Delayed diagnosis of oculopharyngeal muscular dystrophy in Denmark: from initial ptosis to genetic testing

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset dominantly inherited myopathy. Its genetic basis has been identified as a trinucleotide repeat expansion ranging from (GCG)8 to (GCG)13 in the N-terminus polyalanine domain of the PABPN1 gene on chromosome 14q11. Affected members present with progressive ptosis and ophthalmoplegia, swallowing difficulties and proximal limb weakness in a context of a family history with dominant transmission (Brais et al. 1999). This condition is commonly described in French and Canadian families, but some sporadic cases have been reported in various countries (Müller et al. 2006; Rodriguez et al. 2005, Hill et al. 2001). There does not appear to be differences in the clinical course of OPMD based on regions; however, delay in the diagnosis may occur because of the slow progression of symptoms, low prevalence and lack of awareness among ophthalmologists. Our cross-sectional study reports the clinical presentations and treatment of 14 patients from 8 unrelated Danish families with genetically confirmed OPMD. The study was conducted in accordance with the International Conference of Harmonization Good Clinical Practice guidelines and the declaration of Helsinki. The study protocol was approved by the ethics committee for the Capital Region. Written informed consent was obtained for all subjects. Patients were followed at the reference centre for neuromuscular diseases at Rigshospitalet in Copenhagen. Demographic data about sequence of symptoms, diagnosis and treatment were collected. A complete oculo-palpebral examination was performed. DNA was isolated from an EDTA blood sample by standard methods. The GCG repeats were determined by PCR. Onset of symptoms occurred at a mean age of 51 years (range 37–60). Only six patients could report a family history of ptosis and/or other neurological symptoms. A pathogenic trinucleotide expansion was identified and sequenced in all eight families. In 10 patients (77%), ptosis was the initial symptom, occurring at a mean age of 52 years (range 41–64). In three patients, limb weakness was the initial symptom, followed by ptosis. The frequency of ptosis-associated dysphagia, dysarthria and ophthalmoplegia increased with age and disease duration. Table 1 summarizes the clinical findings at inclusion. The mean delay between the presenting signs and genetic confirmation was 8 years (range 5–15). Thirteen patients were operated for ptosis, with an average of 3.5 procedures per patient. Among those, 9 (69%) were operated several times, before referral for genetic testing. As a first procedure, 11 patients underwent aponeurosis surgery and 2 had brow suspension. Six patients (55%), who underwent aponeurosis surgery with immediate insufficient results, had the procedure repeated at least once (range 1–3) before being diagnosed with OPMD. Frontal brow suspension always resulted in good functional and cosmetic results. Sporadic and familial cases of OPMD have been reported in many countries (Hill et al. 2001; Müller et al. 2006; Mihaylova et al. 2008). However, the disease has been poorly investigated in Northern Europe and has never been described in Denmark. The clinical evolution of OPMD is slow, its treatment is symptomatic, and life span is usually normal. In our series, an appropriate OPMD diagnosis at presentation was often missed, and patients were offered an aponeurotic surgery without further investigations. Repeated ptosis interventions were therefore not uncommon. Subsequent success was obtained by frontal brow suspension, which is the appropriate surgery for myopathic ptosis, in which levator palpebrae muscle function is poor (Wong et al. 2002). In conclusion, ptosis is the most common presenting sign of OPMD. An appropriate work-up of bilateral and progressive ptosis in middle-aged adults with dysphagia and/or limb weakness should include genetic screening for OPMD, especially if there is a first-degree family history of similar symptoms.