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By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports no financial relationships relevant to this field of study.
Synopsis: Oculopharyngeal muscular dystrophy is a rare, autosomal dominant neuromuscular disorder that has recently been genetically defined and may be treatable with myoblast transplantation.
Source: Witting N, et al. Ocular, bulbar, limb, and cardiopulmonary involvement in oculopharyngeal muscular dystrophy. Acta Neurol Scand 2014; Mar. 10. DOI: 10.1111/ane.12244 [Epub ahead of print].
Typically presenting in middle-age with ptosis, ophthalmoplegia, dysarthria, and dysphagia, oculopharyngeal muscular dystrophy (OPMD) is a slowly progressive, autosomal dominant genetic disorder that may also be associated with proximal and distal limb weakness. Linked to chromosome 14q11.2-q13, it results from a GCG trinucleotide repeat expansion of the polyadenylate (polyA) binding protein nuclear 1 gene (PABPN1), leading to an expanded polyalanine tract at the N-terminal of the PABPN1 protein. Genetic analysis now permits diagnosis of atypical cases, offering the opportunity to determine what, if any, extra-muscular involvement occurs.
Spearheaded by the Neuromuscular Research Unit, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark, all 19 genetically verified OPMD patients in Denmark, encompassing 11 OPMD families, were invited to participate in this cross-sectional study. Due to logistic issues, five declined and one asymptomatic patient was excluded, leaving 13 patients from eight families to be studied. All patients underwent ophthalmologic evaluation, bulbar function testing including a timed swallow test (80 mL of 5° cold water in ≤ 7 seconds is normal), pulmonary function testing including forced expiratory vital (FEV1) capacity with a facial mask in all (due to facial weakness in some), and cardiac examination including electrocardiography (ECG), transthoracic echocardiography, and 48-hour Holter monitoring.
Among six male and seven female symptomatic OPMD patients, ptosis or limb weakness was the presenting sign in eight and five persons, respectively. All 13 had ptosis, with nine demonstrating ophthalmoplegia, and 11 had dysphagia, with the youngest two patients (41 and 47 years old), spared. Mean "swallow test" time was 34 seconds. Limb strength, both proximal and distal, declined with age, and was worse in legs than arms, but no proximal-distal gradient was found. None had cardiac symptoms or findings considered abnormal for age, while six patients, all older than age 60, had > 20% reduction in FEV1. Pulmonary, but not cardiac, involvement is seen in OPMD and is mild. Dysphagia, though the determinant of prognosis and the cause of poor nutrition and life-threatening aspiration pneumonia, is not a presenting complaint. Limb weakness, however, is common and may be the presenting complaint.
Although no specific treatment currently exists for OPMD, surgery may be offered to correct ptosis and dysphagia, and myoblast transplantation may become an option in the future. In a Phase 1/2a clinical study1 using myoblasts harvested from unaffected quadriceps or sternocleidomastoid muscles, 12 OPMD patients underwent autologous transplantation, with a median of 178 million myoblasts injected into the constrictor muscles of the pharynx following cricopharyngeal myotomy. Over a 2-year period, no adverse effects were noted. Although limb weakness progressed during follow up, no deterioration of swallowing was seen in 10 patients, as measured by videoendoscopic swallowing study (VESS) and videofluoroscopy of swallowing (VFS). Upper esophageal sphincter function improved in six patients using VESS and in two using VFS, and swallowing time on the "swallow test" improved from 23.7 to 10.2 seconds (normal: ≤ 7 seconds). Improved quality of life (QOL), as measured by QOL questionnaires, was appreciated in all. Autologous myoblast transplantation appears safe and effective for OPMD and larger studies are warranted.