Oculopharyngeal Muscular Dystrophy Pathological And Genotypic Studies In The Chinese Population

IntroductionOculopharyngeal muscular dystrophy ( OPMD) is an autosomal dominant disorder of late onset that commonly presents with ptosis and dysphagia. The genetic basis of the condition has been identified recently as a mutation of polyade-nylate - binding protein nuclear 1 gene (PAPBN1) , in which (GCG)6 is the normal repeat length.The pathologic hallmark in the disease is the accumulation of unique intranuclear inclusions (INIs) within skeletal muscle fibers nuclei, and their demonstration by electron microscopy is considered mandatory for the diagnosis.Cases of the OPMD have been described in numerous countries around the world, suggesting a possible independent origin of the mutation. In this study we report the clinical and pathologic characteristics of OPMD in 11 Chinese individuals ( 3 families) . We also want to compare the haplotypes of the carrier chromosomes of Chinese patients with OPMD to the reports over - sea.Methods3 families were recruited. All patients were examined, diagnosis were made by combining clinical, electromyographic, creatine kinase ( CK) , and lactate level determination.The samples of biopsies muscle were fixed in 3% glutaraldehyde in cacody-late buffer treated with osmic acid, embedded in epon, and prepared for EM examination according to standard procedures. DNA was obtained with informedconsent through blood samples from patients (n = 11) and at - risk individuals (n = 16). Amplification of the PABPN1 mutated region was performed by PCR using the conditions designed by Nakamoto et al. The sequences were obtained and compared with the genomic sequence of the human PABPN1 gene.ResultsAll muscle biopsies showed nonspecific myopathic findings for HE stained, including abnormal variation in fiber size, increase in the number of internal nuclei. Intranuclear inclusions formed by tubular filaments of about 8. 5 nm in outer diameter and 3 nm in inner diameter and arranged in palisades or tangles were found by electron microscopy in 4 patients.Molecular analysis of PABPN1 gene showed a PCR product exceeding. Sequence analysis of exon 1 showed abnormal expansions of the GCG - repeat.DiscussionThe definite diagnosis of OPMD in patients with a family history of late onset ptosis and dysphagia transmitted as a dominant trait relies upon the ultran-structural demonstration of the typical intranuclear inclusions in the muscle biopsy. The identification of short trinucleotide - repeat expansions in the PABPN1 gene has unveiled the molecular defect of the disease, and opened the way to mutational analysis.We observed a striking correlation between the presence of intranuclear filaments and PABPN1 mutation. In fact, all the patients whose muscle biopsy showed 8. 5 nm intranuclear filaments had an expanded PABPN1 allele. This observation, although concerning a limited number of patients, highlights the relationship between intranuclear accumulation of filaments and PABPN1 mutations , suggesting that filamentous inclusions may indeed present the product of the muted PABPN1.In this study, we examined the occurrence of PABPN1 mutations in 11 patients belong to 3 unrelated Chinese families diagnosis having OPMD, as well as16 normal individuals. Among our OPMD patients, the (GCG)10 mutation carries had a earlier onset age and more severity pathological character, this may suggest a correlation between length of the expansion and clinical severity.This study shows that PABPNl gene mutations are always present in Chinese patients with the diagnosis of OPMD. It thus confirms the genetic homogeneity of OPMD in different populations and emphasizes the diagnostic value of PABPNl gene testing.ConclusionsThese data 1) further confirm PABPNl gene analysis as a valuable tool in OPMD diagnosis; 2) indicate that PABPNl gene mutations are present among Chinese patients with OPMD, suggesting the genetic homogeneity of the disease; 3) strengthen the putative role of mutated PABPNl in filamentous inclusions accumulation.