Florence Chang

Phenotypic insights into ADCY5‐associated disease

Adenylyl cyclase 5 (ADCY5) mutations is associated with heterogenous syndromes: familial dyskinesia and facial myokymia; paroxysmal chorea and dystonia; autosomal‐dominant chorea and dystonia; and benign hereditary chorea. We provide detailed clinical data on 7 patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations.

Treatment of ADCY5-Associated Dystonia, Chorea, and Hyperkinetic Disorders With Deep Brain Stimulation A Multicenter Case Series

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.

Four cases of orthostatic myoclonus.

Orthostatic unsteadiness (unsteadiness on standing) is a relatively common symptom and can have neurological or non-neurological causes. Glass et al. have recently described a syndrome presenting with unsteadiness or leg jerking during standing or gait initiation difficulty which they have termed orthostatic myoclonus (OM). OM is a disabling syndrome but potentially treatable. It may develop on the background of neurodegenerative disease; other causes include pro-myoclonic drugs such as tricyclic antidepressants. In order to increase awareness of this syndrome, we report four patients with electrophysiologically confirmed OM who were referred to the movement disorder unit for lower limb tremor studies. All four patients presented with unsteadiness on standing. There were no signs suggestive of neurodegenerative disease and three of the patients had a provisional diagnosis of orthostatic tremor. The diagnosis of OM was supported by a surface electromyography showing 9-16Hz, non-rhythmic muscle bursts with burst duration of 50-100ms during standing. OM is unrecognised by many physicians as a cause of orthostatic intolerance. The most common syndrome with which OM may be confused is orthostatic tremor. A correct diagnosis is important as it may respond to treatment with clonazepam, gabapentin or piracetam.

Dancing feet dyskinesias: a clue to parkin gene mutations.

Case 1 is a 61-year-old female who presented at age 30 with bilateral upper limb postural tremor. She was L-dopa responsive when parkinsonian symptoms developed 3 years later. She had slow progression of parkinsonism, and 17 years after commencing L-dopa/carbidopa, on a dose of 250 mg per day, she developed symmetrical peak-dose choreoathetotic ankle dyskinesia. This worsened over 10 years with difficulty walking as a result of dyskinetic ankle inversion and eversion movement (see Video). Increasing the dose resulted in worsening of the dyskinesia, confirming it was peak dose, rather than diphasic dyskinesia. The patient had multiplex ligation-dependent probe amplification analysis, polymerase chain reaction amplification, and sequencing of all 12 exons of the Parkin gene, with subcloning of the DNA, showing compound heterozygous, noncontiguous deletions of exons 2 and 3. Case 2 is a 41-year-old female who presented at age 21 with bilateral postural hand tremor. Five years later, she developed L-dopa responsive lower limb dystonia with diurnal variation and parkinsonism. Ten years after commencement of L-dopa/ benserazide (250 mg/day), she developed wearing off and peak-dose choreoathetotic dyskinesias of the ankles (see Video). Ten years after symptom onset, a single photon-emission computed tomography scan with [I]b-carbomethoxy3b-(4-iodophenyl)tropane showed reduced radiopharmaceutical uptake in both putamen. She had compound heterozygous deletions of exons 2 and 5 to 7 of the Parkin gene.

Postural tremor and chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) typically presents with a combination of sensory and motor impairments. Tremor is recognized as a common and debilitating feature in CIDP, although the underlying mechanisms are unclear.

Reply letter to “ADCY5‐related dyskinesia: Comments on characteristic manifestations and variant‐associated severity”

We thank Raskind and colleagues for their interest in our paper and acknowledge the seminal discoveries of their group from the original syndromic description of familial dyskinesia and facial myokymia, which was subsequently discovered to be secondary to a mutation in the adenylyl cyclase 5 (ADCY5) gene, to their reports expanding the phenotypic spectrum of ADCY5 mutations that include the description of the largest cohort of patients published in the literature to date. With respect to their concerns about the accuracy of the literature review and claims of novelty in our paper, the explanation lies in the timing of submission of our original and revised manuscripts toward the latter stages of which was published their large cohort observations. A reference to their paper was therefore added late in the preparation of our manuscript, albeit not to our listing of known ADCY5 mutations in Table 1, an oversight for which we apologize. Of note, however, is our 2011 conference report titled “Familial Choreoathetosis With Exacerbations During Drowsiness,” which includes 3 of the 6 kindreds in our subsequent publication and describes many of the clinical features of 1 end of the spectrum of ADCY5-associated dyskinesias at a time when ADCY5 gene mutations had not yet been identified as a cause of disease. The detailed clinical and genetic discoveries of Raskind and colleagues ultimately allowed a unifying diagnosis to be made when targeted gene sequencing confirmed ADCY5 gene mutations in all 3 kindreds. We also acknowledge that claiming novelty of both c.1252C>G (p.R418G) and c.1253G>A (p.R418Q) mutations was incorrect as, indeed, the latter had already been reported at the time our manuscript was going through the final stages of revision. However, we respectfully disagree with the claim of Raskind and colleagues that we “suggest that p.R418Q and p.R418G may result in milder disease than p.R418W.” In fact, we simply state that among our patients, “The other two probands who presented with a milder phenotype carried ADCY5 p.R418G and p.R418Q mutations, respectively.” Regarding Raskind and colleagues’ comment that “Though the authors suggest they are first to describe improvement with clonazepam, we previously described response to clonazepam in several patients,” we reference their 2015 paper in our discussion and mention the usefulness of clobazam, both of which were highlighted in our previous report as well as the results of a single case of pallidal DBS (reported in more detail elsewhere). Finally, we do not feel that not specifically mentioning somatic mosaicism in our paper will lead to “incorrect prognoses and recurrence risks” in ADCY5 families, as genetic counseling guidelines for ADCY5 mutation carriers will be based on the growing body of ADCY5 articles, in which mosaicism is a well-described feature. Similar to Raskind and colleagues, we hope that the discovery of larger patient cohorts and collaborative work will result in the development of effective prognostic and therapeutic discoveries for this pleomorphic and intriguing disorder.

Validation of Fear of Falling and Balance Confidence Assessment Scales in Persons with Dystonia

Background and Purpose: Falls are problematic for people living with neurological disorders and a fear of falling can impact on actual falls. Fear of falling is commonly assessed using the Falls Self-Efficacy Scale International (FES-I) or the Activities-specific Balance Confidence (ABC) Scale. These scales can predict risk of falling. We aimed to validate the FES-I and the ABC in persons with dystonia. Methods: We conducted an online survey of people with dystonia, collecting information on demographics, 6-month falls history, dystonia disability, and the FES-I and ABC scales. Scales were validated for structural validity and internal consistency. We also examined goodness-of-fit, convergent validity, and predictive validity, and determined cutoff scores for predicting falls risk. Results: Survey responses (n = 122) showed that both FES-I and ABC scales have high internal validity and convergent validity with the Functional Disability Questionnaire in persons with dystonia. Each scale examines a single factor, fear of falling (FES-I) and balance confidence (ABC). At least one fall was reported by 39% of participants; the cutoff value for falls risk was found to be 29.5 and 71.3 for the FES-I and the ABC respectively. Discussion and Conclusions: The FES-I and the ABC scales are valid scales to examine fear of falling and balance confidence in persons with dystonia. Fear of falling is high and balance confidence is low and both are worse in those with dystonia who have previously fallen. Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A182).