Mark Stefanelli

Clinical and genetic epidemiology of Bardet-Biedl syndrome in Newfoundland: A 22-year prospective, population-based, cohort study

Bardet–Biedl syndrome (BBS) and Laurence–Moon syndrome (LMS) have a similar phenotype, which includes retinal dystrophy, obesity, and hypogenitalism. They are differentiated by the presence of spasticity and the absence of polydactyly in LMS. The aims of this study were to describe the epidemiology of BBS and LMS, further define the phenotype, and examine genotype–phenotype correlation. The study involved 46 patients (26 males, 20 females) from 26 families, with a median age of 44 years (range 1–68 years). Assessments were performed in 1986, 1993, and 2001 and included neurological assessments, anthropometric measurements, and clinical photographs to assess dysmorphic features. The phenotype was highly variable within and between families. Impaired co‐ordination and ataxia occurred in 86% (18/21). Thirty percent (14/46) met criteria for psychiatric illness; other medical problems included cholecystectomy in 37% (17/46) and asthma in 28% (13/46). Dysmorphic features included brachycephaly, large ears, and short, narrow palpebral fissures. There was no apparent correlation of clinical or dysmorphic features with genotype. Two patients were diagnosed clinically as LMS but both had mutations in a BBS gene. The features in this population do not support the notion that BBS and LMS are distinct. The lack of a genotype–phenotype correlation implies that BBS proteins interact and are necessary for the development of many organs.

Factors influencing healthy aging with multiple sclerosis: A qualitative study

Purpose: The purpose of this study was to describe the factors influencing healthy aging from the perspective of the older person with multiple sclerosis (MS) in order to build curricula for MS self-management programs. Method: We sourced participants, older than 55 years with MS for more than 20 years, from a database of MS clinic and outpatient rehabilitation visits. Recruitment continued until data saturation was reached (n = 18). Semi-structured interviews explored perspectives on aging and health and lifestyle habits. Demographic, lifestyle and perceived health status information was also gathered. We analyzed the transcribed text for themes and theme relationships. Results: Work and social engagement, effective and accessible health care, healthy lifestyle habits, and maintaining independence at home were found to be critical proximal factors for healthy aging. The presence of financial flexibility, social support, cognitive and mental health, and resilience provided a supporting foundation to these critical proximal factors. These factors comprised a two-tiered model of healthy aging with MS. Conclusions: This two-tiered conceptual model of health aging, based on the perspectives of older persons with MS, provides a potential framework for the development of MS self-management program curricula aimed at optimizing quality of life. Further empirical testing may validate its utility in predicting healthy aging with MS. Implications for Rehabilitation The views of older people with Multiple Sclerosis (MS), as experts in managing the long term challenges of living with MS, should be considered in the design of self-management programs. Health care, social engagement, lifestyle and independence make critical contributions to health-related quality of life among older people with MS. This contribution depends on less-commonly addressed factors: financial flexibility, mental and cognitive health, resilience and social support. Strategies that target factors are important components of a comprehensive approach to rehabilitation and self-management of MS.

The relation between menarche and the age of first symptoms in a multiple sclerosis cohort

Background Previously, multiple sclerosis (MS) has been thought to be associated with changes in hormone levels. This study investigates the association between the age of menarche and the age of onset of the first symptoms of MS. Methods A complete list of patients diagnosed with MS in the province of Newfoundland and Labrador was constructed. The age of menarche for our entire relapsing remitting female MS (RRMS) population was requested by mailout survey. Age of symptom onset was ascertained by chart review. Results A 74% rate of return on the survey results was obtained (150 RRMS patients). A linear regression model demonstrated that the age of first symptoms increased by 1.16 years as the age of menarche increased by one year (R2=0.69, P=0.04). Another analysis showed that the average age of first symptoms for women with reported menarche from 10 to 12 years was 28.96 years compared with 31.83 years for a reported menarche from 13 to 15 years, a significant difference (P=0.047, t-test). Conclusions This study suggests that menarche may be related to the pathogenesis of MS.

A Locus for Autosomal Dominant Hereditary Spastic Ataxia, SAX1,Maps to Chromosome 12p13

The hereditary spastic ataxias (HSA) are a group of clinically heterogeneous neurodegenerative disorders characterized by lower-limb spasticity and generalized ataxia. HSA was diagnosed in three unrelated autosomal dominant families from Newfoundland, who presented mainly with severe leg spasticity, dysarthria, dysphagia, and ocular-movement abnormalities. A genomewide scan was performed on one family, and linkage to a novel locus for HSA on chromosome 12p13, which contains the as-yet-unidentified gene locus SAX1, was identified. Fine mapping confirmed linkage in the two large families, and the third, smaller family showed LOD scores suggestive of linkage. Haplotype construction by use of 13 polymorphic markers revealed that all three families share a disease haplotype, which key recombinants and overlapping haplotypes refine to about 5 cM, flanked by markers D12S93 and GATA151H05. SAX1 is the first locus mapped for autosomal dominant HSA.

The Canadian survey of health, lifestyle and ageing with multiple sclerosis: methodology and initial results

Objective People with multiple sclerosis (MS) are living longer so strategies to enhance long-term health are garnering more interest. We aimed to create a profile of ageing with MS in Canada by recruiting 1250 (5% of the Canadian population above 55 years with MS) participants and focusing data collection on health and lifestyle factors, disability, participation and quality of life to determine factors associated with healthy ageing. Design National multicentre postal survey. Setting Recruitment from Canadian MS clinics, MS Society of Canada chapters and newspaper advertisements. Participants People aged 55 years or older with MS symptoms more than 20 years. Outcome measures Validated outcome measures and custom-designed questions examining MS disease characteristics, living situation, disability, comorbid conditions, fatigue, health behaviours, mental health, social support, impact of MS and others. Results Of the 921 surveys, 743 were returned (80.7% response rate). Participants (mean age 64.6±6.2 years) reported living with MS symptoms for an average of 32.9±9.5 years and 28.6% were either wheelchair users or bedridden. There was only 5.4% missing data and 709 respondents provided optional qualitative information. According to data derived from the 2012 Canadian Community Health Survey of Canadians above 55 years of age, older people with MS from this survey sample are about eight times less likely to be employed full-time. Older people with MS were less likely to engage in regular physical activity (26.7%) compared with typical older Canadians (45.2%). However, they were more likely to abstain from alcohol and smoking. Conclusions Despite barriers to participation, we were able to recruit and gather detailed responses (with good data quality) from a large proportion of older Canadians with MS. The data suggest that this sample of older people with MS is less likely to be employed, are less active and more disabled than other older Canadians.

A founder effect in three large Newfoundland families with a novel clinically variable spastic ataxia and supranuclear gaze palsy

A distinctive slowly progressive neurodegenerative disorder, which falls under a new category of neurological diseases, the hereditary spastic ataxias (HSA), is described in three independently ascertained Newfoundland kindreds. HSA is a heterogeneous group of disorders in which pyramidal tract features overlap cerebellar characteristics. The families are assumed to have the same condition as, although apparently unrelated, all originate in a historically isolated cluster of rural communities and link to the same locus at 12p13, SAX1. Clinically the phenotype is very variable but lower limb hypertonicity and hyperreflexia are early and prominent generally preceded by eye movement abnormality, an impaired vertical downward saccade and a typical involuntary head jerk. These are followed by variable levels of ataxia, dysarthria, and dysphagia. Onset occurs in the first two decades and can be detected in most by early adulthood. Significant mobility problems are present by the fourth decade with a broad based ataxic and spastic gait. MRI scans of brain and spinal cord were normal. Neuropathology showed degeneration of corticospinal tracts and posterior columns and midbrain neuronal loss. The phenotype is striking in its diversity among and within families and the variability of expression can be observed within the same sibship. Pedigree analysis shows no evidence of anticipation or any sex differences in severity. The condition is unusually prevalent in the province of Newfoundland, which is characteristic of a founder effect followed by isolation and large family size. Fine mapping efforts have reduced the critical interval of the SAX1 locus to 1.9Mb. Identification of the SAX1 gene will help to clarify the pathogenesis of this type of HSA.

The Liberation Procedure Decision- Making Experience for People With Multiple Sclerosis

Despite the absence of scientific evidence demonstrating the efficacy of the “liberation procedure” in treating multiple sclerosis (MS), thousands of MS patients worldwide have undergone the procedure. The study objective was to explore the experience of liberation procedure decision making for individuals with MS. Fifteen adults in Newfoundland and Labrador, Canada, each participated in an in-depth interview. The data analysis revealed three groups of people: “waiters,” “early embracers,” and “late embracers.” Using van Manen’s hermeneutic phenomenological approach, we identified three themes each in the stories of the early and late embracers and four themes in the waiters’ stories. A characteristic of the late embracers and waiters was skepticism, whereas desperation set the embracers apart from the waiters. With a deeper understanding of the experience, nurses can be more attuned to the perspectives of MS patients while helping them make informed decisions about undergoing the liberation procedure.

navigating the "liberation procedure": a qualitative study of motivating and hesitating factors among people with multiple sclerosis

Background The debate within the multiple sclerosis (MS) community initiated by the chronic cerebrospinal venous insufficiency (CCSVI) hypothesis and the subsequent liberation procedure placed some people with MS at odds with health care professionals and researchers. Objective This study explored decision making regarding the controversial liberation procedure among people with MS. Subjects and methods Fifteen people with MS (procedure, n=7; no procedure, n=8) participated in audiotaped semistructured interviews exploring their thoughts and experiences related to the liberation procedure. Data were transcribed and analyzed using an iterative, consensus-based, thematic content-analysis approach. Results Participants described an imbalance of motivating factors affirming the procedure compared to hesitating factors that provoked the participant to pause or reconsider when deciding to undergo the procedure. Collegial conversational relationships with trusted sources (eg, MS nurse, neurologist) and ability to critically analyze the CCSVI hypothesis were key hesitating factors. Fundraising, family enthusiasm, and the ease of navigation provided by medical tourism companies helped eliminate barriers to the procedure. Conclusion Knowledge of factors that helped to popularize the liberation procedure in Canada may inform shared decision making concerning this and future controversies in MS.