Clinical and genetic investigation in autosomal dominant limb‐girdle muscular dystrophy

Gilchrist, James M.; Pericak‐Vance, Margaret A.; Silverman, Larry N.; Roses, Allen D.

doi:10.1212/wnl.38.1.5

Cited by 105 publications

(60 citation statements)

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“…The phenotypic features of different MFMs are like those of muscular dystrophies, and some were first reported as such. For example, myotilinopathy was reported as limb girdle muscular dystrophy 1A by the clinical criteria, 36,37 and the ␣B-crystallinopathy of Canadian aboriginals was reported under the rubric of a fatal infantile muscular dystrophy. 38,39 Finally, the clinical and pathologic features of the FHL1 muscular dystrophies can be typical of MFMs, but MFM pathology has not been described or may have been overlooked in some cases of FHL1-related muscular dystrophies.…”

Section: Org)mentioning

confidence: 99%

Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy

Selcen

Bromberg

Chin³

et al. 2011

Neurology

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Objective: Some pathologic features of the FHL1 myopathies and the myofibrillar myopathies (MFMs) overlap; we therefore searched for mutations in FHL1 in our cohort of 50 patients with genetically undiagnosed MFM. Methods:Mutations in FHL1 were identified by direct sequencing. Polymorphisms were excluded by using allele-specific PCR in 200 control subjects. Structural changes in muscle were analyzed by histochemistry, immunocytochemistry, and electron microscopy. Results:We detected 2 novel and 1 previously identified missense mutation in 5 patients. Patients 1-4 presented before age 30, display menadione-nitro blue tetrazolium-positive reducing bodies, and harbor mutations in the FHL1 LIM2 domain. Patient 5 presented at age 75 and has no reducing bodies, and his mutation is not in a LIM domain. The clinical features include progressive muscle weakness, hypertrophied muscles, rigid spine, and joint contractures, and 1 patient also has peripheral neuropathy. High-resolution electron microscopy reveals the reducing bodies composed of 13-nm tubulofilaments initially emanating from Z-disks. At a more advanced stage, abundant reducing bodies appear in the cytoplasm and nuclei with concomitant myofibrillar disintegration, accumulation of cytoplasmic degradation products, and aggregation of endoplasmic reticulum and sarcotubular profiles. The four-and-a-half LIM domain protein 1 (FHL1), encoded by FHL1, is located on Xq26.3. It is highly expressed in skeletal and cardiac muscle and less abundantly in brain, placenta, lung, liver, kidney, pancreas, and testis.1-3 Mutations in FHL1 have been associated with diverse chronic myopathies. 4 These include late-onset X-linked scapulo-axio-peroneal myopathy with bent spine syndrome, 5 reducing body myopathy, 6,7 X-linked dominant scapuloperoneal muscular dystrophy, 8 rigid spine syndrome, 9 and contractures and cardiomyopathy mimicking Emery-Dreifuss muscular dystrophy. 10,11 Most FHL1 mutations appear in the second or fourth LIM domains with a single mutation in the third LIM domain.Myofibrillar myopathies (MFMs) arise from primary degeneration of the muscle fibers and represent a morphologically distinct but genetically heterogeneous subset of muscular dystrophies. The unifying histologic findings are early disintegration of the Z-disk followed by myofibrillar disintegration, aggregation of degraded filaments into pleomorphic granular or hyaline inclusions, and ectopic expression of multiple Z-disk-related and other proteins in the affected muscle fibers.12-14 Although some pathologic features of the FHL1 muscular dystrophies and the MFMs overlap, reducing bodies have been detected only in FHL1 dystrophies. 7,15 We here report 2 novel

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Section: Org)mentioning

confidence: 99%

Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy

Selcen

Bromberg

Chin³

et al. 2011

Neurology

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“…Also, different forms of MFM have the clinical features of muscular dystrophies and some were first reported as such. For example, myotilinopathy was first classified as LGMD1A by the clinical criteria [4,5] and zaspopathy [6,7] was first reported as a distal muscular dystrophy.…”

Section: Introductionmentioning

confidence: 99%

Myofibrillar myopathies

Selcen¹

2010

Current Opinion in Neurology

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SUMMARYMyofibrillar myopathies represent a group of muscular dystrophies with a similar morphologic phenotype. They are characterized by a distinct pathologic pattern of myofibrillar dissolution associated with disintegration of the Z-disk, accumulation of myofibrillar degradation products, and ectopic expression of multiple proteins and sometimes congophilic material. The clinical features of myofibrillar myopathies are more variable. These include progressive muscle weakness, that often involves or begins in distal muscles but limb-girdle or scapuloperoneal distributions can also occur. Cardiomyopathy and peripheral neuropathy are frequent associated features. EMG of the affected muscles reveals myopathic motor unit potentials and abnormal irritability often with myotonic discharges. Rarely, neurogenic motor unit potentials or slow nerve conductions are present. The generic diagnosis of myofibrillar myopathies is based on muscle biopsy findings in frozen sections. To date, all myofibrillar myopathy mutations have been traced to Z-disk associated proteins, namely, desmin, αB-crystallin, myotilin, ZASP, filamin C and Bag3. However, in the majority of the myofibrillar myopathy patients the disease gene awaits discovery.

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“…Nowadays, many types of muscular diseases are known, based on their clinical and histopathological aspects, and the molecular bases of most of them are elucidated (Weiler and al., 1999;Leturcq and Kaplan, 2000;Urtizberea, 2001;Authier et al, 2008). A particular interest in investigating these pathologies was raised in developed countries around 1980 following the era of advances in molecular genetics (Gilchrist and al., 1988;Beckmann et al, 1991;Ginjaar et al, 2000;Sandona and Betto, 2009). It has been shown that these pathologies derive from anomalies in proteins involved in muscle cell structures or functions.…”

Section: Introductionmentioning

confidence: 99%

“…The diversity of the proteins that are involved in this phenomenon explains the numerous types of myopathies. The majority of myopathies are genetically transmitted, in variable ways: autosomic, Xlinked, recessive, dominant (Eymard et al, 1997;Gilchrist et al, 1988;Bonne et al, 1999;Speer et al, 1999). In spite important similarities, differences also exist in their clinical expression.…”

Section: Introductionmentioning

confidence: 99%

Gamma-sarcoglycanopathy (LGMD 2C) with Del 525T mutation: Report of the first familial case in Niger

Moumouni¹,

Assadeck²,

Guida³

et al. 2012

Int. J. Bio. Chem. Sci

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We are reporting a familial case of limb-girdle muscular dystrophy (LGMD) upon 5 out of 6 siblings from parents showing no evidence of muscular dystrophy. The pedigree of the family up to five generations did not reveal any known case in the past even though consanguinity was reported. The clinical observations revealed wheelchair bound or difficulties for walking in all affected subjects, due to muscular dystrophy involving mainly the pelvic girdle. Creatine phosphoKinase (CK) was higher than normal values in both affected children and their parents. The scanning of thigh showed in all patients, an atrophy of the quadriceps with fatty conversion. Molecular analysis was carried out, first using western blot, which revealed gammasacoglycan deficiency and second, by gene screening, which showed Del 525T mutation. This mutation is most widespread in arabo-berbères tribes including Touaregs. The present cases are in our knowledge the first reported in that part of Africa, south of Maghreb. We make a focus on histological and molecular bases of the LGMD.

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Clinical and genetic investigation in autosomal dominant limb‐girdle muscular dystrophy

Cited by 105 publications

References 0 publications

Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy

Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy

Myofibrillar myopathies

Gamma-sarcoglycanopathy (LGMD 2C) with Del 525T mutation: Report of the first familial case in Niger

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