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  • 1.
    Abdul-Hussein, Saba
    et al.
    Department of Pathology, University of Gothenburg, Gothenburg, Sweden.
    Rahl, Karin
    Department of Pathology, University of Gothenburg, Gothenburg, Sweden.
    Moslemi, Ali-Reza
    Department of Pathology, University of Gothenburg, Gothenburg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, University of Gothenburg, Gothenburg, Sweden / Department of Clinical and Medical Genetics, University of Gothenburg, Gothenburg, Sweden.
    Phenotypes of myopathy-related beta-tropomyosin mutants in human and mouse tissue cultures2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, e72396Article in journal (Refereed)
    Abstract [en]

    Mutations in TPM2 result in a variety of myopathies characterised by variable clinical and morphological features. We used human and mouse cultured cells to study the effects of β-TM mutants. The mutants induced a range of phenotypes in human myoblasts, which generally changed upon differentiation to myotubes. Human myotubes transfected with the E41K-β-TM(EGFP) mutant showed perinuclear aggregates. The G53ins-β-TM(EGFP) mutant tended to accumulate in myoblasts but was incorporated into filamentous structures of myotubes. The K49del-β-TM(EGFP) and E122K-β-TM(EGFP) mutants induced the formation of rod-like structures in human cells. The N202K-β-TM(EGFP) mutant failed to integrate into thin filaments and formed accumulations in myotubes. The accumulation of mutant β-TM(EGFP) in the perinuclear and peripheral areas of the cells was the striking feature in C2C12. We demonstrated that human tissue culture is a suitable system for studying the early stages of altered myofibrilogenesis and morphological changes linked to myopathy-related β-TM mutants. In addition, the histopathological phenotype associated with expression of the various mutant proteins depends on the cell type and varies with the maturation of the muscle cell. Further, the phenotype is a combinatorial effect of the specific amino acid change and the temporal expression of the mutant protein.

  • 2.
    Abdul-Hussein, Saba
    et al.
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    van der Ven, Peter F. M.
    Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
    Tajsharghi, Homa
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden / Department of Clinical and Medical Genetics, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Expression profiles of muscle disease-associated genes and their isoforms during differentiation of cultured human skeletal muscle cells2012In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 13, 262Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The formation of contractile myofibrils requires the stepwise onset of expression of muscle specific proteins. It is likely that elucidation of the expression patterns of muscle-specific sarcomeric proteins is important to understand muscle disorders originating from defects in contractile sarcomeric proteins.

    METHODS: We investigated the expression profile of a panel of sarcomeric components with a focus on proteins associated with a group of congenital disorders. The analyses were performed in cultured human skeletal muscle cells during myoblast proliferation and myotube development.

    RESULTS: Our culture technique resulted in the development of striated myotubes and the expression of adult isoforms of the sarcomeric proteins, such as fast TnI, fast TnT, adult fast and slow MyHC isoforms and predominantly skeletal muscle rather than cardiac actin. Many proteins involved in muscle diseases, such as beta tropomyosin, slow TnI, slow MyBPC and cardiac TnI were readily detected in the initial stages of muscle cell differentiation, suggesting the possibility of an early role for these proteins as constituent of the developing contractile apparatus during myofibrillogenesis. This suggests that in disease conditions the mechanisms of pathogenesis for each of the mutated sarcomeric proteins might be reflected by altered expression patterns, and disturbed assembly of cytoskeletal, myofibrillar structures and muscle development.

    CONCLUSIONS: In conclusion, we here confirm that cell cultures of human skeletal muscle are an appropriate tool to study developmental stages of myofibrillogenesis. The expression of several disease-associated proteins indicates that they might be a useful model system for studying the pathogenesis of muscle diseases caused by defects in specific sarcomeric constituents.

  • 3.
    Cuisset, J. M.
    et al.
    Service de Neuropédiatrie, Centre hospitalier régional universitaire et faculté de médecine, Lille, France.
    Maurage, C. A.
    Service d'Anatomie Pathologique, Centre hospitalier régional universitaire et faculté de médecine, Lille, France.
    Pellissier, J. F.
    Laboratoire de Biopathologie Neuromusculaire, JE 2053, Centre hospitalier universitaire et faculté de médecine de La Timone, Marseille, France.
    Barois, A.
    Service de réanimation pédiatrique, Hôpital Raymond-Poincaré, Garches, France.
    Urtizberea, J. A.
    Institut de Myologie, Hôpital Pitié-Salpétrière, Paris, France.
    Laing, N.
    Center for neuromuscular and neurological disorders, Australian neuromuscular research institute, University of Western Australia, Nedlands, WA, Australia.
    Tajsharghi, H
    Department of pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Vallée, L.
    Service de Neuropédiatrie, Centre hospitalier régional universitaire et faculté de médecine, Lille, France.
    'Cap myopathy': case report of a family2006In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 16, no 4, 277-281 p.Article in journal (Refereed)
    Abstract [en]

    We report the observation of an 18-year-old girl, whose clinical presentation was very suggestive of a congenital myopathy with neonatal onset. A congenital myopathy had been already diagnosed in her brother and in addition her half-cousin died diagnosed with a severe nemaline myopathy at age 4 years. A muscle biopsy performed on both siblings revealed histological and ultrastructural features of 'cap myopathy'. This case report suggests that 'cap myopathy' and some cases of nemaline myopathy with neonatal onset might be two phenotypic expressions of the same genetic disorder. These two entities could therefore, perhaps, be regarded as 'Z-line disorders' possibly caused by defective myofibrillogenesis.

  • 4.
    Darin, Niklas
    et al.
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden / Department of Pediatrics, Queen Silvia Children's Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Östman-Smith, I.
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Gilljam, T.
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    New skeletal myopathy and cardiomyopathy associated with a missense mutation in MYH72007In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 68, no 23, 2041-2042 p.Article in journal (Refereed)
  • 5.
    Hurme, Mikko
    et al.
    Department of Psychology, University of Turku, Finland / Centre for Cognitive Neuroscience, University of Turku, Finland / Turku Brain and Mind Centre, University of Turku, Finland.
    Koivisto, Mika
    Department of Psychology, University of Turku, Finland / Centre for Cognitive Neuroscience, University of Turku, Finland / Turku Brain and Mind Centre, University of Turku, Finland.
    Revonsuo, Antti
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Psychology, University of Turku, Finland / Centre for Cognitive Neuroscience, University of Turku, Finland / Turku Brain and Mind Centre, University of Turku, Finland.
    Railo, Henry
    Department of Psychology, University of Turku, Finland / Centre for Cognitive Neuroscience, University of Turku, Finland / Turku Brain and Mind Centre, University of Turku, Finland.
    Early processing in primary visual cortex is necessary for conscious and unconscious vision while late processing is necessary only for conscious vision in neurologically healthy humans2017In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 150, 230-238 p.Article in journal (Refereed)
    Abstract [en]

    The neural mechanisms underlying conscious and unconscious visual processes remain controversial. Blindsight patients may process visual stimuli unconsciously despite their VI lesion, promoting anatomical models, which suggest that pathways bypassing the VI support unconscious vision. On the other hand, physiological models argue that the major geniculostriate pathway via VI is involved in both unconscious and conscious vision, but in different time windows and in different types of neural activity. According to physiological models, feedforward activity via VI to higher areas mediates unconscious processes whereas feedback loops of recurrent activity from higher areas back to VI support conscious vision. With transcranial magnetic stimulation (TMS) it is possible to study the causal role of a brain region during specific time points in neurologically healthy participants. In the present study, we measured unconscious processing with redundant target effect, a phenomenon where participants respond faster to two stimuli than one even when one of the stimuli is not consciously perceived. We tested the physiological feedforward-feedback model of vision by suppressing conscious vision by interfering selectively either with early or later VI activity with TMS. Our results show that early VI activity (60 ms) is necessary for both unconscious and conscious vision. During later processing stages (90 ms), VI contributes selectively to conscious vision. These findings support the feedforward-feedback-model of consciousness.

  • 6.
    Kimber, Eva
    et al.
    Department of Neuropediatrics, Uppsala University Children's Hospital, Uppsala, Sweden / .
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Sweden.
    Kroksmark, A.-K.
    Queen Silvia Children's Hospital, Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Sweden.
    Tulinius, M.
    Queen Silvia Children's Hospital, Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
    A mutation in the fast skeletal muscle troponin I gene causes myopathy and distal arthrogryposis.2006In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 67, no 4, 597-601 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To describe a three-generation family with distal arthrogryposis associated with myopathy and caused by a mutation in the gene encoding for sarcomeric thin filament protein troponin I, TNNI2.

    METHODS: The authors performed clinical investigations and reviewed medical records. Muscle biopsy specimens were obtained for morphologic analysis. Genomic DNA was extracted from blood and analyzed for mutations in TNNI2.

    RESULTS: The five affected individuals had predominantly distal congenital joint contractures, mild facial involvement (mild micrognathia, narrow palpebral fissures), and no detectable muscle weakness. The four affected adults had slightly increased levels of creatine kinase in blood, and muscle biopsy specimens showed findings of myopathy with changes restricted to type 2 fibers. These included variability of muscle fiber size, internalized nuclei, and increased interstitial connective tissue. Analysis of TNNI2 encoding the troponin I isoform expressed in type 2 muscle fibers disclosed a heterozygous three-base in-frame deletion, 2,918-2,920del, skipping the highly conserved lysine at position 176. The mutation was present in all 5 affected individuals but was not identified in any of the 11 unaffected family members.

    CONCLUSION: Distal arthrogryposis type 1 is genetically heterogeneous, and myopathy due to sarcomeric protein dysfunction may be one underlying cause of the disease.

  • 7.
    Kimber, Eva
    et al.
    Department of Women’s and Children’s Health, Uppsala University Children’s Hospital, Uppsala, Sweden / Department of Paediatrics, Institute of Clinical Sciences, University of Gothenburg, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Kroksmark, Anna-Karin
    Department of Paediatrics, Institute of Clinical Sciences, University of Gothenburg, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Tulinius, Már
    Department of Paediatrics, Institute of Clinical Sciences, University of Gothenburg, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Distal arthrogryposis: clinical and genetic findings2012In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 101, no 8, 877-887 p.Article in journal (Refereed)
    Abstract [en]

    AIM: Distal arthrogryposis is characterized by congenital contractures predominantly in hands and feet. Mutations in sarcomeric protein genes are involved in several types of distal arthrogryposis. Our aim is to describe clinical and molecular genetic findings in individuals with distal arthrogryposis and evaluate the genotype-phenotype correlation.

    METHOD: We investigated 39 patients from 21 families. Clinical history, including neonatal findings, joint involvement and motor function, was documented. Clinical examination was performed including evaluation of muscle strength. Molecular genetic investigations were carried out in 19 index cases. Muscle biopsies from 17 patients were analysed.

    RESULTS: A pathogenic mutation was found in six families with 19 affected family members with autosomal dominant inheritance and in one child with sporadic occurrence. In three families and in one child with sporadic form, the identified mutation was de novo. Muscle weakness was found in 17 patients. Ambulation was affected in four patients and hand function in 28. Fourteen patients reported pain related to muscle and joint affection.

    CONCLUSION: The clinical findings were highly variable between families and also within families. Mutations in the same gene were found in different syndromes suggesting varying clinical penetrance and expression, and different gene mutations were found in the same clinical syndrome demonstrating genetic heterogeneity.

  • 8.
    Li, M.
    et al.
    Department of Clinical Neurophysiology, Uppsala University, Uppsala, Sweden / Department of Neurology, Qilu Hospital, Shandong University, Jinan, China.
    Lionikas, A.
    Department of Clinical Neurophysiology, Uppsala University, Uppsala, Sweden / Center for Developmental and Health Genetics, The Pennsylvania State University, University Park, PA, USA.
    Yu, F.
    Center for Developmental and Health Genetics, The Pennsylvania State University, University Park, PA, USA.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Larsson, L.
    Department of Clinical Neurophysiology, Uppsala University, Uppsala, Sweden / Center for Developmental and Health Genetics, The Pennsylvania State University, University Park, PA, USA.
    Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys)2006In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 16, no 11, 782-791 p.Article in journal (Refereed)
    Abstract [en]

    The pathogenic events leading to the progressive muscle weakness in patients with a E706K mutation in the head of the myosin heavy chain (MyHC) IIa were analyzed at the muscle cell and motor protein levels. Contractile properties were measured in single muscle fiber segments using the skinned fiber preparation and a single muscle fiber in vitro motility assay. A dramatic impairment in the function of the IIa MyHC isoform was observed at the motor protein level. At the single muscle fiber level, on the other hand, a general decrease was observed in the number of preparations where the specific criteria for acceptance were fulfilled irrespective of MyHC isoform expression. Our results provide evidence that the pathogenesis of the MyHC IIa E706K myopathy involves defective function of the mutated myosin as well as alterations in the structural integrity of all muscle cells irrespective of MyHC isoform expression.

  • 9.
    Lossos, Alexander
    et al.
    Department of Neurology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
    Oldfors, Anders
    Department of Pathology, University of Gothenburg, Sahlgrenska Hospital, Gothenburg, Sweden.
    Fellig, Yakov
    Department of Pathology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
    Meiner, Vardiella
    Department of Genetics, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
    Argov, Zohar
    Department of Neurology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
    Tajsharghi, Homa
    Department of Pathology, University of Gothenburg, Sahlgrenska Hospital, Gothenburg, Sweden.
    MYH2 mutation in recessive myopathy with external ophthalmoplegia linked to chromosome 17p13.1-p122013In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 136, no 7, e238Article in journal (Refereed)
  • 10.
    Mohammad, Sameh
    University of Skövde, School of Life Sciences.
    Long-term depression in the rat hippocampus as a memory model: Interrogating the role of protein synthesis in NMDA- and mGluR-dependent synaptic plasticity2010Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Long-term potentiation (LTP) and depression (LTD) are important forms of activity-dependent synaptic plasticity believed to play a role in memory at the cellular level. It has previously been described that synthesis of new proteins is needed to maintain LTP longer than a few hours. Other reports argue that sufficient proteins for stable LTP are already available. The present study aims to examine the role of protein synthesis in LTD, the presumed mirror mechanism of LTP.

    Experiments were carried out in hippocampal slices from young (12-45 days) and old (12-18 weeks) Sprague-Dawley rats. Extracellular techniques were used to study synaptic responses in the Schaffer-collateral-commissural pathway. Plasticity was induced electrically by low frequency stimulation (2-3 trains at 1 Hz for 15 min) or chemically by brief exposure to certain glutamate receptor agonists (NMDA at 20 µM for 3 min or DHPG at 100 µM for 10 min). Whole slice protein synthesis was quantified by assessing 3H-leucine incorporation.

    Stable LTD (> 8 h) was be obtained by either electrical or chemical activation. Protein synthesis inhibitors anisomycin (40 uM) and cycloheximide (100 uM) both failed to influence the magnitude of LTD. Moreover, no age difference was found, in terms of stable LTD in both young and old rats under inhibition of protein synthesis. The potency of the inhibitors was found to be high, depressing synthesis down to a few percent. It is concluded that sufficient proteins for generating stable LTD are normally present in the brain, implying a large safety-margin for cellular memory.

  • 11.
    Moslemi, Ali-Reza
    et al.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Lindberg, Christopher
    Department of Neurology, Institute of Physiology and Neurological Sciences, University of Gothenburg, Gothenburg, Sweden.
    Nilsson, Johanna
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Andersson, Bert
    Department of Cardiology, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Glycogenin-1 deficiency and inactivated priming of glycogen synthesis2010In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 362, no 13, 1203-1210 p.Article in journal (Refereed)
    Abstract [en]

    Glycogen, which serves as a major energy reserve in cells, is a large, branched polymer of glucose molecules. We describe a patient who had muscle weakness, associated with the depletion of glycogen in skeletal muscle, and cardiac arrhythmia, associated with the accumulation of abnormal storage material in the heart. The skeletal muscle showed a marked predominance of slow-twitch, oxidative muscle fibers and mitochondrial proliferation. Western blotting showed the presence of unglucosylated glycogenin-1 in the muscle and heart. Sequencing of the glycogenin-1 gene, GYG1, revealed a nonsense mutation in one allele and a missense mutation, Thr83Met, in the other. The missense mutation resulted in inactivation of the autoglucosylation of glycogenin-1 that is necessary for the priming of glycogen synthesis in muscle.

  • 12.
    Nilsson, J.
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Beta-tropomyosin mutations alter tropomyosin isoform composition2008In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 15, no 6, 573-578 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Tropomyosin (TM) is an actin-binding protein, which is localized head to tail along the length of the actin filament. There are three major TM isoforms in human striated muscle. Mutations in beta-tropomyosin (TPM2) have recently been identified as an important cause of neuromuscular disorders.

    MATERIALS AND METHODS: The expression of TM isoforms in patients carrying mutations in TPM2 was detected using a combination of SDS-PAGE, Western blotting, and a new method to measure the relative abundance of the various TM transcripts.

    RESULTS: The level of gamma-TM is reduced in patients with mutations in TPM2. Beta-tropomyosin was expressed at high levels in muscle specimens of the patients.

    DISCUSSION: Our study indicates that beta-TM gene mutations can alter the expression of other sarcomeric TM isoforms and that the perturbation of TM isoform levels may affect the dimer preference within the thin filaments, which may contribute to muscle weakness as a result of both functional and structural changes in muscle.

  • 13.
    Ochala, Julien
    et al.
    Department of Clinical Neurophysiology, Uppsala University Hospital, Uppsala, Sweden.
    Li, Mingxin
    Department of Clinical Neurophysiology, Uppsala University Hospital, Uppsala, Sweden / Department of Neurology, Qilu Hospital, Shandong University, Shandong, China.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Kimber, Eva
    Department of Neuropaediatrics, Uppsala University Children's Hospital, Sweden.
    Tulinius, Mar
    The Queen Silvia Children's Hospital, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Larsson, Lars
    Department of Clinical Neurophysiology, Uppsala University Hospital, Uppsala, Sweden / Center for Development and Health Genetics, Pennsylvania State University, University Park, PA, United States.
    Effects of a R133W beta-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres2007In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 581, no 3, 1283-1292 p.Article in journal (Refereed)
    Abstract [en]

    A novel R133W beta-tropomyosin (beta-Tm) mutation, associated with muscle weakness and distal limb deformities, has recently been identified in a woman and her daughter. The muscle weakness was not accompanied by progressive muscle wasting or histopathological abnormalities in tibialis anterior muscle biopsy specimens. The aim of the present study was to explore the mechanisms underlying the impaired muscle function in patients with the beta-Tm mutation. Maximum force normalized to fibre cross-sectional area (specific force, SF), maximum velocity of unloaded shortening (V0), apparent rate constant of force redevelopment (ktr) and force-pCa relationship were evaluated in single chemically skinned muscle fibres from the two patients carrying the beta-Tm mutation and from healthy control subjects. Significant differences in regulation of muscle contraction were observed in the type I fibres: a lower SF (P<0.05) and ktr (P<0.01), and a faster V0 (P<0.05). The force-pCa relationship did not differ between patient and control fibres, indicating an unaltered Ca2+ activation of contractile proteins. Collectively, these results indicate a slower cross-bridge attachment rate and a faster detachment rate caused by the R133W beta-Tm mutation. It is suggested that the R133W beta-Tm mutation induces alteration in myosin-actin kinetics causing a reduced number of myosin molecules in the strong actin-binding state, resulting in overall muscle weakness in the absence of muscle wasting.

  • 14.
    Ohlsson, M.
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Quijano-Roy, S.
    AP-HP, Service de Pédiatrie, Centre National de Référence des Maladies Neuromusculaires GNMH, Garches, France.
    Darin, N.
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Brochier, G.
    Institut de Myologie, Groupe Hospitalier Pitie-Salpêtrière, Paris, France.
    Lacène, E.
    Institut de Myologie, Groupe Hospitalier Pitie-Salpêtrière, Paris, France.
    Avila-Smirnow, D.
    AP-HP, Service de Pédiatrie, Centre National de Référence des Maladies Neuromusculaires GNMH, Garches, France.
    Fardeau, M.
    Institut de Myologie, Groupe Hospitalier Pitie-Salpêtrière, Paris, France.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    New morphologic and genetic findings in cap disease associated with beta-tropomyosin (TPM2) mutations2008In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 71, no 23, 1896-1901 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Mutations in the beta-tropomyosin gene (TPM2) are a rare cause of congenital myopathies with features of nemaline myopathy and cap disease and may also cause distal arthrogryposis syndromes without major muscle pathology. We describe the muscle biopsy findings in three patients with cap disease and novel heterozygous mutations in TPM2.

    METHODS: Three unrelated patients with congenital myopathy were investigated by muscle biopsy and genetic analysis.

    RESULTS: All three patients had early-onset muscle weakness of variable severity and distribution. Muscle biopsy demonstrated in all three patients near uniformity of type 1 fibers and an unusual irregular and coarse-meshed intermyofibrillar network. By electron microscopy, the myofibrils were broad and partly split, and the Z lines appeared jagged. In one of the patients caps structures were identified only by electron microscopy, and in one patient they were identified only in a second biopsy at adulthood. Three novel, de novo, heterozygous mutations in TPM2 were identified: a three-base pair deletion in-frame (p.Lys49del), a three-base pair duplication in-frame (p.Gly52dup), and a missense mutation (p.Asn202Lys).

    CONCLUSIONS: Mutations in TPM2 seem to be a frequent cause of cap disease. Because cap structures may be sparse, other prominent features, such as a coarse-meshed intermyofibrillar network and jagged Z lines, may be clues to correct diagnosis and also indicate that the pathogenesis involves defective assembly of myofilaments.

  • 15.
    Ohlsson, M.
    et al.
    Department of Pathology, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Darin, N.
    Department of Pediatrics, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Kyllerman, M.
    Department of Pediatrics, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Follow-up of nemaline myopathy in two patients with novel mutations in the skeletal muscle alpha-actin gene (ACTA1)2004In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 14, no 8-9, 471-475 p.Article in journal (Refereed)
    Abstract [en]

    Nemaline myopathy has been associated with mutations in five different genes, which all encode protein components of the sarcomeric thin filaments. We report follow-up studies in two children with mutations not previously described in skeletal muscle alpha-actin (ACTA1). Case 1 was a male patient who after birth suffered from pronounced muscle weakness and hypotonia. Muscle biopsy showed small fibers with numerous rods. He failed to achieve any motor milestones. At the age of 17 he required 24 h ventilator support. He could not lift his arms against gravity, but he could use his hands to control his electric wheelchair. The muscle biopsy showed marked replacement of muscle tissue by fat and connective tissue. Only few fibers showed nemaline rods. He had a de novo, heterozygous mutation, G268D in ACTA1. Case 2 was a female patient with feeding difficulties and mild hypotonia in the neonatal period. Muscle biopsy showed hypoplastic muscle fibers and numerous rods. At 11 years of age she walked and moved unhindered and could run fairly well. She had a de novo, heterozygous mutation, K373E, in ACTA1. These two patients illustrate the marked variability in the clinical features of nemaline myopathy in spite of similar muscle pathology in early childhood. The severe muscle atrophy with replacement of fat and connective tissue in case 1 demonstrates the progressive nature of nemaline myopathy in some cases. The described two mutations add to the previously reported mutations in ACTA1 associated with nemaline myopathy.

  • 16.
    Ohlsson, Monica
    et al.
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Hedberg, Carola
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Brådvik, Björn
    Department of Clinical Sciences, Division of Neurology, Lund University, Lund, Sweden.
    Lindberg, Christopher
    Department of Neurology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Danielsson, Olof
    Division of Neurology, Department of Clinical and Experimental Medicine, University Hospital Linköping, Linköping, Sweden.
    Melberg, Atle
    Department of Neuroscience, Neurology, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.
    Udd, Bjarne
    Neuromuscular Centre, Tampere University and Hospital, Tampere, Finland / Department of Neurology, Vasa Central Hospital, Vasa, Finland / Folkhälsan Genetic Institute, Department of Medical Genetics, Helsinki University, Helsinki, Finland.
    Martinsson, Tommy
    Department of Clinical Genetics, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin2012In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 135, no 6, 1682-1694 p.Article in journal (Refereed)
    Abstract [en]

    Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T>C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.

  • 17.
    Oldfors, Anders
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Darin, Niklas
    Department of Paediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Lindberg, Christopher
    Department of Neurology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Myopathies associated with myosin heavy chain mutations2004In: Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases, ISSN 1128-2460, Vol. 23, no 2, 90-96 p.Article in journal (Refereed)
    Abstract [en]

    Myosin, a molecular motor, converts chemical energy into mechanical force. The motor domain of myosin heavy chain (MyHC) includes an ATP binding region with ATPase activity and an actin-binding region. Motor function is achieved by conformational changes, at hydrolysis, of ATP causing a shift in the angle between the actin binding head and the rod region of the molecule. The elongated alpha-helical coiled-coil rod region of MyHC molecules constitutes the major part of the thick filaments of the sarcomere. Three major MyHC isoforms are expressed in human skeletal muscle (type I, MYH7, expressed in type 1 fibres; IIa, MYH2, expressed in 2A fibres; IIx, MYH1, expressed in 2B fibres). While mutations in slow/beta cardiac MyHC (MYH7) are a common cause of familial hypertrophic cardiomyopathy, no skeletal myopathies have, until recently, been associated with mutations in MyHC. A heterozygous mutation, Glu706Lys, in the core of the head of MyHC IIa is associated with a familial congenital myopathy, which, in most instances, has shown mild phenotypic expression in children but progressive course in some adults. There is a relationship between the level of expression of mutated MyHC IIa and muscle pathology. Some adults with a progressive course show muscle fibres with rimmed vacuoles and filaments of the type seen in inclusion body myositis/myopathy (IBM). Endurance training in a group of affected patients caused a shift in the expression of myosin from fast (IIx) to slow (I) isoforms but no reduction in the expression of MyHC IIa. A heterozygous mutation, Arg1845Trp, in the distal rod region of slow myosin (type I, MYH7) is associated with familial congenital myopathy, with large deposits of MyHC I in the subsarcolemmal region of type 1 muscle fibres, "Myosin storage myopathy". These patients showed slowly progressive muscle weakness but no overt cardiomyopathy. These two muscle diseases, which are caused by mutations in MyHC, form the basis of a novel entity: "Myosin myopathies".

  • 18.
    Oldfors, Anders
    et al.
    Göteborg, Sweden.
    Tajsharghi, Homa
    Göteborg, Sweden.
    Thornell, L. E.
    Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy2005In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 64, no 3, 580-581 p.Article in journal (Refereed)
  • 19.
    Olivé, Montse
    et al.
    Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology, Barcelona, Spain / CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Barcelona, Spain.
    Abdul-Hussein, Saba
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    González-Costello, José
    Department of Cardiology, Barcelona, Spain.
    van der Ven, Peter F. M.
    Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
    Fürst, Dieter O.
    Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
    González, Laura
    Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology.
    Moreno, Dolores
    Institute of Neuropathology, Department of Pathology, Barcelona, Spain.
    Torrejón-Escribano, Benjamín
    Scientific and Technical Services Facility, Biology Unit, CCiTUB, IDIBELL-University of Barcelona, Barcelona, Spain.
    Alió, Josefina
    Department of Cardiology, Barcelona, Spain.
    Pou, Adolf
    Department of Neurology, Hospital del Mar, Barcelona, Spain.
    Ferrer, Isidro
    Institute of Neuropathology, Department of Pathology, Barcelona, Spain / CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Barcelona, Spain.
    Tajsharghi, Homa
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations: [Human Molecular Genetics, 24, 13, (2015) 3638-3650] DOI: 10.1093/hmg/ddv108 [Erratum]2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 21, 6264-6264 p.Article in journal (Refereed)
  • 20.
    Skillbäck, Tobias
    et al.
    Department of Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Delsing, Louise
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Mattsson, Niklas
    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden / Department of Neurology, Skåne University Hospital, Lund, Sweden.
    Janelidze, Shorena
    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Nägga, Katarina
    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Kilander, Lena
    Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Wimo, Anders
    Centre for Research and Development, Uppsala University/County Council of Gävleborg, Gävle, Sweden / Division for Neurogeriatrics, Department of Neurobiology, Care Sciences, and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden.
    Winblad, Bengt
    Division for Neurogeriatrics, Department of Neurobiology, Care Sciences, and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden / Department Geriatric Medicine, Karolinska University Hospital, Huddinge, Sweden.
    Hansson, Oskar
    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden / Department of Neurology, Skåne University Hospital, Lund, Sweden.
    Blennow, Kaj
    Department of Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Eriksdotter, Maria
    Department Geriatric Medicine, Karolinska University Hospital, Huddinge, Sweden / Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences, and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden.
    Zetterberg, Henrik
    Department of Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden / Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom / UK Dementia Research Institute at UCL, London, United Kingdom.
    CSF/serum albumin ratio in dementias: a cross-sectional study on 1861 patients2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 59, 1-9 p.Article in journal (Refereed)
    Abstract [en]

    A connection between dementias and blood-brain barrier (BBB) dysfunction has been suggested, but previous studies have yielded conflicting results. We examined cerebrospinal fluid (CSF)/serum albumin ratio in a large cohort of patients diagnosed with Alzheimer's disease (AD, early onset [EAD, n = 130], late onset AD [LAD, n = 666]), vascular dementia (VaD, n = 255), mixed AD and VaD (MIX, n = 362), Lewy body dementia (DLB, n = 50), frontotemporal dementia (FTD, n = 56), Parkinson's disease dementia (PDD, n = 23), other dementias (other, n = 48), and dementia not otherwise specified (NOS, n = 271). We compared CSF/serum albumin ratio to 2 healthy control groups (n = 292, n = 20), between dementia diagnoses, and tested biomarker associations. Patients in DLB, LAD, VaD, MIX, other, and NOS groups had higher CSF/serum albumin ratio than controls. CSF/serum albumin ratio correlated with CSF neurofilament light in LAD, MIX, VaD, and other groups but not with AD biomarkers. Our data show that BBB leakage is common in dementias. The lack of association between CSF/serum albumin ratio and AD biomarkers suggests that BBB dysfunction is not inherent to AD but might represent concomitant cerebrovascular pathology.

  • 21.
    Sunnerhagen, Katharina S.
    et al.
    Department of Clinical Neuroscience-Rehabilitation Medicine, University of Göteborg, Sahlgrenska Hospital, Göteborg, Sweden.
    Darin, N.
    Department of Pediatrics, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    The effects of endurance training in persons with a hereditary myosin myopathy2004In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 110, no 2, 80-86 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate muscle performance and its consequences in eight individuals with a hereditary myopathy and the effects of an 8-week endurance training program.

    MATERIAL AND METHODS: Handgrip, muscle strength and endurance and oxygen consumption by breath-by-breath analysis during a stepless bicycle ergonometer test were evaluated. Walking, balance test and activities of daily living (ADL) were assessed, and a questionnaire for activity level and perceived symptoms was used. The design was a before-after trial in comparison with data from a control population, bicycling at 70% of maximal workload, 30 min/day, 5 days/week for 8 weeks.

    RESULTS: The subjects were weaker than age-matched controls. After training, the peak watt increased by almost 20% (P < 0.05). Muscle strength (flexion/extension) and isometric endurance (40% of maximum at 60 degrees ) did not change significantly. The average self-selected walking speed increased significantly (P < 0.05) from 1.25 to 1.45 m/s. Compliance was excellent and no serious adverse events occurred.

    CONCLUSION: Endurance training seems to function for this myopathy.

  • 22.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Thick and thin filament gene mutations in striated muscle diseases2008In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 9, no 7, 1259-1275 p.Article, review/survey (Refereed)
    Abstract [en]

    The sarcomere is the fundamental unit of cardiac and skeletal muscle contraction. During the last ten years, there has been growing awareness of the etiology of skeletal and cardiac muscle diseases originating in the sarcomere, an important evolving field. Many sarcomeric diseases affect newborn children, i. e. are congenital myopathies. The discovery and characterization of several myopathies caused by mutations in myosin heavy chain genes, coding for the major component of skeletal muscle thick filaments, has led to the introduction of a new entity in the field of neuromuscular disorders: myosin myopathies. Recently, mutations in genes coding for skeletal muscle thin filaments, associated with various clinical features, have been identified. These mutations evoke distinct structural changes within the sarcomeric thin filament. Current knowledge regarding contractile protein dysfunction as it relates to disease pathogenesis has failed to decipher the mechanistic links between mutations identified in sarcomeric proteins and skeletal myopathies, which will no doubt require an integrated physiological approach. The discovery of additional genes associated with myopathies and the elucidation of the molecular mechanisms of pathogenesis will lead to improved and more accurate diagnosis, including prenatally, and to enhanced potential for prognosis, genetic counseling and developing possible treatments for these diseases. The goal of this review is to present recent progress in the identification of gene mutations from each of the major structural components of the sarcomere, the thick and thin filaments, related to skeletal muscle disease. The genetics and clinical manifestations of these disorders will be discussed.

  • 23.
    Tajsharghi, Homa
    et al.
    Departments of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Darin, Niklas
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Rekabdar, Elham
    Departments of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Kyllerman, Mårten
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Wahlström, Jan
    Department of Clinical Genetics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Martinsson, Tommy
    Department of Clinical Genetics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Departments of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Mutations and sequence variation in the human myosin heavy chain IIa gene (MYH2)2005In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 13, no 5, 617-622 p.Article in journal (Refereed)
    Abstract [en]

    We recently described a new autosomal dominant myopathy associated with a missense mutation in the myosin heavy chain (MyHC) IIa gene (MYH2). In this study, we performed mutation analysis of MYH2 in eight Swedish patients with familial myopathy of unknown cause. In two of the eight index cases, we identified novel heterozygous missense mutations in MYH2, one in each case: V970I and L1061V. The mutations were located in subfragment 2 of the MyHC and they changed highly conserved residues. Most family members carrying the mutations had signs and symptoms consisting mainly of mild muscle weakness and myalgia. In addition, we analyzed the extent and distribution of nucleotide variation in MYH2 in 50 blood donors, who served as controls, by the complete sequencing of all 38 exons comprising the coding region. We identified only six polymorphic sites, five of which were synonymous polymorphisms. One variant, which occurred at an allele frequency of 0.01, was identical to the L1061V that was also found in one of the families with myopathy. The results of the analysis of normal variation indicate that there is strong selective pressure against mutations in MYH2. On the basis of these results, we suggest that MyHC genes should be regarded as candidate genes in cases of hereditary myopathies of unknown etiology.

  • 24.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Darin, Niklas
    The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tulinius, Mar
    The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Early onset myopathy with a novel mutation in the Selenoprotein N gene (SEPN1)2005In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 15, no 4, 299-302 p.Article in journal (Refereed)
    Abstract [en]

    Mutations in SEPN1 have been associated with three autosomal recessive congenital myopathies, including rigid spine muscular dystrophy, multiminicore disease and desmin-related myopathy with Mallory body-like inclusions. These disorders constitute the SEPN1 related myopathies (SEPN-RM). On the basis of clinical and laboratory features compatible with SEPN-RM, we performed mutation analysis of SEPN1 in 11 unrelated patients and found one case with pathogenic mutations. He showed early onset axial muscle weakness and developed scoliosis with respiratory insufficiency. Muscle biopsy showed increased variability of fiber size and slight, focal increase of connective tissue. A few fibers showed mini-core changes. SEPN1 mutation analysis revealed that the patient was a compound heterozygote: a previously described insertion (713-714 insA), and a novel nonsense mutation (R439stop).

  • 25.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Fyhr, Ing-Marie
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Structural effects of the slow/b-cardiac myosin heavy chain R453C mutation in cardiac and skeletal muscle2008In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 42, no 2, 153-156 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Hypertrophic cardiomyopathy (HCM) represents an important cause of sudden cardiac death particularly in otherwise healthy young individuals. In some families, HCM is caused by distinct mutations of the cardiac beta myosin heavy chain gene (MYH7).

    DESIGN: We have analyzed the expression of the malignant MYH7Arg453Cys mutation, in cardiac and skeletal muscle, and related it to morphological alterations.

    RESULTS: Morphological investigation revealed hypertrophic cardiomyocytes but regularly arranged myofibrils. Skeletal muscle showed no sign of structural alterations.

    CONCLUSIONS: Our results indicate that cardiomyocyte hypertrophy is secondary, due to impaired function, and that the mutation causes no structural alteration in myofibrillar structure in cardiac or skeletal muscle.

  • 26.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Hammans, Simon
    Wessex Neurological Centre, Southampton General Hospital, Southampton, UK.
    Lindberg, Christopher
    Department of Neurology, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska Hospital, Gothenburg, Sweden.
    Lossos, Alexander
    Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
    Clarke, Nigel F.
    Institute for Neuromuscular Research, Children’s Hospital at Westmead and Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia.
    Mazanti, Ingrid
    Cellular Pathology, Southampton General Hospital, Southampton, UK.
    Waddell, Leigh B.
    Institute for Neuromuscular Research, Children’s Hospital at Westmead and Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia.
    Fellig, Yakov
    Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
    Foulds, Nicola
    Wessex Clinical Genetics Services, UHS NHS Foundation Trust, Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
    Katifi, Haider
    Wessex Neurological Centre, Southampton General Hospital, Southampton, UK.
    Webster, Richard
    Department of Neurology, Children’s Hospital at Westmead, Sydney, New South Wales, Australia.
    Raheem, Olayinka
    Neuromuscular Research Unit, Tampere University and Hospital, Tampere, Finland.
    Udd, Bjarne
    Neuromuscular Research Unit, Tampere University and Hospital, Tampere, Finland / Department of Neurology, Vasa Central Hospital, Vasa, Finland / Department of Medical Genetics, Folkhälsan Genetic Institute, Helsinki University, Helsinki, Finland.
    Argov, Zohar
    Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
    Oldfors, Anders
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations2014In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 22, no 6, 801-808 p.Article in journal (Refereed)
    Abstract [en]

    Myosin myopathies comprise a group of inherited diseases caused by mutations in myosin heavy chain (MyHC) genes. Homozygous or compound heterozygous truncating MYH2 mutations have been demonstrated to cause recessive myopathy with ophthalmoplegia, mild-to-moderate muscle weakness and complete lack of type 2A muscle fibers. In this study, we describe for the first time the clinical and morphological characteristics of recessive myosin IIa myopathy associated with MYH2 missense mutations. Seven patients of five different families with a myopathy characterized by ophthalmoplegia and mild-to-moderate muscle weakness were investigated. Muscle biopsy was performed to study morphological changes and MyHC isoform expression. Five of the patients were homozygous for MYH2 missense mutations, one patient was compound heterozygous for a missense and a nonsense mutation and one patient was homozygous for a frame-shift MYH2 mutation. Muscle biopsy demonstrated small or absent type 2A muscle fibers and reduced or absent expression of the corresponding MyHC IIa transcript and protein. We conclude that mild muscle weakness and ophthalmoplegia in combination with muscle biopsy demonstrating small or absent type 2A muscle fibers are the hallmark of recessive myopathy associated with MYH2 mutations.

  • 27.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska Hospital, Gothenburg, Sweden.
    Hilton-Jones, David
    Department of Neurology, West Wing, John Racliffe Hospital, Oxford, UK.
    Raheem, Olayinka
    Neuromuscular Centre, Tampere University and Hospital, Tampere, Finland.
    Saukkonen, Anna Maija
    Department of Neurology, Central Hospital of Northern Karelia, Joensuu, Finland.
    Oldfors, Anders
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska Hospital, Gothenburg, Sweden.
    Udd, Bjarne
    Neuromuscular Centre, Tampere University and Hospital, Tampere, Finland / Department of Neurology, Vasa Central Hospital, Vasa, Finland / Folkhälsan Genetic Institute, Department of Medical Genetics, Helsinki University, Helsinki, Finland.
    Human disease caused by loss of fast IIa myosin heavy chain due to recessive MYH2 mutations2010In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 133, no 5, 1451-1459 p.Article in journal (Refereed)
    Abstract [en]

    Striated muscle myosin heavy chain is a molecular motor protein that converts chemical energy into mechanical force. It is a major determinant of the physiological properties of each of the three muscle fibre types that make up the skeletal muscles. Heterozygous dominant missense mutations in myosin heavy chain genes cause various types of cardiomyopathy and skeletal myopathy, but the effects of myosin heavy chain null mutations in humans have not previously been reported. We have identified the first patients lacking fast type 2A muscle fibres, caused by total absence of fast myosin heavy chain IIa protein due to truncating mutations of the corresponding gene MYH2. Five adult patients, two males and three females, from three unrelated families in UK and Finland were clinically assessed and muscle biopsy was performed in one patient from each family. MYH2 was sequenced and the expression of the corresponding transcripts and protein was analysed in muscle tissue. The patients had early-onset symptoms characterized by mild generalized muscle weakness, extraocular muscle involvement and relatively favourable prognosis. Muscle biopsy revealed myopathic changes including variability of fibre size, internalized nuclei, and increased interstitial connective and adipose tissue. No muscle fibres expressing type IIa myosin heavy chain were identified and the MYH2 transcripts were markedly reduced. All patients were compound heterozygous for truncating mutations in MYH2. The parents were unaffected, consistent with recessive mutations. Our findings show that null mutations in the fast myosin heavy chain IIa gene cause early onset myopathy and demonstrate that this isoform is necessary for normal muscle development and function. The relatively mild phenotype is interesting in relation to the more severe phenotypes generally seen in relation to recessive null mutations in sarcomeric proteins.

  • 28.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Kimber, Eva
    Department of Neuropediatrics, Uppsala University Children's Hospital, Uppsala, Sweden.
    Holmgren, D.
    Division of Pediatric Cardiology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tulinius, M.
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Distal arthrogryposis and muscle weakness associated with a beta-tropomyosin mutation2007In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 68, no 10, 772-775 p.Article in journal (Refereed)
    Abstract [en]

    Tropomyosin (TM), a sarcomeric thin-filament protein, plays an essential part in muscle contraction by regulating actin-myosin interaction. We describe two patients, a woman and her daughter, with muscle weakness and distal arthrogryposis (DA) type 2B, caused by a heterozygous missense mutation, R133W, in TPM2, the gene encoding beta-TM. Our results demonstrate the involvement of muscle dysfunction in the pathogenesis of DA and the fact that DA2B may be caused by mutations in TPM2.

  • 29.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Kimber, Eva
    Departments of Pediatrics, Institute for Clinical Sciences, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden / Department of Neuropediatrics, Uppsala University Children's Hospital, Uppsala, Sweden.
    Kroksmark, Anna-Karin
    Departments of Pediatrics, Institute for Clinical Sciences, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden / Queen Silvia's Children's Hospital, Göteborg, Sweden.
    Jerre, Ragnar
    Department of Orthopedics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tulinius, Mar
    Departments of Pediatrics, Institute for Clinical Sciences, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden / Queen Silvia's Children's Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Embryonic myosin heavy-chain mutations cause distal arthrogryposis and developmental myosin myopathy that persists postnatally2008In: Archives of Neurology, ISSN 0003-9942, E-ISSN 1538-3687, Vol. 65, no 8, 1083-1090 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Myosin is a molecular motor and the essential part of the thick filament of striated muscle. The expression of myosin heavy-chain (MyHC) isoforms is developmentally regulated. The embryonic isoform encoded from MYH3 (OMIM *160720) is expressed during fetal life. Recently, mutations in MYH3 were demonstrated to be associated with congenital joint contractures, that is, Freeman-Sheldon and Sheldon-Hall syndromes, which are both distal arthrogryposis syndromes. Mutations in other MyHC isoforms cause myopathy. It is unknown whether MYH3 mutations cause myopathy because muscle tissue has not been studied.

    OBJECTIVES: To determine whether novel MYH3 mutations are associated with distal arthrogryposis and to demonstrate myopathic changes in muscle biopsy specimens from 4 patients with distal arthrogryposis and MYH3 mutations.

    DESIGN: In a cohort of patients with distal arthrogryposis, we analyzed the entire coding sequence of MYH3. Muscle biopsy specimens were obtained, and in addition to morphologic analysis, the expression of MyHC isoforms was investigated at the protein and transcript levels.

    RESULTS: We identified patients from 3 families with novel MYH3 mutations. These mutations affect developmentally conserved residues that are located in different regions of the adenosine triphosphate-binding pocket of the MyHC head. The embryonic (MYH3) isoform was not detected in any of the muscle biopsy samples, indicating a normal developmental downregulation of MYH3 in these patients. However, morphologic analysis of muscle biopsy specimens from the 4 patients revealed mild and variable myopathic features and a pathologic upregulation of the fetal MyHC isoform (MYH8) in 1 patient.

    CONCLUSIONS: Distal arthrogryposis associated with MYH3 mutations is secondary to myosin myopathy, and postnatal muscle manifestations are variable.

  • 30.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
    Leren, Trond P.
    Medical Genetics Laboratory, Department of Medical Genetics, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
    Abdul-Hussein, Saba
    Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
    Tulinius, Mar
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
    Brunvand, Leif
    Department of Pediatrics, Ullevål University Hospital, Oslo, Norway.
    Dahl, Hilde M.
    Department of Pediatrics, Ullevål University Hospital, Oslo, Norway.
    Oldfors, Anders
    Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
    Unexpected myopathy associated with a mutation in MYBPC3 and misplacement of the cardiac myosin binding protein C2010In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 47, no 8, 575-577 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Myosin binding protein C (MyBPC) is essential for the structure of the sarcomeres in striated muscle. There is one cardiac specific isoform and two skeletal muscle specific isoforms. Mutations in MYBPC3 encoding the cardiac isoform cause cardiomyopathy.

    METHODS AND RESULTS: We have identified an infant with fatal cardiomyopathy due to a homozygous mutation, p.R943X, in MYBPC3. The patient also had an unexpected skeletal myopathy. The patient expressed the cardiac specific MyBPC isoform in skeletal muscle at transcript and protein levels. Numerous muscle fibres expressing the mutant cardiac isoform showed structural abnormalities with disorganisation of sarcomeres and depletion of myosin thick filaments.

    CONCLUSIONS: The surprising identification of a skeletal myopathy in this patient was due to aberrant expression of mutant cardiac MyBPC in skeletal muscle.

  • 31.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Ohlsson, M.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Palm, L.
    Department of Paediatrics Malmö, Skåne University Hospital, Malmö, Sweden.
    Oldfors, A.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Myopathies associated with β-tropomyosin mutations2012In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 22, no 11, 923-933 p.Article, review/survey (Refereed)
    Abstract [en]

    Mutations in TPM2, encoding β-tropomyosin, have recently been found to cause a range of muscle disorders. We review the clinical and morphological expression of the previously reported mutations illustrating the heterogeneity of β-tropomyosin-associated diseases and describe an additional case with a novel mutation. The manifestations of mutations in TPM2 include non-specific congenital myopathy with type 1 fibre predominance, nemaline myopathy, cap disease and distal arthrogryposis. In addition, Escobar syndrome with nemaline myopathy is a manifestation of homozygous truncating β-tropomyosin mutation. Cap disease appears to be the most common morphological manifestation. A coarse intermyofibrillar network and jagged Z lines are additional frequent changes. The dominant β-tropomyosin mutations manifest either as congenital myopathy or distal arthrogryposis. The various congenital myopathies are usually associated with moderate muscle weakness and no congenital joint contractures. The distal arthrogryposis syndromes associated with TPM2 mutations include the less severe forms, with congenital contractures mainly of the hands and feet and mild or no muscle weakness. The dominant TPM2 mutations include amino acid deletions/insertions and missense mutations. There is no clear relation between the type of mutations or the localisation of the mutated residue in the β-tropomyosin molecule and the clinical and morphological phenotype.

  • 32.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Ohlsson, Monica
    Department of Internal Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
    Lindberg, Christopher
    Department of Neurology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Congenital myopathy with nemaline rods and cap structures caused by a mutation in the beta-tropomyosin gene (TPM2)2007In: Archives of Neurology, ISSN 0003-9942, E-ISSN 1538-3687, Vol. 64, no 9, 1334-1338 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To describe the clinical, morphologic, and genetic findings in a family in which one woman had nemaline myopathy, whereas her daughter showed features of cap disease.

    PATIENTS: A 66-year-old woman and her 35-year-old daughter had congenital, slowly progressive muscle weakness. They had weakness in both proximal and distal muscles and facial diplegia with bilateral ptosis, a long narrow face, a high arched palate, and micrognathia.

    RESULTS: Muscle biopsy specimens in the mother at age 57 years had shown nemaline myopathy, whereas a biopsy specimen at age 32 years had demonstrated no rods. Muscle biopsy specimens in the daughter at age 26 years had shown features of cap disease and no apparent nemaline rods. A missense mutation, Glu41Lys, in the beta-tropomyosin gene TPM2 was identified in both patients but was absent in their healthy relatives.

    CONCLUSIONS: The results indicate that mutations in TPM2 may cause nemaline myopathy as well as cap disease with a dominant mode of inheritance. These disorders may thus be phenotypic variants of the same genetic defect.

  • 33.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Myosinopathies: pathology and mechanisms2013In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 125, no 1, 3-18 p.Article, review/survey (Refereed)
    Abstract [en]

    The myosin heavy chain (MyHC) is the molecular motor of muscle and forms the backbone of the sarcomere thick filaments. Different MyHC isoforms are of importance for the physiological properties of different muscle fiber types. Hereditary myosin myopathies have emerged as an important group of diseases with variable clinical and morphological expression depending on the mutated isoform and type and location of the mutation. Dominant mutations in developmental MyHC isoform genes (MYH3 and MYH8) are associated with distal arthrogryposis syndromes. Dominant or recessive mutations affecting the type IIa MyHC (MYH2) are associated with early-onset myopathies with variable muscle weakness and ophthalmoplegia as a consistent finding. Myopathies with scapuloperoneal, distal or limb-girdle muscle weakness including entities, such as myosin storage myopathy and Laing distal myopathy are the result of usually dominant mutations in the gene for slow/β cardiac MyHC (MYH7). Protein aggregation is part of the features in some of these myopathies. In myosin storage myopathy protein aggregates are formed by accumulation of myosin beneath the sarcolemma and between myofibrils. In vitro studies on the effects of different mutations associated with myosin storage myopathy and Laing distal myopathy indicate altered biochemical and biophysical properties of the light meromyosin, which is essential for thick filament assembly. Protein aggregates in the form of tubulofilamentous inclusions in association with vacuolated muscle fibers are present at late stage of dominant myosin IIa myopathy and sometimes in Laing distal myopathy. These protein aggregates exhibit features indicating defective degradation of misfolded proteins. In addition to protein aggregation and muscle fiber degeneration some of the myosin mutations cause functional impairment of the molecular motor adding to the pathogenesis of myosinopathies.

  • 34.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Macleod, Dominic P.
    Department of Respiratory Medicine, Royal London Hospital, United Kingdom.
    Swash, Michael
    Department of Neurology, Royal London Hospital, United Kingdom.
    Homozygous mutation in MYH7 in myosin storage myopathy and cardiomyopathy2007In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 68, no 12, 962- p.Article in journal (Refereed)
  • 35.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Swash, M.
    Department of Neurology, Queen Mary School of Medicine, Royal London Hospital, London, UK.
    Myosin storage myopathy with cardiomyopathy2007In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 17, no 9-10, 725- p.Article in journal (Refereed)
  • 36.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Göteborg University, Sahlgrenska Hospital, Göteborg, Sweden.
    Pilon, Marc
    Chalmers University, Lundberg Laboratory, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Göteborg University, Sahlgrenska Hospital, Göteborg, Sweden.
    A Caenorhabditis elegans model of the myosin heavy chain IIa E706K [corrected] mutation2005In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 58, no 3, 442-448 p.Article in journal (Refereed)
    Abstract [en]

    Mutations in myosin heavy chain (MyHC) genes recently have been shown to be associated with various forms of congenital myopathies: myosin myopathies. The MyHC IIa E706K mutation is associated with congenital joint contractures, early-onset muscle weakness, and progressive course with moderate to severe muscle weakness later in life. To study the pathogenicity of this MyHC mutation, we investigated the effect of the corresponding mutation (E710K) in the major MyHC isoform (MyHC B) of the body wall muscle of the nematode Caenorhabditis elegans. Worms with null mutations in the MyHC B gene (unc-54) are severely paralyzed and depleted of thick filaments in the body wall muscle sarcomeres. unc-54 null mutants with extrachromosomal arrays of a gene construct including the entire wild-type unc-54 gene were partially rescued as determined by a motility assay and by morphological analysis of the body wall muscle. Analysis of unc-54 null mutants with extrachromosomal arrays of the unc-54 gene with the E710K mutation were severely paralyzed but showed formation of thick filaments in the body wall muscle. We conclude that the MyHC E706K (E710K in C. elegans) mutation is pathogenic and that the effect is primarily functional rather than structural because thick filaments are formed. The C. elegans model may be useful to study suspected pathogenic mutations in MyHC genes associated with human muscle diseases.

  • 37.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Sunnerhagen, Katharina Stibrant
    Department of Rehabilitation Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
    Darin, Niklas
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Kyllerman, Mårten
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Induced shift in myosin heavy chain expression in myosin myopathy by endurance training2004In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 251, no 2, 179-183 p.Article in journal (Refereed)
    Abstract [en]

    We recently described a new autosomal dominant myopathy (OMIM #605637) associated with a missense mutation in the myosin heavy chain (MyHC) IIa gene ( MYH2), which encodes for the fast myosin isoform that is expressed in type 2A muscle fibers. There was a correlation between muscle pathology and expression of MyHC IIa. Low expression of the mutation was associated with a milder phenotype. Since physical activity influences MyHC isoform expression in normal individuals, we investigated whether endurance training can alter the expression of MyHC isoforms in patients with the MYH2 mutation. The expression of MyHC I, IIa and IIx was analysed in muscle specimens from six patients before and after an eight-week endurancetraining program by SDS-polyacrylamide gel electrophoresis and immuno-histochemistry. There was a clear and consistent shift from fast to slow MyHC isoform expression, but the training program did not result in the desired reduction of MyHC IIa, which may be due to the limited time period of training. Fiber type transition was further illustrated by the appearance of hybrid muscle fibers expressing more than one MyHC isoform after the training period. All patients showed an increase in maximal workload but no significant change in isometric muscle strength.We conclude that endurance training in patients with myosin myopathy may be an important way to alter the expression of defective MyHC isoforms.

  • 38.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Thornell, Lars-Eric
    Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå.
    Lindberg, Christopher
    Department of Neurology, Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Lindvall, Björn
    Neuromuscular Unit, University Hospital, Linköping, Sweden.
    Henriksson, Karl-Gösta
    Neuromuscular Unit, University Hospital, Linköping, Sweden.
    Oldfors, Anders
    Department of Pathology, Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Myosin storage myopathy associated with a heterozygous missense mutation in MYH72003In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 54, no 4, 494-500 p.Article in journal (Refereed)
    Abstract [en]

    Myosin constitutes the major part of the thick filaments in the contractile apparatus of striated muscle. MYH7 encodes the slow/beta-cardiac myosin heavy chain (MyHC), which is the main MyHC isoform in slow, oxidative, type 1 muscle fibers of skeletal muscle. It is also the major MyHC isoform of cardiac ventricles. Numerous missense mutations in the globular head of slow/beta-cardiac MyHC are associated with familial hypertrophic cardiomyopathy. We identified a missense mutation, Arg1845Trp, in the rod region of slow/beta-cardiac MyHC in patients with a skeletal myopathy from two different families. The myopathy was characterized by muscle weakness and wasting with onset in childhood and slow progression, but no overt cardiomyopathy. Slow, oxidative, type 1 muscle fibers showed large inclusions consisting of slow/beta-cardiac MyHC. The features were similar to a previously described entity: hyaline body myopathy. Our findings indicate that the mutated residue of slow/beta-cardiac MyHC is essential for the assembly of thick filaments in skeletal muscle. We propose the term myosin storage myopathy for this disease.

  • 39.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Thornell, L.-E.
    Department of Anatomy, Umeå University, Umeå, Sweden.
    Darin, Niklas
    Department of Pediatrics, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Martinsson, T.
    Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Kyllerman, M.
    Department of Pediatrics, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Wahlström, J.
    Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Myosin heavy chain IIa gene mutation E706K is pathogenic and its expression increases with age2002In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 58, no 5, 780-786 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The authors recently described a new autosomal dominant myopathy (OMIM 605637 inclusion body myopathy 3) associated with a missense mutation in the myosin heavy chain (MyHC) IIa gene (MyHC IIa, Human Gene Map [HGM] locus MYH2). Young patients showed minor changes in their muscle biopsies, although dystrophic alterations and rimmed vacuoles with 15- to 20-nm tubulofilaments identical to those in sporadic inclusion body myositis (s-IBM) were observed in some of the adult (especially older) patients. The current study was undertaken to investigate the relation between expression of the mutant MyHC IIa and pathologic changes in muscle.

    METHODS: The expression of MyHC IIa in nine muscle specimens from six individuals carrying the mutation was analyzed by immunohistochemistry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and a new reverse transcriptase--PCR method to measure the relative abundance of the various MyHC transcripts.

    RESULTS: Young patients with muscle weakness and minor pathologic changes in muscle expressed MyHC IIa at undetectable levels. MyHC IIa was expressed at high levels in adults with a progressive clinical course and dystrophic muscle changes. In these cases, a large number of muscle fibers were hybrids with expression of more than one MyHC isoform. Both MyHC IIa alleles were equally expressed. The relative level of MyHC IIa transcripts exceeded that of the corresponding protein, indicating an increased turnover of mutated protein. MyHC IIa expression was a consistent finding in muscle fibers with rimmed vacuoles.

    CONCLUSIONS: The clear correlation between pathologic changes and expression of MyHC IIa indicates that defects in MyHC may lead not only to muscle weakness but also to muscle degeneration. The consistent expression of MyHC IIa in muscle fibers with rimmed vacuoles indicates that the breakdown of sarcomeric proteins is a key element in the pathogenesis of rimmed vacuoles of s-IBM type.

  • 40.
    Vondracek, Petr
    et al.
    Department of Pediatric Neurology, University Hospital and Masaryk University, Brno, Czech Republic.
    Hermanova, Marketa
    Department of Pathology, University Hospital and Masaryk University, Brno, Czech Republic.
    Vodickova, Kristina
    Department of Pediatric Ophtalmology, University Hospital and Masaryk University, Brno, Czech Republic.
    Fajkusova, Lenka
    Department of Molecular Biology and Gene Therapy, University Hospital and Masaryk University, Brno, Czech Republic.
    Blakely, Emma L.
    Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, University of Newcastle upon Tyne, UK.
    He, Langping
    Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, University of Newcastle upon Tyne, UK.
    Turnbull, Douglass M.
    Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, University of Newcastle upon Tyne, UK.
    Taylor, Robert W.
    Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, University of Newcastle upon Tyne, UK.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    An unusual case of congenital muscular dystrophy with normal serum CK level, external ophtalmoplegia, and white matter changes on brain MRI2007In: European journal of paediatric neurology, ISSN 1090-3798, E-ISSN 1532-2130, Vol. 11, no 6, 381-384 p.Article in journal (Refereed)
    Abstract [en]

    We report a sporadic case of congenital muscular dystrophy (CMD) in a 13-year-old girl with early manifestation of muscle weakness and hypotonia, severe contractures, bulbar syndrome, progressive external ophtalmoplegia, and white matter changes on magnetic resonance imaging (MRI) of the brain, but no mental defect. Serum creatine kinase (CK) level was normal. Muscle biopsy revealed a dystrophic picture with a prominent inflammatory infiltrate mimicking inflammatory myopathy-typical histological findings in CMD. Immunostaining showed normal expression of merosin, alpha and beta-dystroglycans. Mutation analyses of calpain3, dysferlin, and SEPN1 genes were negative. An electron microscopy revealed the accumulation of abnormally enlarged mitochondria located under the sarcolemma. Measurement of respiratory chain enzyme activities did not reveal any biochemical defect and mitochondrial genetic studies, including sequencing of the entire mitochondrial genome, were unremarkable. Phenotypic presentation of our patient is very unusual and differs considerably from other CMD variants.

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