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Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy.

ABSTRACT: The term myofibrillar myopathies (MFM) refers to uncommon neuromuscular disorders that pathologically are characterized by myofibrillar degeneration and ectopic expression of several proteins. MFM are partly caused by mutations in genes that encode mainly Z-disk-related proteins (desmin, alphaB-crystallin, myotilin, ZASP, filamin C and BAG3). We reviewed clinical, light and electron microscopy, immunohistochemistry, immunoblotting and genetic findings of 21 patients with MFM (15 unrelated patients and three pairs of brothers) investigated at our neuromuscular center. MFM patients begin to show symptoms at any age, from juvenile to late adult life and present a different distribution of muscle weakness. Cardiac involvement and peripheral neuropathy are common. Typical histological features include focal areas with reduction/loss of ATPase and oxidative enzyme activity, and amorphous material (eosinophilic on hematoxylin and eosin and dark blue on Engel-Gomori trichrome) in these abnormal fiber areas. Electron microscopy shows disintegration of myofibrils starting from the Z-disk and accumulation of granular and filamentous material among the myofilaments. Immunohistochemical studies demonstrate focal accumulation of desmin, alphaB-crystallin and myotilin in abnormal muscle fibers while immunoblot analysis does not highlight differences in the expression of these proteins also including ZASP protein. Therefore, unlike immunoblot, immunohistochemistry together with light and electron microscopy is a useful diagnostic tool in MFM. Finally three of our 21 patients have missense mutations in the desmin gene, two brothers carry missense mutations in the gene encoding myotilin, one has a missense mutation in alphaB-crystallin, and none harbour pathogenic variations in the genes encoding ZASP and BAG3.

SUBMITTER: Vattemi G

PROVIDER: S-EPMC3235861 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy.

Vattemi G G Neri M M Piffer S S Vicart P P Gualandi F F Marini M M Guglielmi V V Filosto M M Tonin P P Ferlini A A Tomelleri G G

Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology 20111001 2

The term myofibrillar myopathies (MFM) refers to uncommon neuromuscular disorders that pathologically are characterized by myofibrillar degeneration and ectopic expression of several proteins. MFM are partly caused by mutations in genes that encode mainly Z-disk-related proteins (desmin, alphaB-crystallin, myotilin, ZASP, filamin C and BAG3). We reviewed clinical, light and electron microscopy, immunohistochemistry, immunoblotting and genetic findings of 21 patients with MFM (15 unrelated patien ...[more]

PMID: 22106715

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Project description:BACKGROUND:To report a novel exertional myopathy, myofibrillar myopathy (MFM) in Warmblood (WB) horses. OBJECTIVES:To 1) describe the distinctive clinical and myopathic features of MFM in Warmblood horses and 2) investigate the potential inheritance of MFM in a Warmblood family. STUDY DESIGN:Retrospective selection of MFM cases and prospective evaluation of a Warmblood family. METHODS:Retrospectively, muscle biopsies were selected from Warmblood horses diagnosed with MFM and clinical histories obtained (n = 10). Prospectively, muscle biopsies were obtained from controls (n = 8) and a three generation WB family (n = 11). Samples were assessed for histopathology [scored 0-3], fibre types, cytoskeletal and Z disc protein aggregates, electron microscopic alterations (EM) and muscle glycogen concentrations. RESULTS:Myofibrillar myopathy-affected cases experienced exercise intolerance, reluctance to go forward, stiffness and poorly localised lameness. Abnormal aggregates of the cytoskeletal protein desmin were found in up to 120 type 2a and a few type 2x myofibres of MFM cases. Desmin positive fibres did not stain for developmental myosin, α actinin or dystrophin. Scores for internalised myonuclei (score MFM 0.83 ± 0.67, controls 0.22 ± 0.45), anguloid atrophy (MFM 0.95 ± 0.55, controls 0.31 ± 0.37) and total myopathic scores (MFM 5.85 ± 2.10, controls 1.41 ± 2.17) were significantly higher in MFM cases vs. CONTROLS:Focal Z disc degeneration, myofibrillar disruption and accumulation of irregular granular material was evident in MFM cases. Muscle glycogen concentrations were similar between MFM cases and controls. In the Warmblood family, desmin positive aggregates were found in myofibres of the founding dam and in horses from two subsequent generations. MAIN LIMITATIONS:Restricted sample size due to limited availability of well phenotyped cases. CONCLUSIONS:A distinctive and potentially heritable form of MFM exists in Warmblood horses that present with exercise intolerance and abnormal hindlimb gait. Muscle tissue is characterised by ectopic accumulation of desmin and Z disc and myofibrillar degeneration.

Project description:BackgroundCommercial genetic tests for type 2 polysaccharide storage myopathy (PSSM2) and myofibrillar myopathy (MFM) have not been validated by peer-review, and formal regulation of veterinary genetic testing is lacking.ObjectivesTo compare genotype and allele frequencies of commercial test variants (P variants) in MYOT (P2; rs1138656462), FLNC (P3a; rs1139799323), FLNC (P3b; rs1142918816) and MYOZ3 (P4; rs1142544043) between Warmblood (WB) and Arabian (AR) horses diagnosed with PSSM2/MFM by muscle histopathology, and phenotyped breed-matched controls. To quantify variant frequency in public repositories of ancient and modern horse breeds.Study designCross sectional using archived clinical material and publicly available data.MethodsWe studied 54 control-WB, 68 PSSM2/MFM-WB, 30 control-AR, 30 PSSM2/MFM-AR and 205 public genotypes. Variants were genotyped by pyrosequencing archived DNA. Genotype and allele frequency, and number of variant alleles or loci were compared within breed between controls, PSSM2/MFM combined and MFM or PSSM2 horses considered separately using additive/genotypic and dominant models (Fisher's exact tests). Variant frequencies in modern, early domestic and Przewalski horses were determined from a public data repository.ResultsThere was no significant association between any P locus and a histopathological diagnosis of PSSM2/MFM, and no difference between control and myopathic horses in total loci with alternative alleles, or total alternate alleles when PSSM2/MFM was considered combined or separately as PSSM2 or MFM. For all tests, sensitivity was <0.33. Allele frequencies in WB (controls/cases) were: 8%/15% (P2), 5%/6% (P3a/b) and 9%/13% (P4); in AR, frequencies were: 12%/17% (P2), 2%/2% (P3a/b) and 7%/12% (P4). All P variants were present in early domestic (400- to 5500-year-old) horses and P2 present in the Przewalski.ConclusionsBecause of the lack of significant association between a histopathological diagnosis of PSSM2 or MFM and the commercial genetic test variants P2, P3 and P4 in WB and AR, we cannot recommend the use of these variant genotypes for selection and breeding, prepurchase examination or diagnosis of a myopathy.

Dataset Information

Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy.

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Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy.

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