|Year : 2021 | Volume
| Issue : 2 | Page : 86-88
ADCY5-related dyskinesia with myoclonus-dystonia syndrome: Clues to diagnosis
Udit Saraf, Mitesh Chandarana, KP Divya, Syam Krishnan
Comprehensive Care Centre for Movement Disorders, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India
|Date of Submission||18-Sep-2020|
|Date of Decision||13-Nov-2020|
|Date of Acceptance||21-Nov-2020|
|Date of Web Publication||09-Jun-2021|
Dr. Syam Krishnan
Department of Neurology, SCTIMST, Trivandrum, Kerala.
Source of Support: None, Conflict of Interest: None
ADCY5-related dyskinesia is a childhood-onset autosomal dominant disorder that is caused by gain-of-function mutations in the ADCY5 gene. The core clinical features include a varying combination of hyperkinetic movement disorders (chorea, athetosis, dystonia, or myoclonus), orofacial dyskinesia, nocturnal exacerbations of dyskinesias while falling asleep, and axial hypotonia. We report two patients diagnosed with ADCY5-related dyskinesia, with myoclonus-dystonia presentation, and elaborate the clinical clues for diagnosis.
Keywords: ADCY5, chorea, myoclonus-dystonia
|How to cite this article:|
Saraf U, Chandarana M, Divya K P, Krishnan S. ADCY5-related dyskinesia with myoclonus-dystonia syndrome: Clues to diagnosis. Ann Mov Disord 2021;4:86-8
|How to cite this URL:|
Saraf U, Chandarana M, Divya K P, Krishnan S. ADCY5-related dyskinesia with myoclonus-dystonia syndrome: Clues to diagnosis. Ann Mov Disord [serial online] 2021 [cited 2022 May 27];4:86-8. Available from: https://www.aomd.in/text.asp?2021/4/2/86/318092
| Introduction|| |
ADCY5-related dyskinesia is a relatively novel childhood-onset disorder, with autosomal dominant inheritance.ADCY5 mutations cause a gain-of-function change in ADCY5 protein, and de novo mutations are not uncommon. They present with a wide range of hyperkinetic movements, occurring in isolation or in combination. Knowledge of core clinical features and varying presentations is essential for suspecting the diagnosis. We report here a sporadic case and the first familial case of ADCY5-related dyskinesia from India.
| Case 1|| |
A 22-year-old lady born of non-consanguineous parentage, with normal developmental milestones, presented with paroxysmal involuntary movements since six months of age in the form of abrupt-onset flexed posturing of both upper limbs, followed by slumping to the right side. The event lasted around two minutes, with inability to vocalize, but with preserved consciousness and awareness regarding the event. She used to have four to five such episodes every day initially, and the frequency increased to 10 to 15 per day over the next two years. Most episodes were during sleep, on waking up in the morning hours, and during fasting. She was asymptomatic interictally till 10 years of age. Since 10 years of age, she had jerky movements of the body with dropping of objects, mostly during the morning hours. Soon after this, she also developed rather continual involuntary, brief, and random dance-like movements predominantly affecting the upper limbs. By 16 years of age, she developed dystonic posturing of the neck to the left (left torticollis) with tremor, and later, lower facial dystonia. She had no history of Parkinsonism More Details, ataxia, seizures, cognitive impairment, or behavioral disturbances. There was no family history of similar illness.
Her cognitive status was normal on clinical examination (MMSE was 28). The range of ocular movements was normal, but both horizontal and vertical saccades were slow. She had perioral and lingual dyskinesias with dysarthria. She had cervical dystonia (left torticollis with left laterocollis), finger dystonia (flexion at metacarpophalangeal joints), and striatal toe bilaterally. She had mild choreiform movements involving both upper and lower limbs, proximal upper limb myoclonus, and dyskinetic gait [Video 1]. There was no Parkinsonism, motor weakness, sensory deficit, or cerebellar signs.
Routine hematological and biochemical investigations were normal. MRI brain and EEG were normal. Whole exome sequencing showed pathogenic mutation in ADCY5 gene-c.1252C>T, p.R418W, establishing the diagnosis of ADCY5-related dyskinesia. The patient was treated with Tetrabenazine, Clonazepam and Trihexyphenidyl (limited benefit). She received Botulinum toxin injection for neck dystonia with a moderate improvement for the same.
| Case 2|| |
A 17-year-old girl, the second of two siblings, with normal birth and development till three years of age presented with episodic abnormal jerky, shock-like movements involving both upper limbs (distal>proximal) since three years of age. It occurred predominantly at night during sleep, often awakening her from sleep. At 10 years of age, she developed these jerky movements while writing. By the age of 12 years, these jerky movements appeared even at rest, progressing to involve lower limbs as well. She also developed abnormal posturing of both upper limbs and the neck. By 16 years of age, she noticed perioral involuntary movements and slurring of speech. She did not have a history of seizure, gait ataxia, cognitive deterioration, or behavioral disturbances.
Family history was positive in her elder brother and father, who had similar phenotypic presentations with age at onset of three and six years, respectively [Figure 1].
On examination, she had normal cognition (MMSE was 29). She had facial and lingual dyskinesia with slurred speech, cervical dystonia (right laterocollis and left torticollis). She had bilateral upper limb dystonia with dystonic tremor, along with bilateral striatal toe. She had multifocal myoclonus involving the neck and both upper limbs and dyskinetic gait [Video 2]. There was no rigidity, bradykinesia, motor weakness, or ataxia.
Routine blood investigations and MRI brain were normal. Clinical exome sequencing showed pathogenic mutation in the ADCY5 gene-c.1253G>A, p.R418Q, establishing the diagnosis of ADCY5-related dyskinesia.
| Discussion|| |
In 2001, Fernandez and colleagues reported a five-generation family, including 18 affected members, with a novel autosomal dominant movement disorder. The disorder had an early childhood or adolescent onset, with movements described as choreiform or dystonic paroxysms at early ages, with perioral and periorbital myokymia. It was termed “familial dyskinesia and facial myokymia” (FDFM), although myokymia was neither detected in all the patients nor confirmed electrophysiologically. In 2012, Chen and colleagues identified a mutation in ADCY5 and concluded that FDFM likely results from a missense mutation in ADCY5.ADCY5 mutations were further identified in patients with benign hereditary chorea who were NKX2-1 mutation negative. As more cases were identified, the phenotypic spectrum further expanded and the nomenclature was changed to ADCY5-related dyskinesia.
The core clinical features of ADCY5-related dyskinesias include an onset in infancy-childhood with delayed milestones, mixed movement disorder (chorea, athetosis, dystonia, or myoclonus or a combination), facial dyskinesia, frequent exacerbations of dyskinesias on awakening and while falling asleep, and axial hypotonia. Clinical features such as spasticity, oculomotor abnormalities, cognitive impairment, psychiatric symptoms, and dilated cardiomyopathy may be present. MRI brain and CSF study are typically normal. The presence of core features should prompt the genetic testing.
Case 1 had mixed movement disorder (chorea, dystonia, and myoclonus) with orofacial involvement, nocturnal exacerbations, and oculomotor abnormalities. Case 2 had myoclonus and dystonia with paroxysmal nocturnal episodes in early childhood. Myoclonus-dystonia phenotype has been reported as a presenting feature of ADCY5-related dyskinesia.,, Prominence of chorea in childhood and progression to myoclonus-dystonia over years has been described, which was seen in Case 1. Both the patients did not have axial hypotonia. Additional features such as orofacial involvement, oculomotor abnormalities, and nocturnal paroxysms suggested the diagnosis.
After identification of the first familial mutation, sporadic mutations were also identified and further mutations continue to be described. Autosomal dominance predominates in families, although the majority of newly identified cases result from de novo mutations. The 418 amino acid residue appears to be a hotspot, and it has been affected in both our cases. Phenotypic variability may also be contributed by somatic mosaicism.,
To the best of our knowledge, our Case 2 is the first familial case of ADCY5-related dyskinesia reported from India. Sporadic cases have been previously described from India,,, all demonstrating mutations affecting the 418 amino acid residue.
Dr Udit Saraf: Organization and execution of the project, writing of the first draft Dr Mitesh Chandarana: Organization and execution of the project, writing of the first draft Dr K P Divya: Organization and execution of the project, Review and critique of the manuscript. Dr Syam Krishnan: Conception and organization of the project, Review and critique of the manuscript. There was no statistical analysis involved, as it is a case report.
Ethical compliance statement
Written informed consent was taken from the patients, and permission was taken from the Head of the Institute for publication. This being a case-report, requirement for ethical clearance was waived off by the Institute in accordance with the prevailing norms.
Conflicts of interest
There are no conflicts of interest.
Financial support and sponsorship
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