Several studies indicate that prognosis for survival in Duchenne muscular dystrophy (DMD) has improved in recent decades. However, published evidence is inconclusive and some estimates may be ...obsolete due to improvements in standards of care, in particular the routine use of mechanical ventilatory support in advanced stages of the disease. In this systematic review and meta-analysis (PROSPERO identifier: CRD42019121800), we searched MEDLINE (through PubMed), CINAHL, Embase, PsycINFO, and Web of Science for studies published from inception up until December 31, 2018, reporting results of life expectancy in DMD. We pooled median survival estimates from individual studies using the median of medians, and weighted median of medians, methods. Risk of bias was established with the Newcastle–Ottawa Scale. Results were stratified by ventilatory support and risk of bias. We identified 15 publications involving 2662 patients from 12 countries from all inhabited continents except Africa. Median life expectancy without ventilatory support ranged between 14.4 and 27.0 years (pooled median: 19.0 years, 95% CI 18.0–20.9; weighted pooled median: 19.4 years, 18.2–20.1). Median life expectancy with ventilatory support, introduced in most settings in the 1990s, ranged between 21.0 and 39.6 years (pooled median: 29.9 years, 26.5–30.8; weighted pooled median: 31.8 years, 29.3–36.2). Risk of bias had little impact on pooled results. In conclusion, median life expectancy at birth in DMD seems to have improved considerably during the last decades. With current standards of care, many patients with DMD can now expect to live into their fourth decade of life.
Abstract
The Human Phenotype Ontology (HPO)—a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases—is used by thousands of researchers, clinicians, informaticians and ...electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO’s interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes.
Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their “diagnostic odyssey,” improves disease management, and fosters ...genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.
To evaluate the role of genetic variation at the
locus on symptomatic diversity in 250 adult, ambulant patients with myotonic dystrophy type 1 (DM1) recruited to the Observational Prolonged Trial in ...Myotonic Dystrophy Type 1 to Improve Quality of Life-Standards, a Target Identification Collaboration (OPTIMISTIC) clinical trial.
We used small pool PCR to correct age at sampling biases and estimate the progenitor allele CTG repeat length and somatic mutational dynamics, and AciI digests and repeat primed PCR to test for the presence of variant repeats.
We confirmed disease severity is driven by progenitor allele length, is further modified by age, and, in some cases, sex, and that patients in whom the CTG repeat expands more rapidly in the soma develop symptoms earlier than predicted. We revealed a key role for variant repeats in reducing disease severity and quantified their role in delaying age at onset by approximately 13.2 years (95% confidence interval 5.7-20.7, 2-tailed
test
= -3.7,
= 0.0019).
Careful characterization of the
CTG repeat to define progenitor allele length and presence of variant repeats has increased utility in understanding clinical variability in a trial cohort and provides a genetic route for defining disease-specific outcome measures, and the basis of treatment response and stratification in DM1 trials.
ABSTRACT
Analyzing the type and frequency of patient‐specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial ...planning, and improved clinical care. Locus‐specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT‐NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid‐intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read‐through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).
Analysing the type and frequency of patient specific mutations giving rise to Duchenne Muscular Dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning and improved clinical care. We describe the development and analysis of the TREAT‐NMD DMD Global database (http://umd.be/TREAT_DMD/). We analysed and reported genetic data for 7149 DMD mutations held within the database. Additionally, we identified mutations within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read‐through therapies.
Aim
To conduct a systematic literature review of caregiver burden in Duchenne muscular dystrophy (DMD).
Method
We searched Embase, Web of Science, and PubMed for full‐text articles reporting results ...from studies of caregiver burden in DMD.
Results
We identified 483 unique publications. Of these, 450 were excluded after title and screening, and 12 after full‐text review. A total of 21 articles were included for data synthesis. Results encompassing more than 15 aspects of caregiver burden, investigated through surveys and/or interviews across 15 countries, were identified in the literature. Caregiving in DMD was frequently associated with impaired health‐related quality of life, poor sleep quality, reduced family function, depression, pain, stress, sexual dysfunction, and/or lower self‐esteem, as well as a considerable impact on work life and productivity.
Interpretation
Providing informal care to a patient with DMD can be associated with a substantial burden. Yet, more research is needed to better understand the clinical implications of caregiving in DMD and the relationship between caregiver burden and the progression of the disease. Our data synthesis should be helpful in informing clinical and social support programmes directed to families caring for a patient with DMD.
What this paper adds
A substantial body of evidence describes caregiver burden in Duchenne muscular dystrophy.
Little is known of the family burden beyond caregivers’ self‐assessments.
Resumen
Distrofia muscular de Duchenne y carga del cuidador: una revisión sistemática
Objetivo
Realizar una revisión sistemática de la literatura sobre la sobrecarga en del cuidador de niños con distrofia muscular de Duchenne (DMD).
Método
Se realizaron búsquedas en Embase, Web of Science y PubMed para obtener artículos completos que informaban los resultados de los estudios acerca de la sobrecarga del cuidador en la DMD.
Resultados
Identificamos 483 publicaciones únicas. De estos, 450 se excluyeron después del examen de título y resumen, y 12 después de la revisión del articulo completo. Se incluyeron un total de 21 artículos para la síntesis de datos. En la literatura se identificaron resultados que abarcaron más de 15 aspectos de la carga del cuidador, investigados a través de encuestas y / o entrevistas en 15 países. El cuidado en la DMD se asoció frecuentemente con problemas de calidad de vida relacionados con la salud, mala calidad del sueño, disminución de la función familiar, depresión, dolor, estrés, disfunción sexual y / o baja autoestima, así como un impacto considerable en la vida laboral y productividad.
Interpretación
Proporcionar atención informal por los cuidadores de un paciente con DMD puede asociarse con una sobrecarga sustancial. Sin embargo, se necesita más investigación para comprender mejor las implicaciones clínicas del cuidado en DMD y la relación entre la sobrecarga en el cuidador y la progresión de la enfermedad. Nuestra síntesis de datos es útil para informar a los programas de apoyo clínico y social dirigidos a las familias que cuidan a un paciente con DMD.
Resumo
Distrofia muscular de Duchenne e sobrecarga do cuidador: uma revisão sistemática
Objetivo
Conduzir uma revisão sistemática da literatura sobre a sobrecarga do cuidador em distrofia muscular de Duchenne (DMD).
Método
Pesquisamos as bases Embase, Web of Science, e PubMed para artigos completos relatando resultados dos estudos de sobrecarga do cuidador em DMD.
Resultados
Identificamos 483 publicações únicas. Destas, 450 foram excluídas após leitura de títulos e resumos, e 12 após revisão do texto completo. Um total de 21 artigos foi incluído para síntese dos dados. Resultados incluindo mais de 15 aspectos de sobrecarga do cuidador, investigado por meio de questionários e entrevistas em 15 países, foram identificados na literature. O cuidado em DMD foi frequentemente associado com reduzida qualidade de vida relacionada à saúde, reduzida qualidade do sono, reduzida função familiar, depressão, estresse, disfunção sexual, e/ou reduzida auto‐estima, assim como considerável impacto no trabalho e produtividade.
Interpretação
Prover cuidado informal a um paciente com DMD pode ser associado com sobrecarga substancial. Mais pesquisas são necessárias para compreender melhor as implicações clínicas do cuidar em DMD e a relação entre sobrecarga do cuidador e progressão da doença. Nossa síntese de dados pode ser útil para informar programas de suporte clínico e social para famílias que cuidam de um paciente com DMD.
What this paper adds
A substantial body of evidence describes caregiver burden in Duchenne muscular dystrophy.
Little is known of the family burden beyond caregivers’ self‐assessments.
This article's has been translated into Spanish and Portuguese.
Follow the links from the to view the translations.
Congenital myasthenic syndromes (CMS) are a group of rare, neuromuscular disorders that usually present in childhood or infancy. While the phenotypic presentation of these disorders is diverse, the ...unifying feature is a pathomechanism that disrupts neuromuscular transmission. Recently, two mitochondrial genes-SLC25A1 and TEFM-have been reported in patients with suspected CMS, prompting a discussion about the role of mitochondria at the neuromuscular junction (NMJ). Mitochondrial disease and CMS can present with similar symptoms, and potentially one in four patients with mitochondrial myopathy exhibit NMJ defects. This review highlights research indicating the prominent roles of mitochondria at both the pre- and postsynapse, demonstrating the potential for mitochondrial involvement in neuromuscular transmission defects. We propose the establishment of a novel subcategorization for CMS-mitochondrial CMS, due to unifying clinical features and the potential for mitochondrial defects to impede transmission at the pre- and postsynapse. Finally, we highlight the potential of targeting the neuromuscular transmission in mitochondrial disease to improve patient outcomes.
Defects in mitochondrial translation are among the most common causes of mitochondrial disease, but the mechanisms that regulate mitochondrial translation remain largely unknown. In the yeast ...Saccharomyces cerevisiae, all mitochondrial mRNAs require specific translational activators, which recognize sequences in 5′ UTRs and mediate translation. As mammalian mitochondrial mRNAs do not have significant 5′ UTRs, alternate mechanisms must exist to promote translation. We identified a specific defect in the synthesis of the mitochondrial DNA (mtDNA)-encoded COX I subunit in a pedigree segregating late-onset Leigh syndrome and cytochrome c oxidase (COX) deficiency. We mapped the defect to chromosome 17q by functional complementation and identified a homozygous single-base-pair insertion in CCDC44, encoding a member of a large family of hypothetical proteins containing a conserved DUF28 domain. CCDC44, renamed TACO1 for translational activator of COX I, shares a notable degree of structural similarity with bacterial homologs, and our findings suggest that it is one of a family of specific mammalian mitochondrial translational activators.
In spinal muscular atrophy (SMA), degeneration of motor neurons causes progressive muscular weakness, which is caused by homozygous deletion of the
SMN1
gene. Available epidemiological data on SMA ...are scarce, often outdated, and limited to relatively small regions or populations. Combining data from different sources including genetic laboratories and patient registries may provide better insight of the disease epidemiology. To investigate the incidence of genetically confirmed SMA, and the number of patients who are able and approachable to participate in new clinical trials and observational research, we used both genetic laboratories, the TREAT-NMD Global SMA Patient Registry and the Care and Trial Sites Registry (CTSR). In Europe, 4653 patients were genetically diagnosed by the genetic laboratories in the 5-year period 2011 to 2015, with 992 diagnosed in 2015 alone. The data provide an estimated incidence of SMA in Europe of 1 in 3900–16,000 live births. Patient numbers in the national patient registries and CTSR were considerably lower. By far, most patients registered in the national patient registries and the CTSR live in Europe and are reported to have SMA type II. Considerable differences between countries in patient participation in the registries were observed. Our findings indicate that not all patients with SMA are accessed by specialist healthcare services and these patients may not have access to research opportunities and optimal care.
ABSTRACT
Research into rare diseases is typically fragmented by data type and disease. Individual efforts often have poor interoperability and do not systematically connect data across clinical ...phenotype, genomic data, biomaterial availability, and research/trial data sets. Such data must be linked at both an individual-patient and whole-cohort level to enable researchers to gain a complete view of their disease and patient population of interest. Data access and authorization procedures are required to allow researchers in multiple institutions to securely compare results and gain new insights. Funded by the European Union’s Seventh Framework Programme under the International Rare Diseases Research Consortium (IRDiRC), RD-Connect is a global infrastructure project initiated in November 2012 that links genomic data with registries, biobanks, and clinical bioinformatics tools to produce a central research resource for rare diseases.
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