What is ADCY5‐related movement disorder (ADCY5‐RMD)?

ADCY5‐related movement disorder (ADCY5‐RMD) is a movement disorder that is characterized by several different types of involuntary movements.

As the name suggests, ADCY5‐related movement disorder (ADCY5‐RMD) is caused by changes (mutations) in the ADCY5 gene. It is inherited in an autosomal dominant manner.

• Affected people generally develop sudden jerks, twitches, tremors, muscle tensing, and/or writhing movements between infancy and late adolescence. These abnormal movements are often continuous during waking hours and may persist during sleep, resulting in disrupted sleep cycles

• The arms, legs, neck and face are most commonly involved. Hypotonia and delayed motor milestones (i.e. crawling, walking) may also be present in more severely affected infants

• Treatment is based on the signs and symptoms present in each person and may include medications, physical therapy, and occupational therapy

Signs & Symptoms

The signs and symptoms of ADCY5‐related movement disorder (ADCY5‐RMD) may vary among affected individuals in type and severity. Based on the frequency of symptoms observed, the following information may be noted:

80-99% of the cases have these symptoms
• Facial jerks
• Orofacial dyskinesia

30-79% of the cases have these symptoms
• Chorea
• Difficulty walking
• Dysarthria
• Dystonia
• Limb hypertonia
• Muscular hypotonia of the trunk
• Myoclonus
• Resting tremor

5-29% of the cases have these symptoms
• Congestive heart failure
• Delayed gross motor development
• Dilated cardiomyopathy
• Hyperreflexia
• Motor delay

In addition to the above, the following signs and symptoms may also be present
• Anxiety
• Autosomal dominant inheritance
• Dyskinesia
• Juvenile onset

Related Disorders

Symptoms of the following disorders can be similar to those of ADCY5‐related movement disorder (ADCY5‐RMD). Comparisons may be useful for a differential diagnosis.

Cerebral Palsy
Cerebal palsy is a general term that covers a group of disorders that involve impairment of muscle control or coordination resulting from injury to the brain during its early stages of development (the fetal, perinatal or early childhood stages). There may be problems associated with involuntary movements, vision, hearing, communication skills, perception levels, intellect and seizures. Individuals with cerebral palsy often experience delays in reaching developmental milestones. The specific symptoms associated with cerebral palsy vary greatly from one person to another. Some individuals with cerebral palsy develop dyskinesia and individuals who have ADCY5‐related movement disorder (ADCY5‐RMD) have been misdiagnosed with the dyskinetic form of cerebral palsy.

Movement Disorders
Other disorders can cause movement disorders similar to those seen in ADCY5‐related movement disorder (ADCY5‐RMD) including: Sydenham chorea, benign hereditary chorea, spinocerebellar ataxia, ataxia telangiectasia, familial paroxysmal movement disorders (kinesigenic or non-kinesigenic), various mitochondrial disorders, and metabolic encephalopathies including Lesch-Nyhan disorder and inborn errors of amino acid metabolism such as the urea cycle disorders or organic acidurias. A disorder called myoclonus-dystonia can also resemble ADCY5‐related movement disorder (ADCY5‐RMD); about 30%-50% of these cases are caused by a variation in the SGCE gene. Most of these disorders have additional signs or symptoms that distinguish them from ADCY5‐related movement disorder (ADCY5‐RMD). 

Rare Non-Metabolic Genetic Disorders
There are also rare, non-metabolic genetic disorders that can cause movement disorders that have been linked to specific genes including the GNAO1, NKX2-1, and PDE10A genes. In adolescents and adults, several disorders that doctors may differentiate include Huntington’s disease, multiple sclerosis, tardive dyskinesia, neuroacanthocytosis, and denatorubral-pallidoluysian atrophy.

Treatment

The treatment of ADCY5‐related movement disorder (ADCY5‐RMD) 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 movement disorder (ADCY5‐RMD).

Various medications have been tried to treat individuals or families affected by ADCY5‐related movement disorder (ADCY5‐RMD). 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 movement disorder (ADCY5‐RMD) can be associated with heart abnormalities in some people.

Therapies

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 movement disorder (ADCY5‐RMD). 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 movement disorder (ADCY5‐RMD).

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 website.

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/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/