Expanding the spectrum of KCNJ6-related disorders: Milder phenotype with pathological startle responses.

Keppen-Lubinsky syndrome is caused by pathogenic variants in KCNJ6, which encodes the inwardly rectifying channel subfamily J6. The four confirmed cases reported to date were characterized by severe intellectual disability, global developmental delay, feeding difficulties, and dysmorphic features. All but one of the cases also had a severe form of lipodystrophy, resulting in tightly adherent facial skin and appearance of premature aging. Here, we describe a 36-year-old female with a de novo pathogenic variant in KCNJ6 (NM_002240.5: c.460G>T; p.(Gly154Cys)) presenting with mild intellectual disability, subtle dysmorphic features, obsessive-compulsive disorder, and an exaggerated startle response. This case indicates that KCNJ6-related disorders should be considered in patients with less pronounced dysmorphic features and milder cognitive impairment, as well as in patients with startle disorders.

Novel THAP1 missense variant with incomplete penetrance in a case of generalized young onset dystonia showing good response to deep brain stimulation.

We describe a case of young onset generalized dystonia, harboring a previously unreported likely pathogenic THAP1 missense variant (c.109 G > A; p.Glu37Lys) that was inherited from her unaffected father. Moreover, we report a positive effect of deep brain stimulation, particularly on the cervical component of dystonia.

Reliability, feasibility and satisfaction of telemedicine evaluations for cervical dystonia.

INTRODUCTION: Telemedicine is used successfully for evaluating patients with neurologic diseases, but has not been tested in cervical dystonia (CD). CD is uniquely suited for telemedicine as the scales validated to assess its severity rely only on visual inspection. The study sought to determine reliability, feasibility and satisfaction of telemedicine visits for evaluating CD. METHODS: Patients 18 years and older with a diagnosis of CD and scheduled for botulinum toxin (BoNT) injections were recruited, with a total of 46 enrolled. Dystonia severity was evaluated using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) motor severity subscale. Three total evaluations took place: an initial telemedicine evaluation on the day prior to a scheduled BoNT injection; an in-person evaluation in clinic immediately before injections; and a follow-up telemedicine visit 4-6 weeks after injection with subsequent completion, by both participants and the clinician, of satisfaction questionnaires. Agreement between telemedicine and in-person TWSTRS data was calculated using intra-class correlation coefficients (ICC) and kappa statistics where appropriate. Feasibility was determined by the percent of patients completing all three visits, and satisfaction with telemedicine visits was determined based on answers to satisfaction questionnaires. RESULTS: There was excellent agreement between visit types for the TWSTRS motor severity summary score (κ = 0.890; 95th CI 0.713; 0.949). Only two individual TWSTRS items failed to meet the threshold for moderate agreement. Feasibility and satisfaction were high. DISCUSSION: Telemedicine is reliable and feasible in the evaluation of CD. Some CD patients would prefer telemedicine visits. Participants and the clinician were satisfied with telemedicine visits.

Patient Knowledge and Attitudes towards Genetic Testing in Parkinson's Disease Subjects with Deep Brain Stimulation.

OBJECTIVES: As genetic testing is becoming more widely commercially available for Parkinson's disease (PD) and may have implications regarding clinical outcomes for deep brain stimulation (DBS) and other therapies, we aimed to determine patient knowledge and attitudes towards genetic testing. METHODS: A sample of 88 PD subjects with bilateral STN-DBS completed a Genetic Attitudes Questionnaire (GAQ). Knowledge and attitudes towards genetic testing were assessed. RESULTS: The mean percent of correct responses regarding genetic testing knowledge was 58.5%. Nearly 90% of subjects were unfamiliar with Genetic Information Nondiscrimination Act (GINA). The most important reasons subjects cited in deciding whether to undergo genetic testing included (1) to be a candidate for clinical trials if positive, (2) to learn that they do not carry a mutation, and (3) because a healthcare provider had recommended it. Individuals who influence decision-making include spouses and children. About 88% of subjects would share results with spouses, children, and siblings. DISCUSSION: These results reveal that there is a major knowledge gap regarding genetic testing in PD and the implications of testing results on treatment, work, insurance, and privacy. Also, subjects would mainly seek genetic testing to participate in clinical trials, with spouses and children being the key stakeholders in decision-making.

Acute Stroke in Middle Cerebellar Peduncle in a Patient With FXTAS.

Background: Fragile-X associated tremor/ataxia syndrome (FXTAS) is commonly associated with T2 hyperintensity in the middle cerebellar peduncles (MCP) on magnetic resonance imaging (MRI). However, ischemic stroke in the MCP in a patient with FXTAS has not previously been described. Case Description: A 61-year-old man with hypertension, sleep apnea, obesity, and FXTAS presented to the emergency department with 2 days of worsening balance and nausea which began 2 days after chiropractic neck manipulation. Examination revealed new nystagmus and worsening dysmetria. Workup revealed an acute infarct in the left MCP, atherosclerotic narrowing of the V4 segment of the left vertebral artery, inadequately controlled hypertension, and a LDL of 127. Conclusion: Isolated MCP infarcts are rare and typically associated with hypoperfusion in the setting of vertebral artery disease and neck manipulation. We suspect that underlying neurodegeneration due to FXTAS with superimposed small vessel disease and neck manipulation may have caused preferential damage to the Purkinje cells in the MCP.

Considerations on patient-related outcomes with the use of botulinum toxins: is switching products safe?

INTRODUCTION: Botulinum toxin (BoNT) is the treatment of choice for many neurologic movement disorders, including blepharospasm, hemifacial spasm, and cervical dystonia. There are two serotypes approved for use by the US Food and Drug Administration: three brands of serotype A and one of serotype B. Many attempts have been made at establishing dose conversion ratios between brands and serotypes. This review focuses on the existing data comparing different formulations of the same BoNT serotypes as well as that comparing different serotypes with one another. We focus on existing data regarding switching from one formulation or serotype to another and will also discuss the issue of immunogenicity of BoNT. With this information as a foundation, recommendations on safety of switching agents are addressed. METHOD: Literature review searching PubMed and Google Scholar using the search terms "switching botox", "dosing equivalency in botox", and "comparing botox". RESULTS/CONCLUSION: Overall, there are many studies that demonstrate the efficacy and safety of each of the brands of BoNTs used in clinical practice. However, determination of dosing equivalencies among these brands and serotypes is complex with inconsistencies among the studies. When switching from one brand to another, the clinician should be aware of these issues, and not make the assumption that such ratios exist. Tailoring the dosage of each brand of BoNT to the clinical situation is the most prudent treatment strategy rather than focusing closely on conversion factors and concerns for immunogenicity.

Deep Brain Stimulation in Tourette's Syndrome.

OBJECTIVE: Tourette's syndrome (TS) is defined by 1 year of persistent motor and vocal tics. Often, the tics are refractory to conventional pharmacologic and psychobehavioral interventions. In these patients, deep brain stimulation (DBS) may be an appropriate intervention. This paper reviews different DBS targets in TS, discusses existing evidence on the efficacy of DBS in TS, highlights adverse effects of the procedure, discusses indications and patient selection as well as future directions for DBS in TS. METHODS: A literature review searching PubMed database entries between 2000 and 2015. Search terms included "DBS in Tourette Syndrome", "Deep brain stimulation in Tourette syndrome," and "Surgical management of Tourette Syndrome." RESULTS: Though there are no universally accepted guidelines defining ideal DBS candidates for TS, age, tic severity, and treatment refractoriness are important factors to consider in patient selection. A variety of targets exist for DBS in TS, but thalamic targets and GPi are the most widely studied. Psychiatric side effects that are target specific should be monitored closely and it is possible that these adverse effects may be resolved with programing. Small randomized controlled trials support the efficacy of DBS in TS. CONCLUSION: DBS for TS is safe and feasible, but large multi-center clinical trials are needed to determine the ideal target and optimal location within a particular target.

Therapeutic advances in Huntington's Disease.

Huntington's disease is a rare hereditary degenerative disease with a wide variety of symptoms that encompass movement, cognition, and behavior. The genetic mutation that causes the disease has been known for more than 20 y, and animal models have illuminated a host of intracellular derangements that occur downstream of protein translation. A number of clinical trials targeting these metabolic consequences have failed to produce a single effective therapy, although clinical trials continue. New strategies targeting the protein at the level of transcription, translation, and posttranslational modification and aggregation engender new hope that a successful strategy will emerge, but there is much work ahead. Some of the clinical manifestations of the illness, particularly chorea, affective symptoms, and irritability, are amenable to palliative strategies, but physicians have a poor evidence base on which to select the best agents. Clinical trials since 2013 have dashed hopes that coenzyme Q10 or creatine might have disease-modifying properties but suggested other agents were safe or hinted at efficacy (cysteamine, selisistat, hydroxyquinoline) and could proceed into later-stage disease modification trials. The hunt for effective symptom relief suggested that pridopidine might be shown effective given the right outcome measure. This review summarizes recent progress in HD and highlights promising new strategies for slowing disease progression and relieving suffering in HD.

New observations in the fragile X-associated tremor/ataxia syndrome (FXTAS) phenotype.

PURPOSE: Fragile X-associated tremor/ataxia syndrome (FXTAS) was originally defined as tremor, ataxia, cognitive decline, and parkinsonism in individuals who carry between 55 and 200 CGG repeats in the promoter region of the fragile X mental retardation 1 (FMR1) gene. This paper describes a series of patients who meet the definition of FXTAS who presented for care between 2009 and 2014. METHODS/RESULTS: Retrospective chart review of patients seen in the FXTAS clinic at Rush University in Chicago. CONCLUSIONS: Patients with FXTAS may present with a progressive supranuclear palsy-like phenotype and other eye movement abnormalities are common in these patients as well. Rapid worsening of gait abnormalities in FXTAS may be due to a secondary spinal issue and should be aggressively treated to regain function. Finally, the FXTAS Rating Scale score does not reliably inform the certainty of diagnosis or CGG repeat size in these patients.