Oculopharyngodistal Myopathy

Description

Oculopharyngodistal myopathy (OPDM) is characterized by adult-onset of eye and facial muscle weakness, distal muscle weakness and atrophy, and pharyngeal involvement, resulting in dysphagia and dysarthria. There are variable manifestations of the disorder regarding muscle involvement and severity. Both autosomal recessive and autosomal dominant inheritance have been reported. OPDM is considered distinct from oculopharyngeal muscular dystrophy (OPMD; 164300), which is caused by mutation in the PABPN1 gene (602279) (summary by Durmus et al., 2011).

Clinical Features

Satoyoshi and Kinoshita (1977) described 4 families with a form of oculopharyngeal myopathy characterized by adult-onset of slowly progressive ptosis and extraocular palsy, weakness of the masseter, facial, and bulbar muscles, and distal weakness of the limbs. In 1 autopsy case, no remarkable changes were found in the central and peripheral nervous system. Muscle biopsy specimens in 1 patient from each family showed myopathic patterns.

Uyama et al. (1998) reported 2 Japanese brothers, born of consanguineous parents, with oculopharyngodistal myopathy. Each had weakness of the tibialis anterior muscles, which began after ages 40 and 35 years, respectively. Soon after, they developed distal upper limb weakness, foot drop, ptosis, external ophthalmoplegia, weakness of facial muscles, nasal voice, and dysphagia. Further studies showed areflexia, moderately increased serum creatine kinase, myogenic EMG changes without myotonia. The clinical phenotype was similar to that reported by Satoyoshi and Kinoshita (1977). Skeletal muscle biopsies showed small angulated fibers and rimmed vacuoles with a frequency of 3% in 1 and 6% in the other, autophagic vacuoles, and 15- to 18-nm cytoplasmic inclusions. A comparison of the phenotype with 4 patients with distal myopathy with rimmed vacuoles (DMRV; 605820) and 36 with OPMD indicated that the disorder in the Japanese brothers was distinct. Patients with DMRV did not have oculopharyngeal muscle involvement, and those with OPMD did not have prominent distal muscle involvement. In histologic comparison, the Japanese brothers did not have OPMD-specific intranuclear inclusions on biopsy, but there were some similar ultrastructural characteristics to DMRV, namely the presence of rimmed vacuoles and 15- to 18-nm cytoplasmic inclusions. Uyama et al. (1998) concluded that OPDM is a distinct disorder.

Van der Sluijs et al. (2004) reported 25-year follow-up of 2 Dutch sibs with OPDM. The sister developed distal lower limb weakness, ptosis, and dysphagia at age 25 years, whereas the brother developed ptosis in his late teens. Both had slow progression of the disorder, which ultimately included ptosis, external ophthalmoplegia, facial muscle weakness resulting in myopathic facies, and distal muscle weakness and atrophy of the legs and arms. By age 46, the sister used a wheelchair outdoors and had decreased respiratory flow. The brother developed pneumonia and died at age 55. At that time, he was wheelchair-bound with hypotonic paralysis of both legs, had paresis of both arms, and complete external ophthalmoplegia. Van der Sluijs et al. (2004) concluded that OPDM is a different disorder from OPMD.

Durmus et al. (2011) reported 47 patients from 9 unrelated Turkish families with OPDM. The mean age at onset was 22.1 years (range, 7 to 50 years), and most presented with ptosis and variable degrees of ophthalmoparesis. Those with a disease duration of more than 5 years tended to develop facial muscle wasting, particularly of the orbicularis oris, malar, and zygomatic muscles. There was more variable involvement of other muscles. Thirty-four patients with disease duration of more than 5 years showed slowly progressive weakness initially affecting the distal muscles. However, 4 patients examined early in the disease had clear proximal muscle weakness, especially in the lower extremities. Nine patients had no skeletal muscle weakness; 3 were wheelchair-bound at 15, 21, and 27 years after onset. Most had major swallowing difficulties, resulting in weight loss, and dysarthria. Other common features included tongue weakness, high palate, and bowing of the vocal cords. Two patients had sensorineural hearing loss, and 3 had impaired hearing. Thirteen patients had some evidence of respiratory involvement, even at early stages of the disease. Sternocleidomastoid muscle weakness was not seen until late stages of the disease. Serum creatine kinase levels were normal or increased, and EMG showed myopathic changes with occasional myotonic discharges. Skeletal muscle biopsies of 12 patients showed myopathic changes with rimmed vacuoles. Three patients examined ultrastructurally showed autophagic vacuoles containing multilamellar structures. Molecular genetic studies excluded the pathologic repeat expansion in the PABPN1 gene (602279), and linkage analysis excluded multiple genes known to be involved in various muscular dystrophy and myopathies. Durmus et al. (2011) suggested the term 'faciooculolaryngopharyngeal myopathy with distal and respiratory involvement,' or FOLP-DR, to better describe the features of this disorder.

Inheritance

Both autosomal dominant and autosomal recessive inheritance have been reported. Satoyoshi and Kinoshita (1977) reported 4 families with oculopharyngeal myopathy in which the transmission pattern was consistent with autosomal dominant inheritance. One of their families had affected persons spanning 3 generations with male-to-male transmission.

Among 9 unrelated Turkish families with OPDM, Durmus et al. (2011) found that transmission pattern was consistent with autosomal dominant inheritance in 5 and autosomal recessive inheritance in 1; the pattern could not be determined in the 3 remaining families.