Paroxysmal dyskinesias are characterized by delineated episodes of dystonia and/or chorea resulting from genetic and non-genetic etiologies.1 Paroxysmal dyskinesias are classified by precipitating factor as kinesigenic, non-kinesigenic, exercise-induced or hypnogenic.1–3 ADCY5 mutations have recently been added to the growing list of genetic paroxysmal dyskinesias.4
ADCY5-mutation carriers display mixed hyperkinetic movements including dystonia, chorea, myoclonus and tremor.4 In addition to baseline abnormal movements often associated with axial hypotonia, many exhibit paroxysmal exacerbations.4 Paroxysmal episodes may last minutes with discrete on- and off-set. In addition, motor dysfunction and the presence of paroxysmal episodes may wax and wane over weeks to months.4 We present case videos to illustrate the baseline motor manifestations and pleiotropic paroxysmal dyskinesias encountered in this disorder (video1a;video1b;video2;video3;video4 and table).
Table.
Characteristics of the patients
| CASE ID | AGE (years) | MOTOR DELAY | LANGUAGE DELAY |
MOVEMENT ONSET (months) |
DEVELOPMENTAL REGRESION |
CONTINUOUS MOVEMENTS |
PNKD | PKD | PED | PND | INTERICTAL EEG | ICTAL EEG | AXIAL HYPOTONIA |
LIMB HYPERTONIA |
PYRAMIDAL SIGNS1 |
DYSTONIA | MYOCLONUS | CHOREA | TREMOR | PAIN WITH DYSKINESIA |
MUTATION |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 8 | Y | Y | 15 | Y | Y | Y | Y | Y | Y | ab2 | nl | Y | Y | Y | Y | Y | Y | N | Y | p.R418W (c.1252C>T) |
| 2 | 22 | Y | N | 14 | N | Y | Y | N | N | N | nl | nd | Y | N | N | N | Y | Y | N | N | p.R418Q (c.1253G>A) |
| 3 | 37 | N | N | 12 | N | Y | N | N | N | Y | nl | nd | Y | N | N | Y | Y | Y | N | N | p.R418W (c.1252C>T) |
| 4 | 34 | N | N | 24 | N | Y | Y | N | Y | N | nd | nd | Y | N | N | Y | N | N | Y | N | p.R438P (c.1313G>C) |
PNKD – Paroxysmal Nonkinesigenic Dyskinesia; PKD – Paroxysmal Kinesigenic Dyskinesia; PED – Paroxysmal Exercise Induced Dyskinesia; PND – Paroxysmal Nighttime Dyskinesia; N – not present; Y – present; nd – not done; ab – abnormal; nl - normal.
Pyramidal Signs = hyperreflexia and or extensor plantar reflex.
Routine EEG was normal during sleep and waking. Video EEG at 3 years 9 months showed no epileptiform discharges associated with multiple paroxysmal choreiform/myoclonic spells during waking. During early drowsiness there were two brief bursts of hypnagogic irregular atypical spike wave discharges without associated movement.
An expanding list of genes have been associated with paroxysmal dyskinesia including mutations in PRRT2 (mono- and bi-allelic), PNKD(MR-1), SLC2A1, ATP1A3, GCH1, KCNMA1, SLC16A2(MCT8), PDHA1, PDHX and DLAT.1, 5 Hypnogenic paroxysmal dyskinesia usually is an epileptic condition and may be associated with other gene mutations.2 Recent reports indicate overlap between paroxysmal dyskinesia semiology among the genetic disorders.6 Paroxysmal exacerbations in ADCY5 mutation carriers similarly do not fit clearly within previously identified clinical paroxysmal dyskinesia categories and instead may manifest, even within the same patient, as multiple different paroxysmal dyskinesia sub-types. Uniquely, ADCY5-related paroxysmal dyskinesia patients may have non-epileptic nocturnal paroxysmal dyskinesia, without ictal EEG abnormalities. When present, the combination of various forms of paroxysmal dyskinesia and/or nocturnal paroxysmal dyskinesia is a striking clue to diagnosis of ADCY5 mutation.
ADCY5 patients typically have early-onset protean paroxysmal dyskinesia superimposed upon baseline movement disorder in contrast to patients with mutations in PRRT2 or PNKD, whose interictal examination is usually normal. Additional diagnostic clues to ADCY5-dyskinesia are the presence of axial hypotonia, orofacial jerks, and marked fluctuations, typically without ataxia, marked intellectual disability or seizures. In this setting, the main differential diagnoses include mutations in SLC2A1, ATP1A3, GCH1 and biallelic mutations in PRRT2. In contrast to ADCY5-dyskinesia patients, GCH1 patients have pure dystonia or dystonia-parkinsonism, and rarely dyskinesia, rather than a mixed hyperkinetic disorder with axial hypotonia. Instead of nocturnal paroxysmal dyskinesia as in ADCY5-dyskinesia patients, ATP1A3 patients may experience relief of paroxysms with sleep, often have paroxysmal plegia in addition to paroxysmal dyskinesia and often have intellectual disability. Recessive PRRT2-related paroxysmal dyskinesia differs from ADCY5-related paroxysmal dyskinesia by the frequent occurrence of seizures and episodic ataxia.7 There may be overlap between patients with severe ADCY5-related paroxysmal dyskinesia and patients with SLC2A1, PDHA1, PDHX or DLAT mutations. The latter, are more likely to have mental retardation, seizures, ataxia and attacks triggered by fasting or prolonged exercise.
Classification based upon precipitant factors may guide initial genetic investigations. Elucidation of the molecular underpinnings of paroxysmal dyskinesia sub-types and recent evidence of partial clinical overlap between the different genetic disorders highlight the limitations of such classification. A new classification scheme for paroxysmal dyskinesia based on both clinical characteristics and genetics has been proposed.6 This classification may eventually be highly relevant for targeted therapeutics when pathophysiology is better understood. Our report further supports this classification and suggests that it can be updated by including ADCY5-related paroxysmal dyskinesia.
Supplementary Material
Video 1a: An 8 year old patient with R418W ADCY5 mutation. Clips 1a and 1b demonstrate multiple forms of paroxysmal dyskinesia in this single patient. Baseline: Ability to sit independently varies with degree of axial hypotonia and is markedly impaired. Exercise Induced Dyskinesia: Initially, gait is mildly unsteady; there is asymmetric dystonic posturing of hands and legs with mild axial hypotonia. As the patient continues to ambulate the dyskinetic movements became obvious and gradually worsen eventually resulting in an inability to stand independently. Nocturnal Dyskinesia: nocturnal spell characterized by generalized dyskinetic movements during sleep.
Video 1b: Non-Kinesigenic Dyskinesia. The patient develops generalized myoclonic jerks while lying in bed. Larger amplitude dyskinetic movements occur while patient is sitting on the couch. Kinesigenic Dyskinesia The patient is asked to raise his arms. There is mild bilateral hand dystonia. After a brief delay there are generalized myoclonic dystonia involving the arms, legs and trunk. Similar dyskinetic spells occur when patient changes posture from sitting to standing. Subtle myoclonic jerks are apparent upon standing. Over time, these progressively increase in amplitude and involve trunk, arms, neck and face with associated choreic movements and dystonic posturing.
Video 2: A 22 year-old patient with a R418Q ADCY5 mutation. The first part of the video shows the baseline movement disorder consisting in chorea and myoclonus with prominent orofacial jerky movements, associated with axial hypotonia. The second part of the video features a diurnal episode of paroxysmal non-kinesigenic dyskinesia.
Video 3: A 37 year-old patient with a R418W ADCY5 mutation. The first part of the video shows the mixed hyperkinetic movement disorder and axial hypotonia present at baseline, followed by an episode of nighttime paroxysmal dyskinesia.
Video 4: A 34 year-old patient with a R438P ADCY5 mutation. The video features tremulous dystonia of the upper limbs with slight axial hypotonia at baseline and an episode of paroxysmal exercise induced dyskinesia.
Acknowledgments
Funding sources for study
This work was supported by a research support provided by Merz-Pharma. Dr. Roze is the recipient of a grant “poste d’accueil” AP-HP/CNRS. Dr Méneret is the recipient of a grant from JNLF. Support was also received from NIH R01NS069719 (Drs. Raskind and Chen) and the Department of Veterans Affairs (Dr. Raskind).
Dr Friedman has received travel funding from The Movement Disorders’ Society and Neurocrine Pharmaceuticals.
Dr Méneret is the recipient of a grant from JNLF.
Dr Chen has received funding from the National Ataxia Foundation. She receives license fees from Athena Diagnostics.
Dr Vidailhet has been an invited speaker at ENS, EFNS and MDS International meetings. She is on the scientific advisory board of Novartis and Merz. She has received unrestricted research grants from DHOS-INSERM and ANR (French National Institutes) and from AMADYS and Alliance France Dystonie (patient associations).
Dr Raskind receives funding from the National Institute of Neurologic Diseases and Stroke and from the Department of Veterans Affairs. She receives license fees from Athena Diagnostics.
Dr. Roze received research support from INSERM (COSSEC), AP-HP (DRC-PHRC), Fondation pour la Recherche sur le Cerveau (FRC), Merz-Pharma, Orkyn, IP santé, Ultragenyx; served on scientific advisory boards for Orkyn,Ultragenyx and Merz-pharma; received speech honorarium from Merz-pharma, Novartis, Ipsen-Pharma Ultragenix, and Orkyn, received travel funding from Ipsen-Pharma, Teva, Abbvie, Merz-Pharma, Dystonia Europe, the Georgian Medical and Public Health Association the International Federation of Clinical Neurophysiology, and the Movement Disorders Society.
Footnotes
Full Financial Disclosures of all Authors for the Past 12 months:
Ms Trouillard reports no disclosure.
Conflict of Interest
None.
Author Roles:
1) Research project: A. Conception, B. Organization, C. Execution; 2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3) Manuscript: A. Writing of the first draft, B. Review and Critique.
JRF: 1A, 1B, 1C, 3A; AM: 1B, 1C, 3A; DHC: 1C, 3B; OT: 1C, 3B; MV: 1C, 3B; WHR: 1C, 3B; ER: 1A, 1B, 1C, 3A.
REFERENCES
- 1.Roze E, Meneret A, Vidailhet M. Paroxysmal Movement Disorders: Clinical and Genetic Features. In: LeDoux MS, editor. Movement Disorders. 2nd Edition. 2015. pp. 767–778. [Google Scholar]
- 2.Waln O, Jankovic J. Paroxysmal movement disorders. Neurol Clin. 2015;33:137–152. doi: 10.1016/j.ncl.2014.09.014. [DOI] [PubMed] [Google Scholar]
- 3.Demirkiran M, Jankovic J. Paroxysmal dyskinesias: clinical features and classification. Ann Neurol. 1995;38:571–579. doi: 10.1002/ana.410380405. [DOI] [PubMed] [Google Scholar]
- 4.Chen DH, Méneret A, Friedman JR, et al. ADCY5-related dyskinesia: broader spectrum and genotype/phenotype correlations. Neurology. 2015 doi: 10.1212/WNL.0000000000002058. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.McWilliam CA, Ridout CK, Brown RM, McWilliam RC, Tolmie J, Brown GK. Pyruvate dehydrogenase E2 deficiency: a potentially treatable cause of episodic dystonia. Eur J Paediatr Neurol. 2010;14:349–353. doi: 10.1016/j.ejpn.2009.11.001. [DOI] [PubMed] [Google Scholar]
- 6.Erro R, Sheerin UM, Bhatia KP. Paroxysmal dyskinesias revisited: a review of 500 genetically proven cases and a new classification. Mov Disord. 2014;29:1108–1116. doi: 10.1002/mds.25933. [DOI] [PubMed] [Google Scholar]
- 7.Delcourt M, Riant F, Mancini J, et al. Severe phenotypic spectrum of biallelic mutations in PRRT2 gene. J Neurol Neurosurg, Psychiatry. 2015;86:782–785. doi: 10.1136/jnnp-2014-309025. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Video 1a: An 8 year old patient with R418W ADCY5 mutation. Clips 1a and 1b demonstrate multiple forms of paroxysmal dyskinesia in this single patient. Baseline: Ability to sit independently varies with degree of axial hypotonia and is markedly impaired. Exercise Induced Dyskinesia: Initially, gait is mildly unsteady; there is asymmetric dystonic posturing of hands and legs with mild axial hypotonia. As the patient continues to ambulate the dyskinetic movements became obvious and gradually worsen eventually resulting in an inability to stand independently. Nocturnal Dyskinesia: nocturnal spell characterized by generalized dyskinetic movements during sleep.
Video 1b: Non-Kinesigenic Dyskinesia. The patient develops generalized myoclonic jerks while lying in bed. Larger amplitude dyskinetic movements occur while patient is sitting on the couch. Kinesigenic Dyskinesia The patient is asked to raise his arms. There is mild bilateral hand dystonia. After a brief delay there are generalized myoclonic dystonia involving the arms, legs and trunk. Similar dyskinetic spells occur when patient changes posture from sitting to standing. Subtle myoclonic jerks are apparent upon standing. Over time, these progressively increase in amplitude and involve trunk, arms, neck and face with associated choreic movements and dystonic posturing.
Video 2: A 22 year-old patient with a R418Q ADCY5 mutation. The first part of the video shows the baseline movement disorder consisting in chorea and myoclonus with prominent orofacial jerky movements, associated with axial hypotonia. The second part of the video features a diurnal episode of paroxysmal non-kinesigenic dyskinesia.
Video 3: A 37 year-old patient with a R418W ADCY5 mutation. The first part of the video shows the mixed hyperkinetic movement disorder and axial hypotonia present at baseline, followed by an episode of nighttime paroxysmal dyskinesia.
Video 4: A 34 year-old patient with a R438P ADCY5 mutation. The video features tremulous dystonia of the upper limbs with slight axial hypotonia at baseline and an episode of paroxysmal exercise induced dyskinesia.