ADCY5-Related Dyskinesia

ADCY5-Related Dyskinesia

Overview

ADCY5-related dyskinesia is a rare neurological disorder characterized by various movement abnormalities. People with this condition have dyskinesia, a movement disorder characterized by trouble controlling voluntary movements, which are movements that a person does intentionally, such as lifting their arms, walking, or turning their heads. Instead, they experience uncontrolled, involuntary movements like sudden jerks, writhing motions, twitches, twisting, or tremors. These movements typically affect the arms, legs, neck and face.

Symptoms can begin in babies, young children or teenagers and continue throughout life, though there can be periods without symptoms (remission). The severity varies greatly from one person to another, but intelligence and life span are generally unaffected. This condition is caused by a change (variant) in the ADCY5 gene.

The disease-causing variant may be inherited from a parent, or it may occur spontaneously as a new variant without a previous family history (de novo).

Treatment is symptomatic and supportive.

Symptoms

The core symptoms include a hyperkinetic movement disorder (dystonia, chorea, myoclonus and/or tremor) that can be temporary (paroxysmal), permanent or, typically, a combination of both. However, 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. It is important to note that affected individuals may not have all the symptoms discussed below.

All people affected with this disease have abnormal, uncontrolled movements, especially in the arms, legs, face, or neck with onset that usually occurs during infancy, childhood or throughout the teen-aged years. These movements can be:

Choreiform, which are continuous rapid, jerky, and sometimes writhing movements

Myoclonic, which are rapid, brief muscle contractions causing sudden jerky or twitching movements

Dystonic, which are sustained and sometimes repetitive muscle contractions leading to muscle spasms and abnormal postures

Movements can occur throughout the day and night, disrupting sleep and causing daytime fatigue and often worsen with voluntary actions, anxiety, stress, tiredness, excitement, inactivity, or illness. Some movements can be painful, while others are not.

Babies and young children may have the following signs and symptoms:

Poor muscle tone (hypotonia) particularly affecting the trunk, which is all the body except for the head and arms and legs (axial hypotonia) making them seem “floppy”

Swallowing difficulty (dysphagia)

Severe irritability

Developmental delays that become evident as the affected infants and children age and may include:

Delays in attaining developmental milestones especially motor milestones like crawling, sitting up, or walking because of the abnormal movements

In severely affected patients, abnormal movements may make walking extremely difficult requiring assistance to walk or use of an ambulatory device such as a wheelchair

Mildly affected people may have minor problems walking, but may appear a little clumsy

Some affected people can walk but have a slow, uncoordinated manner of walking (abnormal gait), while others may fall frequently

Axial hypotonia improves with age. Although, in some people, residual low muscle tone affecting the neck (cervical hypotonia) can remain. Cervical hypotonia can cause the head to droop or hang toward the chest (neck flexion).

Other signs and symptoms include:

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

Facial twitching in infants and young children can sometimes lead to delays in attaining speech and/or difficulty being understood due to poor articulation of words (dysarthria)

Difficulty staring at a fixed object (gaze impersistence)

Oculomotor apraxia, in which there are problems moving the eyes voluntarily

The disease is typically non-progressive. Symptoms can be continuous or episodic, lasting from seconds to hours, and can change over time. Some affected people have long periods of remission, while others see their symptoms improve during middle age.

There have been reports of heart abnormalities and possible neuropsychiatric issues like depression, anxiety and psychosis. These issues may be coincidental or part of the condition. More research is needed to fully understand these possible complications.

Causes

ADCY5-related dyskinesia is caused by changes (variants) in the ADCY5 gene.

Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant in a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.

The ADCY5 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.

The exact reason a variant in the ADCY5 gene causes dyskinesia is not fully understood.

Nearly all ADCY5 gene variants reported in the medical literature (98%) are missense variants, where a single nucleotide change results in a different amino acid in the protein. Most missense variants result in ADCY5 “gain-of-function” (change the gene product such that its effect gets stronger) leading to increased cAMP levels and subsequent increased cellular activity.

The ADCY5 protein has two catalytic cyclase domains called C1 and C2, which subdivide into catalytic (C1a and C2a) and regulatory (C1b and C2b) subdomains. The catalytic subdomains interact to form an ATP-binding pocket.

The C1 and C2 are catalytic domains and are responsible for ATP binding. Most of the variants affect these two domains which lead to an increased affinity to stimulatory factors. Domains are distinct functional and/or structural units in a protein. Usually, they are responsible for a particular function or interaction, contributing to the overall role of a protein. Catalytic domains are the parts of the protein where the chemical reaction takes place.

Recent studies have shown that there are some differences based on how the specific ADCY5 gene variants affect the different domains in the protein:

C1b domain variants: The variants affecting the C1b domain are associated with the mildest form of the disease. Patients with variants in the C1b domain typically do not have axial hypotonia (reduced muscle tone in the trunk), which is common in people with other variants.

C1a and C2a domain variants: Variants in these regions tend to cause more severe forms of the disorder.

M1 and M2 domain variants: These variants are associated with specific symptoms of spastic paraparesis, which involves stiffness and weakness in the legs.

In addition, genetic mosaicism, where an individual has two or more genetically different sets of cells, is common in ADCY5-related dyskinesia. This can result in milder symptoms, with some patients showing only paroxysmal episodes and maintaining the ability to walk without other major clinical features. Mosaicism can also explain why some family members with the same variant have different symptoms.

ADCY5-related dyskinesia follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

As commented above, some individuals develop ADCY5-related dyskinesia from somatic mosaicism. In somatic mosaicism, the variant in the ADCY5 gene that causes the disorder occurs after fertilization and is not inherited. The disease-causing variant 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 their cells.

Rarely, ADCY5-related dyskinesia can be inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent

Understanding these details can help in diagnosing and managing ADCY5-related dyskinesia, as well as guiding potential therapeutic approaches.

Affected populations

ADCY5-related dyskinesia affects males and females equally. The exact number of people with this disorder is unknown, as it is likely underdiagnosed. As of 2022, about 450 patients were reported in medical literature.

Disorders with Similar Symptoms

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 have 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 like 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. Most of these disorders have additional signs or symptoms that distinguish them from ADCY5-related dyskinesia.

A disorder called myoclonus-dystonia can also resemble ADCY5-related dyskinesia; about 30%-50% of these patients have a variant in the SGCE gene.

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 consider when making a diagnosis 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.)

Diagnosis

Diagnosis involves identifying characteristic symptoms, taking a detailed patient and family history and conducting clinical evaluations and specialized tests.

Clues which may be helpful in diagnosis include facial abnormalities and nocturnal disturbances, but not all individuals have these symptoms.

The diagnosis is confirmed with genetic testing that identifies a variant in the ADCY5 gene.

Whole exome sequencing (WES) is a molecular genetic test that examines the genes in humans that contain instructions for creating proteins (protein-encoding genes). This is called the exome. WES can detect variants in the ADCY5 gene that are known to cause disease or variants in other genes known to cause symptoms similar to this syndrome.

Before genetic testing, imaging techniques like CT scans and MRIs may be used to rule out other conditions as imaging tests for ADCY5-related dyskinesia are usually normal.

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 organs and bodily tissues, including the brain. These scans can show structural abnormalities or brain damage causing movement disorders.

Standard Therapies

Treatment focuses on managing specific symptoms. A team of specialists, including pediatricians, neurologists, ophthalmologists and therapists is often needed.

Current treatment may include:

Medication: Various medications have been tried with variable effectiveness including acetazolamide, propranolol, levetiracetam, tetrabenazine, benzodiazepines and trihexyphenidyl.

Treatments are based on case reports and small series of patients.

Caffeine has shown benefits for paroxysmal and permanent movement disorders. Ongoing studies are looking at the effects and safety of A2A receptor antagonists such as caffeine and theophylline.

Istradefylline was beneficial for one patient.

Benzodiazepines are useful for nocturnal dyskinesias.

Propranolol might improve chorea.

Deep brain stimulation (DBS)—This is a surgical procedure that involves placing electrodes in the brain connected to a neurostimulator that sends electrical pulses to block or interfere with nerve signals causing symptoms.

More research is needed to determine the long-term safety and effectiveness of DBS for ADCY5-related dyskinesia.

Other therapies: Physical, occupational and speech therapy can be helpful. Psychological counseling may assist with anxiety management.

Regular evaluation for heart abnormalities is recommended.

Genetic counseling is recommended for affected individuals and their families.

To better understand and treat this condition, it will be necessary to learn more about how each person’s disease develops and find specific signs of cAMP levels in a part of the brain called the striatum. Personalized treatments may vary depending on whether a patient has a variant that increases or decreases the function of the ADCY5 gene.

ADCY5-related dyskinesia has a complex and variable clinical picture, making individualized treatment and ongoing research essential for improving patient outcomes.

Type of Doctor Department : A Neurologist