ADCY5‐related dyskinesia is a rare childhood‐onset disorder characterized by clinical features of axial hypotonia, delayed milestones, facial chorea or dystonia, episodic painful dystonic posturing, and “ballistic bouts” that may increase with drowsiness. 1 , 2 Brain magnetic resonance imaging is normal. The diagnosis is confirmed by the detection of a pathogenic variant in ADCY5. The condition may be inherited in an autosomal dominant manner or as a de novo mutation. 1 , 2 , 3 The natural long‐term course of the disorder is variable and poorly understood. 4
We report a video‐documented case of ADCY5‐related dyskinesia who was followed up for nearly 2 decades during which the phenotype of “ballistic bouts” evolved into a nonparoxysmal mixed‐motor disorder consisting of severe dystonia and gait abnormalities. Our patient carried a de novo missense variant NM_183357.2:c.3086T>A; p.Met1029Lys in the ADCY5 gene. 5
Case Report
The boy was assessed, and videos were documented on 2 occasions.
At the first visit (age 4 years), the boy born to nonconsanguineous parents had mild delays in motor milestones and mild cognitive deficits in early childhood. He developed almost continuous fidgety movements involving the face and arms at the age of 1 year. A year later, they gave way to “ballistic bouts” that appeared 10 to 15 times per day, and each episode lasted about 10 to 15 minutes. They persisted in sleep albeit with lesser severity. Rarely he presented brief tonic spasms of the whole body without loss of consciousness. He had bilateral extensor plantar responses without significant spasticity of the limbs. Inter‐ictal gait pattern was normal. A “ballistic bout” was video documented (Video S1). A magnetic resonance imaging scan of the brain and cerebrospinal fluid analysis were normal.
At the second visit (age 22 years), it was reported that the “ballistic bouts” of early childhood had progressively reduced in frequency as well as severity and finally ceased by the age of 12 years. During this transitional phase, his gait became progressively clumsy with jerky components. This disease progression left him restricted to a chair for the next 3 years. There was associated worsening in his speech and all motor activities as well as cognition. On examination he had a myopathic‐like face with open mouth, drooling of saliva, and severe dysarthria. There was extensor cervical dystonia along with dystonic flexed posturing of all extremities associated with early contractures. There was evidence of axial hypotonia with a tendency to lean backward. He had a jerky dystonic gait. When left alone, he could ambulate on the floor, sliding himself using his hands, buttocks, and heels (Video S2).
Discussion
Previous reports have highlighted the variable long‐term course of the disorder. 2 Chen and colleagues 1 have previously described a family of 3 generations affected with the same p.Mel1029Lys mutation as in our case. Patients suffered severe hypotonia, dystonia, and chorea. Long‐term follow‐up showed worsening of these features (detailed in Table 1). Long‐term follow‐up of our case showed a distinct clinical presentation that progressed from “ballistic bouts” to a severe generalized dystonia associated with axial hypotonia and a jerky dystonic gait (Table 1). The evolving clinical manifestations in this case may reflect the progression of the underlying disease process. Awareness of the longitudinal phenotypic evolution of ADCY5‐related disease may facilitate the recognition of this disorder.
TABLE 1.
Summary of the early and late clinical features of patients carrying the p.Met1029Lys ADCY5 mutation as presented previously by Chen and colleagues 1 and the present case
| Affected individual | Early phase (<20 y) | Late phase (>20 y) |
|---|---|---|
|
Chen et al, proband (II‐2) with mosaicism |
Age, 19 y: paroxysmal choreoathetosis | Age, 68 y: progressive improvement in the abnormal movements eventually becoming asymptomatic by the seventh decade |
|
Chen et al, probandʼs daughter (III‐6) |
Age, 8 y: delayed milestones, dysarthria, and marked chorea, which were continuous in daytime but absent during sleep; appearance of contractures in the lower limbs | In her 20s, the early features continued while newer features such as periods of unresponsiveness, severe jerks, spasms, and lingual dystonia appeared; additional features were unresponsiveness, severe jerks, spasms, and lingual dystonia; psychotic depression with delusions and auditory hallucinations in her 40s |
|
Chen et al, proband's granddaughter (IV‐4) |
Hypotonia in infancy, delayed milestones, severe dystonia, and jerky movements of the trunk and limbs with mobility restricted to a chair | Age, 20 y: the same clinical features continued along with normal cognition |
|
Chen et al, probandʼs granddaughter (IV‐5) |
Hypotonia in infancy, delayed milestones, severe dystonia, and jerky movements of the trunk and limbs | Age, 22 y: the same clinical features continued along with normal cognition |
| Present case | Age, 4 y: delayed milestones, mild cognitive deficits, generalized choreiform movements followed by “ballistic bouts” that were less severe during sleep; they stopped by the age of 12 y | Age, 22 y: worsening of cognition and severe dysarthria and severe generalized dystonia associated with a clumsy jerky dystonia gait; there was evidence of axial hypotonia as well |
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
G.M.W.: 1A, 1B, 1C, 2A
G.W.: 2A, 2B
K.R.K.: 2B
C.M.S.: 2B
Disclosures
Ethical Compliance Statement: We confirm that we have read the Journalʼs position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work. Informed consent was obtained from the patient.
Funding Sources and Conflicts of Interest: No specific funding was received for this work, and the authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for Previous 12 Months: G.W. has received grant funding from the Hereditary Spastic Paraplegia Foundation, Australia, and the Spastic Paraplegia Foundation, USA for hereditary spastic paraplegia research. C.M.S. is a Medical Research Future Fund (MRFF) and National Health and Medical Research Council (NHMRC) practitioner fellow (APP1136800). K.R.K. receives a philanthropic grant from the Paul Ainsworth Family Foundation and a Working Group Co‐Lead Award from the Michael J. Fox Foundation, Aligning Science Across Parkinsonʼs initiative. G.M.W has nothing to report.
Supporting information
Video S1. Video of the boy when evaluated at age 4 years. It shows terminal part of a “ballistic bout,” which lasted about 10 minutes.
Video S2. This video recorded 18 years later shows evidence of truncal dystonia associated with limb dystonia and a jerky dystonic gait with a tendency to lean backward. The latter part of the video shows evidence of self‐ambulation using his hands, buttocks, and heels.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
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Associated Data
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Supplementary Materials
Video S1. Video of the boy when evaluated at age 4 years. It shows terminal part of a “ballistic bout,” which lasted about 10 minutes.
Video S2. This video recorded 18 years later shows evidence of truncal dystonia associated with limb dystonia and a jerky dystonic gait with a tendency to lean backward. The latter part of the video shows evidence of self‐ambulation using his hands, buttocks, and heels.