title: Complex sarcolemmal invaginations mimicking myotendinous junctions in a case of Laing early-onset distal myopathy.
abstract: Distal myopathies are a group of clinically and pathologically overlapping muscle diseases that are genetically complex and can represent a diagnostic challenge. Laing early-onset distal myopathy (MPD1) is a form of distal myopathy caused by mutations in the MYH7 gene, which encodes the beta myosin heavy chain protein expressed in type 1 skeletal muscle fibers and cardiac myocytes. Here, we present a case of genetically confirmed MPD1 with a typical clinical presentation but distinctive light microscopic and ultrastructural findings on muscle biopsy. A 39-year-old professional male cellist presented with a bilateral foot drop that developed by age 8; analysis of the family pedigree showed an autosomal dominant pattern of inheritance. The physical exam demonstrated bilateral weakness of ankle dorsiflexors, toe extensors and finger extensors; creatine kinase level was normal. Biopsy of the quadriceps femoris muscle showed predominance and hypotrophy of type 1 fibers, hybrid fibers with co-expression of slow and fast myosin proteins (both in highly atrophic and normal size range), moth-eaten fibers and mini-cores, lack of rimmed vacuoles and rare desmin-positive eosinophilic sarcoplasmic inclusions. In addition to these abnormalities often observed in MPD1, the biopsy demonstrated frequent clefted fibers with complex sarcolemmal invaginations; on ultrastructural examination, these structures closely mimicked myotendinous junctions but were present away from the tendon and were almost exclusively found in type 1 fibers. Sequencing analysis of the MYH7 gene in the index patient and other affected family members demonstrated a previously described heterozygous c.4522_4524delGAG (p.Glu1508del) mutation. This case widens the pathologic spectrum of MPD1 and highlights the pathologic and clinical variability that can accompany the same genetic mutation, suggesting a significant role for modifier genes in MPD1 pathogenesis.
authors.affiliation: Department of Pathology, University of California, San Francisco, CA, USA.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Reis
authors.affiliation: Palo Alto Medical Foundation, Santa Cruz, CA, USA.
authors.forename: Grant
authors.initials: G
authors.lastname: de la Motte
authors.affiliation: Neurogenetics Unit, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gooding
authors.affiliation: Centre for Medical Research, University of Western Australia and Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, Australia.
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
authors.affiliation: Department of Pathology, University of California, San Francisco, CA, USA.
authors.forename: Marta
authors.identifier: http://orcid.org/0000-0001-6889-2488
authors.initials: M
authors.lastname: Margeta
mesh_terms: D000328:Adult; D049310:Distal Myopathies / Q000473:pathology*; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000648:ultrastructure; D010375:Pedigree; D012508:Sarcolemma / Q000648:ultrastructure*
keywords: clefted fibers; distal myopathy; myotendinous junction-like structures; slow myosin; type 1 fibers