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Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker., (Published by Oxford University Press on behalf of the Guarantors of Brain 2024.)

Background: Pathogenic variants in TTN cause a spectrum of autosomal dominant and recessive cardiovascular, skeletal muscle and cardioskeletal disease with symptom onset across the lifespan. The aim of this study was to characterise the genotypes and phenotypes in a cohort of TTN +paediatric patients., Methods: Retrospective chart review was performed at four academic medical centres. Patients with pathogenic or truncating variant(s) in TTN and paediatric-onset cardiovascular and/or neuromuscular disease were eligible., Results: 31 patients from 29 families were included. Seventeen patients had skeletal muscle disease, often with proximal weakness and joint contractures, with average symptom onset of 2.2 years. Creatine kinase levels were normal or mildly elevated; electrodiagnostic studies (9/11) and muscle biopsies (11/11) were myopathic. Variants were most commonly identified in the A-band (14/32) or I-band (13/32). Most variants were predicted to be frameshift truncating, nonsense or splice-site (25/32). Seventeen patients had cardiovascular disease (14 isolated cardiovascular, three cardioskeletal) with average symptom onset of 12.9 years. Twelve had dilated cardiomyopathy (four undergoing heart transplant), two presented with ventricular fibrillation arrest, one had restrictive cardiomyopathy and two had other types of arrhythmias. Variants commonly localised to the A-band (8/15) or I-band (6/15) and were predominately frameshift truncating, nonsense or splice-site (14/15)., Conclusion: Our cohort demonstrates the genotype-phenotype spectrum of paediatric-onset titinopathies identified in clinical practice and highlights the risk of life-threatening cardiovascular complications. We show the difficulties of obtaining a molecular diagnosis, particularly in neuromuscular patients, and bring awareness to the complexities of genetic counselling in this population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the parent-proxy version of the pediatric Charcot Marie Tooth specific quality of life (pCMT-QOL) outcome instrument for children aged 7 or younger with CMT. We have previously developed and validated the direct-report pCMT-QOL for children aged 8-18 years and a parent proxy version of the instrument for children 8-18 years old. There is currently no CMT-QOL outcome measure for children aged 0-7 years old., Methods: Testing was conducted in parents or caregivers of children aged 0-7 years old with CMT evaluated at participating INC sites from the USA, United Kingdom, and Australia. The development of the instrument was iterative, involving identification of relevant domains, item pool generation, prospective pilot testing and clinical assessments, structured focus group interviews, and psychometric testing. The parent-proxy instrument was validated rigorously by examining previously identified domains and undergoing psychometric tests for children aged 0-7., Results: The parent-proxy pCMT-QOL working versions were administered to 128 parents/caregivers of children aged 0-7 years old between 2010 and 2016. The resulting data underwent rigorous psychometric analysis, including factor analysis, internal consistency, and convergent validity, and longitudinal analysis to develop the final parent-proxy version of the pCMT-QOL outcome measure for children aged 0-7 years old., Conclusions: The parent-proxy version of the pCMT-QOL outcome measure, known as the pCMT-QOL (0-7 years parent-proxy) is a valid and sensitive proxy measure of health-related QOL for children aged 0-7 years with CMT., (© 2023 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. PNPLA6 encodes Neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a clinical meta-analysis of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6 -associated clinical diagnoses unambiguously reclassified 10 variants as likely pathogenic and 36 variants as pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship and the generation of a preclinical animal model pave the way for therapeutic trials, using NTE as a biomarker.

Charcot-Marie-Tooth disease (CMT) reduces health-related quality of life (QOL) in children. We have previously developed and validated the English and Italian versions of the pediatric CMT-specific QOL outcome measure (pCMT-QOL) for children aged 8 to 18. There is currently no parent-proxy CMT QOL outcome measure for use in clinical trials, which could provide complementary information in these children and adolescents. This study describes the validation studies conducted to develop the parent-proxy version of the pCMT-QOL outcome measure for children aged 8 to 18 years old. Development and validation of the parent-proxy version of the pCMT-QOL outcome measure for children aged 8 to 18 years old was iterative, involving identifying relevant domains, item pool generation, prospective pilot testing and clinical assessments, structured focus-group interviews, and psychometric testing, conducted on parents of children with CMT seen at participating sites from the USA, United Kingdom, and Australia. We utilized previously described methods to develop a working parent-proxy version of the pCMT-QOL measure. From 2010 to 2016, the parent-proxy pCMT-QOL working version was administered to 358 parents of children with CMT aged 8 to 18, seen at the participating study sites of the Inherited Neuropathies Consortium. The resulting data underwent rigorous psychometric analysis, including factor analysis, test-retest reliability, internal consistency, convergent validity, IRT analysis, and longitudinal analysis, to develop the final parent-proxy version of the pCMT-QOL outcome measure for children aged 8 to 18 years old. The parent-proxy version of the pCMT-QOL outcome measure is a reliable, valid, and sensitive proxy measure of health-related QOL for children aged 8 to 18 with CMT., (© 2023 Peripheral Nerve Society.)

Objective: The paucity of longitudinal natural history studies in MPZ neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ neuropathies across 13 sites of the Inherited Neuropathies Consortium., Methods: Change in Charcot-Marie-Tooth Examination Score (CMTES) and Rasch modified CMTES (CMTES-R) were evaluated using longitudinal regression over a 5-year period in subjects with MPZ neuropathy. Data from 139 patients with MPZ neuropathy were examined., Results: The average baseline CMTES and CMTES-R were 10.84 (standard deviation [SD] = 6.0, range = 0-28) and 14.60 (SD = 7.56, range = 0-32), respectively. A mixed regression model showed significant change in CMTES at years 2-5 (mean change from baseline of 0.87 points at 2 years, p = 0.008). Subgroup analysis revealed greater change in CMTES at 2 years in subjects with axonal as compared to demyelinating neuropathy (mean change of 1.30 points [p = 0.016] vs 0.06 points [p = 0.889]). Patients with a moderate baseline neuropathy severity also showed more notable change, by estimate, than those with mild or severe neuropathy (mean 2-year change of 1.14 for baseline CMTES 8-14 [p = 0.025] vs -0.03 for baseline CMTES 0-7 [p = 0.958] and 0.25 for baseline CMTES ≥ 15 [p = 0.6897]). The progression in patients harboring specific MPZ mutations was highly variable., Interpretation: CMTES is sensitive to change over time in adult patients with axonal but not demyelinating forms of MPZ neuropathy. Change in CMTES was greatest in patients with moderate baseline disease severity. These findings will inform future clinical trials of MPZ neuropathies. ANN NEUROL 2023;93:563-576., (© 2022 American Neurological Association.)

Background and Objectives: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and often presents during childhood. Guidelines for the optimal management of common problems experienced by individuals with CMT do not exist, for either children or adults. We formed the Paediatric CMT Best Practice Guidelines Consortium to develop evidence and consensus-based recommendations for the clinical management of children and adolescents with CMT, with the primary objective of promoting optimal, standardised care globally., Methods: Development of this clinical practice guideline involved a series of systematic reviews covering 10 clinical questions, modified Delphi methodology involving an international panel of clinicians to generate consensus where evidence did not exist, and application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate the body of literature and formulate recommendations., Results: The final guideline includes three evidence-based and 31 consensus-based recommendations. They encompass the management of muscle weakness, balance and mobility impairment, sensory symptoms, muscle cramps, impaired upper limb function, respiratory impairment, maintenance of joint range of motion and non-surgical management of joint deformity. Consensus was not achieved in some management areas, reflecting differences in practice between clinicians and healthcare settings, and highlighting the need for further research., Conclusions: This clinical practice guideline provides practical and implementable guidance on the management of common clinical problems experienced by children with CMT and advocates for improved access to multidisciplinary care. Successful dissemination and implementation of these recommendations will be critical in ensuring their application across multiple healthcare settings., Competing Interests: Competing interests: MES has received consulting fees or honoraria from Inflectis Bioscience, Passage Biosci and Mitochondria in Motion, Temple University and Albert Einstein Medical College, and is the Chair of the CMT and Related Disorders (CMTR) Consortium of the Peripheral Nerve Society. SR has been employed at the Janssen Pharmaceutical Companies of Johnson & Johnson since January 2021 and has restricted stock options. Her contributions to the paper were made prior to her current employment. IM is a board member of the CMTR Consortium of the Peripheral Nerve Society. CES is a voluntary advisory board member of the CMT Association. EMY, PB, JBa, SKB, NB, KdV, TE, MAF, RSF, JH, RAK, GAN, MaMR, KR, SWY, MPM, MoMR and JBu report no competing interests., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Charcot-Marie-Tooth disease (CMT) reduces health-related quality of life (QOL), especially in children. Defining QOL in pediatric CMT can help physicians monitor disease burden clinically and in trials. We identified items pertaining to QOL in children with CMT and conducted validation studies to develop a pediatric CMT-specific QOL outcome measure (pCMT-QOL)., Methods: Development and validation of the pCMT-QOL patient-reported outcome measure were iterative, involving identifying relevant domains, item pool generation, prospective pilot testing and clinical assessments, structured focus-group interviews, and psychometric testing. Testing was conducted in children with CMT seen at participating sites from the USA, United Kingdom, and Australia., Results: We conducted systematic literature reviews and analysis of generic QOL measures to identify 6 domains relevant to QOL in children with CMT. Sixty items corresponding to those domains were developed de novo, or identified from literature review and CMT-specific modification of items from the pediatric Neuro-QOL measures. The draft version underwent prospective feasibility and face content validity assessments to develop a working version of the pCMT-QOL measure. From 2010 to 2016, the pCMT-QOL working version was administered to 398 children aged 8 to 18 years seen at the participating study sites of the Inherited Neuropathies Consortium. The resulting data underwent rigorous psychometric analysis, including factor analysis, test-retest reliability, internal consistency, convergent validity, item response theory analysis, and longitudinal analysis, to develop the final pCMT-QOL patient-reported outcome measure., Interpretation: The pCMT-QOL patient-reported outcome measure is a reliable, valid, and sensitive measure of health-related QOL for children with CMT. ANN NEUROL 2021;89:369-379., (© 2020 American Neurological Association.)

Objective: To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A)., Methods: Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models., Results: Baseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4-87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99-1.97, p < 0.0001, for baseline CMTES-R score 0-9)., Conclusion: The CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A., Clinicaltrialsgov Identifier: NCT01193075., (© 2020 American Academy of Neurology.)

Genetic counseling has been a profession for over 40 years, and training programs accredited by the Accreditation Council for Genetic Counseling are required to have students supervised in at least 50 patient-facing cases prior to graduation. However, there is no standardized information or training for supervisors of genetic counseling students. As a first step toward creating formal and standardized supervision training, we undertook a systematic review of the genetic counseling student supervision literature. A formal systematic review was conducted including establishing a research question with inclusion and exclusion criteria, establishing search terms, searching databases, reading/screening abstracts, examining full texts for inclusion, assessing for quality, and finally extracting data with a standardized form to provide the basis of the review. In all, 151 papers were screened, of which 19 and two erratum were found to meet inclusion criteria and pass quality measures. Main themes from these papers were as follows: Training Model, Competencies, Investigation of Techniques, Difficulties in Supervision, and Barriers. In total, 19 papers provided evidence for the way that supervision is currently being performed and suggestions for what needs further investigation to direct supervision training. Recommendations for genetic counseling student supervision include the following: provide a review of training models to supervisors; provide a copy of the supervision competencies to supervisors; use competencies with lowest self-efficacy to inform future supervision trainings; and find ways to support genetic counselors in becoming student supervisors., (© 2019 National Society of Genetic Counselors.)

Huntington's disease (HD) is a predominantly adult-onset, genetic, neurodegenerative condition. Children of affected individuals have a 50% risk of inheriting HD and often assume caregiving roles for their parent. Studies specifically focused on HD young caregivers have proposed that the genetic risk component of HD "exacerbates" the caregiving experience and identified common responsibilities, burdens, and support needs, but none have explored the relationship between the caregiving role and perception of genetic risk. In an attempt to understand this relationship, we conducted a qualitative study to explore the interaction between a young caregiver's perception of genetic risk, the caregiving experience, and thoughts about and plans for predictive testing. Thirteen individuals between 15 and 25 years who provided care for a parent with HD were recruited from two HD youth groups and local support groups. Interviews were recorded, transcribed, and analyzed thematically. Two themes emerged: (1) caregiving and thoughts about risk and (2) caregiving and perceived opinions towards genetic testing. Our findings suggest that the genetic risk colors the caregiving experience by evoking feelings about the future and a potential diagnosis of HD, in addition to impacting plans for predictive testing. Genetic counselors can use these findings to inform their understanding of caregiver experiences, which can aid them when helping patients explore their motivations for testing during a genetic counseling session. Future studies should explore the extent to which health care providers acknowledge the work of young caregivers in the home and provide support to these individuals.

Background: New therapies that could modify the disease course of Huntington's disease (HD) are entering clinical trials. However, conceptions about clinical research from the HD community are unknown. This knowledge could help inform patient-clinician discussions surrounding clinical trial participation., Objective: The purpose of this study was to assess clinical trial attitudes and understanding in the HD community., Methods: We developed a survey incorporating two measures of trial understanding and attitudes and the impact of therapeutic route of administration on hypothetical trial participation. The survey was distributed via emails, flyers, and social media through HD-related organizations., Results: There were 73 responses. Individuals self-reported as clinically diagnosed with HD, gene positive but asymptomatic, or primary caregivers. Respondents viewed clinical trials positively and generally viewed trials as safe. Individuals with prior HD-related research experience were less likely to have negative expectations about trials than those without research experience (p = 0.002), and women had higher information needs than men (p = 0.001). Individuals with HD were more likely than the other groups to experience therapeutic misconception (p = 0.002). All respondents were able to appraise risks and benefits of research but exhibited optimism about trial outcomes. Willingness to participate was highest when the route of administration was minimally invasive., Conclusions: While the HD community views clinical trials positively, patients with HD are at high risk for therapeutic misconception and all groups are optimistic about trial outcomes. Limitations of this study include a small sample that may be inclined to view research positively given past trial participation and interest in participating in HD surveys. However, the findings from this study can be used to strengthen informed consent during HD clinical trial recruitment.

Background: Spinal muscular atrophy (SMA) is a genetic disorder characterized by muscle loss. In December 2016 the FDA approved the first and only treatment drug for SMA: Spinraza (nusinersen). Despite excitement and optimism, there are no published data on the perceptions of individuals with SMA and their families about the benefits, risks, and challenges associated with treatment., Objective: This qualitative interview study sought to characterize the perspectives of patients/families with SMA who did not want, or were unsure about, receiving this new innovative treatment for a previously untreatable and often fatal condition., Methods: Individuals and families were recruited via advertisements on Facebook groups related to SMA and through the Stanford Neuromuscular Contact Registry. Participants completed a demographic questionnaire and participated in a semi-structured interview via voice conferencing. Interview questions focused on: 1) experiences with SMA, 2) opinions about Spinraza treatment, and 3) factors considered in decisions regarding treatment., Results: Thirteen people were interviewed: ten adults with SMA (ages 27-48, nine with Type II) and three parents of minor children with SMA (one each of Types I, II and III). Qualitative content analysis identified a range of opinions about Spinraza treatment: five were uninterested (2 adults, 3 parents), four adults were still deciding whether to pursue treatment, three adults were interested or in the process of pursuing treatment, and one adult was currently receiving the drug after overcoming significant reluctance. Participants described several key factors influencing their treatment decisions, including: concerns about risk factors and side effects, high cost, insurance coverage, time involvement, and lack of data about efficacy. Participants reported learning about most of these factors through parent/patient testimonials on SMA-specific social media groups., Conclusions: Participants reported basing decisions about pursuing Spinraza on a variety of practical and value-based considerations. They described carefully weighing the perceived potential benefits and risks of treatment through the lens of their current quality of life and prognosis. These findings suggest that providers should be aware that some patients and parents, especially those with Types II-IV, may approach treatment decisions differently than parents of children with SMA I. Informed treatment decisions can be supported through: 1) the collection and dissemination of better data on Spinraza treatment in these populations; 2) clear communication about risks, side effects and eligibility; 3) improved access to payment and treatment facilities; and 4) facilitation of discussions between providers and patients/families about identity and disability in the context of goals of care and other life and support challenges.

We describe a family with Charcot Marie Tooth disease type 4J presenting with features of Charcot Marie Tooth disease plus parkinsonism and aphemia. Genetic testing found two variants in the FIG4 gene: c.122T>C (p.I41T) - the most common Charcot Marie Tooth disease type 4J variant - and c.1949-10T>G (intronic). Proband fibroblasts showed absent FIG4 protein on western blot, and skipping of exon 18 by RT-PCR. As most patients with Charcot Marie Tooth disease type 4J do not have central nervous system deficits, we postulate the intronic variant and I41T mutation together are causing loss of FIG4 protein and subsequently the central nervous system findings in our family.

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Huntington disease (HD) is an autosomal dominant, progressive neurodegenerative disorder for which there is no cure. Predictive testing for HD is available to asymptomatic at-risk individuals. Approximately half of the population undergoing predictive testing for HD consists of young adults (≤35 years old). Finishing one's education, starting a career, engaging in romantic relationships and becoming a parent are key milestones of young adulthood. We conducted a qualitative study to explore how testing gene-positive for HD influences young adults' attainment of these milestones, and to identify major challenges that pre-symptomatic young adults face to aid the development of targeted genetic counseling. Results of our study demonstrate that 1) knowing one's gene-positive status results in an urgency to reach milestones and positively changes young adults' approach to life; 2) testing positive influences young adults' education and career choices, romantic relationships, and family planning; 3) young adults desire flexible and tailored genetic counseling to address needs and concerns unique to this population. Findings of this study contribute to the understanding of the impact of predictive testing for HD on young adults, and highlight issues unique to this population that call for further research, intervention and advocacy.

We aimed to characterize genotype-phenotype correlations and establish baseline clinical data for peripheral neuropathies caused by mutations in the myelin protein zero (MPZ) gene. MPZ mutations are the second leading cause of Charcot-Marie-Tooth disease type 1. Recent research makes clinical trials for patients with MPZ mutations a realistic possibility. However, the clinical severity varies with different mutations and natural history data on progression is sparse. We present cross-sectional data to begin to define the phenotypic spectrum and clinical baseline of patients with these mutations. A cohort of patients with MPZ gene mutations was identified in 13 centres of the Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC) between 2009 and 2012 and at Wayne State University between 1996 and 2009. Patient phenotypes were quantified by the Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and the Charcot-Marie-Tooth disease paediatric scale outcome instruments. Genetic testing was performed in all patients and/or in first- or second-degree relatives to document mutation in MPZ gene indicating diagnosis of Charcot-Marie-Tooth disease type 1B. There were 103 patients from 71 families with 47 different MPZ mutations with a mean age of 40 years (range 3-84 years). Patients and mutations were separated into infantile, childhood and adult-onset groups. The infantile onset group had higher Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and slower nerve conductions than the other groups, and severity increased with age. Twenty-three patients had no family history of Charcot-Marie-Tooth disease. Sixty-one patients wore foot/ankle orthoses, 19 required walking assistance or support, and 10 required wheelchairs. There was hearing loss in 21 and scoliosis in 17. Forty-two patients did not begin walking until after 15 months of age. Half of the infantile onset patients then required ambulation aids or wheelchairs for ambulation. Our results demonstrate that virtually all MPZ mutations are associated with specific phenotypes. Early onset (infantile and childhood) phenotypes likely represent developmentally impaired myelination, whereas the adult-onset phenotype reflects axonal degeneration without antecedent demyelination. Data from this cohort of patients will provide the baseline data necessary for clinical trials of patients with Charcot-Marie-Tooth disease caused by MPZ gene mutations., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To characterize 2 novel TRPV4 mutations in 2 unrelated families exhibiting the Charcot-Marie-Tooth disease type 2C (CMT2C) phenotype., Methods: Direct CMT gene testing was performed on 2 unrelated families with CMT2C. A 4-fold symmetric tetramer model of human TRPV4 was generated to map the locations of novel TRPV4 mutations in these families relative to previously identified disease-causing mutations (neuropathy, skeletal dysplasia, and osteoarthropathy). Effects of the mutations on TRPV4 expression, localization, and channel activity were determined by immunocytochemical, immunoblotting, Ca(2+) imaging, and cytotoxicity assays., Results: Previous studies suggest that neuropathy-causing mutations occur primarily at arginine residues on the convex face of the TRPV4 ankyrin repeat domain (ARD). Further highlighting the key role of this domain in TRPV4-mediated hereditary neuropathy, we report 2 novel heterozygous missense mutations in the TRPV4-ARD convex face (p.Arg237Gly and p.Arg237Leu). Generation of a model of the TRPV4 homotetramer revealed that while ARD residues mutated in neuropathy (including Arg237) are likely accessible for intermolecular interactions, skeletal dysplasia-causing TRPV4 mutations occur at sites suggesting disruption of intramolecular and/or intersubunit interactions. Like previously described neuropathy-causing mutations, the p.Arg237Gly and p.Arg237Leu substitutions do not alter TRPV4 subcellular localization in transfected cells but cause elevations of cytosolic Ca(2+) levels and marked cytotoxicity., Conclusions: These findings expand the number of ARD residues mutated in TRPV4-mediated neuropathy, providing further evidence of the central importance of this domain to TRPV4 function in peripheral nerve.

Background: The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them., Methods: We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES)., Results: 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported., Conclusions: Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT., Clinical Trial Registration: ID number NCT01193075., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Introduction: Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a PMP22 gene duplication. CMT1A has a robust electrical phenotype that can be used to direct genetic testing. We compared specialty CMT center CMT1A diagnosis rates to those of outside physicians., Methods: Charts were reviewed for 102 patients with CMT1A seen at a specialty CMT clinic between 2001 and 2009. Nerve conduction studies, family history, date of genetic testing, and type of genetic testing (single gene vs. panel) were collected., Results: Although the specialty clinic ordered more PMP22 duplication testing alone beginning at an earlier year, thereby reducing costs, both the specialty clinic and outside physicians began the decade doing panel testing and ended the decade looking at only PMP22., Conclusions: Specialty centers adapt earlier to changes in testing practice than non-specialty centers. As the landscape of genetic testing changes, the algorithms for testing will also likely change., (Copyright © 2013 Wiley Periodicals, Inc.)

Charcot Marie Tooth disease (CMT) encompasses the inherited peripheral neuropathies. While four genes have been found to cause over 90 % of genetically identifiable causes of CMT (PMP22, GJB1, MPZ, MFN2), at least 51 genes and loci have been found to cause CMT when mutated, creating difficulties for clinicians to find a genetic subtype for families. Here, the classic features of CMT as well as characteristic features of the most common subtypes of CMT are described, as well as methods for narrowing down the possible subtypes. Psychosocial concerns particular to the CMT population are identified. This is the most inclusive publication for CMT-specific genetic counseling.

Introduction: CMT1A is the most common form of Charcot-Marie-Tooth disease (CMT), a slowly progressive neuropathy in which impairment is length dependent. Fibular nerve conduction studies to the anterior tibialis muscle (AT) may serve as a physiological marker of disease progression in patients with CMT1A. The objective of this study is to determine whether the AT compound muscle action potential (CMAP) amplitude correlates with impairment in patients with CMT1A., Methods: We correlated AT CMAP amplitudes and impairment measured by the CMT Neuropathy Score (CMTNS) in a cross-section of 121 patients with CMT1A and a subset of 27 patients with longitudinal data., Results: AT CMAP amplitudes correlated with impairment as measured by the CMTNS in cross sectional analysis. Longitudinal changes in the AT CMAP showed a strong inverse correlation with leg strength but not other components of the CMTNS., Conclusions: AT CMAP amplitude may serve as a useful outcome measure for physiological changes in natural history studies and clinical trials for patients with CMT1A., (Copyright © 2012 Wiley Periodicals, Inc.)

X-linked Charcot-Marie-Tooth disease (CMT1X) is the second most common inherited neuropathy, caused by mutations in gap junction beta-1 (GJB1). Males have a uniformly moderately severe phenotype while females have a variable phenotype, suggested to be due to X inactivation. We aimed to assess X inactivation pattern in females with CMT1X and correlate this with phenotype using the CMT examination score to determine whether the X inactivation pattern accounted for the variable phenotype in females with CMT1X. We determined X inactivation pattern in 67 females with CMT1X and 24 controls using the androgen receptor assay. We were able to determine which X chromosome carried the GJB1 mutation in 30 females. There was no difference in X inactivation pattern between patients and controls. In addition, there was no correlation between X inactivation pattern in blood and phenotype. A possible explanation for these findings is that the X inactivation pattern in Schwann cells rather than in blood may explain the variable phenotype in females with CMT1X., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Charcot-Marie-Tooth disease (CMT) encompasses the heritable motor and sensory neuropathies that comprise most of the inherited peripheral neuropathies. Due to the great genetic heterogeneity of the condition, it can be difficult to determine what type of CMT a person has. The major phenotypic features of the CMT subtypes are delineated, as well as recommendations for focused genetic testing., (© Thieme Medical Publishers.)

Background: Charcot Marie Tooth disease (CMT) affects one in 2500 people. Genetic testing is often pursued for family planning purposes, natural history studies and for entry into clinical trials. However, identifying the genetic cause of CMT can be expensive and confusing to patients and physicians due to locus heterogeneity., Methods: We analyzed data from more than 1000 of our patients to identify distinguishing features in various subtypes of CMT. Data from clinical phenotypes, neurophysiology, family history, and prevalence was combined to create algorithms that can be used to direct genetic testing for patients with CMT., Findings: The largest group of patients in our clinic have slow motor nerve conduction velocities (MNCV) in the upper extremities. Approximately 88% of patients in this group have CMT1A. Those who had intermediate MNCV had primarily CMT1X (52.8%) or CMT1B (27.8%). Patients with very slow MNCV and delayed walking were very likely to have CMT1A (68%) or CMT1B (32%). No patients with CMT1B and very slow MNCV walked before 15 months of age. Patients with CMT2A form our largest group of patients with axonal forms of CMT., Interpretation: Combining features of the phenotypic and physiology groups allowed us to identify patients who were highly likely to have specific subtypes of CMT. Based on these results, we created a series of algorithms to guide testing. A more detailed review of this data is published in Annals of Neurology (1).

Charcot-Marie-Tooth disease type 1X (CMT1X) is the second most common inherited peripheral neuropathy. Women with CMT1X typically have a less severe phenotype than men, perhaps because of X-inactivation patterns. Our objective was to determine the phenotype of women with CMT1X and whether X-inactivation patterns in white blood cells (WBCs) differ between females with CMT1X and controls. Thirty-one women with CMT1X were evaluated using the CMT neuropathy score (CMTNS) and the CMT symptom score in cross-sectional and longitudinal analyses. Lower scores correspond to less disability. WBCs were analyzed for X-inactivation pattern by androgen receptor X-inactivation assay in 14 patients and 23 controls. The 31 women's mean CMTNS was 8.35. Two-thirds of the cohort had a mild CMTNS (mean 4.85) and one-third had a moderate CMTNS (mean 14.73). Three patients had a CMTNS of 0. The pattern of X-inactivation did not differ between the affected and control groups. Women with CMT1X presented with variable impairment independent of age, type of mutation, or location of mutation. No evidence supported the presence of a gap junction beta-1 (GJB1) mutation affecting the pattern of X-inactivation in blood. Further studies are planned to determine whether X-inactivation is the mechanism for CMT1X females' variable phenotypes., (© 2011 Peripheral Nerve Society.)

Objective: Charcot-Marie-Tooth disease (CMT) affects 1 in 2,500 people and is caused by mutations in more than 30 genes. Identifying the genetic cause of CMT is often necessary for family planning, natural history studies, and for entry into clinical trials. However genetic testing can be both expensive and confusing to patients and physicians., Methods: We analyzed data from 1,024 of our patients to determine the percentage and features of each CMT subtype within this clinic population. We identified distinguishing clinical and physiological features of the subtypes that could be used to direct genetic testing for patients with CMT., Results: Of 1,024 patients evaluated, 787 received CMT diagnoses. A total of 527 patients with CMT (67%) received a genetic subtype, while 260 did not have a mutation identified. The most common CMT subtypes were CMT1A, CMT1X, hereditary neuropathy with liability to pressure palsies (HNPP), CMT1B, and CMT2A. All other subtypes accounted for less than 1% each. Eleven patients had >1 genetically identified subtype of CMT. Patients with genetically identified CMT were separable into specific groups based on age of onset and the degree of slowing of motor nerve conduction velocities., Interpretation: Combining features of the phenotypic and physiology groups allowed us to identify patients who were highly likely to have specific subtypes of CMT. Based on these results, we propose a strategy of focused genetic testing for CMT, illustrated in a series of flow diagrams created as testing guides., (Copyright © 2010 American Neurological Association.)

Huntington disease (HD) is a disorder characterized by chorea, dystonia, bradykinesia, cognitive decline and psychiatric comorbidities. Balance and gait impairments, as well as falls, are common manifestations of the disease. The importance of compensatory rapid stepping to maintain equilibrium in older adults is established, yet little is known of the role of stepping response times (SRTs) in balance control in people with HD. SRTs and commonly-used clinical measures of balance and mobility were evaluated in fourteen symptomatic participants with HD, and nine controls at a university mobility research laboratory. Relative and absolute reliability, as well as minimal detectable change in SRT were quantified in the HD participants. HD participants exhibited slower SRTs and poorer dynamic balance, mobility and motor performance than controls. HD participants also reported lower balance confidence than controls. Deficits in SRT were associated with low balance confidence and impairments on clinical measures of balance, mobility, and motor performance in HD participants. Measures of relative and absolute reliability indicate that SRT is reliable and reproducible across trials in people with HD. A moderately low percent minimal detectable change suggests that SRT appears sensitive to detecting real change in people with HD. SRT is impaired in people with HD and may be a valid and objective marker of disease progression., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a 1.4 Mb duplication on chromosome 17p11.2, which contains the peripheral myelin protein-22 (PMP22) gene. Increased levels of PMP22 in compact myelin of peripheral nerves have been demonstrated and presumed to cause the phenotype of CMT1A. The objective of the present study was to determine whether an extra copy of the PMP22 gene in CMT1A disrupts the normally coordinated expression of PMP22 protein in peripheral nerve myelin and to evaluate PMP22 over-expression in patients with CMT1A and determine whether levels of PMP22 are molecular markers of disease severity. PMP22 expression was measured by taking skin biopsies from patients with CMT1A (n = 20) and both healthy controls (n = 7) and patients with Hereditary Neuropathy with liability to Pressure Palsies (HNPP) (n = 6), in which patients have only a single copy of PMP22. Immunological electron microscopy was performed on the skin biopsies to quantify PMP22 expression in compact myelin. Similar biopsies were analysed by real time PCR to measure PMP22 mRNA levels. Results were also correlated with impairment in CMT1A, as measured by the validated CMT Neuropathy Score. Most, but not all patients with CMT1A, had elevated PMP22 levels in myelin compared with the controls. The levels of PMP22 in CMT1A were highly variable, but not in HNPP or the controls. However, there was no correlation between neurological disabilities and the level of over-expression of PMP22 protein or mRNA in patients with CMT1A. The extra copy of PMP22 in CMT1A results in disruption of the tightly regulated expression of PMP22. Thus, variability of PMP22 levels, rather than absolute level of PMP22, may play an important role in the pathogenesis of CMT1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a duplication of PMP22 on chromosome 17 and is the most commonly inherited demyelinating neuropathy. Diabetes frequently causes predominantly sensory neuropathy. Whether diabetes exacerbates CMT1A is unknown. We identified 10 patients with CMT1A and diabetes and compared their impairment with 48 age-matched control patients with CMT1A alone. Comparisons were made with the Charcot-Marie-Tooth disease (CMT) neuropathy score (CMTNS) and by electrophysiology. The CMTNS was significantly higher in patients with diabetes (20.25 +/- 2.35) compared with controls (15.19 +/- 0.69; p = 0.01). Values were particularly higher for motor signs and symptoms. Seven of the 10 diabetic patients had CMTNS >20 (severe CMT), while only 7 of the 48 age-matched controls had scores >20. There was a trend for CMT1A patients with diabetes to have low compound muscle action potentials and sensory nerve action potentials, although nerve conduction velocities were not slower in diabetic patients compared with controls. Diabetes was associated with more severe motor and sensory impairment in patients with CMT1A.