What Is Oculopharyngodistal Myopathy?

By Michael Rubin, MD

Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: Distal limb myopathies are rare disorders and are difficult to diagnose. Current muscle biopsy technology, coupled with genetic analysis, offers the best hope for an accurate diagnosis of these unusual neuromuscular disorders. Unfortunately, treatments remain elusive.

SOURCE: Shimizu T, Ishiura H, Hara M, et al. Expanded clinical spectrum of oculopharyngodistal myopathy type 1. Muscle Nerve 2022;66:679-685.

Not to be confused with oculopharyngeal muscular dystrophy (OPMD), where proximal weakness is common but facial and distal weakness are not, oculopharyngodistal myopathy (OPDM) is a rare (200 cases reported), adolescent or adult-onset myopathy with facial and distal limb weakness, combined with ptosis, ophthalmoplegia, dysphagia, and dysarthria. Muscle biopsy is characterized by increased variability of muscle fiber diameter, rimmed vacuoles, and connective tissue hyperplasia.

OPMD is a triplicate repeat disease, with GCG/GCA repeats in polyadenylate-binding protein nuclear 1 (PABPN1). OPDM, designated OPDM type 1, is caused by CGG repeats in low-density lipoprotein receptor-related protein 12 (LRP12). Genetic analysis thus allows for improved delineation of the clinical phenotype of OPDM type 1.

Ten patients from seven families, seen between 2003 and 2020 at the University of Tokyo Hospital, Bunkyo-ku, Tokyo, were the study subjects, whose medical records, imaging results, and muscle biopsy specimens were reviewed by the study authors, all neurologists. OPMD was excluded based on analysis of GCG/GCA repeat expansions in PABPN1, and Southern blot hybridization was performed to determine the lengths of the expanded repeats in LRP12.

Muscle biopsies underwent histochemical and immunostaining, and electrodiagnostic studies were performed in the standard fashion. Written informed consent was obtained from all patients, and the study was approved by the institutional review board of the University of Tokyo Hospital.

Heterozygous CGG repeat expansions in LRP12 were found in seven patients, confirmed by repeat-primed polymerase chain reaction (PCR) and Southern blot analysis. Limb weakness in these seven patients, symmetric in all but two, was the presenting symptom in six of the seven, distal in five and proximal in one. Pharyngeal weakness was present in five of the seven, with ptosis or ophthalmoparesis in three each, and a median interval of 13.5 years between the onset of initial limb weakness and subsequent oculopharyngeal symptoms.

Four patients mimicked isolated distal myopathy, as their oculopharyngeal symptoms were very subtle. Facial weakness was present in six of the seven, as was neck weakness, with dropped head syndrome in one. Cardiac muscle was not affected in any patient, and spirometry was normal in five patients so tested. Electrodiagnostic studies were performed on three patients, with nerve conduction studies revealing normal sensory nerve action potential amplitudes but decreased compound muscle action potential amplitudes.

Needle electromyography demonstrating significant amounts of positive sharp waves, particularly in distal muscles, with myopathic- or neurogenic-appearing motor units in three patients each. Complex repetitive discharges and myotonic discharges were seen in distal muscles in one and two patients each, respectively. Chronic myopathic changes, including increased fiber size variation, increased internalized nuclei, and atrophic fiber clustering with rimmed vacuoles and p62-positive granular aggregates, were the pathological findings. Brain magnetic resonance imaging, performed in three, was normal. LRP12 genetic analysis should be performed in patients with isolated distal myopathy.

COMMENTARY

Four subtypes of OPDM, all presenting with the same phenotype, presently are identified, designated OPDM 1-4, based on four gene mutations involving CGG repeats in the 5’-untranslated region of LRP12 (8q22.3), GIPC1 (19p13.12), NOTCH2NLC (1q21.2), and RILPL1 (12q24.31).

Mechanistically, it remains unclear how these repeats result in disease, but studies suggest a gain-of-function mechanism at the ribonucleic acid or protein level, or both, which is toxic to the nervous system, without resulting in acute neuronal cell death.¹ Genetic analysis is essential for the accurate diagnosis of this disorder.

REFERENCE

1. Yu J, Deng J, Wang Z. Oculopharyngodistal myopathy. Curr Opin Neurol 2022;35:637-644.