A Novel Variant of ATP5MC3 Associated with Both Dystonia and Spastic Paraplegia.

BACKGROUND: In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31. OBJECTIVE: The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia. METHODS: Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the "GeneMatcher" program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient-derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function. RESULTS: Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM_001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper-limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility. CONCLUSION: A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity.

Essential tremor impairs the ability to suppress involuntary action impulses.

Essential tremor (ET) is a movement disorder characterized primarily by action tremor which affects the regulation of movements. Disruptions in cerebello-thalamocortical networks could interfere with cognitive control over actions in ET, for example, the ability to suppress a strong automatic impulse over a more appropriate action (conflict control). The current study investigated whether ET impacts conflict control proficiency. Forty-one ET patients and 29 age-matched healthy controls (HCs) performed a conflict control task (Simon task). Participants were instructed to give a left or right response to a spatially lateralized arrow (direction of the arrow). When the action signaled by the spatial location and direction of the arrow were non-corresponding (induced conflict), the inappropriate action impulse required suppression. Overall, ET patients responded slower and less accurately compared to HCs. ET patients were especially less accurate on non-corresponding conflict (Nc) versus corresponding (Cs) trials. A focused analysis on fast impulsive response rates (based on the accuracy rate at the fastest reaction times on Nc trials) showed that ET patients made more fast errors compared to HCs. Results suggest impaired conflict control in ET compared to HCs. The increased impulsive errors seen in the ET population may be a symptom of deficiencies in the cerebello-thalamocortical networks, or, be caused by indirect effects on the cortico-striatal pathways. Future studies into the functional networks impacted by ET (cortico-striatal and cerebello-thalamocortical pathways) could advance our understanding of inhibitory control in general and the cognitive deficits in ET.

Anatomical texture patterns identify cerebellar distinctions between essential tremor and Parkinson's disease.

Voxel-based morphometry is an established technique to study focal structural brain differences in neurologic disease. More recently, texture-based analysis methods have enabled a pattern-based assessment of group differences, at the patch level rather than at the voxel level, allowing a more sensitive localization of structural differences between patient populations. In this study, we propose a texture-based approach to identify structural differences between the cerebellum of patients with Parkinson's disease (n = 280) and essential tremor (n = 109). We analyzed anatomical differences of the cerebellum among patients using two features: T1-weighted MRI intensity, and a texture-based similarity feature. Our results show anatomical differences between groups that are localized to the inferior part of the cerebellar cortex. Both the T1-weighted intensity and texture showed differences in lobules VIII and IX, vermis VIII and IX, and middle peduncle, but the texture analysis revealed additional differences in the dentate nucleus, lobules VI and VII, vermis VI and VII. This comparison emphasizes how T1-weighted intensity and texture-based methods can provide a complementary anatomical structure analysis. While texture-based similarity shows high sensitivity for gray matter differences, T1-weighted intensity shows sensitivity for the detection of white matter differences.

A Phase 2 Proof-of-Concept, Randomized, Placebo-Controlled Trial of CX-8998 in Essential Tremor.

BACKGROUND: Available essential tremor (ET) therapies have limitations. OBJECTIVES: The objective of this study was to evaluate CX-8998, a selective T-type calcium channel modulator, in essential tremor. METHODS: Patients 18-75 years old with moderate to severe essential tremor were randomized 1:1 to receive CX-8998 (titrated to 10 mg twice daily) or placebo. The primary end point was change from baseline to day 28 in The Essential Tremor Rating Assessment Scale performance subscale scored by independent blinded video raters. Secondary outcomes included in-person blinded investigator rating of The Essential Tremor Rating Assessment Scale performance subscale, The Essential Tremor Rating Assessment Scale activities of daily living subscale, and Kinesia ONE accelerometry. RESULTS: The video-rated The Essential Tremor Rating Assessment Scale performance subscale was not different for CX-8998 (n = 39) versus placebo (n = 44; P = 0.696). CX-8998 improved investigator-rated The Essential Tremor Rating Assessment Scale performance subscale (P = 0.017) and The Essential Tremor Rating Assessment Scale activities of daily living (P = 0.049) but not Kinesia ONE (P = 0.421). Adverse events with CX-8998 included dizziness (21%), headache (8%), euphoric mood (6%), and insomnia (6%). CONCLUSIONS: The primary efficacy end point was not met; however, CX-8998 improved some assessments of essential tremor, supporting further clinical investigation. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Prevalence of Comorbid Spasticity and Urinary Incontinence in Residents of a Long-Term Care Facility.

The current study evaluated the prevalence of comorbid spasticity and urinary incontinence (UI) in a long-term care facility. Medical history, presence of UI, and activities of daily living (ADL) dependency were obtained from medical records and Minimum Data Set 3.0. Quality of life was assessed with the EuroQoL-5D-5L (EQ-5D). Comorbid spasticity and UI presented in 29% of participants (14 of 49). Participants with spasticity and UI had higher ADL dependency and lower EQ-5D than participants without both conditions (4.9, 95% confidence interval [CI] [1.6, 80.], p = 0.003; -0.17, 95% CI [-0.33, 0.00], p = 0.044; respectively). More than one half of participants with lower limb spasticity had severe UI, compared to only 10% without lower limb spasticity (relative risk = 5.5; 95% CI [1.9, 15.9]; p = 0.006). Comorbid spasticity and UI may be common in the long-term care setting and negatively associated with ADL and quality of life. Further investigation is needed to confirm these findings. [Journal of Gerontological Nursing, 46(10), 35-42.].

Effects of repeated abobotulinumtoxinA injections in upper limb spasticity.

INTRODUCTION: The efficacy of single injections of abobotulinumtoxinA (Dysport) is established in adults with upper limb spasticity. In this study we assessed the effects of repeated injections of abobotulinumtoxinA over 1 year. METHODS: Patients (n = 258, safety population) received 500 U, 1,000 U, or 1,500 U (1,500-U dose included 500-U shoulder injections) for up to 4 or 5 treatment cycles. Assessments included treatment-emergent adverse events (TEAEs), muscle tone, passive and active range of motion (XV1, XA ), angle of catch (XV3 ), Disability Assessment Scale (DAS) score, Modified Frenchay Scale (MFS) score, and Physician Global Assessment (PGA) score. RESULTS: The incidence of TEAEs decreased across cycles. Muscle tone reduction and XV1 remained stable across cycles, whereas XV3 and XA continued to improve at the finger, wrist, and elbow flexors. DAS and PGA improved across cycles. MFS improved best with 1,500 U. DISCUSSION: A favorable safety profile and continuous improvements in active movements and perceived and active function were associated with repeated abobotulinumtoxinA injections in upper limb muscles. Muscle Nerve 57: 245-254, 2018.

Confined Thalamic Deep Brain Stimulation in Refractory Essential Tremor.

BACKGROUND: Thalamic ventral intermediate nucleus (VIM) deep brain stimulation (DBS) is an effective therapy for medication-refractory essential tremor (ET). However, 13-40% of patients with an initially robust tremor efficacy lose this benefit over time despite reprogramming attempts. At our institution, a cohort of ET patients with VIM DBS underwent implantation of a second anterior (ventralis oralis anterior; VOA) DBS lead to permit "confined stimulation." We sought to assess whether confined stimulation conferred additional tremor capture compared to VIM or VOA stimulation alone. METHODS: Seven patients participated in a protocol-based programming session during which a video-recorded Fahn-Tolosa-Marin Part A (FTM-A) tremor rating scale was used in the following 4 DBS states: off stimulation, VIM stimulation alone, VOA stimulation alone, and dual lead (confined) stimulation. RESULTS: The average (SD) baseline FTM-A off score was 17.6 (4.0). VIM stimulation alone lowered the average FTM-A total score to 6.9 (4.0). Confined stimulation further attenuated the tremor, reducing the total score to 5.7 (2.8). CONCLUSIONS: Confined thalamic DBS can provide additional symptomatic benefits in patients with unsatisfactory tremor control from VIM or VOA stimulation alone.

The Allure of High-Risk Rewards in Huntington's disease.

OBJECTIVES: Huntington's disease (HD) is a neurodegenerative disorder that produces a bias toward risky, reward-driven decisions in situations where the outcomes of decisions are uncertain and must be discovered. However, it is unclear whether HD patients show similar biases in decision-making when learning demands are minimized and prospective risks and outcomes are known explicitly. We investigated how risk decision-making strategies and adjustments are altered in HD patients when reward contingencies are explicit. METHODS: HD (N=18) and healthy control (HC; N=17) participants completed a risk-taking task in which they made a series of independent choices between a low-risk/low reward and high-risk/high reward risk options. RESULTS: Computational modeling showed that compared to HC, who showed a clear preference for low-risk compared to high-risk decisions, the HD group valued high-risks more than low-risk decisions, especially when high-risks were rewarded. The strategy analysis indicated that when high-risk options were rewarded, HC adopted a conservative risk strategy on the next trial by preferring the low-risk option (i.e., they counted their blessings and then played the surer bet). In contrast, following a rewarded high-risk choice, HD patients showed a clear preference for repeating the high-risk choice. CONCLUSIONS: These results indicate a pattern of high-risk/high-reward decision bias in HD that persists when outcomes and risks are certain. The allure of high-risk/high-reward decisions in situations of risk certainty and uncertainty expands our insight into the dynamic decision-making deficits that create considerable clinical burden in HD.

PARK2 patient neuroprogenitors show increased mitochondrial sensitivity to copper.

Poorly-defined interactions between environmental and genetic risk factors underlie Parkinson's disease (PD) etiology. Here we tested the hypothesis that human stem cell derived forebrain neuroprogenitors from patients with known familial risk for early onset PD will exhibit enhanced sensitivity to PD environmental risk factors compared to healthy control subjects without a family history of PD. Two male siblings (SM and PM) with biallelic loss-of-function mutations in PARK2 were identified. Human induced pluripotent stem cells (hiPSCs) from SM, PM, and four control subjects with no known family histories of PD or related neurodegenerative diseases were utilized. We tested the hypothesis that hiPSC-derived neuroprogenitors from patients with PARK2 mutations would show heightened cell death, mitochondrial dysfunction, and reactive oxygen species generation compared to control cells as a result of exposure to heavy metals (PD environmental risk factors). We report that PARK2 mutant neuroprogenitors showed increased cytotoxicity with copper (Cu) and cadmium (Cd) exposure but not manganese (Mn) or methyl mercury (MeHg) relative to control neuroprogenitors. PARK2 mutant neuroprogenitors also showed a substantial increase in mitochondrial fragmentation, initial ROS generation, and loss of mitochondrial membrane potential following Cu exposure. Our data substantiate Cu exposure as an environmental risk factor for PD. Furthermore, we report a shift in the lowest observable effect level (LOEL) for greater sensitivity to Cu-dependent mitochondrial dysfunction in patients SM and PM relative to controls, correlating with their increased genetic risk for PD.

The optimal pallidal target in deep brain stimulation for dystonia: a study using a functional atlas based on nonlinear image registration.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus internus is established as efficacious for dystonia, yet the optimal target within this structure is not well defined. Published evidence suggests that spatial normalization provides a better estimate of DBS lead location than traditional methods based on standard stereotactic coordinates. METHODS: We retrospectively reviewed our pallidal implanted dystonia population. Patient imaging scans were morphed into an MRI atlas using a nonlinear image registration algorithm. Active contact locations were projected onto the atlas and clusters analyzed for the degree of variance in two groups: (1) good and poor responders and (2) cervical (CD) and generalized dystonia (GD). RESULTS: The average active contact location between CD and GD good responders was distinct but not significantly different. The mean active contact for CD poor responders was significantly different from CD responders and GD poor responders in the dorsoventral direction. CONCLUSIONS: A normalized imaging space is arguably more accurate in visualizing postoperative leads. Despite some separation between groups, this data suggests there was not an optimal pallidal target for common dystonia patients. Degrees of variance overlapped due to a large degree of individual target variation. Patient selection may ultimately be the key to maximizing patient outcomes.

Hereditary spastic paraplegia-causing mutations in atlastin-1 interfere with BMPRII trafficking.

Disruption of the bone morphogenic protein (BMP)-linked signaling pathway has been suggested as an important factor in the development of hereditary spastic paraplegia (HSP). HSP-causing proteins spastin, spartin and NIPA1 were reported to inhibit the BMP pathway. We have previously shown a strong interaction of NIPA1 and atlastin-1 proteins. Hence, we investigated the role of another HSP-associated protein atlastin-1 in this signaling cascade. Endogenous and expressed atlastin-1 showed a strong interaction with BMP receptors II (BMPRII) and analyzed missense, HSP-causing mutations R239C and R495W disrupted BMPRII trafficking to the cell surface. BMPRII does not require the presence of atlastin-1 because knockdown expression of atlastin-1 did not alter endogenous BMPRII cellular distribution. Expression of mutant forms of atlastin-1 also interfered with the signaling response to BMP4 stimulation and reduced phosphorylation of Smad 1/5 proteins. Our results suggest that HSP-causing atlastin-1 mutations exhibit a dominant-negative effect on trafficking of BMPRII, which disrupts the BMP pathway in neurons. This, together with previously demonstrated inhibition of atlastin-1 of BMP pathway, further supports the role of this signaling cascade in axonal maintenance and axonal degeneration, which is seen in various types of HSP.

Neurologist consistency in interpreting information provided by an interactive visualization software for deep brain stimulation postoperative programming assistance.

INTRODUCTION: Postoperative programming in deep brain stimulation (DBS) therapy for movement disorders can be challenging and time consuming. Providing the neurologist with tools to visualize the electrode location relative to the patient's anatomy along with models of tissue activation and statistical data can therefore be very helpful. In this study, we evaluate the consistency between neurologists in interpreting and using such information provided by our DBS programming assistance software. METHODS: Five neurologists experienced in DBS programming were each given a dataset of 29 leads implanted in 17 patients. For each patient, probabilistic maps of stimulation response, anatomical images, models of tissue activation volumes, and electrode positions were presented inside a software framework called CRAnialVault Explorer (CRAVE) developed in house. Consistency between neurologists in optimal contact selection using the software was measured. RESULTS: With only the efficacy map, the average consistency among the five neurologists with respect to the mode and mean of their selections was 97% and 95%, respectively, while these numbers were 93% and 89%, respectively, when both efficacy and an adverse effect map were used simultaneously. Fleiss' kappa statistic also showed very strong agreement among the neurologists (0.87 when using one map and 0.72 when using two maps). CONCLUSION: Our five neurologists demonstrated high consistency in interpreting information provided by the CRAVE interactive visualization software for DBS postoperative programming assistance. Three of our five neurologists had no prior experience with the software, which suggests that the software has a short learning curve and contact selection is not dependent on familiarity with the program tools.

Novel polymerase gamma (POLG1) gene mutation in the linker domain associated with parkinsonism.

BACKGROUND: Mutations in the POLG1 gene have variable phenotypic presentations and a high degree of clinical suspicion is necessary for their recognition. Parkinsonism and ataxia are the most common movement disorders associated with POLG1 mutations but no phenotype-genotype correlation has been established. CASE PRESENTATION: We identified a male patient with progressive external ophthalmoplegia who also developed a progressive bradykinesia, rigidity and camptocormia in the third decade. Parkinsonism was partially responsive to dopaminegic replacement. His father and brother had reportedly similar clinical problems. Genetic analysis identified a novel mutation p.K512M in the POLG1 gene. CONCLUSION: This report further expands the spectrum of POLG1-associated neurologic problems with the report of a novel mutation in the linker region of the gene, which are rarely associated with parkinsonism.

"Because it is a rare disease it needs to be brought to attention that there are things out of the norm": a qualitative study of patient and physician experiences of Wilson disease diagnosis and management in the US.

BACKGROUND: Wilson disease (WD) is a genetic disorder of copper metabolism that leads to copper accumulation in various organs, primarily the liver and brain, resulting in heterogenous hepatic, neurologic, and psychiatric symptoms. Diagnosis can occur at any age, requiring lifelong treatment, which can involve liver transplantation. This qualitative study aims to understand the wider patient and physician experience of the diagnosis and management of WD in the US. METHODS: Primary data were collected from 1:1 semi structured interviews with US-based patients and physicians and thematically analyzed with NVivo. RESULTS: Twelve WD patients and 7 specialist WD physicians (hepatologists and neurologists) were interviewed. Analysis of the interviews revealed 18 themes, which were organized into 5 overarching categories: (1) Diagnosis journey, (2) Multidisciplinary approach, (3) Medication, (4) The role of insurance, and (5) Education, awareness, and support. Patients who presented with psychiatric or neurological symptoms reported longer diagnostic journeys (range 1 to 16 years) than those presenting with hepatic symptoms or through genetic screening (range 2 weeks to 3 years). All were also affected by geographical proximity to WD specialists and access to comprehensive insurance. Exploratory testing was often burdensome for patients, but receipt of a definitive diagnosis led to relief for some. Physicians emphasized the importance of multidisciplinary teams beyond hepatology, neurology, and psychiatry and recommended a combination of chelation, zinc, and a low-copper diet; however, only half the patients in this sample were on a chelator, and some struggled to access prescription zinc due to insurance issues. Caregivers often advocated for and supported adolescents with their medication and dietary regimen. Patients and physicians recommended more education and awareness for the healthcare community. CONCLUSIONS: WD requires the coordination of care and medication among several specialists due to its complex nature, but many patients do not have access to multiple specialties due to geographical or insurance barriers. Because some patients cannot be treated in Centers of Excellence, easy access to reliable and up-to-date information is important to empower physicians, patients, and their caregivers in managing the condition, along with general community outreach programs.

Progressive Multifocal Encephalopathy Holmes Tremor Successfully Treated with Bilateral Deep Brain Stimulation.

Background: We report a patient with bilateral HT treated with DBS. Case report: A 58-year-old man diagnosed with HIV/AIDS and progressive multifocal leukoencephalopathy (PML) presented with 20 years of bilateral arm tremor refractory to therapy. DBS was implanted on the left ventral intermediate nucleus and posterior subthalamic area (VIM/PSA). One year later, a right VIM/PSA DBS was implanted. At twelve months, there were no significant side-effects. With his DBS turned off and on, the Fahn-Tolosa-Marin scale was rated 82 and 58, respectively. Discussion: To our knowledge, this is the first report of bilateral DBS VIM/PSA treating HT with no significant side effects. Highlights: We report a successful treatment using deep brain stimulation of bilateral Holmes tremor that was caused by progressive multifocal encephalopathy. The patient achieved 30% improvement in tremor control with a meaningful improvement in his activities of daily living.

Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3.

Distal myopathies represent a heterogeneous group of inherited skeletal muscle disorders. One type of adult-onset, progressive autosomal-dominant distal myopathy, frequently associated with dysphagia and dysphonia (vocal cord and pharyngeal weakness with distal myopathy [VCPDM]), has been mapped to chromosome 5q31 in a North American pedigree. Here, we report the identification of a second large VCPDM family of Bulgarian descent and fine mapping of the critical interval. Sequencing of positional candidate genes revealed precisely the same nonconservative S85C missense mutation affecting an interspecies conserved residue in the MATR3 gene in both families. MATR3 is expressed in skeletal muscle and encodes matrin 3, a component of the nuclear matrix, which is a proteinaceous network that extends throughout the nucleus. Different disease related haplotype signatures in the two families provided evidence that two independent mutational events at the same position in MATR3 cause VCPDM. Our data establish proof of principle that the nuclear matrix is crucial for normal skeletal muscle structure and function and put VCPDM on the growing list of monogenic disorders associated with the nuclear proteome.

Maternal intrachromosomal insertional translocation leads to recurrent 1q21.3q23.3 deletion in two siblings.

We identified a novel 6.33 Mb deletion of 1q21.3q23.3 (hg18; chr1: 153035245-159367106) in two siblings presenting with blepharophimosis, ptosis, microbrachycephaly, severe psychomotor, and intellectual disability. Additional common features include small corpus callosum, normal birth length and head circumference, postnatal growth restriction, low anterior hairline, upturned nose, bilateral preauricular pits, widely spaced teeth, gingival hypertrophy, left ventricular dilatation with decreased biventricular systolic function, delayed bone age, 5th finger clinodactyly, short 3rd digit, hyperconvex nails, obstructive and central sleep apnea, and bilateral heel contractures. Fluorescence in situ hybridization (FISH) performed in the mother of both children showed an apparently balanced, intrachromosomal insertional translocation of 1q21.3q23.3 to 1q42.12. The sibling recurrence likely arose by a maternal meiotic crossing over on the rearranged chromosome 1 between the deleted region and the insertion. We hypothesize that the decreased cardiac function and contractures may be related to LMNA haploinsufficiency. This case illustrates the importance of FISH when attempting to determine inheritance of a copy-number variation and emphasize the value of evaluating known haploinsufficiency phenotypes for genes in deleted regions.

Novel PRRT2 mutation in an African-American family with paroxysmal kinesigenic dyskinesia.

BACKGROUND: Recently, heterozygous mutations in PRRT2 (Chr 16p11.2) have been identified in Han Chinese, Japanese and Caucasians with paroxysmal kinesigenic dyskinesia. In previous work, a paroxysmal kinesigenic dyskinesia locus was mapped to Chr 16p11.2 - q11.2 in a multiplex African-American family. METHODS: Sanger sequencing was used to analyze all four PRRT2 exons for sequence variants in 13 probands (9 Caucasian, 1 Caucasian-Thai, 1 Vietnamese and 2 African-American) with some form of paroxysmal dyskinesia. RESULTS: One patient of mixed Caucasian-Thai background and one African-American family harbored the previously described hotspot mutation in PRRT2 (c.649dupC, p.R217Pfs*8). Another African-American family was found to have a novel mutation (c.776dupG, p.E260*). Both of these variants are likely to cause loss-of-function via nonsense-mediated decay of mutant PRRT2 transcripts. All affected individuals had classic paroxysmal kinesigenic dyskinesia phenotypes. CONCLUSIONS: Heterozygous PRRT2 gene mutations also cause paroxysmal kinesigenic dyskinesia in African-Americans. The c.649dupC hotspot mutation in PRRT2 is common across racial groups.

The effect of HSP-causing mutations in SPG3A and NIPA1 on the assembly, trafficking, and interaction between atlastin-1 and NIPA1.

Despite its genetic heterogeneity, hereditary spastic paraplegia (HSP) is characterized by similar clinical phenotypes, suggesting that a common biochemical pathway underlies its pathogenesis. In support of this hypothesis, we used a combination of immunoprecipitation, confocal microscopy, and flow cytometry to demonstrate that two HSP-associated proteins, atlastin-1 and NIPA1, are direct binding partners, and interestingly, that the endogenous expression and trafficking of these proteins is highly dependent upon their coexpression. In addition, we demonstrated that the cellular distribution of atlastin-1:NIPA1 complexes was dramatically altered by HSP-causing mutations, as missense mutations in atlastin-1 (R239C and R495W) and NIPA1 (T45R and G106R) caused protein sequestration in the Golgi complex (GC) and endoplasmic reticulum (ER), respectively. Moreover, we demonstrated that HSP-causing mutations in both atlastin-1 and NIPA1 reduced axonal and dendritic sprouting in cultured rat cortical neurons. Together, these findings support the hypothesis that NIPA1 and atlastin-1 are members of a common biochemical pathway that supports axonal maintenance, which may explain in part the characteristic degeneration of long spinal pathways observed in patients with HSP.

Patient and Caregiver Perspectives on Telehealth Use in a Multidisciplinary Huntington's Disease Clinic: A Single-Institution Experience.

BACKGROUND: The coronavirus pandemic saw technology evolve as outpatient clinics faced restriction of in-person visits. Reliance on telemedicine using two-way audio-video communication significantly increased. Telemedicine was observed to be convenient, cost-effective, reduced no-show rates, and fostered sustained engagement. Enhanced flexibility from short notice scheduling benefitted patients and their caregivers. Greater time value was perceived by patients, and reduced reliance on caregivers. Disadvantages included barriers of access to internet connectivity or equipment. OBJECTIVE: We aimed to retrospectively survey patients with Huntington's disease (HD) seen via telehealth in our HDSA Center for Excellence Multidisciplinary clinic. We evaluated usability, learnability, interface quality, reliability, and future use. METHODS: This qualitative survey used the 21-item Telehealth Usability Questionnaire. Close-ended responses ranged from strongly disagree to strongly agree scored on Likert scale (1 through 7). Averages were calculated to examine attitudes towards telemedicine. Spearman correlation test was performed to detect attitude biases between patients and caregivers. RESULTS: Respondents were more likely than not to strongly agree with survey statements. Average attitude score of 5.92 (range 2.95-7.00) suggested favorability and improved convenience when telehealth was used in complement to in-person visits, without detriment to patient-provider communication. Spearman correlation coefficient between patient and family/caregiver groups was 0.023, which is below the cutoff of 0.344 for a = 0.05 at N = 24. This suggests there was no bias between patient and caregiver attitudes. CONCLUSION: This study demonstrated telehealth is favored by caregivers and patients with HD. This population with specific physical, cognitive and psychiatric needs can benefit from adaptive systems that enhance compliance.