Broad spectrum of Pompe disease in patients with the same c.-32-13T->G haplotype.
BACKGROUND
Pompe disease (acid maltase deficiency, glycogen storage disease type II; OMIM 232300) is an autosomal recessive lysosomal storage disorder characterized by acid alpha-glucosidase deficiency due to mutations in the GAA gene. Progressive skeletal muscle weakness affects motor and respiratory functions and is typical for all forms of Pompe disease. Cardiac hypertrophy is an additional fatal symptom in the classic infantile subtype. c.-32-13T-->G is the most common mutation in adults.


OBJECTIVE
To delineate the disease variation among patients with this mutation and to define the c.-32-13T-->G haplotypes in search for genotype-phenotype correlations.


METHODS
We studied 98 compound heterozygotes with a fully deleterious mutation (11 novel mutations are described) and the common c.-32-13T-->G mutation.


RESULTS
All patients were Caucasian. None had the classic infantile form of Pompe disease. The clinical course varied far more than anticipated (age at diagnosis <1 to 78 years; age at onset: <1 to 52 years). The acid alpha-glucosidase activities in a subset of patients ranged from 4 to 19.9 nmol/mg/h. Twelve different c.-32-13T-->G haplotypes were identified based on 17 single-nucleotide polymorphisms located in the GAA gene. In 76% of the cases, c.-32-13T-->G was encountered in the second most common GAA core haplotype (DHRGEVVT). In only one case was c.-32-13T-->G encountered in the major GAA core haplotype (DRHGEIVT).


CONCLUSIONS
Patients with the same c.-32-13T-->G haplotype (c.q. GAA genotype) may manifest first symptoms at different ages, indicating that secondary factors may substantially influence the clinical course of patients with this mutation.
Kroos
M A
MA
Department of Clinical Genetics, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
Pomponio
R J
RJ
Hagemans
M L
ML
Keulemans
J L M
JL
Phipps
M
M
DeRiso
M
M
Palmer
R E
RE
Ausems
M G E M
MG
Van der Beek
N A M E
NA
Van Diggelen
O P
OP
Halley
D J J
DJ
Van der Ploeg
A T
AT
Reuser
A J J
AJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006009:Glycogen Storage Disease Type II / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D038622:Internationality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D018570:Risk Assessment / Q000379:methods*; D000520:alpha-Glucosidases / Q000235:genetics*
C509951:GAA protein, human; D000520:alpha-Glucosidases