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Genotype-phenotype correlation in Pompe disease, a step forward.

ABSTRACT: Pompe's disease is a progressive myopathy caused by mutations in the lysosomal enzyme acid alphaglucosidase gene (GAA). A wide clinical variability occurs also in patients sharing the same GAA mutations, even within the same family.For a large series of GSDII patients we collected some clinical data as age of onset of the disease, presence or absence of muscular pain, Walton score, 6-Minute Walking Test, Vital Capacity, and Creatine Kinase. DNA was extracted and tested for GAA mutations and some genetic polymorphisms able to influence muscle properties (ACE, ACTN3, AGT and PPAR? genes).We compared the polymorphisms analyzed in groups of patients with Pompe disease clustered for their homogeneous genotype.We have been able to identify four subgroups of patients completely homogeneous for their genotype, and two groups homogeneous as far as the second mutation is defined "very severe" or "potentially less severe". When disease free life was studied we observed a high significant difference between groups. The DD genotype in the ACE gene and the XX genotype in the ACTN3 gene were significantly associated to an earlier age of onset of the disease. The ACE DD genotype was also associated to the presence of muscle pain.We demonstrate that ACE and ACTN3 polymorphisms are genetic factors able to modulate the clinical phenotype of patients affected with Pompe disease.

SUBMITTER: De Filippi P

PROVIDER: S-EPMC4249737 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Genotype-phenotype correlation in Pompe disease, a step forward.

De Filippi Paola P Saeidi Kolsoum K Ravaglia Sabrina S Dardis Andrea A Angelini Corrado C Mongini Tiziana T Morandi Lucia L Moggio Maurizio M Di Muzio Antonio A Filosto Massimiliano M Bembi Bruno B Giannini Fabio F Marrosu Giovanni G Rigoldi Miriam M Tonin Paola P Servidei Serenella S Siciliano Gabriele G Carlucci Annalisa A Scotti Claudia C Comelli Mario M Toscano Antonio A Danesino Cesare C

Orphanet journal of rare diseases 20140808

<h4>Background</h4>Pompe's disease is a progressive myopathy caused by mutations in the lysosomal enzyme acid alphaglucosidase gene (GAA). A wide clinical variability occurs also in patients sharing the same GAA mutations, even within the same family.<h4>Methods</h4>For a large series of GSDII patients we collected some clinical data as age of onset of the disease, presence or absence of muscular pain, Walton score, 6-Minute Walking Test, Vital Capacity, and Creatine Kinase. DNA was extracted an ...[more]

PMID: 25103075

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Project description:BackgroundPompe disease is a lysosomal storage disorder caused by the deficiency of enzyme acid alpha-glucosidase (GAA) which results in accumulation of glycogen, particularly in the skeletal, cardiac, and smooth muscles. The late-onset form with symptoms presenting in childhood through adulthood, is characterized by proximal muscle weakness, respiratory insufficiency, and unlike the infantile-onset form often with no cardiac involvement.MethodsWe report our experience with 18 adult patients (14 males/4 females) with Pompe disease, several of whom had unique findings and novel pathogenic variants. Patients ranged in ages from 22-74 years (mean 53.7 years) and were diagnosed at an age range of 11-65 years (mean 43.6 years), often after a history of progressive muscle disease of several years' duration. All 18 patients were treated with alglucosidase alfa (Lumizyme) and their response to treatment was monitored by measurements of their pulmonary function and muscle weakness, six-minute walk test (6MWT), and other functional studies.ResultsGenetic sequencing revealed that 16 out of 18 individuals had the common c.-32-13T>G splicing variant, and six patients, including two sibships had four novel pathogenic variants: c.1594G>A, c.2655_2656delCG, c.1951-1952delGGinsT, and c.1134C>G. A male with the c.1594G>A variant developed an intracerebral aneurysm at the age of 43 years treated with surgery. Two siblings with the c.2655_2656delCG developed very high antibody titers, one of whom developed a severe infusion reaction. Other clinical features included BiPAP requirement in twelve, tinnitus in seven, scoliosis in five, cardiomyopathy in three, one individual was diagnosed with a cerebral aneurysm who underwent successful Penumbra coil placement, and another individual was diagnosed with both Graves' disease and testicular cancer.ConclusionsOur study illustrates significant variability in the range of clinical features, and the variable clinical response to enzyme replacement therapy. It also alerts us to the importance of careful monitoring and early management of complications. Possible genotype-phenotype associations with the novel mutations identified may emerge with larger studies.

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Genotype-phenotype correlation in Pompe disease, a step forward.

Publications

Genotype-phenotype correlation in Pompe disease, a step forward.

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