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Last updated:
June 07, 2019
Years published: 2019
NORD gratefully acknowledges Marisela E. Dy-Hollins, MD, Department of Neurology, Massachusetts General Hospital, and ADCY5.org, for assistance in the preparation of this report.
Summary
ADCY5-related dyskinesia is a neurologic disorder with a variety of movement abnormalities. Dyskinesia means that affected individuals have trouble controlling voluntary movements. Voluntary movements are any movements that a person does intentionally such as lifting their arms, walking, or turning one’s head. Affected individuals experience uncontrolled, involuntary movements including sudden jerks, writhing motions, twitches, twisting, or tremors. The arms and legs, neck, and face are commonly affected. Symptoms usually begin during infancy, childhood, or adolescence and continue throughout life, although there are periods of time when no symptoms occur (remission). The severity of the disorder can vary significantly from one person to another. Intelligence and life span are generally not affected. ADCY5-related dyskinesia is caused by a variation (mutation) in the ADCY5 gene. This variation may be inherited from a parent, or it may occur spontaneously as a new variation without a previous family history (de novo mutation).
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about ADCY5-related dyskinesia is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes or additional factors influencing the disorder, prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below.
All affected individuals have episodes of abnormal, uncontrolled movements especially affecting the arms and legs, face, or neck. These movements can be choreiform, myoclonic, or dystonic. Choreiform movements are continuous rapid, jerky and sometimes writhing (athetotic) movements. Myoclonic movements are rapid, brief muscle contractions that cause sudden jerky or twitching movements. Dystonic movements are characterized by sustained and sometimes repetitive muscle contractions leading to muscle spasms and abnormal postures. Abnormal movements can occur continuously during the day and, sometimes, can occur at night disturbing sleep. Disrupted sleep can result in fatigue and sleepiness during the day. Some individuals experience ballistic (large amplitude) movements at night or upon awaking. Ballism is the abrupt contraction of muscles, particularly those of arm and legs muscles causing flailing, swinging movements of the arms and legs.
Abnormal movements are more common when affected individuals attempt to make deliberate, voluntary movements such as changing positions or reaching for things. Episodes of abnormal movements can be worsened or triggered by anxiety or stress. In some individuals, the disorder is worsened when drowsy or tired. In some people, episodes or symptoms are more common or worse in the morning. Prolonged inactivity, excitement, and being sick have also been reported as possible triggers. Abnormal movements can be painful, but some are not.
The onset of abnormal movements usually occurs during infancy, childhood, or throughout the teen-aged years. During infancy, affected infants may experience diminished muscle tone (hypotonia), particularly affecting the trunk, which is all of the body except for the head and arms and legs (axial hypotonia). These infants may be described as being “floppy.” Some affected infants have had difficulty swallowing (dysarthria), while others have been described as extremely irritable. As affected infants and children age, there may be delays in attaining developmental milestones especially motor milestones like crawling, sitting up, or walking because of the abnormal movements. In severely-affected individuals, abnormal movements may make walking extremely difficult requiring assistance to walk or use of an ambulatory device such as a wheelchair. Mildly-affected individuals may have little problems walking, but may appear a little clumsy. Some affected individuals will walk, but have a slow, uncoordinated manner of walking (abnormal gait), while others may fall frequently. Axial hypotonia improves with age. Although, in some individuals, residual diminished muscle tone affecting the neck (cervical hypotonia) can remain. Cervical hypotonia can cause the head to droop or hang toward the chest (neck flexion).
A characteristic finding that occurs in some affected individuals is facial twitching. Mild abnormal movements including those of facial muscles can result in frustration or awkwardness in social situations. Facial twitching usually involves the muscles around the eyes and mouth. In some instances, facial twitching in infants and young children can lead to delays in attaining speech and/or difficulty being understood due to poor articulation (dysarthria). Some individuals have difficulty staring at a fixed object (gaze impersistence) and also experience oculomotor apraxia, in which there are problems moving the eyes voluntarily.
How the disorder affects people over time can be very different. Movement disorders may be continual or may come and go (episodic). They can last from a few seconds to hours or longer. Their frequency and duration can change over time. Some affected individuals have long periods of time where the symptoms go away (remission). For some people, symptoms remain generally stable throughout life. Sometimes, symptoms get slowly worse during childhood and adolescence before stabilizing; in other people the disorder has gone into remission in the teenage years. Several reports state that in many people symptoms improved on their own during middle age.
There have been reports of heart (cardiac) abnormalities in some affected individuals. It is not yet known whether these heart abnormalities are potential complications of the disorder or coincidental findings. Some researchers have speculated as to whether neuropsychiatric abnormalities like depression, anxiety, and psychosis are also complications of this disorder. More research is necessary to fully understand the complex and highly variable signs and symptoms associated with ADCY5-related dyskinesia.
ADCY5-related dyskinesia is caused by a variation (mutation) in the ADCY5 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation in a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
The ADCY5 gene produces a specialized protein (enzyme) called adenylate cyclase 5. Researchers do not fully understand all of the functions of this enzyme. One function is that the enzyme changes (converts) a molecule called adenosine triphosphate into a different molecule called cyclic adenosine monophosphate or cAMP. Adenosine triphosphate helps to supply energy for the cells’ activities, while cyclic adenosine monophosphate has several functions including activating or stimulating other proteins to perform a variety of functions. The exact reason a variation in the ADCY5 gene causes dyskinesia is not fully understood.
ADCY5-related dyskinesia can be inherited from a parent or it can occur as a new (sporadic or de novo) mutation, which means that the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. Affected individuals can then pass on the altered gene in an autosomal dominant pattern.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Some individuals develop ADCY5-related dyskinesia from somatic mosaicism. In somatic mosaicism, the variation in the ADCY5 gene that causes the disorder occurs after fertilization and is not inherited. The disease-causing (pathogenic) variation is found in some cells of the body, but not in other cells. The severity of the disorder in these individuals depends on the percentage of cells affected, and is less severe than individuals who have a disease-causing variation in all of their cells.
ADCY5-related dyskinesia affects males and females in equal numbers. The exact number of people who have this disorder is unknown. Rare disorders like ADCY5-dyskinesia often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. The disorder is almost certainly underrecognized and underdiagnosed.
A diagnosis of ADCY5-related dyskinesia is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. There are no published guidelines for diagnosis. A diagnosis is suspected in infants, children or adolescents with characteristic movement symptoms (e.g. choreiform, myoclonic, dystonic movements) who do not have a structural abnormality of the brain. Clues which may be helpful in diagnosis include facial abnormalities and nocturnal disturbances, but not all individuals experience or have these symptoms. A diagnosis is confirmed through molecular genetic testing.
Clinical Testing and Workup
Molecular genetic testing can detect disease-causing variations in the ADCY5 gene, but is available only as a diagnostic service at specialized laboratories. Doctors will take a blood sample of individuals suspected of having ADCY5-related dyskinesia and the sample will undergo whole exome sequencing (WES). WES is a molecular genetic testing method that examines the genes in humans that contain instructions for creating proteins (protein-encoding genes). This is called the exome. WES can detect variations in the ADCY5 gene that are known to cause disease, or variations in other genes known to cause symptoms similar to this syndrome.
Before molecular genetic testing, affected individuals may undergo specialized imaging techniques to rule out other conditions. These techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI, which is the preferred method of imaging, uses a magnetic and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. These specialized imaging techniques can show structural abnormalities or damage to the brain that can cause movement disorders.
Treatment
The treatment of ADCY5-related dyskinesia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric and adult neurologists (physicians who specialize in diagnosing and treating disorders of the brain and central nervous system), ophthalmologists (physicians specializing in the diagnosis and treatment of eye disorders), speech therapists, physical therapists, occupational therapists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is of benefit for affected individuals and their families.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with ADCY5-related dyskinesia.
Various medications have been tried to treat individuals or families affected by ADCY5-related dyskinesia. The effectiveness of these medications is variable and when beneficial may eventually become less effective over time. Specific medications that have been tried to treat affected individuals include acetazolamide, propranolol, levetiracetam, tetrabenazine, benzodiazepines, and trihexyphenidyl, as well as other medications.
Affected individuals may benefit from counseling to learn how to best deal with anxiety, which is known to trigger episodes and worsen symptoms. Affected infants and children may benefit from physical therapy, occupational therapy, and speech therapy as necessary. Periodic reassessments and adjustment of services should be provided to all children. Additional medical, social, and/or vocational services including specialized learning programs may be beneficial for some individuals. Periodic evaluation for heart abnormalities may also be recommended because of the possibility that ADCY5-related dyskinesia can be associated with heart abnormalities in some people.
Some researchers have treated affected individuals with deep brain stimulation (DBS). DBS involves the surgical placement of very thin electrodes into certain areas of the brain. The leads from these electrodes are then connected to a small device called a neurostimulator that is surgically implanted usually near the collarbone. These stimulators send small electrical pulses to the brain. After the DBS is placed, the stimulators are programmed for optimal outcome. The electrical pulses block or interfere with the nerve signals that cause the symptoms of ADCY5-related dyskinesia. More research is necessary to determine the long-term safety and effectiveness of DBS for treating affected individuals and to determine whether it has a role as a treatment of ADCY5-related dyskinesia.
Information on current clinical trials is posted on the Internet at https://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
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Balint B, Antelmi E, Mencacci NE, et al. Oculomotor apraxia and disrupted sleep with nocturnal ballistic bouts in ADCY5-related disease. Parkinsonism Relat Disord. 2018;54:103-106. https://www.ncbi.nlm.nih.gov/pubmed/29680308
Vijiaratnam N, Newby R, Kempster PA. Depression and psychosis in ADCY5-related dyskinesia – part of the phenotypic spectrum? J Clin Neurosci. 2018;57:167-168. https://www.ncbi.nlm.nih.gov/pubmed/30172639
Carecchio M, Mencacci NE, Iodice A, et al. ADCY5-related movement disorders: frequency, disease course and phenotypic variability in cohort of paediatric patients. Parkinsonism Relat Disord. 2017;41:37-43. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549507/
Douglas AGL, Andreoletti G, Talbot K, et al. ADCY5-related dyskinesia presenting as familial myoclonus-dystonia. Neurogenetics. 2017;18:111-117. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359383/
Dy ME, Chang FC, Jesus SD, et al. Treatment of ADCY5-associated dystonia, chorea, and hyperkinetic disorders with deep brain stimulation: a multicenter case series. J Child Neurol. 2016;31:1027-1035. https://www.ncbi.nlm.nih.gov/pubmed/27052971
Chang FC, Westenberger A, Dale RC, et al. Phenotypic insights into ADCY5-associated disease. Mov Disord. 2016;31:1033-1040. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950003/
Chen DH, Meneret A, Friedman JR, et al. ADCY5-related dyskinesia: broader spectrum and genotype-phenotype correlations. Neurology. 2015;85:2026-2035. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676753/
Mencacci NE, Erro R, Wiethoff S, et al. ADCY5 mutations are another cause of benign hereditary chorea. Neurology. 2015;85:80-88. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501937/
Chen YZ, Friedman JR, Chen DH, et al. Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia. Ann Neurol. 2014;75:542-549. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457323/
INTERNET
Shaw C, Hisama F, Friedman J, et al. ADCY5-Related Dyskinesia. 2014 Dec 18 [Updated 2015 Dec 17]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK263441/ Accessed April 1, 2019.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:606703; Last Update:06/05/2017. Available at: https://omim.org/entry/606703 Accessed April 1, 2019.
Genetics Home Reference. ADCY5-related dyskinesia. August 2017. Available at: https://ghr.nlm.nih.gov/condition/adcy5-related-dyskinesia Accessed April 1, 2019.
Genetics and Rare Diseases Information Center. ADCY5-related dyskinesia. October 23, 2017. Available at: https://rarediseases.info.nih.gov/diseases/12722/adcy5-related-dyskinesia Accessed April 1, 2019.
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