Abstract
ADCY5 mutations have been reported as a cause of early onset hyperkinetic movements associated with delayed motor milestones, hypotonia, and exacerbation during sleep. The movement disorder may be continuous or episodic, and can vary considerably in severity within families and in individuals. The authors report a case series of 3 patients with ADCY5 mutations treated with deep brain stimulation after unsuccessful medication trials. All had extensive imaging, metabolic, and genetic testing prior to confirmation of their ADCY5 mutation. Two of the patients had the c.1252C>T; p.R418W mutation, while the youngest and most severely affected had a de novo c.2080_2088del; p.K694_M696 mutation. All had variable and incomplete, but positive responses to deep brain stimulation. The authors conclude that deep brain stimulation may provide benefit in ADCY5-related movement disorders. Long-term efficacy remains to be confirmed by longitudinal observation. ADCY5 should be considered in the differential diagnosis of early onset hyperkinetic movement disorders, and may respond to deep brain stimulation.
Childhood chorea has a broad differential diagnosis, 1,2 including many hereditary and acquired causes. When other movement disorders are coincident with chorea, and when historical, laboratory, and imaging evidence for a primary injury causing the movement abnormalities are absent, the list of potential causes narrows substantially. Previously, mutations in the transcription factor NKX2.1 were identified as a cause of childhood-onset hyperkinetic movements (referred to as benign hereditary chorea). 3 More recently, mutations in the adenylyl cyclase 5 gene (ADCY5; OMIM 600293) have been identified as an alternate cause of early onset hyperkinetic movements. 1,4 -9
All isoforms of adenylyl cyclase convert adenosine triphosphate to cyclic adenosine 3’, 5’ monophosphate, which in turn regulates a broad array of downstream effectors (e.g., kinases, transcription factors). 7 Expression of isoform 5 (ADCY5) within the brain is remarkably selective, with high levels of expression in the striatum, nucleus accumbens, and olfactory tubercle and sparse expression in all other brain regions. 10 This anatomic specificity may underlie the relative-selectivity of the impact of ADCY5 mutations on movement. The first recognized phenotypic description of ADCY5 mutations was published in 2001, 8 with linkage to chromosome 3p21-3q21. 9 Identification of causative ADCY5 gene mutations followed in 2012. 7 The original family (a 5-generation German kindred) was described as “familial dyskinesia and facial myokymia” (OMIM 606703), an autosomal dominant disorder with childhood-to-adolescent onset of a range of paroxysmal hyperkinetic movements. 8 More recent reports have reassessed the term myokymia, describing the frequent, irregular facial movements as dyskinesias. 1 Subsequently, other ADCY5-related cases were reported with paroxysmal or continuous hyperkinetic movements, isolated dystonia or chorea, or a combination of choreo-dystonic movements. 4 -7 Sleep-related symptoms and severe sleep dysregulation are common. 1,5,6 It has been hypothesized that gain-of-function mutations in ADCY5 lead to hyperkinetic movements based on rodent models of global 11 and local 12 ADCY5 knock out. Familial cases were all inherited in an autosomal dominant pattern, with de novo mutations generally producing an earlier onset and more severe phenotype. 1,4 -8
As the ADCY5 gene and its phenotypic manifestations have only recently been described, optimal treatment for these patients is uncertain. The authors describe 3 cases of infantile- to late adolescent-onset generalized hyperkinetic movements with prominent sleep-related symptoms, and a more severe phenotype including delayed motor milestones and hypotonia in affected infants. The youngest previously reported onset of symptoms was 6 months, with subsequent normal development and plateaued/improvement of symptoms in adulthood. 4 The authors present a series of patients with hyperkinetic movements associated with mutations in the ADCY5 gene who were treated with deep brain stimulation. The authors also highlight an early presentation of ADCY5-related disorder at 5 months of age who underwent successful deep brain stimulation surgery at 3 years of age.
Patients and Methods
The 3 patients were identified for inclusion based on conversations between senior authors (MSO, VSCF, and JLW), but each was evaluated and treated prior to recognition of the other cases. Subjects were evaluated in the Neurology Department and Division of Genetics and Genomics at Boston Children’s Hospital/Massachusetts General Hospital (patient 1), University of Florida Health Center for Movement Disorders and Neurorestoration (patient 2), and Westmead Hospital, Sydney, Australia (patient 3). Detailed diagnostic evaluations were obtained at respective institutions. Records were reviewed for clinical history, examination, and response to medications and deep brain stimulation, summarized in Table 1. For patient 1, the authors consolidated growth charts derived from disparate clinics in 3 institutions to generate Figure 1; each institution utilized differing growth chart formats and normative curves. The authors made a good-faith effort to reflect both the reported value and relative percentile for each measure, and to combine those measures into a meaningful composite, based on the WHO 0-5 years growth charts for boys. All patients provided written consent for identifying information to be published. Patient 3 has been reported in part elsewhere. 13
Demographic Features of the Authors’ Patients and ADCY5-Related Symptoms.
Abbreviation: DBS, deep brain stimulation.
Growth curves for patient 1. Growth curves for the authors’ most severely affected subject (patient 1) illustrate marked weight loss following symptom onset and progression, while head circumference and height measures were unaffected. Symptoms began at 5 months (solid arrow) and progressed in severity through the subsequent 3 years. Failure to thrive and difficulty of feeding and administering medications necessitated gastrostomy tube placement (open arrow). Given the intractable nature of his movements, a deep brain stimulator was placed at 3.5 years (arrowhead). Note that his weight continued at a decreased percentile following gastrostomy tube placement, but began to recover in the months prior to stimulator placement. It appears that both supplemental feeds and suppression of his severe hyperkinetic movements was necessary to normalize his weight percentile.
Results
Clinical Presentations
Patient 1
Patient 1 was a 3-year-old Caucasian/Puerto Rican boy with severe choreoathetosis. He was born at 39 weeks via repeat Cesarean section, complicated by a 7-day neonatal intensive care unit stay for poor feeding and dehydration, with discharge at 11 days of life. Developmental milestones were met until 4 months of age. At 5 months, in the context of a febrile illness, he developed global hypotonia and marked developmental regression. He was initially clinically diagnosed with botulism and treated with botulinum immunoglobulin, with no improvement. He developed severe choreoathetosis soon after with diurnal exacerbations involving the face, all limbs, and trunk (Video 1). His hyperkinetic movements continued into the drowsy state, leading to severe insomnia refractory to multiple sleep aids. Chorea erupted with even slight arousal, waking him continuously and contributing to his profound sleep disturbance. The large amplitude of his chorea led to self-injury, as he would strike himself and nearby objects, and limited his ability to participate in physical therapy. The combination of increased caloric expenditure and the impediment of feeding by orolingual dyskinesias resulted in a failure to thrive. Placement of a gastrostomy tube at 10 months of age substantially improved the ease of nutrition and medication administration, but did not lead to substantial changes in weight (persisting between the 15th and 25th percentiles; Figure 1).
His examination demonstrated a nonverbal, alert child appearing uncomfortable due to continuous choreoathetotic movements of all limbs, neck, face, lips, and tongue. He had profound axial and appendicular hypotonia with no dystonia or myoclonus. Extensive imaging, metabolic, and genetic work-up was unrevealing. Whole-exome sequencing revealed a heterozygous de novo deletion in the ADCY5 gene (c.2080_2088del; p.K694_M696; Table 1). The variant causes an in-frame deletion of 3 highly conserved amino acids and was not represented in databases of common benign variants, suggesting that this variant was a disease-causing mutation. Prior treatment trials included amantadine, carbidopa-levodopa, tetrabenazine, chloral hydrate, zolpidem, haloperidol, propranolol, and phenobarbital (Table 2). Tetrabenazine provoked left calf and foot dystonia. The other medications provided transient or no benefit, leading us to pursue deep brain stimulation.
Treatment and Response in ADCY5-Related Hyperkinetic Movement Disorders.
Abbreviations: BFM, Burke-Fahn-Marsden; DBS, deep brain stimulation; GPi, globus pallidus interna.
Bilateral deep brain stimulation electrodes were placed stereotactically in the globus pallidus interna with guidance by microelectrode recordings. Immediately following deep brain stimulation, the family reported 2 weeks of transient improvement in hyperkinetic movements. As of this writing (10 months postoperative and following 9 program changes), his current settings are left C+ 2−: 2.1 V, 120 ms, 130 Hz and right C+ 9−: 2.1 V, 130 ms, 130 Hz. Interestingly, when voltages bilaterally were transiently increased to 2.3 V he had episodes of unexplained crying, with no associated worsening of hyperkinesia; these episodes resolved when voltages were reduced. At 6 months postimplantation, the charge of his deep brain stimulation battery was accidentally allowed to fully discharge, inactivating his stimulator. At that visit his sleep and hyperkinetic movements had substantially worsened, a decline that reversed with reactivation of his stimulator. Diazepam and lorazepam were continued for hyperkinetic movements, and trazodone was started to provide further improvement in sleep maintenance. He had moderate improvement in the amplitude and frequency of his chorea, which translated into much-improved sleep maintenance, and some recovery of development (attempting to coordinate midline hand movements). He also began to vocalize and attempt meaningful expressive communication (Video 1). In parallel with the decrease in amplitude and persistence of his choreiform movements, the authors noted steadily increasing weight gain (Figure 1). While his head circumference consistently followed the 50th percentile, and his height consistently followed the 85th percentile, his pre–deep brain stimulation weight dipped below the 3rd percentile and recovered to >80th percentile following deep brain stimulation. This weight gain partially preceded deep brain stimulation placement, perhaps reflecting improved nutrition via gastrostomy tube feedings, but recovered more substantially and persistently after deep brain stimulation placement.
Patient 2
Patient 2 was an 8-year-old right-handed Caucasian girl, born without complications at 38 weeks gestation (Table 1). Developmental motor milestones were delayed (sat at 18 months of age, walked at 3 years of age). Exaggerated Moro and startle reflex were present since birth, and any stimulation or movement agitated her. She smiled and rolled over appropriately at 6 months of age. Thereafter, she was diagnosed with benign congenital hypotonia and developmental delay. Severe sleep-onset myoclonus began at 1 year of age, which would persist in the drowsy state and disrupt sleep, leading to profound insomnia. Clonazepam calmed the sleep myoclonus sufficiently to allow for improved sleep, as myoclonus resolved with sleep onset. Hyperkinetic movements began at 2 years of age, and ultimately evolved to disabling paroxysmal dyskinesia, dystonia, and myoclonus (both at-rest and action-induced). Extensive investigations, including muscle biopsy, brain imaging, electroencephalography, sleep studies, and metabolic screens were unrevealing. Multiple medication trials, including clonazepam, tetrabenazine, carbamazepine, amantadine, carbidopa-levodopa, baclofen, and diphenhydramine produced only mild, transient or no clinical response (Table 2). Whole-exome sequencing revealed a de novo heterozygous c.1252C>T (p.R418W) mutation in the ADCY5 gene. Deep brain stimulation surgery was performed for refractory, debilitating dystonia and myoclonus.
The pre–deep brain stimulation examination revealed a severe, flaccid dysarthria with hyperkinetic features including an intermittent strained/strangled voice, facial dyskinesia, generalized dystonia, myoclonic jerks, choreoathetosis, and axial hypotonia with marked neck and truncal weakness. She was able to ambulate short distances without assistance before increased hyperkinetic movements led to falls. The preoperative unified dystonia rating scale score was 57 and Burke-Fahn-Marsden Dystonia Rating Scale score was 45. The 6 month postoperative Unified Dystonia Rating Scale score was 47 and Burke-Fahn-Marsden Dystonia Rating Scale score was 38. She had a complete preoperative evaluation by a multidisciplinary team (neurology, neurosurgery, neuropsychology, psychiatry, physical, occupational, speech/swallow therapy). Bilateral stereotactic deep brain stimulation placement in the globus pallidus interna was guided by microelectrode recordings. Immediately following lead placement all hyperkinetic movements ceased. However, over several weeks the movements gradually reemerged. Two Medtronic Activa SC implantable pulse generators were implanted 1 month after the leads. Following 7 months of deep brain stimulation therapy, she remains substantially impaired but with a decrease in frequency and duration of myoclonic storms, and improvement of head control and balance. Interestingly, small increases in current density have consistently resulted in delayed hyperkinetic movements (e.g., stimulation induced dyskinesias). This phenomenon has required lower current densities and a slower programming strategy (Video 2). Her most recent visit revealed significant improvement in her walking. As of this writing, her current settings are left C+ 1, 1−,2−: 1.0 V, 120 ms, 60 Hz and right C+ 1−,2−: 1.0 V, 120 ms, 60 Hz. She has the flexibility to vary her voltage from 0-2 V.
Patient 3
Patient 3 was a 32-year-old Caucasian female born at term, complicated by respiratory difficulty requiring a 4-day hospitalization. She had failure to thrive, poor suck, and hypotonia at 9 months of age, initially attributed to gastroesophageal reflux. At 13 months of age she developed episodic generalized choreiform movements with dystonic posturing (Table 1). She had severe axial hypotonia and continuous orobuccal chorea with upper and lower limb dystonic posturing between episodes of chorea. The episodic nature of the involuntary movements led to an initial diagnosis of epilepsy, with trials of phenobarbital, sodium valproate (20 mg/kg/day), carbamazepine (400 mg/day), and levodopa (20 mg/kg/day) without improvement. Paroxysmal movements were exacerbated by action, sleep, and intercurrent illness. Abnormal movements were severe during drowsiness and prevented restful sleep. There was mild reduction in sleep-induced involuntary movements with clonazepam (3 mg/day). Developmental motor milestones were delayed (sat at 18 months, walked with assistance at 2.5 years of age). She was diagnosed with dyskinetic cerebral palsy at 20 months of age.
As a child, severe axial hypotonia prevented her from supporting her torso and her ambulation was also distinctive and “frog-like.” She would sit on her crossed legs and propel her body forward, while also using her arms to commando crawl (Video 3). Language abilities were also delayed, achieving the skills of a 9-month-old at age 19 months. At age 22 years, she continued to have generalized chorea with dystonic posturing. Paroxysmal movements were exacerbated by caffeine and menstruation. However, having lost ambulation for a few years, she regained the ability to walk independently for 3 meters on carbidopa-levodopa (1000 mg/day) and clonazepam (3 mg/day). At 26 years of age, mobility and communication regressed due to increased frequency of involuntary movements. She could no longer walk independently and required assistance.
At 28 years of age she had intermittent, generalized, action-induced choreoathetoid movements on a background of continuous orobuccal chorea and dystonic posturing of the bilateral upper and lower limbs. She had a slow, negative (“no-no”) head tremor as well as rest tremor of both upper limbs and the right leg. She had motor impersistence of tongue protrusion and axial hypotonia with head drop. She had absent vertical saccades and initiated horizontal saccades with head thrust, but subsequent visual pursuit was normal (Video 3). There was lower limb spasticity with generalized hyperreflexia, ankle clonus and bilateral extensor plantar response. Sensory and coordination examination was normal. Extensive imaging, metabolic, and genetic work-up was unrevealing.
At 30 years of age, she underwent bilateral insertion of deep brain stimulation electrodes in the bilateral globus pallidus interna as episodic movements became more frequent and of longer duration (Table 2). Preoperative Burke-Fahn-Marsden Dystonia Rating Scale was 75.5 with a disability score of 25. The episodic choreoathetoid and dystonic movements improved within days after surgery. Three years following deep brain stimulation insertion, her Burke-Fahn-Marsden Dystonia Rating Scale was 38 with a disability score of 24. During temporary cessation of deep brain stimulation as part of impendence checks, upper limb choreoathetosis with dystonic posturing reemerged within seconds. She can now use a communication board more effectively and steer her electric wheelchair with a joystick. However, axial hypotonia did not improve, and she still requires assistance for walking. Her current settings are left C+ 0−: 3.5 V, 120 ms, 130 Hz and right C+ 8−: 3.5 V, 120 ms, 130 Hz.
Following deep brain stimulation placement the authors noted the similarity between prior ADCY5 clinical reports and the authors’ patient. Sanger sequencing revealed a c.1252C>T (p.R418W) mutation in the ADCY5 gene. Limited details were available about her mother, who also had an infantile-onset movement disorder, associated with mild developmental delay, dysarthria, bilateral generalized choreoathetosis and dystonic posturing of the lower limbs. The authors presume that her mother carried this same mutation. The patient’s 4 half-siblings were unaffected.
Phenotypic Variation in ADCY5 Mutations (Table 3)
Two of the 3 patients had mutations in c.1252C>T p.R418W, a variant which has been previously reported. 5,6 Other mutations that have been reported to be associated with this disorder include c.2176G>A; p.A726T, 7 and c.2088+1G>A in a 5’ donor site of intron 8. 4 Interestingly, cases with mutations in c.1252C>T p.R418W 5,6 had normal-to-delayed development while other cases had normal development. 4,8 The patients with p.R418W mutations in the authors’ series had paroxysmal mixed movement disorders similar to other reported cases. 5,6 The youngest and most-severely affected patient in the authors’ case series had a de novo deletion (c.2080_2088del; p.K694_M696), leading to continuous, rather than episodic or paroxysmal, movements and more severe developmental delay (Table 1, Video 1).
Reported ADCY5 Cases in the Extant Literature.
Abbreviation: DBS = Deep brain stimulation
Discussion
The authors’ case series highlights the clinical severity and difficulty in treating movement disorders resulting from ADCY5 mutations. The substantial disability suffered by the authors’ patients led to extensive medication trials (at least 6 different medications for each patient), all of which proved ineffective or intolerable. The authors suggest that deep brain stimulation may provide a new avenue for treating ADCY5-related movement disorders. It remains undetermined whether deep brain stimulation should be a “last resort” therapy for ADCY5-related disorders, or if early deep brain stimulation may have greater efficacy and prevent longer-term disability, similar to that demonstrated in pediatric primary dystonias. 14,15 Postmortem transcriptome studies in human brain demonstrated that ADCY5 gene transcription progressively increases throughout development. 6 This suggests that the movement disorders caused by ADCY5 mutations may worsen with age, arguing against expectant management. It is unknown whether deep brain stimulation can affect disease progression, and also which targets, or if multiple brain targets would provide greater benefit than globus pallidus interna stimulation.
The small number of cases and the limited duration of deep brain stimulation therapy for 2 of the authors’ 3 cases are major limitations of this series. While all of the authors’ patients have had generally positive responses to stimulation, the short duration of therapy in these 2 cases makes it difficult to predict long-term efficacy. ADCY5 gene mutations were only recently recognized as a cause of hyperkinetic movement disorders. Clinicians may not have had the opportunity to revisit diagnostic testing in established patients, suggesting that a pool of older patients with ADCY5-related disorders could be available for assessment. Patients with previously idiopathic generalized chorea, dyskinesias, and/or dystonia who have been treated with deep brain stimulation may prove to be ADCY5 mutation carriers; indeed, the authors’ patient 3 underwent deep brain stimulation prior to knowledge of her mutation status. These cases could give a more definitive understanding of the long-term benefits of deep brain stimulation in treating ADCY5-related movement disorders.
The molecular mechanisms by which ADCY5 gene mutations lead to hyperkinetic movement disorders remain unknown. The adenylyl cyclase family of genes regulates a diverse array of downstream effectors, making it difficult to identify which involved pathways are pathological. Indeed, simultaneous involvement of multiple pathways might explain why patients with ADCY5 gene mutations are refractory to medications. The mechanisms through which deep brain stimulation reduces abnormal movements are also unknown. 16 However, deep brain stimulation may provide benefit in ADCY5-related disorders precisely because stimulation of the globus pallidus interna, a primary integrator of striatal efferents, modulates neuronal activity independently of upstream molecular pathology. This point will need clarification by future studies.
Each of the authors’ patients had early onset hyperkinetic movement abnormalities, sleep disturbances, hypotonia, and developmental delay – a syndrome highly suggestive of an ADCY5-related disorder. However, the authors’ patients had extensive imaging, metabolic, and genetic testing prior to recognition of their ADCY5 mutations. These patients serve as a reminder that establishing a genetic cause of childhood chorea can be difficult. The authors suggest that if a child presents with early onset hyperkinetic movements, hypotonia, prominent facial dyskinesias, sleep disturbance, and/or developmental delay, this should prompt the clinician to evaluate for mutations in ADCY5, and NKX2.1. If both genes are normal, and imaging and clinical history do not provide further diagnostic clues then one should consider whole-exome sequencing. However, it is important to recall that whole-exome sequencing has its own limitations, such as variable genomic coverage, limited ability to detect small deletions, inconsistent detection of copy number changes, and the inability to detect splice-site and promoter mutations. Primary disorders of biogenic amine metabolism and transport (ie, neurotransmitter disorders) should also be evaluated in a child with developmental delay, hypotonia, hyperkinetic movement disorder, and normal neuroimaging since timely recognition and treatment of these disorders can markedly improve outcome. Furthermore, cases of neurotransmitter disorders with no identifiable mutations (e.g., rare cases of GTP cyclohydrolase deficiency) have been reported. 17,18 Though the authors are cautiously optimistic about the authors’ patients’ response to deep brain stimulation, the authors must emphasize that the ideal mode of treatment in these disorders remains uncertain and deep brain stimulation treatment for newly identified patients must be considered on a case-by-case basis. Also, the authors must emphasize that deep brain stimulation seems to help hyperkinetic aspects of the disorder, but not the other features.
The increasing awareness of ADCY5-related disorders will likely yield new cases and expand the recognized phenotypic expression. The authors encourage clinicians to enroll these subjects in clinical databases and engage with researchers attempting to characterize the molecular implications of ADCY5 mutations. Such clinical research efforts will be integral to improving the care provided to children and families with ADCY5-related disorders.
Footnotes
Acknowledgements
We would like to thank our patients and their families for the opportunity to publish this case series.
Author Contributions
MED, FCFC, and SDJ made equal authorship contributions. MED, FCFC, SDJ made substantial contributions to the concept and design, and drafted the initial manuscript, which was read and approved by all authors. All authors provided clinical care to the patients. MSO, VSCF, JLW made substantial contributions to the concept and design, revised the draft critically for important intellectual content, and approved the version to be published. IA, NM, PZ, LHR, KDF, WHT, EE, and NS made a contribution by acquisition of data, revised the draft critically for important intellectual content, and approved the version to be published.
Authors’ Note
This manuscript was authenticated via the iThenticate system provided by the University of Florida, and the first authors take full responsibility for ensuring originality.
Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FCFC is the recipient of the Neville-Brown scholarship from the University of Sydney and received honorarium from UCB and Abbvie. VSCF receives a salary from NSW Health, has received research grants from the National Health and Medical Research Council of Australia and Abbvie, and is on Advisory Boards and/or has received travel grants from Abbott/Abbvie, Allergan, Boehringer-Ingelheim, Hospira, Ipsen, Lundbeck, Merz, Novartis, Global Kinetics, Solvay and UCB. NM has received honorarium from Lundbeck. KDF received grant support from Medtronic, St. Jude, Boston Scientific, Neuropace; and is a consultant for Medtronic, Neuropace. MSO serves as a consultant for the National Parkinson Foundation, and has received research grants from NIH, NPF, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. MSO has previously received honoraria, but in the past >60 months has received no support from industry. MSO has received royalties for publications with Demos, Manson, Amazon, Smashwords, Books4Patients, and Cambridge (movement disorders books). MSO is an associate editor for New England Journal of Medicine Journal Watch Neurology. MSO has participated in CME and educational activities on movement disorders (in the last 36) months sponsored by PeerView, Prime, Quantia, Henry Stewart, and by Vanderbilt University. The institution and not MSO receives grants from Medtronic, Abbvie, and ANS/St. Jude, and the PI has no financial interest in these grants. MSO has participated as a site PI and/or co-I for several NIH-, foundation-, and industry-sponsored trials over the years but has not received honoraria.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval
The authors obtained written consent from all patients for identifying information to be published.
Supplemental Material
Prior to DBS:
Clip 1: This clip demonstrates severe oro-facial dyskinesias. Patient appears very uncomfortable. Clip 2: This clip demonstrates orofacial dyskinesias as well as generalized, confluent chorea. Dystonic posturing of the neck and intermittent, lower-amplitude dystonia of the bilateral hands is also evident.
Post-DBS:
Clips 3-6: At 5 months post-DBS placement, there is a reduction in the frequency and amplitude of facial dyskinesias. There is decreased amplitude of choreoathetosis in both upper and lower extremities. At 6 months following DBS, his battery was accidentally discharged. This lead to larger amplitude movements, increased choreoathetosis and marked right upper and left lower extremity dystonia.
Prior to DBS:
Clip 1: There are marked facial dyskinesias. Clip 2: This clip also demonstrates facial dyskinesias and generalized chorea. Clip 3: This clip demonstrates the patient’s gait instability due to generalized chorea and axial hypotonia. The patient has an unsteady, wide-based gait.
Post-DBS:
Clips 4-6: At 5 months post-DBS, facial dyskinesias are less prominent. While sitting, there is less chorea, especially in her trunk. While walking, her gait is more stable and less unsteady. Her truncal hypotonia is more evident with her diminished chorea, but is likely unchanged from earlier clips.
Prior to DBS at 20 years of age:
Clip 1: This clip demonstrates significant dysarthria and motor impersistence with tongue protrusion. Clip 2: She has chorea of her upper extremities. In addition, there is prominent intermittent loss of head tone that led to quick head jerks. Clip 3: She has “frog-like” ambulation and axial hypotonia.
Prior to DBS at 22 years of age:
Clip 4: She was treated with carbidopa-levodopa. There was some improvement in her ability to ambulate, but required assistance. Her gait is unsteady. Clip 5: She has chorea of her upper extremities and trunk.
Three years post-DBS at age 32:
Clip 6: She has improved chorea with improved motor control of both upper and lower extremities. The amplitude and frequency of chorea is less prominent.
References
Supplementary Material
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