19 research outputs found
Validation of the Parent-Proxy Version of the Pediatric Charcot-Marie-Tooth Disease Quality of Life Instrument for children aged 0-7âyears
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 8-18âyears and a parent proxy version of the instrument for children 8-18âyears old. There is currently no CMT-QOL outcome measure for children aged 0-7âyears old. METHODS: Testing was conducted in parents or caregivers of children aged 0-7âyears 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 0-7âyears 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 0-7âyears old. CONCLUSIONS: The parent-proxy version of the pCMT-QOL outcome measure, known as the pCMT-QOL (0-7âyears parent-proxy) is a valid and sensitive proxy measure of health-related QOL for children aged 0-7âyears with CMT. This article is protected by copyright. All rights reserved
This Could Be Me : Exploring the Impact of Genetic Risk for Huntington\u27s Disease Young Caregivers
Huntingtonâs 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 âexacerbatesâ 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 caregiverâs 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
A comparison study of three physical activity measurement tools examining acceptability in people with psychosis
Objective: To compare the acceptability of three distinct physical activity measurement tools in people with psychosis: an objective measurement tool, a self-report measure, and an exercise capacity test.Methods: We measured the completion rate for each measurement tool. Participants rated the ease/difficulty of each measure using a 7-point Likert scale. Participants were also asked to rank the three tools in order of the ease of use.Results: Sixty-six per cent (46/69) of participants completed all three assessment tools, and 60.9% (42/69) completed the acceptability questionnaire. The majority of the participants found it easy to complete all three measurement tools. The majority (52.8%) of the participants ranked the objective measurement tool as the easiest to use.Conclusion: All three measures were acceptable to people with psychosis, but objective measurement tools may be easier to use
Exome Sequencing Allows for Rapid Gene Identification in a Charcot-Marie-Tooth Family
OBJECTIVE: Charcot-Marie-Tooth (CMT) disease comprises a large number of genetically distinct forms of inherited peripheral neuropathies. The relative uniform phenotypes in many patients with CMT make it difficult to decide which of the over 35 known CMT genes are affected in a given patient. Genetic testing decision trees are therefore broadly based on a small number of major subtypes (eg, CMT1, CMT2) and the observed mutation frequency for CMT genes. Since conventional genetic testing is expensive many rare genes are not being tested for at all. METHODS: Whole-exome sequencing has recently been introduced as a novel and alternative approach. This method is capable of resequencing a nearly complete set of coding exons in an individual. We performed whole-exome sequencing in an undiagnosed family with CMT. RESULTS: Within over 24,000 variants detected in 2 exomes of a CMT family, we identified a nonsynonymous GJB1 (Cx32) mutation. This variant had been reported previously as pathogenic in X-linked CMT families. Sanger sequencing confirmed complete cosegregation in the family. Affected individuals had a marked early involvement of the upper distal extremities and displayed a mild reduction of nerve conduction velocities. INTERPRETATION: We have shown for the first time in a genetically highly heterogeneous dominant disease that exome sequencing is a valuable method for comprehensive medical diagnosis. Further improvements of exon capture design, next-generation sequencing accuracy, and a constant price decline will soon lead to the adoption of genomic approaches in gene testing of Mendelian disease
Development and Validation of the Pediatric CharcotâMarieâTooth Disease Quality of Life Outcome Measure
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/166254/1/ana25966_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/166254/2/ana25966.pd
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Novel mutations highlight the key role of the ankyrin repeat domain in TRPV4-mediated neuropathy
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, Ca2+ 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 dysplasiaâcausing 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 Ca2+ 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
Novel heterozygous truncating titin variants affecting the Aâband are associated with cardiomyopathy and myopathy/muscular dystrophy
Abstract Background Variants in TTN are frequently identified in the genetic evaluation of skeletal myopathy or cardiomyopathy. However, due to the high frequency of TTN variants in the general population, incomplete penetrance, and limited understanding of the spectrum of disease, interpretation of TTN variants is often difficult for laboratories and clinicians. Currently, cardiomyopathy is associated with heterozygous Aâband TTN variants, whereas skeletal myopathy is largely associated with homozygous or compound heterozygous TTN variants. Recent reports show pathogenic variants in TTN may result in a broader phenotypic spectrum than previously recognized. Methods Here we report the results of a multisite study that characterized the phenotypes of probands with variants in TTN. We investigated TTN genotypeâphenotype correlations in probands with skeletal myopathy and/or cardiomyopathy. Probands with TTN truncating variants (TTNtv) or pathogenic missense variants were ascertained from two academic medical centers. Variants were identified via clinical genetic testing and reviewed according to the American College of Medical Genetics criteria. Clinical and family history data were documented via retrospective chart review. Family studies were performed for probands with atypical phenotypes. Results Fortyânine probands were identified with TTNtv or pathogenic missense variants. Probands were classified by clinical presentation: cardiac (n = 30), skeletal muscle (n = 12), or both (cardioskeletal, n = 7). Within the cardioskeletal group, 5/7 probands had heterozygous TTNtv predicted to affect the distal (3â) end of the Aâband. All cardioskeletal probands had onset of proximalâpredominant muscle weakness before diagnosis of cardiovascular disease, five pedigrees support dominant transmission. Conclusion Although heterozygous TTNtv in the Aâband is known to cause dilated cardiomyopathy, we present evidence that these variants may in some cases cause a novel, dominant skeletal myopathy with a limbâgirdle pattern of weakness. These findings emphasize the importance of multidisciplinary care for patients with Aâband TTNtv who may be at risk for multisystem disease
Validation of the parent-proxy pediatric Charcot-Marie-Tooth disease quality of life outcome measure
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 18âyears old. Development and validation of the parent-proxy version of the pCMT-QOL outcome measure for children aged 8 to 18âyears 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 18âyears 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