Living with muscular dystrophy: health related quality of life consequences for children and adults

<p>Abstract</p> <p>Background</p> <p>Muscular dystrophies are chronic diseases manifesting with progressive muscle weakness leading to decreasing activities and participation. To understand the impact on daily life, it is important to determine patients' quality of life.</p> <p>Objective</p> <p>To investigate Health Related Quality of Life (HRQoL) of children and adults with muscular dystrophy (MD), and to study the influence of type and severity of MD on HRQoL in adult patients.</p> <p>Methods</p> <p>Age-related HRQoL questionnaires were administered to 40 children (8–17 years), and 67 adult patients with muscular dystrophies.</p> <p>Results</p> <p>Significant differences in HRQoL were found in children and adults with MD compared to healthy controls. Patients with Becker muscular dystrophy reported a better HRQoL on the several scales compared to patients with other MDs. Severity was associated with worse fine motor functioning and social functioning in adult patients.</p> <p>Conclusion</p> <p>This is one of the first studies describing HRQoL of patients with MD using validated instruments in different age groups. The results indicate that having MD negatively influences the HRQoL on several domains.</p

Cone-rod dystrophy can be a manifestation of Danon disease

Background Danon disease is a neuromuscular disorder with variable expression in the eye. We describe a family with Danon disease and cone-rod dystrophy (CRD). Methods Affected males of one family with Danon were invited for an extensive ophthalmologic examination, including color vision testing, fundus photography, Goldmann perimetry, full-field electroretinogram (ERG), and SD-OCT. Previous ophthalmologic data were retrieved from medical charts. The LAMP2 and RPGR gene were analyzed by direct sequencing. Results Two siblings had no ocular phenotype. The third sibling and a cousin developed CRD leading to legal blindness. Visual acuity deteriorated progressively over time, color vision was severely disturbed, and ERG showed reduced photopic and scotopic responses. SD-OCT revealed thinning of the photoreceptor and RPE layer. Visual fieldsdemonstrated central scotoma. The causal mutation was p. Gly384Arg in LAMP2; no mutations were found in RPGR. Conclusions This is the first description of CRD in Danon disease. The retinal phenotype was a late onset but severe dystrophy characterized by loss of photoreceptors and RPE cells. With this report, we highlight the importance of a comprehensive ophthalmologic examination in the clinical work-up of Danon disease

Low and High Expressing Alleles of the LMNA Gene: Implications for Laminopathy Disease Development

Today, there are at least a dozen different genetic disorders caused by mutations within the LMNA gene, and collectively, they are named laminopathies. Interestingly, the same mutation can cause phenotypes with different severities or even different disorders and might, in some cases, be asymptomatic. We hypothesized that one possible contributing mechanism for this phenotypic variability could be the existence of high and low expressing alleles in the LMNA locus. To investigate this hypothesis, we developed an allele-specific absolute quantification method for lamin A and lamin C transcripts using the polymorphic rs4641C/T LMNA coding SNP. The contribution of each allele to the total transcript level was investigated in nine informative human primary dermal fibroblast cultures from Hutchinson-Gilford progeria syndrome (HGPS) and unaffected controls. Our results show differential expression of the two alleles. The C allele is more frequently expressed and accounts for ∼70% of the lamin A and lamin C transcripts. Analysis of samples from six patients with Hutchinson-Gilford progeria syndrome showed that the c.1824C>T, p.G608G mutation is located in both the C and the T allele, which might account for the variability in phenotype seen among HGPS patients. Our method should be useful for further studies of human samples with mutations in the LMNA gene and to increase the understanding of the link between genotype and phenotype in laminopathies

Mobile element insertions in rare diseases: a comparative benchmark and reanalysis of 60,000 exome samples

Mobile element insertions (MEIs) are a known cause of genetic disease but have been underexplored due to technical limitations of genetic testing methods. Various bioinformatic tools have been developed to identify MEIs in Next Generation Sequencing data. However, most tools have been developed specifically for genome sequencing (GS) data rather than exome sequencing (ES) data, which remains more widely used for routine diagnostic testing. In this study, we benchmarked six MEI detection tools (ERVcaller, MELT, Mobster, SCRAMble, TEMP2 and xTea) on ES data and on GS data from publicly available genomic samples (HG002, NA12878). For all the tools we evaluated sensitivity and precision of different filtering strategies. Results show that there were substantial differences in tool performance between ES and GS data. MELT performed best with ES data and its combination with SCRAMble increased substantially the detection rate of MEIs. By applying both tools to 10,890 ES samples from Solve-RD and 52,624 samples from Radboudumc we were able to diagnose 10 patients who had remained undiagnosed by conventional ES analysis until now. Our study shows that MELT and SCRAMble can be used reliably to identify clinically relevant MEIs in ES data. This may lead to an additional diagnosis for 1 in 3000 to 4000 patients in routine clinical ES

Low incidence of limb-girdle muscular dystrophy type 2C revealed by a mutation study in Japanese patients clinically diagnosed with DMD

<p>Abstract</p> <p>Background</p> <p>Limb-girdle muscular dystrophy type 2C (LGMD2C) is an autosomal recessive muscle dystrophy that resembles Duchenne muscular dystrophy (DMD). Although DMD is known to affect one in every 3500 males regardless of race, a widespread founder mutation causing LGMD2C has been described in North Africa. However, the incidence of LGMD2C in Japanese has been unknown because the genetic background remains uncharacterized in many patients clinically diagnosed with DMD.</p> <p>Methods</p> <p>We enrolled 324 patients referred to the Kobe University Hospital with suspected DMD. Mutations in the dystrophin or the SGCG genes were analyzed using not only genomic DNA but also cDNA.</p> <p>Results</p> <p>In 322 of the 324 patients, responsible mutations in the dystrophin were successfully revealed, confirming DMD diagnosis. The remaining two patients had normal dystrophin expression but absence of γ-sarcoglycan in skeletal muscle. Mutation analysis of the SGCG gene revealed homozygous deletion of exon 6 in one patient, while the other had a novel single nucleotide insertion in exon 7 in one allele and deletion of exon 6 in the other allele. These mutations created a stop codon that led to a γ-sarcoglycan deficiency, and we therefore diagnosed these two patients as having LGMD2C. Thus, the relative incidence of LGMD2C among Japanese DMD-like patients can be calculated as 1 in 161 patients suspected to have DMD (2 of 324 patients = 0.6%). Taking into consideration the DMD incidence for the overall population (1/3,500 males), the incidence of LGMD2C can be estimated as 1 per 560,000 or 1.8 per million.</p> <p>Conclusions</p> <p>To the best of our knowledge, this is the first study to demonstrate a low incidence of LGMD2C in the Japanese population.</p

Galectin-9 and CXCL10 as biomarkers for disease activity in juvenile dermatomyositis: a longitudinal cohort study and multi-cohort validation

OBJECTIVE: Objective evaluation of disease activity is challenging in patients with juvenile dermatomyositis (JDM) due to lack of biomarkers, but crucial to avoid both under- and overtreatment. Recently, we identified two proteins that highly correlate with JDM disease activity: galectin-9 and CXCL10. Here, we validate galectin-9 and CXCL10 as biomarkers for disease activity, assess disease-specificity and investigate their potency to predict flares. METHODS: Galectin-9 and CXCL10 were measured in serum samples of 125 unique JDM patients in three international cross-sectional cohorts and a local longitudinal cohort, by multiplex immunoassay. Disease-specificity was examined in 50 adults with (dermato)myositis and 61 patients with other systemic autoimmune diseases. RESULTS: Galectin-9 and CXCL10 outperformed the currently used marker creatine kinase (CK) to distinguish between JDM patients with active disease and remission, both cross-sectionally and longitudinally (area ROC curve: 0.86-0.90 for galectin-9 and CXCL10, 0.66-0.68 for CK). The sensitivity and specificity were 0.84 and 0.92 for galectin-9, and 0.87 and 1.00 for CXCL10. In 10 prospectively followed patients with a flare, continuously elevated or rising biomarker levels suggested an imminent flare up to several months before symptoms, even in absence of elevated CK. Galectin-9 and CXCL10 distinguished between active disease and remission in adults with (dermato)myositis and were suited for measurement in minimally-invasive dried blood spots. CONCLUSIONS: Galectin-9 and CXCL10 were validated as sensitive and reliable biomarkers for disease activity in (J)DM. Implementation of these biomarkers into clinical practice, as tools to monitor disease activity and guide treatment, might facilitate personalized treatment strategies

Fatigue in neuromuscular disorders: focus on Guillain–Barré syndrome and Pompe disease

Fatigue accounts for an important part of the burden experienced by patients with neuromuscular disorders. Substantial high prevalence rates of fatigue are reported in a wide range of neuromuscular disorders, such as Guillain–Barré syndrome and Pompe disease. Fatigue can be subdivided into experienced fatigue and physiological fatigue. Physiological fatigue in turn can be of central or peripheral origin. Peripheral fatigue is an important contributor to fatigue in neuromuscular disorders, but in reaction to neuromuscular disease fatigue of central origin can be an important protective mechanism to restrict further damage. In most cases, severity of fatigue seems to be related with disease severity, possibly with the exception of fatigue occurring in a monophasic disorder like Guillain–Barré syndrome. Treatment of fatigue in neuromuscular disease starts with symptomatic treatment of the underlying disease. When symptoms of fatigue persist, non-pharmacological interventions, such as exercise and cognitive behavioral therapy, can be initiated