an ADCY5 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an ADCY5 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• To date, the heterozygous parents of individuals with autosomal recessive ADCY5-MD have exhibited no clinical manifestations of ADCY5-MD.

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 heterozygous, and a 25% chance of inheriting neither of the familial ADCY5 pathogenic variants.
• Heterozygous sibs of a proband with autosomal recessive ADCY5-MD are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an individual with biallelic ADCY5 pathogenic variants has children with an individual with ADCY5 pathogenic variant(s), 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 heterozygous for an ADCY5 pathogenic variant.

Heterozygote 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 and preimplantation genetic testing for ADCY5-MD are possible.

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

Molecular Pathogenesis

ADCY5 encodes the enzyme adenylyl cyclase 5 (ADCY5), which converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), a critical second messenger involved in various intracellular signaling pathways. ADCY5 is highly expressed in the striatum, where it plays a pivotal role in dopaminergic signaling and the regulation of voluntary and involuntary movements.

Mechanism of disease causation

• Autosomal dominant ADCY5-MD. Gain-of-function ADCY5 variants encoding ADCY5 result in elevated levels of cAMP within cells, thus disrupting the normal inhibitory control of motor pathways, leading to hyperkinetic movements such as chorea, dystonia, or myoclonus. By enhancing the activity of the enzyme, these variants cause an abnormal increase in cAMP production, which in turn affects downstream signaling pathways and neuronal excitability. This dysregulation is thought to reduce inhibitory activity in the motor circuits, thereby contributing to the involuntary movements characteristic of ADCY5-related disorder [Chen et al 2015, Ferrini et al 2021].
• Autosomal recessive ADCY5-MD. Loss-of-function ADCY5 variants (which frequently localize to the C1 catalytic domain of ADCY5) result in reduced or absent production of functional ADCY5, which is crucial for converting ATP to cAMP, a second messenger involved in various intracellular signaling pathways [Bohlega et al 2019, Okamoto et al 2021].

Author Notes

Dr Kathryn Yang and Dr Darius Ebrahimi-Fakhari (ude.dravrah.snerdlihc@sredrosiDtnemevoM) are actively involved in clinical research regarding individuals with ADCY5-related movement disorder (ADCY5-MD). They would be happy to communicate with persons who have any questions regarding diagnosis of ADCY5-MD or other considerations.

Active research studies include:

• "A Retrospective Survey-Based Multicenter Study to Delineate the Molecular and Phenotypic Spectrum of Epilepsy-Dyskinesia Syndromes." Sponsor: Boston Children's Hospital. ClinicalTrials.gov ID: NCT06585605
• "Deep Brain Stimulation (DBS) MatchMaker (DBSMatchMaker)." Sponsor: Boston Children's Hospital. ClinicalTrials.gov ID: NCT06912841

Acknowledgments

The authors thank Dr Thomas D Bird, Dr Jennifer Friedman, Dr Fuki M Hisama, Dr Wendy H Raskind, and Chris Shaw for their work on earlier versions of this chapter.

The authors are also grateful to their patients with ADCY5-related disorder and their families for contributing to research and education on movement disorders.

Author History

Thomas D Bird, MD (2014-2025)
Darius Ebrahimi-Fakhari, MD, PhD (2025-present)
Jennifer Friedman, MD (2014-2025)
Fuki M Hisama, MD (2014-2025)
Wendy H Raskind, MD, PhD (2020-2025)
Chris Shaw, BS; University of Washington (2014-2020)
Kathryn Yang, MBChB, FRCPC (2025-present)

Revision History

• 26 June 2025 (bp) Comprehensive update posted live
• 30 July 2020 (bp) Comprehensive update posted live
• 18 December 2014 (me) Review posted live
• 29 August 2014 (fh) Original submission

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