Mitochondrial Variants in Pompe Disease: A Comparison between Classic and Non-Classic Forms.

Objective: Pompe disease (PD) is a progressive neuromuscular disorder that is caused by glucosidase acid alpha (GAA) deleterious mutations. Mitochondrial involvement is an important contributor to neuromuscular diseases. In this study the sequence of MT-ATP 6/8 and Cytochrome C oxidase I/II genes along with the expression levels of the former genes were compared in classic and non-classic patients.

Materials And Methods: In this case-control study, the sequence of MT-ATP 6/8 and Cytochrome C oxidase was analyzed by polymerase chain reaction (PCR)-Sanger sequencing and expression of MT-ATP genes were quantified by real time-PCR (RT-PCR) in 28 Pompe patients. The results were then compared with 100 controls. All sequences were compared with the revised Cambridge reference sequence as reference.

Results: Screening of MT-ATP6/8 resulted in the identification of three novel variants, namely T9117A, A8456C and A8524C. There was a significant decrease in MT-ATP6 expression between classic (i.e. adult) and control groups (P=0.030). Additionally, the MT-ATP8 expression was significantly decreased in classic (P=0.004) and non-classic (i.e. infant) patients (P=0.013). In total, 22 variants were observed in Cytochrome C oxidase, five of which were nonsynonymous, one leading to a stop codon and another (C9227G) being a novel heteroplasmic variant. The A8302G in the lysine tRNA gene was found in two brothers in a pedigree, while a T7572C variant in the aspartate tRNA gene was observed in two brothers in another pedigree.

Conclusion: The extent of mitochondrial involvement in the classic group was more significant than in the non-classic form. Beside GAA deleterious mutations, it seems that mtDNA variants have a secondary effect on PD. Understanding, the role of mitochondria in the pathogenesis of Pompe may potentially be helpful in developing new therapeutic strategies.