Genotype-phenotype correlation in Pompe disease, a step forward

Abstract

BackgroundPompe’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.MethodsFor 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 PPARα genes).We compared the polymorphisms analyzed in groups of patients with Pompe disease clustered for their homogeneous genotype.ResultsWe 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.ConclusionsWe demonstrate that ACE and ACTN3 polymorphisms are genetic factors able to modulate the clinical phenotype of patients affected with Pompe disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0102-z) contains supplementary material, which is available to authorized users.

The influence of a polymorphism in the gene encoding angiotensin converting enzyme (ACE) on treatment outcomes in late onset Pompe patients receiving alglucosidase alfa

“…In a larger cohort of Pompe patients (N = 85), individuals with the D/D ACE genotype presented with an earlier onset of disease and muscle pain, confirming the previous observation [7]. The relationship between ACE genotype and clinical parameters in a cohort of LOPD patients who received biweekly infusions of alglucosidase alfa for N 2 years also was reported [14].…”

“…We also demonstrated the presence of this association regardless of baseline disease severity and anti-GAA IgG antibody levels. However, unlike patients in earlier studies [7,13], LOTS patients with the D/D genotype did not present with an earlier onset of disease or a longer duration of disease at study entry.…”

“…However, individual responsiveness to ERT varies across the patient populations [4][5][6]. Studies have examined the effect of individual mutations in the GAA gene and other genetic factors [7,8] with one gene of interest encoding angiotensin converting enzyme (ACE).…”

Observational clinical study of 22 adult-onset Pompe disease patients undergoing enzyme replacement therapy over 5years

“…11 out of 17 patients with known genotype carry the c.-32-13TN G mutation. The correlation between genotype and phenotype is most likely blurred by being a small cohort and other modifying factors described previously [36,37,38]. Kroos et al [38] reported that the presence of at least one mutation allows the production of a protein with some residual activity that leads to the late-onset forms.…”

Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease

“…A European newborn screening study showed that the carrier frequency of c.-32-13T > G in the European general population is 1 in 154; the exon 18 deletion, 1 in 187; and c.525delT, 1 in 284 [28]. Currently, > 400 pathogenic variants have been reported in the GAA gene (http://cluster15.erasmusmc.nl/klgn/pompe/mutations.html?lang=en accessed May 22, 2017) [29,30]. The c.-32-13T > G variant, seen in 68–90% of Caucasian patients with LOPD in a heterozygous or homozygous state [31–36], results in alternatively spliced transcripts with deletion of exon 2 and leakage of some normal transcripts [32,37].…”