Value of insoluble PABPN1 accumulation in the diagnosis of oculopharyngeal muscular dystrophy

Abstract

Background and purpose The aim was to assess the value of insoluble PABPN1 muscle fibre nuclei accumulation in the diagnosis of atypical cases of oculopharyngeal muscular dystrophy (OPMD). Methods Muscle biopsies from a selected cohort of 423 adult patients from several Italian neuromuscular centres were analysed by immunofluorescence: 30 muscle biopsies of genetically proven OPMD, 30 biopsies from patients not affected by neuromuscular disorders, 220 from genetically undiagnosed patients presenting ptosis or swallowing disturbances, progressive lower proximal weakness and/or isolated rimmed vacuoles at muscle biopsy and 143 muscle biopsies of patients affected by other neuromuscular diseases. Results The detection of insoluble nuclear PABPN1 accumulation is rapid, sensitive (100%) and specific (96%). The revision of our cohort allowed us to discover 23 new OPMD cases out of 220 patients affected with nonspecific muscle diseases. Conclusions Oculopharyngeal muscular dystrophy is often misdiagnosed leading to diagnosis delay, causing waste of time and resources. A great number of these cases present symptoms and histological findings frequently overlapping with other muscle diseases, i.e. inclusion body myositis and progressive external ophthalmoplegia. PABPN1 nuclear accumulation is a reliable method for diagnostic purposes and it is safe and useful in helping pathologists and clinicians to direct genetic analysis in the case of suspected OPMD, even when clinical and histological clues are deceptive.

Oculopharyngeal Muscular Dystrophy Ptosis, Mueller’s Muscle Involvement, and a Review of Management Over 34 Years

“…8,30 PABPN1 is essential for cell vitality playing critical roles at multiple steps in posttranscriptional regulation of gene expression and is expressed in all cells. 27 Exactly how the expanded PABPN1 causes muscle weakness in the affected muscles (such as LPS and pharyngeal muscles) is not known. 26 The involvement of Mueller’ muscle in this disease, a smooth muscle, is of interest as it has not been described by any other author in the literature to our knowledge.…”

“…Late changes include increased fibrous connective tissue and deposition of adipose tissue. [25][26][27] Despite the marked disappearance of the levator palpebrae superioris (LPS) muscle cells and the extensive degenerative changes, Johnson and Kuwabara reported that Mueller's smooth muscle was unaffected. 5 This has not been the author's (D.R.J.)…”

Recent Progress in Oculopharyngeal Muscular Dystrophy

“…A more specific finding is intranuclear tubulofilamentous aggregates of 8.5 nm outer diameter, which were observed approximately in 4% of the myonuclei by electron microscopy [39]. Of note, the detection of PABPN1-positive insoluble intranuclear aggregates was reportedly 100% sensitive and 96% specific for OPMD diagnosis [43].…”

Differential diagnosis of POLG related disorders: What to keep in mind when multiorgan system is involved?

“…This disorder may mimic the clinical manifestations of the POLG-related disorders in which PEO is the predominant feature. OPMD is caused by pathogenic variants in PABPN1 and inherited in either an autosomal dominant or an autosomal recessive manner [48]. d) Amish lethal microcephaly: It is characterized by microcephaly and early death.…”

“…CPEO is sometimes complicated by mild proximal muscle weakness and dysphagia, and can be considered to lie on a spectrum of disease from pure CPEO to Kearns-Sayre syndrome phenotype. Some individuals with CPEO (< 20%) have a pathogenic single-nucleotide variant of mtDNA (e.g., m.3243A>G) [48]. f) Kearns-Sayre syndrome (KSS): A mtDNA deletion syndrome, is a multisystem disorder de ined by the triad of onset before age 20 years, pigmentary retinopathy, and progressive external ophthalmoplegia (PEO).…”