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)

Sixty-six individuals with Limb-Girdle Syndrome (LGS) were evaluated over a 10-yr period and classified into three types: 19 severe autosomal recessive muscular dystrophy of childhood (ARMDC), alternatively referred to by some as SCARMD, 18 autosomal dominant late onset (ADLO), and 29 pelvifemoral (PF) individuals. ARMDC subjects showed the greatest weakness, 2.5 +/- 1.0, mean Manual Muscle Test (MMT) grade for all muscles combined, and the only significant progression of loss of strength, -0.59 MMT unit decline per decade. Strength loss in ADLO and PF types was about the same, 3.7 +/- 0.7 and 4.0 +/- 0.7 grades, respectively. Quantitative strength measurements in ADLO and PF types were more sensitive than MMTs, showing losses of 30-40% strength in muscle groups with MMT grades of 4 or higher. All three types showed greater proximal and lower extremity weakness but usually no difference between flexor and extensor strength. There was a high percentage (44%) of mild very slowly progressive scoliosis in ARMDC, but spine deformity was unusual in ADLO and PF (11%) LGS. Contractures were few, slowly progressive, and usually mild in severity in all types, although more frequent in ARMDC. There also was a low frequency of severe restrictive lung disease in all types (10%) but a high percentage of electrocardiogram abnormalities (62-73%). The most common electrocardiogram abnormalities were increased R/S ratio in V1 and infranodal conduction defects. Intellectual and cognitive functions were within normal limits. Mobility and extremity function reflected the strength differences between the ARMDC and other types of LGS. Eight-five percent of ARMDC individuals relied on a wheelchair for all or part of their mobility, and all were unable to complete timed motor performance tests within the 99th percentile range for controls.
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PMID:Profiles of neuromuscular diseases. Limb-girdle syndromes. 757 19

Severe autosomal recessive muscular dystrophy (SCARMD), McKusick n. 253700, has been originally described in North-African populations, in which significant linkage has been established with DNA markers mapping to the proximal region of the long arm of chromosome 13, without evidence for heterogeneity of the SCARMD locus in these populations. A striking feature of this disease is the isolated deficiency of adhalin, a sarcolemmal 50 kDa dystrophin-associated glycoprotein. We report a non-inbred French family with a milder progressive form of muscular dystrophy affecting subjects of both sexes. The parents are not affected suggesting an autosomal recessive transmission. In 4 siblings displaying mild to overt clinical signs of muscular dystrophy, serum creatine kinase was high, and muscle specimens showed variable degree of necrosis-regeneration with little fibrosis. In the 4 cases adhalin was completely absent in muscle sections, whereas dystrophin and the other members of the dystrophin-associated protein complex were normal, except for the 35 kDa dystrophin-associated glycoprotein which was decreased as usually observed in SCARMD. Linkage and homogeneity analysis using 4 microsatellite markers of chromosome 13q that are linked to the North-African SCARMD locus were performed in this family. Results show that the morbid locus involved in this family does not map to the same region as the SCARMD locus. This second locus may be involved in sporadic cases of muscular dystrophy with adhalin deficiency that have been reported in Europe.
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PMID:Genetic heterogeneity of severe childhood autosomal recessive muscular dystrophy with adhalin (50 kDa dystrophin-associated glycoprotein) deficiency. 798 94

Recently, we have demonstrated the specific deficiency of the 50-kDa dystrophin-associated glycoprotein (50DAG) in severe childhood autosomal recessive muscular dystrophy with Duchenne-like phenotype (SCARMD or AR-DLMD), a disease first reported in Tunisia and now presumed to be prevalent in North Africa and the Middle East. Here we demonstrate the deficiency of the 50DAG in one caucasoid and 5 negroid Brazilian patients with severe muscular dystrophy, which confirms that AR-DLMD with the 50DAG deficiency is not confined to the Arab populations. Without the analysis of both dystrophin and 50DAG, isolated male patients with this condition could be undiagnosed or misdiagnosed as having Duchenne or severe Becker muscular dystrophy. We also report, for the first time, the normal expression of the 50DAG and other dystrophin-associated proteins in one negroid and 2 caucasoid Brazilian patients with a phenotype indistinguishable from that of AR-DLMD with 50DAG deficiency. This is consistent with the genetic heterogeneity for the phenotype of AR-DLMD.
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PMID:Assessment of the 50-kDa dystrophin-associated glycoprotein in Brazilian patients with severe childhood autosomal recessive muscular dystrophy. 806 4

Autosomal recessive limb-girdle muscular dystrophies (AR LGMD) represent a heterogeneous group of diseases with a wide spectrum of clinical variability, classified phenotypically into two main groups, the most severe forms (Duchenne-like muscular dystrophy, DLMD, or severe childhood autosomal recessive muscular dystrophy, SCARMD) and the milder forms. Four genes causing AR LGMD have been mapped: the 15q (LGMD2a), the 2p (LGMD2b), the 13q locus (LGMD2c) and the adhalin gene on chromosome 17q (LGMD2d). In the present report we have performed linkage analysis with 17q markers in three mild AR LGMD and in four DLMD families with adhalin deficiency and unlinked to 2p, 15q or 13q genes. Linkage was observed only among the mild cases. Patients from these three 17q-linked families showed near or total deficiency of adhalin in muscle biopsies. An identical missense mutation was identified in all three 17q-linked unrelated families. These results indicate that AR LGMD with a mild phenotype is caused by mutations in the adhalin gene. In addition, they demonstrate that there is at least one other locus for DLMD associated with adhalin deficiency.
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PMID:A common missense mutation in the adhalin gene in three unrelated Brazilian families with a relatively mild form of autosomal recessive limb-girdle muscular dystrophy. 852 3

Two forms of inherited childhood nonsyndromic deafness (DFNB1 and DFNA3) and a Duchenne-like form of progressive muscular dystrophy (LGMD2C) have been mapped to the pericentromeric region of chromosome 13. To clone the genes responsible for these diseases we constructed a yeast artificial chromosome (YAC) contig spanning an 8-cM region between the polymorphic markers D13S175 and D13S221. The contig comprises 24 sequence-tagged sites, among which 15 were newly obtained. This contig allowed us to order the polymorphic markers centromere-D13S175-D13S141-D13S143-D13S115-AF M128yc1-D13S292-D13S283-AFM323vh5- D13S221-telomere. Eight expressed sequence tags, previously assigned to 13q11-q12 (D13S182E, D13S183E, D13S502E, D13S504E, D13S505E, D13S837E, TUBA2, ATP1AL1), were localized on the YAC contig. YAC screening of a cDNA library derived from mouse cochlea allowed us to identify an alpha-tubulin gene (TUBA2) that was subsequently precisely mapped within the candidate region.
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PMID:A YAC contig and an EST map in the pericentromeric region of chromosome 13 surrounding the loci for neurosensory nonsyndromic deafness (DFNB1 and DFNA3) and limb-girdle muscular dystrophy type 2C (LGMD2C). 853 67

We have partially sequenced rabbit skeletal muscle gamma-sarcoglycan, an integral component of the dystrophin-glycoprotein complex. Specific antibodies were produced against a gamma-sarcoglycan peptide and used to examine the expression of gamma-sarcoglycan in skeletal muscle of patients with severe childhood autosomal muscular dystrophy linked to chromosome 13q12 (SCARMD). We show by immunofluorescence and Western blotting that in skeletal muscle from these patients gamma-sarcoglycan is completely absent and alpha- and beta-sarcoglycan are greatly reduced in abundance, whereas other components of the DGC are preserved. In addition, we show that in normal muscle alpha-, beta-, and gamma-sarcoglycan constitute a tightly associated sarcolemma complex which cannot be disrupted by SDS treatment.
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PMID:Absence of gamma-sarcoglycan (35 DAG) in autosomal recessive muscular dystrophy linked to chromosome 13q12. 864 26

alpha-Sarcoglycan (adhalin), a 50-kDa component of the dystrophin-associated complex of proteins, participates in the stabilization of the myofiber plasma membrane in the membrane cytoskeleton. Deficiencies of alpha-sarcoglycan cause a subset of childhood-onset muscular dystrophy (SCARMD) cases. However, secondary deficiencies of alpha-sarcoglycan are common. To begin to establish the rates of false positives (secondary deficiencies), we used immunofluorescence to screen 30 Italian dystrophin-normal muscular dystrophy patient biopsies and identified 4 patients with partial alpha-sarcoglycan deficiency and 2 patients with complete deficiency. The entire alpha-sarcoglycan gene was screened for mutations using RT-PCR and SSCP of messenger RNA isolated from muscle biopsies in each of the six patients. Aberrant SSCP conformers and novel mutations were found only in the two complete immunohistochemical deficient patients. One patient was homozygous for a R34H amino acid substitution, while the other was a compound heterozygote (R77C, D97G). These three missense mutations, with additional mutations we and others have previously described, are all localized in the extracellular domain of alpha-sarcoglycan, and most result in the loss or gain of a positively charged amino acid. These data have strong implications for structure/function maps of the alpha-sarcoglycan molecule. Our results suggest that most patients showing partial alpha-sarcoglycan deficiency exhibit this as a secondary consequence of genetically distinct disorders. In support of this, we show biochemical data indicating that secondary deficiency patients show decreased immunostaining with antibodies directed against alpha-sarcoglycan, while having nearly normal quantities of alpha-sarcoglycan protein on immunoblot. This data also suggests that approximately 5% of childhood-onset dystrophin-normal muscular dystrophy patients will show a primary alpha-sarcoglycan deficiency.
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PMID:alpha-Sarcoglycan (adhalin) deficiency: complete deficiency patients are 5% of childhood-onset dystrophin-normal muscular dystrophy and most partial deficiency patients do not have gene mutations. 886 24

We investigated the molecular basis of a severe form of early onset autosomal recessive muscular dystrophy with sarcoglycan (SG) deficiency in seven large Gypsy families living in different parts of Western Europe and apparently not closely related. They were linked to the LGMD2C locus (13q12) suggesting a primary defect in the gamma-SG gene coding for the 35 kDa dystrophin-associated glycoprotein. All of the 18 investigated patients were homozygous for the same G-->A transition in codon 283 producing the replacement of a conserved cysteine of the extra-cellular domain of the protein by a tyrosine. All affected chromosomes in homozygous and heterozygous relatives carried the same allele 5 of the intragenic marker D13S232. Flanking markers were studied to delineate a common ancestral haplotype, the size of which was used to compute the date of the founding mutation. We found evidence that the mutation occurred between 60 and 200 generations ago, therefore possibly predating the commonly accepted date of migration of the Gypsy ancestors out of India.
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PMID:A founder mutation in the gamma-sarcoglycan gene of gypsies possibly predating their migration out of India. 896 57

Malignant limb-girdle muscular dystrophy (MLGMD) was proposed by Miyoshi et al. in 1966 as a clinical and genetic entity of muscular dystrophy, with clinical features similar to Duchenne muscular dystrophy but showing autosomal recessive inheritance. Recently, deficiency of alpha-sarcoglycan (adhalin), which is one of the components of dystrophin-glycoprotein complex, in the skeletal muscle has been found in several patients with MLGMD or severe childhood autosomal recessive muscular dystrophy. To investigate alpha-sarcoglycan gene mutations in patients with MLGMD, we analyzed cDNA prepared from skeletal muscle by reverse transcription polymerase chain reaction (RT-PCR), or genomic DNA prepared from peripheral blood leukocytes by PCR, using single-strand conformation polymorphism (SSCP). When products amplified by RT-PCR or PCR showed aberrant conformers on SSCP analysis, these products were sequenced by the fluorescence-based dideoxy termination method. We found missense mutations, insertions or deletions in the alpha-sarcoglycan gene in 6 families with MLGMD. In the literature, alpha-sarcoglycan gene mutations have been identified in 21 families with MLGMD/SCARMD including our 6 families. Half of the families have the cytosine to thymidine substitution at nt.229, resulting in the replacement of Arg by Cys at codon 77, and most of the mutations have been found in the region coding extracellular domain of alpha-sarcoglycan. Analysis of the alpha-sarcoglycan gene is indispensable for diagnosis, assessment of prognosis, genetic counseling, and future gene therapy in patients with autosomal recessive childhood-onset muscular dystrophy.
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PMID:[Gene analysis in patients with muscular dystrophy: alpha-sarcoglycan (adhalin) gene mutations in patients with malignant limb-girdle muscular dystrophy]. 912 Sep 97

The group of autosomal recessive (AR) muscular dystrophies includes, among others, two main clinical entities, the limb-girdle muscular dystrophies (LGMDs) and the distal muscular dystrophies. The former are characterized mainly by muscle wasting of the upper and lower limbs, with a wide range of clinical severity. This clinical heterogeneity has been demonstrated at the molecular level, since the genes for six AR forms have been cloned and/or have been mapped to 15q15.1 (LGMD2A), 2p12-16 (LGMD2B), 13q12 (LGMD2C), 17q12-q21.33 (LGMD2D),4q12 (LGMD2E), and 5q33-34 (LGMD2F). The AR distal muscular dystrophies originally included two subgroups, Miyoshi myopathy, characterized mainly by extremely elevated serum creatine kinase (CK) activity and by a dystrophic muscle pattern, and Nonaka myopathy, which is distinct from the others because of the normal to slightly elevated serum CK levels and a myopathic muscle pattern with rimmed vacuoles. With regard to our unclassified AR LGMD families, analysis of the affected sibs from one of them (family LG61) revealed some clinical and laboratory findings (early involvement of the distal muscles, mildly elevated serum CK levels, and rimmed vacuoles in muscle biopsies) that usually are not observed in the analysis of patients with LGMD2A-LGMD2F. In the present investigation, through a genomewide search in family LG61, we demonstrated linkage of the allele causing this form of muscular dystrophy to a 3-cM region on 17q11-12. We suggest that this form, which, interestingly, clinically resembles AR Kugelberg-Welander disease, should be classified as LGMD2G. In addition, our results indicate the existence of still another locus causing severe LGMD.
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PMID:The seventh form of autosomal recessive limb-girdle muscular dystrophy is mapped to 17q11-12. 924 96


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