ADCY5-related Dyskinesia Summary
© 2015
Acknowledgement
ADCY5.ORG gratefully acknowledges RareScience.org

Summary
Dyskinesia is a type of hyperkinetic movement disorder characterized by abnormal involuntary movements. Paroxysmal dyskinesias are episodic abnormal involuntary movements resulting from attacks of dystonia (involuntary sustained contraction of a group of muscles), chorea (an abrupt, unsustained contraction of different muscle groups), athetosis (prolonged contraction of the trunk muscle), or ballism (abrupt contraction of the limb muscles).


Dyskinesia linked to a mutation in the adenylyl cyclase V gene (ADCY5) was identified in three families with affected members across multiple generations and in two individuals having no other affected family members. The disorder was initially classified as familial dyskinesia with facial myokymia (FDFM) or benign hereditary chorea (BHC), until the causative mutation in ADCY5 was discovered by genetic mapping techniques.
Symptoms of ADCY5-related dyskinesia present in infancy to late adolescence and vary in severity in the small number of cases identified to date. Symptoms include episodes of abnormal movements affecting the limbs, face, and/or neck, and these symptoms are exacerbated by anxiety. In mild cases, the abnormal movements minimally affect function but can be socially debilitating, whereas more severe cases may affect the ability to ambulate, leading to confinement in a wheelchair. Treatment with medication approved for other movement disorders has shown variable effectiveness in suppressing symptoms. Affected individuals have normal intellect and life span.


Introduction
As of 2014, ADCY5-related dyskinesia has been reported in two individuals who represent simplex cases, meaning they were the only affected cases in their respective families, and in individuals representing familial cases in three families, meaning there were affected cases across multiple generations in the same family. The symptoms in these individuals vary in severity but generally involve abnormal involuntary movements in the limbs, face, and/or neck.


Symptoms
Symptoms of ADCY5-related dyskinesia present in infancy to late adolescence, and include paroxysmal choreiform, myoclonic, or dystonic movements involving the limbs, face, and/or neck. Patients experience chorea (rapid, jerky, involuntary movements), myoclonus (brief involuntary muscle contractions), and/or dystonia (sustained muscle contractions). Facial twitching, previously thought to be myokymia (a localized, rippling motion of muscles under the skin), and hypotonia (low muscle tone) may be present.


Wideranging clinical severity of the disease has been reported. In milder cases, the abnormal movements involve the face and distal limbs and minimally affect function, but may cause social distress. In more severe cases, hypotonia and delays in motor milestones may be present during infancy. The hypotonia or abnormal movements in severely affected individuals may diminish the ability to ambulate, requiring the use of wheelchairs. Of note, five affected individuals from the same family had congestive heart failure, suggesting that the mutation in ADCY5 may lead to heart disease.


Abnormal movements occur continuously during waking hours and sometimes persist into sleep, in some cases causing sleep disruptions. In all cases, symptoms are exacerbated by anxiety, but not by being startled nor by caffeine or alcohol. In some cases, episodes occur more frequently in the morning, when the individual is tired, or during extended periods of physical inactivity. Some affected individuals have long periods of remission lasting days to weeks.


Intellect and life span are normal in affected individuals. In most, the abnormal movements that present in childhood slowly progress and increase in severity and frequency and then may stabilize or even improve in early middle age.


Causes
The human genome is composed of approximately 20,000 genes. A great majority of these genes, including the ADCY5 gene, are expressed as two copies (one copy inherited from each parent). In familial cases, ADCY5-related dyskinesia is inherited in an autosomal dominant manner. This mean that only a single copy of the pathogenic variant of the ADCY5 gene is sufficient to cause the disorder. Each child of an affected individual has a 50% chance of inheriting the ADCY5 pathogenic variant. Prenatal testing is possible if the ADCY5 pathogenic variant has been identified in an affected family member.


De novo mutation has also been reported, meaning that the abnormal gene was not inherited from either parent, and was likely the result of spontaneous mutation(s). The new mutation occurs spontaneously in the sperm or egg cells of one of the parents, without the influence of an environmental risk factor.


The ADCY5 gene encodes for adenylyl cyclase V, a member of a family of proteins responsible for generating cyclic adenosine monophosphate (cAMP) in cells. The regulation of cAMP levels is important because cAMP is a messenger that helps regulate levels of sugar and lipids in the body and mediates skeletal muscle processes.


Affected Populations
Based on the few cases of ADCY5-related dyskinesia reported to date, the disorder appears to be equally prevalent in males and females. The onset of the disorder is between infancy and late adolescence.


As of 2014, ADCY5-related dyskinesia has been identified in three unrelated families with affected individuals in three or more generations (18 in one family, 11 in the second family, and 4 in the third family). In addition, two simplex cases of ADCY5-related dyskinesia have been found. It should be noted that the two simplex cases, who had de novo mutations in the gene, had more severe disease symptoms than those with inherited pathogenic variants.


ADCY5-related dyskinesia is probably under-recognized; most cases identified to date were reported by a clinical team from a single center.
Related Disorders


Several movement disorders have similar features as those described for ADCY5related dyskinesia. However, these disorders differ from ADCY5-related dyskinesia in specific aspects such as age of onset, course of the disease, triggers, response to specific medications, or diagnostic results.


Diagnosis
There are no established guidelines for the diagnosis of ADCY5-related dyskinesia.
Individuals who have paroxysmal choreiform, myoclonic, and/or dystonic movements of the limbs, neck, and/or face beginning during the period from infancy to late adolescence and who have no evidence of structural abnormalities on brain magnetic resonance imaging (MRI) scans may have ADCY5-related dyskinesia.


The diagnosis of ADCY5-related dyskinesia can be established with genetic testing to detect a pathogenic variant in ADCY5. Genetic testing methods may include sequence analysis of ADCY5 or use of a multi-gene panel that includes ADCY5 and other genes of interest.


Clinical Testing and Work-Up
Genetic testing provides definitive diagnosis of ADCY5-related dyskinesia.


Treatment
There are no known disease-altering treatments for ADCY5-related dyskinesia. Several approaches to managing the manifestations of the disease have been attempted. Treatment with medication has been variably effective in suppressing symptoms. Assessing drug effects is complicated by the fact that some patients experience remission of symptoms for long durations, making it difficult to determine whether the medication led to symptom improvement or whether the lack of symptoms are part of the disease course. A number of patients with ADCY5-related dyskinesia received medications used for other movement disorders, with mixed results:


Acetazolamide was shown to improve dyskinesia, particularly in one individual who had no episodes of dyskinesia for an extended but non-sustained period of time.
Levetiracetam, an anti-convulsant, helped decrease the severity of adventitious movements in one patient.
Tetrabenazine, used as a symptomatic treatment for other hyperkinetic disorders, resulted in subjective symptom improvement in one patient.
Propanolol, used to suppress dyskinesia in other disorders, has had variable success in ADCY5-related dyskinesia.
Benzodiazepines, used in symptomatic treatment for other hyperkinetic disorders, have been associated with variable improvement in ADCY5-related dyskinesia.
Administration of other treatments, including primidone, chlordiazepoxide, amitriptyline, trifluoperazine, trihexylphenidyl, vitamin C, coenzyme Q10, carbamazepine, and valproic acid, had little to no effect on symptoms of the disease.


Anxiety and stress have been reported to worsen symptoms in all patients with ADCY5related dyskinesia. Therefore, studies of affected patients are needed to find out whether stress reduction will lead to improvement in symptoms. Other less frequently reported triggers include intercurrent illness, prolonged inactivity, fatigue, or excitement.


Affected individuals may need to be re-evaluated annually to document disease progression and determine which interventions are necessary. Physical and occupational therapy may assist patients in maintaining mobility and function.


Investigational Therapies
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.


For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222 TTY: (866) 411-1010 Email: prpl@cc.nih.gov For information about clinical trials sponsored by private sources, contact: www.centerwatch.com.


References
Chen DH, Méneret A, Friedman JR, et al. ADCY5-related dyskinesia: Broader spectrum and genotype–phenotype correlations. Neurology. 2015
Chen YZ, Friedman JR, Chen DH, et al. Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia. Ann Neurol. 2014;75(4):542-549.
Chen YZ, Matsushita MM, Robertson P, et al. Autosomal dominant familial dyskinesia and facial myokymia: single exome sequencing identifies a mutation in adenylate cyclase 5. Ann Neurol. 2012;69(5):630-635.
Fernandez M, Raskind W, Wolff J, et al. Familial dyskinesia and facial myokymia (FDFM): A novel movement disorder. Ann Neurol. 2001;49:486-492.
Hao SS, Feng YH, Zhang GB, Wang AP, Wang F, Wang P. Neuropathophysiology of paroxysmal, systemic, and other related movement disorders. Eur Rev Med Pharmacol Sci. 2015:19:2452-2460.
Mencacci NE, Erro R, Wiethoff S, et al. ADCY5 mutations are another cause of benign hereditary chorea. Neurology. 2015;85:80-88.
Raskind WH, Matsushita M, Peter B, et al. Familial dyskinesia and facial myokymia (FDFM): Follow-up of a large family and linkage to chromosome 3p21-3q21. Am J Med Genet B Neuropsychiatr Genet. 2009;150B(4):570–574.
Shaw C, Hisama F, Friedman J, Bird TD. ADCY5-related dyskinesia. GeneReviews. 2014.