Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycogen-storage disease type II (GSD II, acid maltase deficiency, Pompe's disease) is caused by defects in the lysosomal acid alpha-glucosidase (GAA) gene. Clinically, patients with the severe infantile form of GSD II have muscle weakness and cardiomyopathy eventually leading to death before the age of two years. Patients with the juvenile or the adult form of GSD II present with myopathy with a slow progression over several years or decades. Apart from a common base substitution in intron1, designated IVS1(-13T-->G) and resulting in the aberrant splicing of exon 2, the other mutations recently discovered in the GAA gene are rare and often unique to single patients. In this paper, we identified a two-base frameshift deletion in three unrelated adult-onset GSD II patients. This small deletion lies in the first coding exon (exon 2) and results in a premature stop codon at the very 5' end of the coding sequence of the GAA gene. The three patients were compound heterozygotes and two of them had the common IVS1(-13G-->T) mutation on the second allele. We speculate that this novel deletion may be relatively frequent among French patients, possibly leading to the severe infantile phenotype of GSD II if it occurs in homozygous form.
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PMID:Glycogen-storage disease type II (acid maltase deficiency): identification of a novel small deletion (delCC482+483) in French patients. 919 50

Friedreich ataxia (FRDA) is a common autosomal recessive degenerative disease (1/50,000 live births) characterized by a progressive-gait and limb ataxia with lack of tendon reflexes in the legs, dysarthria and pyramidal weakness of the inferior limbs. Hypertrophic cardiomyopathy is observed in most FRDA patients. The gene associated with the disease has been mapped to chromosome 9q13 (ref. 3) and encodes a 210-amino-acid protein, frataxin. FRDA is caused primarily by a GAA repeat expansion within the first intron of the frataxin gene, which accounts for 98% of mutant alleles. The function of the protein is unknown, but an increased iron content has been reported in hearts of FRDA patients and in mitochondria of yeast strains carrying a deleted frataxin gene counterpart (YFH1), suggesting that frataxin plays a major role in regulating mitochondrial iron transport. Here, we report a deficient activity of the iron-sulphur (Fe-S) cluster-containing subunits of mitochondrial respiratory complexes I, II and III in the endomyocardial biopsy of two unrelated FRDA patients. Aconitase, an iron-sulphur protein involved in iron homeostasis, was found to be deficient as well. Moreover, disruption of the YFH1 gene resulted in multiple Fe-S-dependent enzyme deficiencies in yeast. The deficiency of Fe-S-dependent enzyme activities in both FRDA patients and yeast should be related to mitochondrial iron accumulation, especially as Fe-S proteins are remarkably sensitive to free radicals. Mutated frataxin triggers aconitase and mitochondrial Fe-S respiratory enzyme deficiency in FRDA, which should therefore be regarded as a mitochondrial disorder.
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PMID:Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. 932 46

It is the hypothesis of the senior author (GAA) that high circumference measurements are not an accurate reflection of thigh muscle cross-sectional area or muscle strength after standard rehabilitation following anterior cruciate ligament reconstruction. Likewise, normal quadriceps femoris strength is not achieved in these patients despite aggressive rehabilitation. The purpose of our study was to quantify thigh muscle size and strength and correlate thigh circumference, muscle cross-sectional area by magnetic resonance imaging (MRI), and isokinetic strength in our patients. Thirty-three patients with anterior cruciate ligament repair utilizing autografts of iliotibial band (N = 28), semitendinosus autograft (N = 3), and bone-patellar tendon-bone autograft (N = 2) were retrospectively evaluated 48.7 +/- 6.91 months after surgery. We compared involved operated extremities with uninjured, uninvolved contralateral extremities, measuring thigh circumference, isokinetic peak torque, and cross-sectional area by MRI. We found a significant 1.8% decrease in thigh circumference, a 10% decrease in average quadriceps torque, and a 8.6% decrease in quadriceps cross-sectional area by MRI in the involved extremities compared with the uninvolved extremities. A positive correlation between MRI cross-sectional area, quadriceps, and hamstring peak torque was recorded in involved and uninvolved extremities. A positive correlation between thigh circumference, quadriceps, and hamstring peak torque was found in uninvolved extremities but not in operated extremities. The authors concluded that thigh circumference underestimates atrophy and is not correlated with cross-sectional thigh muscle area by MRI or strength in operated extremities. Persistent quadriceps weakness and decreased cross-sectional area at 49 months postsurgery and rehabilitation continue to challenge our efforts. The pathophysiology of the decrease in thigh muscle size and quadriceps femoris strength is discussed.
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PMID:Thigh muscle size and strength after anterior cruciate ligament reconstruction and rehabilitation. 935 86

The enzyme acid alpha-glucosidase catalyzes the breakdown of lysosomal glycogen. Absence of this enzyme results in infantile Pompe disease, characterized by hypertrophic cardiomyopathy, skeletal muscle weakness and fatal heart failure by 2 years of age. We have examined the possibility of gene replacement therapy for this disease, by constructing an E1-deleted recombinant adenovirus encoding human acid alpha-glucosidase (Ad-GAA). The dose-response in fibroblasts from patients with Pompe disease transduced with this vector is linear over the range tested (one to 2000 plaque forming units (p.f.u.) of Ad-GAA per cell), and acid alpha-glucosidase activity comparable to that of normal fibroblasts is achieved at 100 p.f.u. per cell. Targeting of the recombinant protein to the lysosomal compartment was confirmed by immunocytochemistry. In vivo expression was examined by injecting Ad-GAA into newborn rats; intracardiac administration produced 10 times the normal level of acid alpha-glucosidase activity in whole heart lysates, while a hind-limb i.m. injection increased activity in that muscle to six times the normal level. Western blotting of these tissues defected species at 76 kDa consistent with the size of processed lysosomal enzyme, and levels of expression as high as 1.0 mg recombinant protein per gram of tissue wet weight were produced. These data demonstrate high-level, lysosomal expression of recombinant acid alpha-glucosidase in treated target tissues and support the feasibility of gene replacement strategies for Pompe disease.
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PMID:Complete correction of acid alpha-glucosidase deficiency in Pompe disease fibroblasts in vitro, and lysosomally targeted expression in neonatal rat cardiac and skeletal muscle. 961 71

We analyzed the clinical and genetic aspects of 28 FRDA patients from 20 families. 19 families were consanguineous. The onset was between 4 and 13 1/2 years of age (mean 15.4 +/- 6.2). Three patients presented with cardiomyopathy, one with weakness, and the rest with ataxia. There were two patients with preserved lower-limb deep tendon reflexes. Sensory nerve action potentials were reduced in 14/14 patients. Cardiac echograms were abnormal in 17/19 cases, and this was between 6 and 16 years of age (mean 10.1 +/- 3.5). Four families were multiplex. Clinical intra-familial variability was observed. Increased GAA repeats of the X25 gene were found in 27/28 patients studied, all in a homozygous state. 88.9% of patients had a smaller allele larger than 500 repeats, and 66.7% had more than 700 repeats. The patient who did not have increased GAA repeats in both alleles had peculiar findings. Significant correlation of expansion was obtained for the early onset, and cardiomyopathy as the onset.
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PMID:Clinical and genetic correlate in childhood onset Friedreich ataxia. 1040 88

We have studied a man with an atypical form of Friedreich's ataxia (FRDA), who presented at age 26 years with a 2-year history of unsteadiness and clumsiness. The predominant feature of his initial neurological examination was a spastic paraparesis, along with a mild distal weakness and hyperreflexia of the upper limbs. He also displayed limb ataxia. Frataxin GAA repeat sizes were 1,040/690. This unusual FRDA presentation is not dissimilar to that of Acadian spastic ataxia.
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PMID:Friedreich's ataxia presenting as adult-onset spastic paraparesis. 1073 7

Autosomal recessive deficiency of lysosomal acid maltase (GAA) or glycogen storage disease type II (GSDII) results in a spectrum of phenotypes including a rapidly fatal infantile disorder (Pompe's), juvenile, and a late-onset adult myopathy. The infantile onset form presents as hypotonia with massive accumulation of glycogen in skeletal and heart muscle, with death due to cardiorespiratory failure. Adult patients with the slowly progressive form develop severe skeletal muscle weakness and respiratory failure. Particle bombardment is a safe, efficient physical method in which high-density, subcellular-sized particles are accelerated to high velocity to carry DNA into cells. Because it does not depend on a specific ligand, receptor, or biochemical features on cell surfaces, particle-mediated gene transfer can be readily applied to a variety of systems. We evaluated particle bombardment as a delivery system for therapy of GSDII. We utilized a vector carrying the CMV promoter linked to the human GAA cDNA. Human GSDII cell lines (fibroblasts and lymphoid) as well as ex vivo with adult-onset peripheral blood cells (lymphocytes and monocytes) were transiently transfected by bombardment with a Helios gene gun delivering gold particles coated with the GAA expression plasmid. All cell types showed an increase in human GAA activity greater than 50% of normal activity. Subsequently, GAA -/- mice were treated every 2 weeks for 4 months by particle bombardment to the epidermis of the lower back and hind limbs. Muscle weakness in the hind and forelimbs was reversed. These data suggest that particle delivery of the GAA cDNA by the Helios gene gun may be a safe, effective treatment for GSDII.
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PMID:Helios gene gun particle delivery for therapy of acid maltase deficiency. 1244 41

Mutations in the human caveolin-3 gene (cav-3) on chromosome 3p25 have been described in limb girdle muscular dystrophy, rippling muscle disease, hyperCKemia, and distal myopathy. Here, we describe the genetic, myopathological, and clinical findings in a large German family harboring a novel heterozygous mutation (GAC-->GAA) in codon 27 of the cav-3 gene. This missense mutation causes an amino acid change from asparagine to glutamate (Asp27Glu) in the N-terminal region of the Cav-3 protein, which leads to a drastic decrease of Cav-3 protein expression in skeletal muscle tissue. In keeping with an autosomal dominant mode of inheritance, this novel cav-3 mutation was found to cosegregate with neuromuscular involvement in the reported family. Ultrastructural analysis of Cav-3-deficient muscle showed an abnormal folding of the plasma membrane as well as multiple vesicular structures in the subsarcolemmal region. Neurological examination of all nine subjects from three generations harboring the novel cav-3 mutation showed clear evidence of rippling muscle disease. However, only two of these nine patients showed isolated signs of rippling muscle disease without muscle weakness or atrophy, whereas five had additional signs of a distal myopathy and two fulfilled the diagnostic criteria of a coexisting limb girdle muscular dystrophy. These findings indicate that mutations in the human cav-3 gene can lead to different and overlapping clinical phenotypes even within the same family. Different clinical phenotypes in caveolinopathies may be attributed to so far unidentified modifying factors/genes in the individual genetic background of affected patients.
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PMID:Consequences of a novel caveolin-3 mutation in a large German family. 1255 91

Patients with glycogen storage disease type II (GSDII, Pompe disease) suffer from progressive muscle weakness due to acid alpha-glucosidase deficiency. The disease is inherited as an autosomal recessive trait with a spectrum of clinical phenotypes. We have investigated 29 cases of GSDII and thereby identified 55 pathogenic mutations of the acid alpha-glucosidase gene (GAA) encoding acid maltase. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and two other mutations with an unpredictable effect on acid alpha-glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice-site mutation was investigated by real-time PCR analysis. The outcome of our analysis underscores the notion that the clinical phenotype of GSDII is largely dictated by the nature of the mutations in the GAA alleles. This genotype-phenotype correlation makes DNA analysis a valuable tool to help predict the clinical course of the disease.
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PMID:Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II. 1469 32

Glycogen storage disease type II (GSD-II; Pompe disease) is caused by a deficiency of acid alpha-glucosidase (GAA; acid maltase) and manifests as muscle weakness, hypertrophic cardiomyopathy, and respiratory failure. Adeno-associated virus vectors containing either a liver-specific promoter (LSP) (AAV-LSPhGAApA) or a hybrid CB promoter (AAV-CBhGAApA) to drive human GAA expression were pseudotyped as AAV8 and administered to immunocompetent GAA-knockout mice. Secreted hGAA was detectable in plasma between 1 day and 12 weeks postadministration with AAV-LSPhGAApA and only from 1 to 8 days postadministration for AAV-CBGAApA. No anti-GAA antibodies were detected in response to AAV-LSPhGAApA (<1:200), whereas AAV-CBhGAApA provoked an escalating antibody response starting 2 weeks postadministration. The LSP drove approximately 60-fold higher GAA expression than the CB promoter in the liver by 12 weeks following vector administration. Furthermore, the detected cellular immunity was provoked by AAV-CBhGAApA, as detected by ELISpot and CD4+/CD8+ lymphocyte immunodetection. GAA activity was increased to higher than normal and glycogen content was reduced to essentially normal levels in the heart and skeletal muscle following administration of AAV-LSPhGAApA. Therefore, liver-restricted GAA expression with an AAV vector evaded immunity and enhanced efficacy in GSD-II mice.
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PMID:Evasion of immune responses to introduced human acid alpha-glucosidase by liver-restricted expression in glycogen storage disease type II. 1600 63


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