Overview

• Hyperkinetic movement disorder, more prominent in the face and arms than legs.

Nomenclature

• Previous terms:
  • Familial essential ("benign") chorea (term discouraged due to potential disability/progression).
  • Familial dyskinesia facial myokymia.
• Recommended designation: DYT-ADCY5.

Clinical Findings

• Neurologic Manifestations

  • Movement Disorders:
    • Choreiform, myoclonic, and/or dystonic movements affecting limbs, face, and neck.
    • Continuous during waking hours; can persist during sleep.
    • Triggers: Anxiety, stress, drowsiness, fatigue, caffeine, or enforced inactivity.
    • Social impact: Can be debilitating due to clumsiness or facial twitching.
  • Spectrum of Severity:
    • Mild: Involves face and distal limbs with minimal functional impact.
    • Severe: Axial hypotonia in infancy, developmental delays, wheelchair dependency.
  • Associated Features:
    • Dysarthria, hypotonia, hyperreflexia, intermittent tremors, alternating hemiplegia.
    • Intellectual disability in severe cases with early childhood onset.
    • Static or slowly progressive abnormal movements, often stabilizing with age.
  • Curious Features:
    • Long periods (days to weeks) of remission reported in some cases.
    • Facial "twitches" often observed, previously misclassified as myokymia.

• Cardiac Complications

  • Potential link to congestive heart failure due to ADCY5's role in the myocardium.
  • Further studies are required to confirm cardiac pathology associations.

     

  • Diagnostic Studies

    • Electromyography (EMG):
      • Centralized irregular muscle movements observed.
      • No fibrillations, fasciculations, myokymia, or myotonia noted.
• Imaging:
  • Brain MRI/CT: Normal.
  • Neuropathology: Normal gross pathology; tau deposits in some brain regions reported.

     

Diagnosis

• Criteria:
  • Hyperkinetic movement disorder.
  • Absence of structural brain abnormalities.
  • No consensus diagnostic guidelines available
• Genetic basis:
  • Heterozygous pathogenic/likely pathogenic variants in ADCY5.
  • Rarely, biallelic pathogenic/likely pathogenic variants.
  • Molecular genetic testing confirms the diagnosis.
• Combination of clinical findings and genetic testing:
  • Hyperkinetic movement disorder.
  • No structural brain abnormalities.
  • Pathogenic/likely pathogenic variants in ADCY5:
    • Heterozygous (common).
    • Rare biallelic.
  • • Note: Variants of uncertain significance (VUS) do not confirm or exclude diagnosis.

Molecular Genetics

• Genotype-Phenotype Correlations

  • Limited data due to small sample sizes.
  • Missense variant p.Ala726Thr associated with milder phenotype.
  • Somatic mosaicism linked to variability in severity.
• Family History
  • Autosomal dominant (AD) inheritance:
    • Affected males and females across generations.
  • Rarely autosomal recessive (AR) inheritance:
    • Affected siblings and/or parental consanguinity.
  • Absence of family history does not preclude diagnosis.
• Gene-Targeted Testing
  • Single-Gene Testing
    • Sequence analysis of ADCY5:
      • Detects intragenic deletions/insertions, missense, nonsense, splice site variants.
      • Mosaicism of pathogenic variants has been reported.
    • Gene-targeted deletion/duplication analysis:
      • Not typically useful due to gain-of-function mechanism.
  • Multigene Panel
    • Includes ADCY5 and other relevant genes.
    • Advantages:
      • Limits identification of irrelevant variants.
      • Tailored panels may focus on phenotype.
    • Methods:
      • Sequence analysis, deletion/duplication analysis, other non-sequencing-based tests.
• Comprehensive Genomic Testing
  • Whole Exome sequencing
  • Whole Genome sequencing

• Key Points

  • Sequence analysis of ADCY5:
    • 100% of probands with pathogenic variants detectable.
    • Germline mosaicism may complicate interpretation.
  • Gene-targeted deletion/duplication analysis:
    • Not applicable due to lack of reported large intragenic deletions/duplications.

• Penetrance: 

  100% penetrance in men and women with molecularly confirmed cases.

• Prevalence: 

  Likely underdiagnosed due to variability in presentation, onset, and high rate of de novo variants.

• Genetic Counseling

  • Inheritance Patterns
    • Autosomal Dominant (AD): Most cases; de novo variants common.
    • Autosomal Recessive (AR): Reported in two families.
  • Risk to Offspring
    • AD: 50% chance of inheritance per affected parent.
  • Family Planning
  • Prenatal testing and preimplantation genetic testing available once pathogenic variants are identified in the family

Management 

• Multidisciplinary Team Approach
• Medications (treatment of manifestations):
  • Chorea & dyskinesia:
    • Acetazolamide: Up to 30 mg/kg/day.
    • Others (variable benefits):
      • Trihexyphenidyl, tetrabenazine, clonazepam, propranolol.
      • Levocarnitine, levetiracetam, methylphenidate.
  • Medications for sleep-related movements:
    • Clonazepam.
    • Melatonin.
  • Avoid exacerbating agents.
  • Caffeine as a Treatment for ADCY5-Related Dyskinesia
    • Caffeine inhibits A2A receptors which reduces the activity of ADCY5, which in turn decreases hyperkinetic movement disorders.
    • Effectiveness
    • In a retrospective study of 30 patients 87% of reported at least a 40% improvement in involuntary movements (Méneret et al., 2022)
    • Additional Benefits:
      • Improved gait, hypotonia, and dysarthria.
      • Reduction in pain and drooling.
      • Enhanced attention, concentration, mood, sleep quality, and fine motor skills.
    • Safety Profile: Well-Tolerated; Safe for use, even in pediatric populations.
    • Reported Side Effects:Hyperactivity in some patients.
    • Dosage
      • Example Regimen:Moderately strong cappuccino three times a day.
      • Third dose no later than 6 PM to avoid interference with sleep.
      • Total daily caffeine dose: 60 mg.

• Surgical Intervention:
  • Deep brain stimulation (DBS):
    • Beneficial in refractory movement disorders (fewer than five cases reported).
• Supportive Therapies:
  • Speech therapy:
    • Address dysarthria; consider digital communication aids.
  • PT/OT:
    • Mobility aids (e.g., canes, walkers).
    • Durable medical equipment (e.g., wheelchairs, bath chairs).
    • Home safety adaptations.
  • Developmental delay:
    • Individualized education plan (IEP) or 504 plan for school accommodations.
    • Transition planning for teens.
  • Psychiatric Care:
    • Cognitive-behavioral therapy.
    • Medications as needed.
  • Family Support:

• Surveillance
  • Annual evaluations for:
    • Neurologic changes (e.g., tone, scoliosis, movement disorders).
    • Dysarthria and communication needs.
    • Musculoskeletal function (mobility, adaptive devices).
  • As needed:
    • Developmental progress, educational needs.
    • Psychiatric status (mood, attention, psychosis, OCD).
    • Cardiac monitoring (EKG, echocardiogram).
• Agents/Circumstances to Avoid
  • Stress and Anxiety:
    • Stress management techniques may help reduce movement episodes.
    • Avoidance of caffeine and alcohol if they exacerbate symptoms.
• Evaluation of At-Risk Relatives
  • Genetic testing for family members when pathogenic variants are identified.
• Therapies Under Investigation
  • Clinical trials for ADCY5 dyskinesia are searchable at ClinicalTrials.gov (US) and EU Clinical Trials Register (Europe).

Genetically Related (Allelic) Disorders

• No other phenotypes are currently associated with germline pathogenic variants in the ADCY5 gene.

Differential Diagnosis: Hereditary Disorders

• ANO3:

  • Disorder: DYT-ANO3 (Hereditary Dystonia).
  • MOI: Autosomal dominant (AD).
  • Overlapping Features: Focal dystonia and tremor.
  • Distinguishing Features: Affects neck, laryngeal muscles, and arms.

• ATP1A3:

  • Disorder: Alternating hemiplegia of childhood.
  • MOI: AD.
  • Overlapping Features: Alternating hemiplegia, movement disorder.
  • Distinguishing Features: Episodic hemiplegia.

• CHRNA2/CHRNA4/CHRNB2/CRH/DEPDC5/KCNT1:

  • Disorder: AD nocturnal frontal lobe epilepsy.
  • MOI: AD.
  • Overlapping Features: Sleep-related motor and behavioral disorders.
  • Distinguishing Features: Focal interictal epileptiform discharges on video-EEG.

• GCH1:

  • Disorder: GTP cyclohydrolase 1-deficient dopa-responsive dystonia.
  • MOI: AD.
  • Overlapping Features: Dystonia.
  • Distinguishing Features: Dramatic response to L-dopa.

• HTT:

  • Disorder: Huntington disease.
  • MOI: AD.
  • Overlapping Features: Chorea.
  • Distinguishing Features: Onset typically 35-44 years; progressive and constant chorea.

• NKX2-1:

  • Disorder: Benign hereditary chorea.
  • MOI: AD.
  • Overlapping Features: Onset <5 years; chorea.
  • Distinguishing Features: Improves by late adolescence; often accompanied by hypothyroidism.

• PDE10A:

  • Disorder: Infantile-onset limb and orofacial dyskinesia.
  • MOI: Autosomal recessive (AR).
  • Overlapping Features: Childhood-onset chorea.
  • Distinguishing Features: Diurnal fluctuation; striatal lesions on brain MRI.

• PNKD:

  • Disorder: Familial paroxysmal nonkinesigenic dyskinesia.
  • MOI: AD.
  • Overlapping Features: Involuntary movements, dystonic posturing.
  • Distinguishing Features: Precipitated by alcohol or caffeine; occurs while awake.

• PRRT2:

  • Disorder: Paroxysmal kinesigenic dyskinesia.
  • MOI: AD.
  • Overlapping Features: Involuntary movements precipitated by sudden movement.
  • Distinguishing Features: Often affects men; precipitated by voluntary motion or startle.

• SGCE:

  • Disorder: SGCE myoclonus-dystonia.
  • MOI: AD.
  • Overlapping Features: Myoclonus-dystonia.
  • Distinguishing Features: Improves with alcohol; more common psychiatric manifestations.

• SLC2A1:

  • Disorder: Paroxysmal choreoathetosis with spasticity.
  • MOI: AD/AR.
  • Overlapping Features: Dystonic paroxysms.
  • Distinguishing Features: No distinguishing clinical characteristics.

• Other Differential Diagnoses

  1. Mitochondrial Disorders:
     • May present with dystonia or other abnormal movements.
  2. Drug-Induced and Acquired Disorders:
     • Tardive Dyskinesia:
       • Associated with long-term use of dopamine receptor-blocking agents.
       • Often precipitated by dose reduction or drug change.
     • Sydenham Chorea:
       • Associated with acute rheumatic fever.
       • Typically occurs between ages 5-12.
       • May be the only sign of rheumatic fever.
       • Elevated antistreptolysin O (ASO) titers.
     • Multiple Sclerosis:
       • Causes facial myokymia due to lesions impinging on the facial nerve.
       • Brain MRI abnormalities are key for diagnosis.
  3. Distinguishing ADCY5 Dyskinesia from Epilepsy:
     • Normal EEGs.
     • Lack of impaired consciousness during movements.
     • Lack of response to antiepileptic medication.

References

Méneret, A., Mohammad, S. S., Cif, L., Doummar, D., DeGusmao, C., Anheim, M., … Roze, E. (2022). Efficacy of caffeine in ADCY5-related dyskinesia: A retrospective study. Movement Disorders: Official Journal of the Movement Disorder Society, 37(6), 1294–1298. doi:10.1002/mds.29006

Hisama FM, Friedman J, Raskind WH, et al. ADCY5 Dyskinesia. 2014 Dec 18 [Updated 2020 Jul 30]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK263441/