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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 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).

ADCY5-related dyskinesia is a movement disorder; the term “dyskinesia” refers to abnormal involuntary movements. The abnormal movements that occur in ADCY5-related dyskinesia typically appear as sudden (paroxysmal) jerks, twitches, tremors, muscle tensing (dystonia), or writhing (choreiform) movements, and can affect the limbs, neck, and face. The abnormal movements associated with ADCY5-related dyskinesia usually begin between infancy and late adolescence. They can occur continually during waking hours, and frequently also disturb sleep. The involuntary movements often occur when changing position, such as from sitting to standing, or when deliberately making other movements.

Causes

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 is 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 in individuals who have a disease-causing variation in all of their cells.

As its name suggests, ADCY5-related dyskinesia is caused by mutations in the ADCY5 gene. This gene provides instructions for making an enzyme called adenylate cyclase 5. This enzyme helps convert a molecule called adenosine triphosphate (ATP) to another molecule called cyclic adenosine monophosphate (cAMP). ATP is a molecule that supplies energy for cells’ activities, including muscle contraction, and cAMP is involved in signaling for many cellular functions. Some ADCY5 gene mutations that cause ADCY5-related dyskinesia are thought to increase adenylate cyclase 5 enzyme activity and the level of cAMP within cells. Others prevent production of adenylate cyclase 5. It is unclear how either type of mutation leads to the abnormal movements that occur in this disorder.

Related Disorders

Symptoms of the following disorders can be similar to those of ADCY5-related dyskinesia. Comparisons may be useful for a differential diagnosis.

Cerebral 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 dyskinesia have been misdiagnosed with the dyskinetic form of cerebral palsy.

Other disorders can cause movement disorders similar to those seen in ADCY5-related dyskinesia 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 dyskinesia; 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 dyskinesia. 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. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

Symptoms

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 waking. Ballism is the abrupt contraction of muscles, particularly those of arm and leg 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 the 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 persistence) and also experience oculomotor apraxia, in which problems are 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 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.

Diagnosis

A diagnosis of ADCY5-related dyskinesia is based upon the 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 that 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 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.

ADCY5-Related Dyskinesia

Causes

Diagnosis

Treatment

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