Elucidating the ultrarare genetic disorder, ADCY5-related movement disorder

Identified in 2012, ADCY5-related movement disorder is a rare autosomal dominant hyperkinetic movement disorder caused by mutations in the ADCY5 gene.

Introduction

ADCY5-RMD (related movement disorder) is a rare autosomal dominant (and less commonly de novo) hyperkinetic movement disorder caused by mutations in the ADCY5 gene [1] [2] [3] [4].  This disorder is characterized by varying levels of dyskinesia in the form of chorea, athetosis, dystonia, myoclonus, or a combination of these abnormal movement disorders primarily affecting the face and/or arms [3] [13].  While there is currently no cure for this disorder, patients can work with specialists and use available treatment options to manage symptoms.

While the first patient was recorded in 1976 with facial movements only, it wasn’t until 2012 that specific mutations were identified that showed the condition could have a full-body presentation [1] [10] [11].  Due to these more recent discoveries, there is still much research needed on ADCY5-RMD and several scientists and physicians are dedicating their careers to meeting this need.

Tell me about this rare disease.

Genetic basis: ADCY5-RMD is a hyperkinetic movement disorder caused by variations in the ADCY5 gene, locus 3q21.1 [1] [2] [3] [4].  These variations can be inherited in an autosomal dominant manner or may occur as de novo mutations [1].  Some of these variations can be seen below in Figure 1. The ADCY5 gene encodes for a type of membrane-bound adenylyl cyclase enzyme, also known as Adenylate Cyclase 5 [5] [7].  This enzyme is responsible for converting adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP).  ADCY5 is highly expressed in the striatum, a part of the brain involved in controlling movement [1] [5] [7].

There is evidence that mutations causing ADCY5-RMD are typically gain-of-function mutations which lead to an increase in adenylate cyclase activity and an overproduction of cAMP, which is thought to cause the symptoms seen in ADCY5-RMD individuals [6] [8].

Other polymorphisms of the ADCY5 gene have also been linked to low birth weights and an increased risk of type 2 diabetes [4] [5].

Figure 1: Location of mutations thought to cause ADCY5-RMD along the ADCY5 protein [8].

Clinical Presentation: The symptoms of ADCY5-RMD manifest in a wide range of severity [3].  Affected individuals may experience the onset of symptoms starting anywhere between infancy to late adolescence [3].  These symptoms typically start with dyskinesia in the form of chorea, athetosis, dystonia, myoclonus, or a combination of these abnormal movement disorders, primarily affecting the face and/or arms [3] [13].  Dyskinesia symptoms are very variable, and paroxysmal events can occur during the daytime or nighttime and may last seconds, minutes, or hours [12].  An example of some of these different paroxysmal events and their genetic correlations can be seen below in Figure 2 [17].  Some patients experience fluctuations in severity of their symptoms with no clear cause, while other times symptoms may be provoked due to stress, anxiety, strong emotion, tiredness, temperature changes/heat, menstruation, or hunger [12].  These severity fluctuations may occur within the period of a day, couple of days, weeks, or months [12].  Dyskinesia is one of the main causes of sleep disturbances in patients with ADCY5-RMD and can cause poor sleep efficiency and frequent awakenings [17].  Dyskinesia movement symptoms generally stabilize and may improve in early middle age, but less commonly these movements can slowly progress in severity [3].

In addition to dyskinesia, some individuals experience infantile axial hypotonia resulting in gross motor delays [2] [3].  Together, these symptoms can result in many individuals experiencing language delays, speech impairments, and difficulties walking [2] [3] [12].

Figure 2: Different Types of paroxysmal dyskinesias (not all-encompassing) [17]

Incidence: ADCY5-RMD affects males and females equally [1] [9].  There are at least 400 known diagnoses worldwide; however, this disorder is thought to be underdiagnosed due to its wide range of symptoms and closely resembling other, more common conditions such as cerebral palsy [1] [5].

Brief history:

• 1976 & 1978: Dr. Wendy Raskind and Dr. Thomas Bird saw the first patients experiencing familial dyskinesia and facial myokymia (FDFM) symptoms of ADCY5-RMD [1]

• 2001: The first patients identified by Dr. Wendy Raskind and Dr. Thomas Bird were described as having the same unknown disease [1]

• 2009: The ADCY5 gene was localized on the human genome [1]

• 2012: Identified ADCY5 as the causative gene linked to the symptoms of ADCY5-RMD [1] [10] [11]

• 2014: IDIOM study found more evidence that FDFM symptoms are caused by gain-of-function mutations in ADCY5 [6]

The State of the Disease Today:  Today, patients with this disease rely on symptom-specific treatments that are individually derived to meet the patient’s needs.  Specialists such as neurologists, ophthalmologists, cardiologists, speech therapists, physical therapists, and occupational therapists may all help manage symptoms [1].  Various medications and physical therapy have been effective in reducing dyskinetic events [8].  Occupational therapy is also advised, as symptoms are often exacerbated by increased anxiety and stress [1] [3].  However, more targeted approaches to combating ADCY5-RMD have yet to be developed.

What is it like to be a patient with this disease?

Who are the patients?  ADCY5-RMD affects all genders/sexes equally and is not thought to affect lifespan, so patients may be any age, sex, or gender [1] [12].

What do current treatment options look like?  There are currently no guidelines on treatment or targeted therapies for ADCY5-related disorders.  Current treatment options include managing symptoms of the disorder.  For example, benzodiazepines have been prescribed to treat dyskinetic episodes and have reduced muscle tone and dystonic spasms in some patients [12].  Adenosine 2A (A2A) receptor antagonists have been used to treat hyperkinetic movement disorders and are hypothesized to work by reducing cAMP levels in neurons, as seen below in Figure 3 [12].  Istradefylline, an A2A receptor antagonist has been shown to improve chorea-dystonic movements, dexterity, and gait in one patient [12].  Caffeine is another A2A receptor that has been observed to dramatically reduce paroxysmal dyskinesias in some patients with ADCY5-related disorders [8] [12] [16].   Deep brain stimulation may also reduce hyperkinetic movement disorders and paroxysmal episodes [12].

Figure 3:  Cyclic AMP catalysis by adenyl cyclase 5 is modulated by D2 and A2A receptors.  A2A receptor antagonists, such as caffeine and istradefylline reduce cAMP production by reducing αolf activity [12].

Are there advocacy organizations?  Yes, ADCY5.org is a global Patient Advocacy Organization founded by Gay and Steve Grossman after their daughter, Lilly, was diagnosed with ADCY5-RMD full-body presentation at age fifteen, in 2012 [1] [22].  Through its outreach efforts, ADCY5.org also identified the first patient that used caffeine to alleviate ADCY5-RMD symptoms and referred the patient to see lead researchers.

Are there genetic tests?  Yes! It can be diagnosed through deletion/duplication analysis, sequence analysis of the entire coding region, targeted variant analysis, or through some combination of those [15].  ADCY5.org recommends the Dystonia Panel test through GeneDx, which is a deletion/duplication analysis of many genes, including ADCY5 [14].  This is typically done as a follow-up to single-gene testing.  As an alternative, patients could also do more comprehensive genetic testing, such as whole exome sequencing.

How do scientists and clinicians study this disease?

Are there good/any model systems scientists can use to develop drugs?  There are currently four mouse models each with different ADCY5 mutations available on the Jackson Laboratory website [23]: A727T [24], M1030K [25], R1014C [26], and an ADCY5 deletion mutant [27].  In addition to these, Dr. Emmanuel Flamand-Roze's lab from the Paris Brain Institute developed a mouse model of ADCY5 with a R418W mutation [28].  An ADCY5 knock-in mouse model with constitutively active ADCY5 has not been developed, however, ADCY5 knock-out mouse models exist for Parkinsonism research [8].

Neurons derived from patient stem cells may be differentiated into control medium spiny neuron (MSN) cells, which could then be studied by co-culturing with related cell types, like cholinergic interneurons, culturing MSNs in organoids, or with biomaterials to interrogate ADCY5 pathogenesis its natural environment [8].

Have natural history studies been done?  Natural history studies of ADCY5-RMD are limited, and therefore the generalized knowledge of disease prognosis, genotype-phenotype correlation, and the number of patients worldwide is still poorly understood [2].  Carecchio M, Mencacci NE, Iodice A, et al. studied a cohort of 44 patients with pediatric onset hyperkinetic movement disorder from five different European Centers.  This study documented disease progression, heterogeneity, and variability in unrelated patients with pathogenic ADCY5 mutations.  They found five patients with ADCY5 mutations and included detailed reports of each patient’s symptoms, which aided efforts at consolidating the understanding of ADCY5.  However, more comprehensive natural history studies with larger patient populations are still needed.

Certain physicians or centers that are experts?  ADCY5.org keeps a running list of clinicians worldwide reported to treat this disease, sorted by country and city [1].  They also have a forum to submit additional clinicians you know of to help fellow families!  This network works to advance ADCY5-RMD research, including model systems, therapeutics, and clinical research across the globe.

What are the major challenges in studying and curing this disease?  Phenotypes of patients with ADCY5-related disorders are variable, with no one treatment being efficacious for all patients [12].  Additionally, the natural history of ADCY5-related disorders is not fully understood, making it difficult to cure because of the lack of consensus on clinical guidelines and therapeutic approaches [12].

The Cure Corner: What is needed for a cure?

What are current therapies and treatments lacking?  There are currently no targeted therapeutics for ADCY5-related disorders.  However, A2A receptor antagonists such as caffeine have been used to reduce the production of cAMP in neurons, which have helped some patients manage symptoms [12].

Are there companies already developing drugs?  A2A receptor agonists are currently being investigated as therapeutics for their role in reducing cAMP levels [18].  There are ongoing clinical trials focused on ADCY5-related disorders studying the effects of theophylline on ADCY5 activation, and a clinical trial studying the efficacy of caffeine for this population [19] [20].

Could an RNA therapeutic fit the need?  RNA therapeutics could be a potential option for treating ADCY5-RMD [8].  A possible therapeutic avenue for gain-of-function mutations could be to use a small interfering RNA or antisense oligonucleotide (ASO) to silence the pathogenic allele of the gene [8].  n-Lorem, a foundation that specializes in ASO technology to treat nano-rare diseases, is currently working on an RNA therapeutic for ADCY5-related disorders [21].

Conclusion

Like many rare diseases, more research needs to be done on ADCY5-related movement disorder.  This includes improved diagnostics, increased awareness, the continued development of model systems, and better clinical characterization of symptoms.  We are hopeful that in the next few years there will be an increase in not only awareness and knowledge, but also a cure for this rare disorder.

A special thanks to our summer interns Sancia Milton and Lauren Wolff who helped start this piece, and to Lilly, Gay, and Steve Grossman from ADCY5.org for taking the time to review our article prior to publication.

---

[1] ADCY5-related movement disorder — ADCY5.org. ADCY5.org. https://www.adcy5.org/adcy5

[2] Carecchio M, Mencacci NE, Iodice A, et al. ADCY5-related movement disorders: Frequency, disease course and phenotypic variability in a cohort of paediatric patients. Parkinsonism Relat Disord. 2017;41:37-43. doi:10.1016/j.parkreldis.2017.05.004

[3] 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/

[4] ADCY5 adenylate cyclase 5 [Homo sapiens (human)] - Gene - NCBI. https://www.ncbi.nlm.nih.gov/gene/111

[5] ADCY5 gene: MedlinePlus Genetics. https://medlineplus.gov/genetics/gene/adcy5/#conditions

[6] Chen YZ, Friedman JR, Chen DH, et al. Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia. Ann Neurol. 2014;75(4):542-549. doi:10.1002/ana.24119

[7] ADCY5 Gene - Adenylate Cyclase 5. GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=ADCY5

[8] Ferrini A, Steel D, Barwick K, Kurian MA. An Update on the Phenotype, Genotype and Neurobiology of ADCY5-Related Disease. Mov Disord. 2021;36(5):1104-1114. doi:10.1002/mds.28495

[9] ADCY5-Related Dyskinesia - Symptoms, Causes, Treatment | NORD. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/adcy5-related-dyskinesia/

[10] Raskind WH, Matsushita M, Peter B, et al. Familial dyskinesia and facial myokymia (FDFM): Follow-up of a large family and linkage to chromosome 3p21-3q21. Am J Med Genet B Neuropsychiatr Genet. 2009;150B(4):570-574. doi:10.1002/ajmg.b.30879

[11] Chen YZ, Matsushita MM, Robertson P, et al. Autosomal dominant familial dyskinesia and facial myokymia: single exome sequencing identifies a mutation in adenylyl cyclase 5. Arch Neurol. 2012;69(5):630-635. doi:10.1001/archneurol.2012.54

[12] Menon PJ, Nilles C, Silveira-Moriyama L, et al. Scoping Review on ADCY5-Related Movement Disorders. Mov Disord Clin Pract. 2023;10(7):1048-1059. Published 2023 Jun 6. doi:10.1002/mdc3.13796

[13] Huizen J. What you need to know about dyskinesia. Published February 15, 2023. https://www.medicalnewstoday.com/articles/319744

[14] Dystonia Panel | Test catalog for genetic & genomic testing | GeneDx. https://providers.genedx.com/tests/detail/dystonia-panel-1004

[15] Dyskinesia with orofacial involvement, autosomal dominant - NIH Genetic Testing Registry (GTR) - NCBI. https://www.ncbi.nlm.nih.gov/gtr/conditions/C5551343/?_ga=2.228636510.351420091.1721076056-1371458586.1721076056

[16] Méneret A, Mohammad SS, Cif L, et al. Efficacy of Caffeine in ADCY5-Related Dyskinesia: A Retrospective Study. Mov Disord. 2022;37(6):1294-1298. doi:10.1002/mds.29006

[17] Méneret A, Roze E, Maranci JB, et al. Sleep in ADCY5-Related Dyskinesia: Prolonged Awakenings Caused by Abnormal Movements. J Clin Sleep Med. 2019;15(7):1021-1029. Published 2019 Jul 15. doi:10.5664/jcsm.7886

[18] Tänzler D, Kipping M, Lederer M, Günther WF, Arlt C, et al. (2023) Effects of theophylline on ADCY5 activation—From cellular studies to improved therapeutic options for ADCY5-related dyskinesia patients. PLOS ONE 18(3): e0282593. https://doi.org/10.1371/journal.pone.0282593

[19] Effect of Theophylline on ADCY5 Activation - From Cellular Studies to Improved Therapeutic Options for ADCY5-Related Dyskinesia Patients. German Clinical Trials Register.

 https://drks.de/search/en/trial/DRKS00029154

[20] Caffeine Efficacy in ADCY5-related Dyskinesia (ADCY5-CAF). ClicalTrials.gov.

https://clinicaltrials.gov/study/NCT04469283?cond=ADCY5-related%20Dyskinesia&rank=1

[21] Pursuing Diagnoses and Sequencing. nLorem.org. https://www.nlorem.org/pursuing-diagnoses-and-sequencing/

[22] ADCY5. Rare Connect. https://www.rareconnect.org/de/posts/da063329-08b1-45e5-8e06-e3b193109b04

[23] JAXMice Search. The Jackson Laboratory. https://mice.jax.org/?sharedlink=1&c&term=adcy5&sortbyname=Most%20Relevant

[24] C57BL/6J-Adcy5em2Lutzy/Mmjax. The Jackson Laboratory. https://www.jax.org/strain/033183

[25] C57BL/6J-Adcy5em6Lutzy/Mmjax. The Jackson Laboratory. https://www.jax.org/strain/033187

[26] C57BL/6J-Adcy5em9Lutzy/Mmjax. The Jackson Laboratory. https://www.jax.org/strain/033193

[27] C57BL/6J-Adcy5em4Lutzy/Mmjax. The Jackson Laboratory. https://www.jax.org/strain/033185

[28] Molecular mechanism and experimental therapeutics of ADCY5-related movement disorder: study of a new genetic mouse model and identification of therapeutic targets. FENS 2022. https://www.world-wide.org/fens-22/molecular-mechanism-experimental-therapeutics-21b8da0b/#poster-details-anchor