Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the LMNA gene result in diverse phenotypes including Emery Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy with conduction system disease, Dunnigan type familial partial lipodystrophy, mandibulo acral dysplasia, Hutchinson Gilford progeria syndrome, restrictive dermopathy and autosomal recessive Charcot Marie Tooth type 2. The c.1930C > T (R644C) missense mutation has previously been reported in eight unrelated patients with variable features including left ventricular hypertrophy, limb girdle muscle weakness, dilated cardiomyopathy and atypical progeria. Here we report on the details of nine additional patients in eight families with this mutation. Patients 1 and 2 presented with lipodystrophy and insulin resistance, Patient 1 having in addition focal segmental glomerulosclerosis. Patient 3 presented with motor neuropathy, Patient 4 with arthrogryposis and dilated cardiomyopathy with left ventricular non-compaction, Patient 5 with severe scoliosis and contractures, Patient 6 with limb girdle weakness and Patient 7 with hepatic steatosis and insulin resistance. Patients 8 and 9 are brothers with proximal weakness and contractures. Nonpenetrance was observed frequently in first degree relatives. This report provides further evidence of the extreme phenotypic diversity and low penetrance associated with the R644C mutation. Possible explanations for these observations are discussed.
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PMID:Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C. 1847 90

Alpha-dystroglycan (alpha-DG) is a glycoprotein that binds to laminin in the basal lamina and helps provide mechanical support. A group of muscular dystrophies are caused by glycosylation defects of alpha-DG and are hence collectively called alpha-dystroglycanopathy (alpha-DGP). Alpha-DGP is clinically characterized by a combination of muscular dystrophies, structural brain anomalies, and ocular involvement. So far, 6 causative genes have been identified: LARGE, POMGNT1, POMT1, POMT2, FKRP, and FKTN. Initially, alpha-DGP was classified under congenital muscular dystrophies; however, the clinical phenotype is now expanded to include a markedly wide spectrum ranging from the most severe, lethal congenital muscular dystrophy with severe brain deformity to the mildest limb girdle muscular dystrophy with minimal muscle weakness. This is exemplified by Fukuyama congenital muscular dystrophy (FCMD), which is the most prevalent alpha-DGP in Japan, and is caused by mutations in FKTN. FCMD is clinically characterized by a triad of mental retardation, brain deformities, and congenital muscular dystrophy, and a majority of FCMD patients have a homozygous 3-kb retrotransposal insertion in the 3'non-coding region. Typically, they are able to sit but never attain independent ambulation in their lives. Recently, a patient from Turkey harboring homozygous 1-bp insertion reportedly showed a severe brain deformity with hydrocephalus and died 10 days after birth. In contrast, the mildest FKTN phenotype, LGMD2L, was identified in 6 cases from 4 families in Japan. These patients harbored compound heterozygous mutation with 3-kb retrotransposal insertion in the 3'non-coding region and a novel missense mutation in the coding region. Clinically, these patients presented with minimal muscle weakness and dilated cardiomyopathy and had normal intelligence. These data clearly indicate that FKTN mutations can cause a broad spectrum of muscular dystrophies. Therefore, clinicians should always bear in mind the possibility of alpha-DGP when they have a patient suspected to have muscular dystrophy.
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PMID:[Fukuyama congenital muscular dystrophy and related alpha-dystroglycanopathies]. 1897 3

The pathogenesis of dilated cardiomyopathy in Emery- Dreifuss muscular dystrophy (EDMD) is still unknown. Autoimmune mechanisms have recently been taken into account. The aim of this investigation was to determine whether the level of circulating antibodies to heart proteins which were previously detected, correlates with disease progression. Troponin I was chosen as the target. Ten patients with EDMD and 10 age-matched normal controls were tested. An enzyme linked immunoassay (ELISA) technique was used to determine the possible relation between the level of anti-troponin I antibodies at diagnosis and at followup. Autoantibodies against troponin I were detected in all EDMD patients. At diagnosis the level was higher in the X-linked EDMD form (X-EDMD), as compared to the autosomal dominant form (AD-EDMD). At follow-up the elevated level of the autoantibodies persisted in all the EDMD cases. However, in the AD-EDMD form, the level was found to be significantly rising with disease progression, in the X-EDMD form, on the other hand, it was declining. No clear-cut relationship between the level of the circulating antibodies and cardiac symptomatology was present. Detection of anti-troponin I antibodies may provide a non-invasive marker of early stages of dilated cardiomyopathy in EDMD.
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PMID:Circulating autoantibodies to troponin I in Emery-Dreifuss muscular dystrophy. 1910 70

Two unrelated young women presented with similar dysmorphic features including severe retrognathia, beaked nose, narrow chest, sloping shoulders, and an acrogeric appearance of the hands and feet. Neither had any evidence of skeletal myopathy, but both developed progressive dilated cardiomyopathy, both experienced premature ovarian failure, and both were found to have the same heterozygous novel missense mutation c.176T>G in exon 1 of the LMNA gene, resulting in a leucine to arginine change at codon 59 (Leu59Arg). Mutations in the LMNA gene cause a variety of disorders including dilated cardiomyopathy, muscular dystrophy, familial lipodystrophy, progeria, atypical progeroid syndromes, and mandibuloacral dysplasia. Genotype-phenotype correlation has been reported for some of these conditions. Our patients are the only ones known to have the specific mutation Leu59Arg and also share a set of features not entirely consistent with any of the laminopathies previously described. A previously reported patient with an adjacent mutation (Ala57Pro) had "atypical Werner syndrome" with dilated cardiomyopathy, hypogonadism, and sloping shoulders. While each of these clinical features does occur in other laminopathy syndromes, these patients form a phenotypic cluster distinct from other laminopathies and clinically overlapping with Malouf syndrome. LMNA sequencing should be considered for patients presenting with dilated cardiomyopathy and hypergonadotropic hypogonadism, including those previously diagnosed with Malouf syndrome.
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PMID:Ovarian failure and dilated cardiomyopathy due to a novel lamin mutation. 1924 81

Reduction of neuronal nitric oxide synthase (nNOS) has been associated with the pathogenesis and clinical expression of inherited myopathies. To determine whether a defect in nNOS might be an adverse modulating factor in the course of limb-girdle muscular dystrophy, we investigated cytosolic and sarcolemmal nNOS expression in muscle biopsies from 32 patients with 7 forms of limb-girdle muscular dystrophy. Primary calpainopathy, dysferlinopathy, and caveolinopathy biopsies showed normal levels of cytosolic nNOS and preserved sarcolemmal nNOS immunoreactivity. By contrast, the cytosolic nNOS levels in sarcoglycanopathy muscles were variably reduced. Sarcolemmal nNOS immunoreactivity varied from absent to reduced, depending on the integrity of the sarcoglycan complex. In muscles with loss of the entire sarcoglycan complex, sarcolemmal nNOS was absent; it otherwise depended on the specific sarcoglycan gene and type of mutation. The integrity of the entire sarcoglycan complex is, therefore, essential for the stabilization of nNOS to the sarcolemma. Absence of sarcolemmal nNOS in sarcoglycanopathy muscle was always associated with severe muscular dystrophy and sometimes with dilated cardiomyopathy, supporting the hypothesis that nNOS defect might contribute to skeletal and cardiac muscle disease progression. These results emphasize the value of nNOS immunohistochemical analysis in limb-girdle muscular dystrophy and provide additional insights for future therapeutic interventions in these disorders.
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PMID:Sarcolemmal neuronal nitric oxide synthase defect in limb-girdle muscular dystrophy: an adverse modulating factor in the disease course? 1928 13

A common gene deletion or mutation of delta-sarcoglycan (delta-SG) in dystrophin-related proteins (DRPs) is identified in both TO-2 strain hamsters and human families with dilated cardiomyopathy. We have succeeded in the long-lasting in vivo supplementation of a normal delta-SG gene by recombinant adeno-associated virus vector, restoration of the morphological and functional degeneration, and improvement in the prognosis of the TO-2 hamster. To evaluate the integrity of the sarcolemma (SL) and the subsequent change of organelles in cardiomyocytes of the TO-2 strain hamster, we examined electron microscopy (EM) images focusing on the sarcolemmal stability at the end stage of heart failure. Two types of sarcolemmal degradation were detected: the widened and locally thickened SL, and blurred and discontinuous SL. Bizarrely formed mitochondria of varying sizes were also observed. Immuno-EM revealed clear expression of dystrophin in the SL and intense expression at the costamere as well as at the T-tubules in the control F1B strain hearts, but a patchy deposition of dystrophin was observed along the SL without the transgene of delta-SG. In contrast to the previous reports that dystrophin's integrity was intact, the present results suggest that the gene deletion of delta-SG and the loss of delta-SG protein in the SL cardioselectively cause the morphological and functional deterioration of dystrophin and the resultant instability of the SL. The sarcolemmal fragility may be similar to Duchenne-type progressive muscular dystrophy in skeletal muscle. In addition to the mechanical role, another aspect of DRPs for the intracellular signal transmission is also discussed.
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PMID:Sarcolemmal fragility secondary to the degradation of dystrophin in dilated cardiomyopathy, as estimated by electron microscopy. 1964 52

Inherited mutations cause approximately 30% of all dilated cardiomyopathy cases, with autosomal dominant mutations in the LMNA gene accounting for more than one third of these. The LMNA gene encodes the nuclear envelope proteins lamins A and C, which provide structural support to the nucleus and also play critical roles in transcriptional regulation. Functional deletion of a single allele is sufficient to trigger dilated cardiomyopathy in humans and mice. However, whereas Lmna(-/-) mice develop severe muscular dystrophy and dilated cardiomyopathy and die by 8 weeks of age, heterozygous Lmna(+/-) mice have a much milder phenotype, with changes in ventricular function and morphology only becoming apparent at 1 year of age. Here, we studied 8- to 20-week-old Lmna(+/-) mice and wild-type littermates in a pressure overload model to examine whether increased mechanical load can accelerate or exacerbate myocardial dysfunction in the heterozygotes. While overall survival was similar between genotypes, Lmna(+/-) animals had a significantly attenuated hypertrophic response to pressure overload as evidenced by reduced ventricular mass and myocyte size. Analysis of pressure overload-induced transcriptional changes suggested that the reduced hypertrophy in the Lmna(+/-) mice was accompanied by impaired activation of the mechanosensitive gene Egr-1. In conclusion, our findings provide further support for a critical role of lamins A and C in regulating the cellular response to mechanical stress in cardiomyocytes and demonstrate that haploinsufficiency of lamins A and C alone is sufficient to alter hypertrophic responses and cardiac function in the face of pressure overload in the heart.
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PMID:Attenuated hypertrophic response to pressure overload in a lamin A/C haploinsufficiency mouse. 1991 44

In the past decade, a wide range of fascinating monogenic diseases have been linked to mutations in the LMNA gene, which encodes the A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. These diseases include dilated cardiomyopathy with variable muscular dystrophy, Dunnigan-type familial partial lipodystrophy, a Charcot-Marie-Tooth type 2 disease, mandibuloacral dysplasia, and Hutchinson-Gilford progeria syndrome. Several diseases are also caused by mutations in genes encoding B-type lamins and proteins that associate with the nuclear lamina. Studies of these so-called laminopathies or nuclear envelopathies, some of which phenocopy common human disorders, are providing clues about functions of the nuclear envelope and insights into disease pathogenesis and human aging.
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PMID:Diseases of the nuclear envelope. 2018 15

The Duchenne and Becker forms of muscular dystrophy are associated with dilated cardiomyopathy and are diseases in which pulmonary function peaks and then progressively declines. In this report, the authors quantify cardiopulmonary function variability among brothers. Brothers in 3 of 7 eligible sibships had discordant pulmonary function, with significant differences between the brothers' peak forced vital capacities and their vital capacities at last comparable age. There was no relationship between pulmonary and cardiac function among the siblings. The authors concluded that despite identical genetic mutations, cardiac and pulmonary function variability was common among brothers in their clinic with Duchenne or Becker muscular dystrophy. If confirmed by larger studies, these results have negative implications for the use of genetic testing to predict cardiopulmonary course and response to therapies in Duchenne or Becker muscular dystrophy.
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PMID:Cardiac and pulmonary function variability in Duchenne/Becker muscular dystrophy: an initial report. 2050 85

Emery-Dreifuss muscular dystrophy is a rare form of muscular dystrophy involving both cardiac and skeletal muscles. Cardiac involvement frequently leads to dilated cardiomyopathy, arrhythmias and may precipitate sudden cardiac death. Skeletal involvement is characterised by early contractures and muscle weakness in the humeroperoneal distribution. We describe the anaesthetic management of a 29-year-old patient with Emery-Dreifuss muscular dystrophy presenting for elective caesarean section and discuss the disorder and its potential anaesthetic implications.
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PMID:Elective caesarean section for a woman with Emery-Dreifuss muscular dystrophy. 2071 41


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