Penetrance

To date, penetrance in autosomal dominant ADCY5-MD has been 100% in both males and females. However, it is possible that penetrance is lower due to undetected somatic mosaicism and/or the milder phenotypes seen in individuals with mosaic ADCY5-MD.

Source: GeneReviews — "ADCY5-Related Movement Disorder"

Diagnostic Criteria

No consensus clinical diagnostic criteria for ADCY5-related movement disorder (ADCY5-MD) have been published.

Suggestive Findings

ADCY5-MD should be suspected in individuals with the following clinical and imaging findings and family history.

Clinical findings

Source: GeneReviews — "ADCY5-Related Movement Disorder"

Differential Diagnosis

Movement disorder. In early childhood, some individuals with ADCY5-related movement disorder (ADCY5-MD) may be misdiagnosed with dyskinetic cerebral palsy because of the overlap in clinical features (e.g., global developmental delay, hypotonia, early-onset dystonia and spasticity). Also, the hyperkinetic movements of ADCY5-MD may mistakenly be thought to be epileptiform; however, normal EEGs, lack of impaired consciousness, and/or lack of response to anti-seizure medications distinguish epilepsy from ADCY5-MD. Genetic disorders characterized by an early-onset hyperkinetic movement disorder with paroxysmal exacerbations of interest in the differential diagnosis of ADCY5-MD are listed in . Table 2. Genes of Interest in the Differential Diagnosis of ADCY5-Related Movement Disorder

Management Guidelines

No clinical practice guidelines for ADCY5-related movement disorder (ADCY5-MD) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ADCY5-MD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

ADCY5-Related Movement Disorder: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Neurologic

involvement | Eval by a neurologist | • Assess neurologic findings incl movement disorder, nocturnal dyskinesia, sleep disruption, speech impairment.

• Assess response or lack of response to medications.

• Refer to movement disorder specialist for consideration of treatment options.

Oculomotor

involvement | Complete ophthalmologic exam | Assess best corrected visual acuity; nystagmus, saccades, ocular pursuit movements (i.e., oculomotor apraxia); vertical horizontal gaze limitation; ptosis.

Musculoskeletal

| Orthopedics/ physical medicine rehab/ PT OT eval | To incl assessment of:

• Gross motor fine motor skills

• Need for PT (to improve gross motor skills) /or OT (to improve fine motor skills)

• Mobility, self-help skills, activities of daily living, need for adaptive devices

DD/ Cognitive

Source: GeneReviews — "ADCY5-Related Movement Disorder"

Therapies Under Investigation

Emerging therapies for ADCY5-MD focus on modulating cyclic AMP signaling, particularly through antagonism of the adenosine A2A receptor that is highly expressed in the striatum. Antagonizing this receptor may counteract the excessive cAMP production associated with pathogenic gain-of-function ADCY5 variants. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "ADCY5-Related Movement Disorder"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 5. ADCY5-Related Movement Disorder: Recommended Surveillance

Source: GeneReviews — "ADCY5-Related Movement Disorder"