MOLECULAR ANALYSIS OF POMPE DISEASE AND TREATMENT

Abstract

Pompe disease (OMIM 232300) is also known as Glycogen storage disease or acid maltase deficiency. It is a rare
autosomal recessive lysosomal disorder of glycogen metabolism with an estimated prevalence of 1 in 40000 in
Caucasians. It is caused by the deficient activity of acid α-glucosidase enzyme (E.C 3.2.1.20) due to mutation in the GAA
gene. The enzymatic deficiency leads to the accumulation of glycogen within the lysosomes in multiple tissues, including
cardiac, skeletal and smooth muscle cells. Clinically, the disease has been classically classified in infantile and
childhood/adult forms. The clinical features are cardiomyopathy and generalized muscle weakness that rapidly progress
to death from cardiorespiratory failure in the first year of life. The GAA gene has been localized to chromosomes
17q25.2-q25.3 and to date, 582 mutations distributed throughout the whole gene in HGMD. All types of mutation have
been described and among that missense mutation are the most frequent followed by deletions. Indeed, there are
missense, small deletions, in frame, splicing variants, nonsense, small insertions/duplications, gross insertions/deletions,
small indels and complex rearrangements. The mutations known to cause severe disease were coding mutation,
c.2560C>T (p. Arg854X), and the splice acceptor site, c.1327-2 A>G. The splice site mutation c.1327-2A>G is very
common in the patients of Caucasian origin with the frequency ranging from 40% to 70%. This disease can be treated by
enzyme replacement therapy (ERT) and currently there is one approved drug available for its treatment: ERT with
intravenous infusion of rhGAA (Myozyme, Lumizyme). Early diagnosis and ERT can benefit infants with this disease. This
diagnostic test can facilitate prenatal diagnosis and help in identifying carriers in families with the identified mutations.