title: Homozygosity for the common GAA gene splice site mutation c.-32-13T>G in Pompe disease is associated with the classical adult phenotypical spectrum.
abstract: Homozygosity for the common Caucasian splice site mutation c.-32-13T>G in intron 1 of the GAA gene is rather rare in Pompe patients. We report on the clinical, biochemical, morphological, muscle imaging, and genetic findings of six adult Pompe patients from five unrelated families with the c.-32-13T>G GAA gene mutation in homozygous state. All patients had decreased GAA activity and elevated creatine kinase levels. Five patients, aged between 43 and 61 years (median 53 years), initially presented with myalgia, hyperCKaemia, and/or exercise induced fatigue at an age of onset (12-55 years). All but one had proximal lower limb weakness combined with axial weakness and moderate respiratory insufficiency; the sixth patient presented with hyperCKaemia only. Muscle biopsies showed PAS-positive vacuolar myopathy with lysosomal changes and reduced GAA activity. Muscle MRI of lower limb muscles revealed a moderate adipose substitution of the gluteal muscles, biceps femoris and slight fatty infiltration of all thigh muscles. One MRI of the respiratory muscles revealed a diaphragmatic atrophy with unilateral diaphragm elevation. So, the common Caucasian, so called mild, splice site mutation c.-32-13T>G in intron 1 of the GAA gene in a homozygote status reflects the full adult Pompe disease phenotype severity spectrum.
authors.affiliation: Department of Neurosciences, University of Messina, Messina, Italy.
authors.forename: Olimpia
authors.initials: O
authors.lastname: Musumeci
authors.affiliation: Department of Neurology, Erfurt, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Thieme
authors.affiliation: Department of Neurology, RWTH Aachen University, Aachen, Germany; Institute of Neuropathology, RWTH Aachen University, Aachen, Germany.
authors.forename: Kristl G
authors.initials: KG
authors.lastname: Claeys
authors.affiliation: Department of Neurology, Klinikum Munich, Friedrich-Baur-Institute, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wenninger
authors.affiliation: Department of Neurology, University Hospital Bergmannsheil, Ruhr-University Bochum, Germany.
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: Kley
authors.affiliation: Genetikum, Center for Human Genetics, Neu-Ulm, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Kuhn
authors.affiliation: Institute of Clinical Chemistry, Germany; Department of Pediatrics Hamburg, University Medical Center Hamburg, Germany.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Lukacs
authors.affiliation: Department of Neurology, Halle-University, Halle, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Deschauer
authors.affiliation: Department of Radiology, School of Medicine, University of Messina, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Gaeta
authors.affiliation: Department of Neurosciences, University of Messina, Messina, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Toscano
authors.affiliation: Genetikum, Center for Human Genetics, Neu-Ulm, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Gläser
authors.affiliation: Department of Neurology, Klinikum Munich, Friedrich-Baur-Institute, Germany. Electronic address: bschoser@med.uni-muenchen.de.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
mesh_terms: D000328:Adult; D018450:Disease Progression; D005260:Female; D006009:Glycogen Storage Disease Type II / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D022821:RNA Splice Sites; D000520:alpha-Glucosidases / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; C509951:GAA protein, human; D000520:alpha-Glucosidases
keywords: GAA mutation; GAA-MLPA; Glycogen storage disease type 2; Homozygosity; Pompe disease