A de novo PABPN1 germline mutation in a patient with oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominantly inherited disorder characterized by dysphagia, ptosis, and proximal limb weakness and is caused by germline mutations (triplet repeat expansions) in the polyadenylate binding protein nuclear 1 (PABPN1) gene.

To describe a 70-year-old female patient with OPMD on the clinical and molecular genetic level and to develop a rapid and efficient molecular genetic screening method to study large patient groups.

Detailed family history and clinical assessment of the OPMD patient were followed by mutation analysis of the PABPN1 gene by direct DNA sequencing and by our newly developed method, fluorescent PABPN1 polymerase chain reaction (PCR) product (flPPP) method. A cohort of 50 healthy Swiss probands was screened using the flPPP to assess the frequency of the (GCG)7 allele in the Swiss population. Cricopharyngeal myotomy was performed as treatment for dysphagia.

A heterozygous (GCG)9 triplet repeat expansion in PABPN1 was identified. Since the family history proved to be negative, the mutation is likely to have occurred de novo. The frequency of the (GCG)7 allele among healthy Swiss controls amounted to 1%. The flPPP method showed a sensitivity and specificity of 100%. Two years after cricopharyngeal myotomy, the patient is still relieved of dysphagia.

An otolaryngologist should include OPMD in the differential diagnosis of a patient presenting with dysphagia, as this symptom can be the first sign of the disease and family history can be negative. Molecular genetic testing represents a highly accurate and rapid way to confirm the clinical diagnosis of OPMD. Cricopharyngeal myotomy relieves the patient of dysphagia in the majority of cases.