A cross-sectional single-centre study on the spectrum of Pompe disease, German patients: molecular analysis of the GAA gene, manifestation and genotype-phenotype correlations.
BACKGROUND
Pompe disease (Glycogen storage disease type II, GSD II, acid alpha-glucosidase deficiency, acid maltase deficiency, OMIM # 232300) is an autosomal-recessive lysosomal storage disorder due to a deficiency of acid alpha-glucosidase (GAA, acid maltase, EC 3.2.1.20, Swiss-Prot P10253). Clinical manifestations are dominated by progressive weakness of skeletal muscle throughout the clinical spectrum. In addition, the classic infantile form is characterised by hypertrophic cardiomyopathy.


METHODS
In a cross-sectional single-centre study we clinically assessed 3 patients with classic infantile Pompe disease and 39 patients with non-classic presentations, measured their acid alpha-glucosidase activities and analysed their GAA genes.


RESULTS
Classic infantile patients had nearly absent residual enzyme activities and a typical clinical course with hypertrophic cardiomyopathy until the beginning of therapy. The disease manifestations in non-classic patients were heterogeneous. There was a broad variability in the decline of locomotive and respiratory function. The age of onset ranged from birth to late adulthood and correlated with enzyme activities. Molecular analysis revealed as many as 33 different mutations, 14 of which are novel. All classic infantile patients had two severe mutations. The most common mutation in the non-classic group was c.-32-13T>G. It was associated with a milder course in this subgroup.


CONCLUSIONS
Disease manifestation strongly correlates with the nature of the GAA mutations, while the variable progression in non-classic Pompe disease is likely to be explained by yet unknown modifying factors. This study provides the first comprehensive dataset on the clinical course and the mutational spectrum of Pompe disease in Germany.
Center for Pediatric and Adolescent Medicine, University Medical Center, Mainz, Germany.
Andreas
A
Herzog
Ralf
R
Hartung
Arnold J J
AJ
Reuser
Pia
P
Hermanns
Heiko
H
Runz
Nesrin
N
Karabul
Seyfullah
S
Gökce
Joachim
J
Pohlenz
Christoph
C
Kampmann
Christina
C
Lampe
Michael
M
Beck
Eugen
E
Mengel
D000293:Adolescent; D000328:Adult; D002312:Cardiomyopathy, Hypertrophic / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D003430:Cross-Sectional Studies; D056947:Enzyme Replacement Therapy; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005858:Germany; D006009:Glycogen Storage Disease Type II / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000503:physiopathology; D009154:Mutation; D055815:Young Adult; D000520:alpha-Glucosidases / Q000235:genetics*
C509951:GAA protein, human; D000520:alpha-Glucosidases