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The Neurologist Jul 2015Mutations in the CAV3 gene are usually inherited in an autosomal dominant manner and lead to distinct disorders including limb-girdle muscular dystrophy 1C, rippling...
INTRODUCTION
Mutations in the CAV3 gene are usually inherited in an autosomal dominant manner and lead to distinct disorders including limb-girdle muscular dystrophy 1C, rippling muscle disease, and isolated creatine kinase elevation.
PATIENTS AND METHODS
The features of the first patients with caveolin-3 deficiency from Greece are presented. Patients' phenotypes ranged from asymptomatic creatine kinase elevation to severe weakness of lower extremities. Clinical evaluation disclosed muscle hypertrophy in 2 patients, whereas percussion-induced muscle mounding was a consistent finding in all of them. Muscle histopathology was variable and unrelated with disease severity. The diagnosis was based on the immunohistochemical study of caveolin-3 expression and molecular analysis of the caveolin-3 gene.
CONCLUSIONS
Clinical manifestations and histochemical findings in caveolinopathy patients may be mild or nonspecific or overlapping with features of other muscular dystrophies. Immunohistochemical study of caveolin-3 expression on muscle biopsy should be routinely performed when investigating isolated hyperCKemia or undetermined myopathy especially in the presence of percussion-induced muscle mounding.
Topics: Adult; Aged; Caveolin 3; Creatine Kinase; Family Health; Female; Greece; Humans; Male; Middle Aged; Muscle, Skeletal; Muscular Dystrophies; Mutation
PubMed: 26185955
DOI: 10.1097/NRL.0000000000000036 -
Orphanet Journal of Rare Diseases Jul 2021LAMA2-related muscular dystrophy including LAMA2-related congenital muscular dystrophy (LAMA2-CMD) and autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23) is...
BACKGROUND
LAMA2-related muscular dystrophy including LAMA2-related congenital muscular dystrophy (LAMA2-CMD) and autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23) is caused by LAMA2 pathogenic variants. We aimed to describe the natural history and establish genotype-phenotype correlations in a large cohort of Chinese patients with LAMA2-related muscular dystrophy.
METHODS
Clinical and genetic data of LAMA2-related muscular dystrophy patients enrolled from ten research centers between January 2003 and March 2021 were collected and analyzed.
RESULTS
One hundred and thirty patients (116 LAMA2-CMD and 14 LGMDR23) were included. LAMA2-CMD group had earlier onset than LGMDR23 group. Head control, independent sitting and ambulation were achieved in 76.3%, 92.6% and 18.4% of LAMA2-CMD patients at median ages of 6.0 months (range 2.0-36.0 months), 11.0 months (range 6.0-36.0 months), and 27.0 months (range 18.0-84.0 months), respectively. All LGMDR23 patients achieved independent ambulation at median age of 18.0 months (range 13.0-20.0 months). Motor regression in LAMA2-CMD mainly occurred concurrently with rapid progression of contractures during 6-9 years old. Twenty-four LAMA2-related muscular dystrophy patients died, mostly due to severe pneumonia. Seizures occurred in 35.7% of LGMDR23 and 9.5% of LAMA2-CMD patients. Forty-six novel and 97 known LAMA2 disease-causing variants were identified. The top three high-frequency disease-causing variants in Han Chinese patients were c.7147C > T (p.R2383*), exon 4 deletion, and c.5156_5159del (p.K1719Rfs*5). In LAMA2-CMD, splicing variants tended to be associated with a relatively mild phenotype. Nonsense variants were more frequent in LAMA2-CMD (56.9%, 66/116) than in LGMDR23 (21.4%, 3/14), while missense disease-causing variants were more frequent in LGMDR23 (71.4%, 10/14) than in LAMA2-CMD (12.9%, 15/116). Copy number variations were identified in 26.4% of survivors and 50.0% of nonsurvivors, suggesting that copy number variations were associated with lower rate of survival (p = 0.029).
CONCLUSIONS
This study provides better understandings of natural history and genotype-phenotype correlations in LAMA2-related muscular dystrophy, and supports therapeutic targets for future researches.
Topics: Child; Child, Preschool; China; DNA Copy Number Variations; Humans; Infant; Laminin; Muscular Dystrophies; Muscular Dystrophies, Limb-Girdle
PubMed: 34281576
DOI: 10.1186/s13023-021-01950-x -
Clinical Genetics Sep 2016Congenital myopathies and muscular dystrophies constitute a genetically and phenotypically heterogeneous group of rare inherited diseases characterized by muscle... (Review)
Review
Congenital myopathies and muscular dystrophies constitute a genetically and phenotypically heterogeneous group of rare inherited diseases characterized by muscle weakness and atrophy, motor delay and respiratory insufficiency. To date, curative care is not available for these diseases, which may severely affect both life-span and quality of life. We discuss prenatal diagnosis and genetic counseling for families at risk, as well as diagnostic possibilities in sporadic cases.
Topics: Genetic Counseling; Humans; Muscular Dystrophies; Myotonia Congenita; Prenatal Diagnosis
PubMed: 27197572
DOI: 10.1111/cge.12801 -
Expert Review of Neurotherapeutics Sep 2018Limb-girdle muscular dystrophies (LGMDs) encompass a clinically heterogeneous group of rare, genetic progressive muscle disorders presenting with weakness and atrophy of... (Review)
Review
Limb-girdle muscular dystrophies (LGMDs) encompass a clinically heterogeneous group of rare, genetic progressive muscle disorders presenting with weakness and atrophy of predominant pelvic and shoulder muscles. The spectrum of disease severity ranges from severe childhood-onset muscular dystrophy to adult-onset dystrophy. Areas covered: The review presents an update of the clinical phenotypes and diagnostic options for LGMD including both dominant and recessive LGMD and consider their differential clinical and histopathological features. An overview of most common phenotypes and of possible complications is given. The management of the main clinical respiratory, cardiac, and central nervous system complications are covered. The instrumental, muscle imaging, and laboratory exams to assess and reach diagnosis are described. The use of recent genetic techniques such as next generation sequencing (NGS), whole-exome sequencing compared to other techniques (e.g. DNA sequencing, protein analysis) is covered. Currently available drugs or gene therapy and rehabilitation management are focused on. Expert commentary: Many LGMD cases, which for a long time previously remained without a molecular diagnosis, can now be investigated by NGS. Gene mutation analysis is always required to obtain a certain molecular diagnosis, fundamental to select homogeneous group of patients for future pharmaceutical and gene trials.
Topics: Adult; Age of Onset; Biomarkers; Child; Diagnosis, Differential; Humans; Muscular Dystrophies, Limb-Girdle; Phenotype
PubMed: 30084281
DOI: 10.1080/14737175.2018.1508997 -
Clinical Transplantation Jun 2022Cardiac involvement may occur in many forms of muscular dystrophy (MD). While cardiac disease may progress to warrant heart transplantation (HTx), there may be...
INTRODUCTION
Cardiac involvement may occur in many forms of muscular dystrophy (MD). While cardiac disease may progress to warrant heart transplantation (HTx), there may be contraindications related to extra-cardiac disease including pulmonary and skeletal muscle involvement that limit overall survival and impairs post-transplant rehabilitation efforts. This study describes the MD HTx experience at a single high-volume center.
METHODS
We examined the clinical characteristics and outcomes of patients with MD with heart failure (HF) (n = 28), patients with MD status post HTx (n = 20) and non-MD HTx control group (n = 40) matched 2:1 for age at transplant, sex, listing status, and antibody sensitization.
RESULTS
Patients with MD who underwent HTx had increased ventilator days (2 vs. 1 days, p = .013), increased hospital length of stay (20 vs. 12 days, p = .022), and increased discharge to inpatient rehab (60% vs. 8%, p < .001). By 1 year post HTx, patients with MD more often required assistive devices for walking (55% vs. 10%, p = .01). Nonetheless, post-HTx survival was similar at 1 year (100% vs. 97.5%, p = .48) and 5 years (95.0% vs. 87.5%, p = .36). Of the HTx recipients with MD, 95% were followed by a neurologist, 60% by a neuromuscular specialist as part of the Muscular Dystrophy Association Clinic at our center.
CONCLUSION
Transplantation is a feasible option for patients with MD and advanced HF. MD patients who undergo transplantation may benefit from multidisciplinary specialized care to optimize MD-related morbidity.
Topics: Heart Diseases; Heart Failure; Heart Transplantation; Humans; Muscular Dystrophies; Risk Factors; Time Factors; Treatment Outcome
PubMed: 35293038
DOI: 10.1111/ctr.14645 -
Neurologic Clinics Feb 2021Increased understanding of disease pathophysiology and advances in gene therapies and drug technologies are revolutionizing treatment of muscular dystrophies and motor... (Review)
Review
Increased understanding of disease pathophysiology and advances in gene therapies and drug technologies are revolutionizing treatment of muscular dystrophies and motor neuron disorders (MNDs). New drugs have been approved for Duchenne muscular dystrophy, spinal muscular atrophy, and amyotrophic lateral sclerosis. For other diseases, new targets have been identified, and new therapies are in clinical trials. The impact of such therapies will be fully understood only in the next decades. Cost burden and accessibility are major challenges in the wide application of new drugs. This article reviews advances in gene therapies, newly approved drugs, and therapeutic promises in muscular dystrophies and MNDs.
Topics: Genetic Therapy; Humans; Motor Neuron Disease; Muscular Dystrophies; Neuroprotective Agents
PubMed: 33223091
DOI: 10.1016/j.ncl.2020.09.005 -
Neurological Sciences : Official... Oct 2020Anoctamin 5 (ANO5) is a putative intracellular calcium-activated chloride channel. Recessive mutations in ANO5 may present from asymptomatic hyperCKemia and...
OBJECTIVE
Anoctamin 5 (ANO5) is a putative intracellular calcium-activated chloride channel. Recessive mutations in ANO5 may present from asymptomatic hyperCKemia and exercise-induced myalgia to proximal and/or distal muscle weakness. Here we describe the clinical, pathological, and molecular findings of three unrelated patients with ANO5-related muscular dystrophy.
METHODS
In this retrospective study, we analyzed our database which includes 1700 muscle biopsies performed for diagnostic purposes from October 2004 to February 2019. Patients were attended by two myology experts, who performed and analyzed the muscle biopsies. Muscle biopsies were frozen in cooled isopenthane, cryostat sectioned, and routinely stained and reacted (minimum 16 stainings). A custom panel, including 115 genes (Nextera Rapid Capture, Illumina) and whole-exome sequencing analysis, was used for next-generation sequencing in cases without a definite pathological diagnosis.
RESULTS
Three patients were diagnosed with ANO5-related muscular dystrophy, with all presenting the common exon 5 mutation c.191dup plus a compound heterozygous missense mutation. They showed three different phenotypes (distal myopathy, LGMD2L, and asymptomatic hyperCKemia). Curiously, all three muscle biopsies showed different patterns, but numerous ragged-red fibers with little endomysial inflammation and partial invasion cell by T lymphocytes were observed in one.
CONCLUSION
ANO5-related muscular dystrophy is a heterogeneous disease with different clinical phenotypes as well as different histological patterns, which may even mimic a mitochondrial myopathy. The results of this study provide further knowledge of the clinical, histological, and pathological features related to ANO5 mutations.
Topics: Anoctamins; Humans; Muscular Dystrophies; Muscular Dystrophies, Limb-Girdle; Mutation; Phenotype; Retrospective Studies
PubMed: 32399949
DOI: 10.1007/s10072-020-04453-y -
Journal of Neuromuscular Diseases 2023Neuromuscular disease (NMD) research is experiencing tremendous growth as a result of progress in diagnostics and therapeutics yet there continues to be a significant...
BACKGROUND
Neuromuscular disease (NMD) research is experiencing tremendous growth as a result of progress in diagnostics and therapeutics yet there continues to be a significant clinical data shortage for these rare diseases. To maximize the development and impact of new therapies, the Muscular Dystrophy Association (MDA) created the neuroMuscular ObserVational Research Data Hub (MOVR) as an observational research study that collects disease-specific measures from individuals living with NMDs in the United States.
OBJECTIVE
This manuscript provides a description of MOVR, participants enrolled in MOVR, and longitudinal data availability.
METHODS
MOVR collects longitudinal data from individuals diagnosed with ALS, BMD, DMD, FSHD, LGMD, Pompe disease, or SMA, and who are seen for care at a participating MDA Care Center. Data are entered from medical records into standardized electronic case report forms (eCRFs). These eCRFs capture participants' demographics, diagnostic journeys, clinical visits, and discontinuation from the study.
RESULTS
From January 2019 to May 2022, MOVR collected data from 50 participating care centers and 1,957 participants. Data from 1,923 participants who participated in MDA's pilot registry were migrated into MOVR, creating a total of 3,880 participants in MOVR. Initial analysis of aggregated data demonstrated that 91% of eCRFs were complete. Forty-three percent of participants had 3 or more encounters and 50% of all encounters were 5 months or less from the previous encounter.
DISCUSSION
As a centralized data hub for multiple NMDs, MOVR serves as a platform that can be used to inform disease understanding, guide clinical trial design, and accelerate drug development for NMDs.
Topics: Humans; Muscular Dystrophies; Neuromuscular Diseases; Rare Diseases; Glycogen Storage Disease Type II; Registries
PubMed: 36911943
DOI: 10.3233/JND-221551 -
Neuromuscular Disorders : NMD Aug 2022LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON(SEPN1)-related myopathy (SELENON-RM) are rare neuromuscular diseases caused by mutations in the LAMA2 and SELENON... (Review)
Review
LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON(SEPN1)-related myopathy (SELENON-RM) are rare neuromuscular diseases caused by mutations in the LAMA2 and SELENON (SEPN1) gene, respectively. Systematic reviews on cardiac features in both neuromuscular diseases are lacking. This scoping review aims to elucidate the cardiac involvement in LAMA2-MD or SELENON-RM. Three electronic databases (PubMed, Embase and Cochrane) were searched. All studies, case reports and case series with information on cardiac features in LAMA2-MD or SELENON-RM patients were included. Study selection and data extraction were performed by two independent reviewers. 31 Articles on LAMA2-MD and 17 articles on SELENON-RM met the inclusion criteria, resulting in the inclusion of 131 LAMA2-MD and 192 SELENON-RM cases. In 41% of LAMA2-RM cases, a cardiac abnormality was present. Left ventricular systolic dysfunction and arrhythmia were most frequently described. In 15% of SELENON-RM cases, a cardiac abnormality was reported, of which pulmonary hypertension, including right ventricular dysfunction secondary to pulmonary failure, was most prevalent. We conclude that in LAMA2-MD primary left ventricular dysfunction and in SELENON-RM secondary right ventricular dysfunction are frequently reported. Optimal cardiorespiratory surveillance by screening of asymptomatic patients every two years with ECG, Holter and echocardiography is necessary for early detection and/or treatment of cardiac manifestations.
Topics: Humans; Laminin; Mallory Bodies; Muscular Diseases; Muscular Dystrophies; Mutation; Scoliosis; Ventricular Dysfunction, Right
PubMed: 35868898
DOI: 10.1016/j.nmd.2022.06.004 -
Current Neurology and Neuroscience... May 2020Muscular dystrophies are a heterogeneous group of inherited muscular disorders characterized by progressive muscle weakness and in many cases cardiac and respiratory... (Review)
Review
PURPOSE OF REVIEW
Muscular dystrophies are a heterogeneous group of inherited muscular disorders characterized by progressive muscle weakness and in many cases cardiac and respiratory muscle involvement. Historically, these disorders are considered incurable with grave prognoses. The genes responsible for most muscular dystrophies are known, and early diagnosis is achievable with proper clinical recognition and advanced genetic testing. This article reviews recent advances in the development of novel treatments and biomarkers in the realm of muscular dystrophies commonly encountered in pediatric population.
RECENT FINDINGS
The therapeutic landscape of muscular dystrophies has changed with the development of new approved treatments for Duchenne muscular dystrophy (DMD), the most common and severe muscular dystrophy. This has paved the way for the development of novel therapeutic strategies for not only DMD but also other muscular dystrophies. This article reviews recent advances in the development of novel treatments and biomarkers in the realm of muscular dystrophies commonly encountered in pediatric population.
Topics: Biomarkers; Child; Genetic Testing; Humans; Muscular Dystrophy, Duchenne; Prognosis
PubMed: 32409939
DOI: 10.1007/s11910-020-01034-6