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  • 1.
    Aldenbratt, Annika
    et al.
    Sahlgrens Univ Hosp, Dept Nephrol, Gothenburg, Sweden.
    Lindberg, Christopher
    Sahlgrens Univ Hosp, Dept Neurol, Neuromuscular Ctr, Gothenburg, Sweden.
    Svensson, Maria K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Reduced renal function in patients with Myotonic Dystrophy type 1 and the association to CTG expansion and other potential risk factors for chronic kidney disease2017In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 27, no 11, p. 1038-1042Article in journal (Refereed)
    Abstract [en]

    Myotonic dystrophy type 1 (DM1) affects several organs. Disease severity and age at onset are correlated to the CTG repeat expansion. The aim of this study was to assess renal function and the association to numbers of CTG repeat expansion in patients with DM1. Ninety-eight patients with DM1 were included. Glomerular filtration rate (measured GFR) was measured using iohexol clearance. Data on CTG repeats were available in 83/98 (85%) patients. The overall mGFR was 74 (16) ml/min/1.73 m(2) (range 38-134). Sixty-four patients (69%) had a mild and sixteen patients (17%) a moderate decrease in renal function (mGFR 60-89 and 30-59 ml/min/1.73 m(2), respectively). No correlations were found between CTG repeats and mGFR (r = 0.10, p = 0.4) or between CTG repeats and serum cystatin C (r = 0.12, p = 0.29). CTG repeats was positively correlated to creatinine-based estimates of GFR (eGFR) (modified diet in renal disease r = 0.49, p < 0.001, CKD-EPI creatinine equation; r = 0.50, p < 0.001), but analyses using Structural Equation Modeling showed no correlation. The correlation was explained by an indirect effect via serum creatinine and skeletal muscle mass index. In conclusion, patients with DM1 seem to have a slight decrease in renal function but there is no association between renal function and the number of CTG repeats, a marker of disease severity.

  • 2. Arkblad, Eva L.
    et al.
    Darin, Niklas
    Berg, Kerstin
    Kimber, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Brandberg, Göran
    Lindberg, Christopher
    Holmberg, Eva
    Tulinius, Mar
    Nordling, Margareta
    Multiplex ligation-dependent probe amplification improves diagnostics in spinal muscular atrophy2006In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 16, no 12, p. 830-838Article in journal (Refereed)
    Abstract [en]

    Spinal muscular strophy (SMA) is an autosomal recessive disease caused by decreased levels of survival motor neuron protein (SMN). In the majority of cases, this decrease is due to absence of the SMN1 gene. Multiplex ligation-dependent probe amplification (MLPA) is a modern quantitative molecular method. Applied in SMA cases. it improves diagnostics by simultaneously identifying the number of copies of several target sequences in the SMN1 gene and in neary genes. Using MLPA in clinical diagnostics, we have identified a previously unreported, partial deletion of SMN1 (exons 1-6) in two apparently unrelated Swedish families. this mutation would not have been detected by conventional diagnostic methods. This paper illustrates the broad clinical and genetic spectrum of SMA and includes reports of MLPA results and clinical dexcriptions of a patient with homozygous absence of SMN1 and only one SMN2 (prenatal onset SMA type 1), an asymptomatic woman with five SMN2 (lacking SMN1) and representative patients with SMA types 1,2 and 3.

  • 3. Caliandro, P.
    et al.
    Evoli, A.
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Granata, G.
    Tonali, P.
    Padua, L.
    The difficulty in confirming clinical diagnosis of myasthenia gravis in a seronegative patient: a possible neurophysiological approach2009In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 19, no 12, p. 825-827Article in journal (Refereed)
    Abstract [en]

    In seronegative myasthenia gravis repetitive nerve stimulation and single-fibre EMG have a crucial diagnostic value but they may be negative, particularly in repetitive nerve stimulation studies. We report the case of a 43-year-old patient with generalized seronegative myasthenia gravis with negative 3Hz repetitive nerve stimulation at Erb’s point and voluntary single-fibre EMG in the orbicularis oculi. We also performed 6 and 12Hz repetitive nerve stimulation at Erb and stimulated single-fibre EMG in the extensor digitorum communis and our findings were pathological. Our data suggest that, for individual patients with an atypical picture characterised by dissociation between a severe clinical pattern and no definite neurophysiological findings on conventional tests, repetitive nerve stimulation with a stimulation rate higher than 3Hz and/or stimulated single-fibre EMG with an increasing stimulation rate may be helpful.

  • 4.
    Casar-Borota, Olivera
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Jacobsson, J.
    Libelius, R.
    Moslemi, A. R.
    Hedberg, C.
    Oldfors, A.
    A novel dynamin-2 gene mutation associated with a late-onset centronuclear myopathy with unusual clinical presentation and necklace fibres2012In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 22, no 9-10, p. 843-843Article in journal (Other academic)
    Abstract [en]

    Nuclear centralisation and internalisation, sarcoplasmic radiating strands and type 1 muscle fibre predominance and hypotrophy are morphologic features of centronuclear myopathy (CNM) related to dynamin-2 (DNM2) gene defects, whereas necklace fibres characterise late-onset myopathy associated with myotubularin-1 (MTM1) gene defects. We report a 40-year-old woman with 1-year history of pain and paresthesia in the left shoulder and arm that was clinically interpreted as brachial plexus neuritis. Electromyography revealed both myopathic and neuropathic abnormalities, and because of the myopathic changes a muscle biopsy was performed. The typical morphologic features of dynamin-2 CNM with additional numerous necklace fibres were found in the muscle biopsy. Sequencing of the DNM2 and MTM1 genes revealed a not previously described heterozygous missense mutation in exon 18 of DNM2 leading to replacement of highly conserved Proline in position 647 by Arginine. The muscle symptoms have not progressed during the two-year follow-up, but the patient has developed bilateral subtle lens opacities. Necklace fibres were originally described as fibres that had usually a small diameter and internalized nuclei aligned in a basophilic ring at a few micrometers beneath the sarcolemma. They were described in association with myopathies caused by MTM1 mutations, and similar but not identical fibres have also been reported in a case of DNM2 associated CNM. Our findings support the concept that necklace fibres are not specific but indicate common pathogenic mechanisms in DNM2 and MTM1 associated CNM. This case report expands the clinical, morphological and molecular genetic variability of DNM2 associated CNM.

  • 5.
    Casar-Borota, Olivera
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Jacobsson, Johan
    Libelius, Rolf
    Oldfors, Carola Hedberg
    Malfatti, Edoardo
    Romero, Norma Beatriz
    Oldfors, Anders
    A novel dynamin-2 gene mutation associated with a late-onset centronuclear myopathy with necklace fibres2015In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 25, no 4, p. 345-348Article in journal (Refereed)
    Abstract [en]

    Nuclear centralisation and internalisation, sarcoplasmic radiating strands and type 1 muscle fibre predominance and hypotrophy characterise dynamin-2 (DNM2) associated centronuclear myopathy, whereas necklace fibres are typically seen in late onset myotubularin-1 (MTM1)-related myopathy.

    We report a woman with unilateral symptoms probably related to brachial plexus neuritis. Electromyography revealed localised neuropathic and generalised myopathic abnormalities. The typical features of DNM2 centronuclear myopathy with additional necklace fibres were found in the muscle biopsy. Sequencing of the DNM2 and MTM1 genes revealed a novel heterozygous missense mutation in exon 18 of the DNM2, leading to replacement of highly conserved proline at position 647 by arginine. The muscle symptoms have not progressed during the 3-year follow-up. However, the patient has developed bilateral subtle lens opacities.

    Our findings support the concept that necklace fibres may occasionally be found in DNM2-related myopathy, possibly indicating a common pathogenic mechanism in DNM2 and MTM1 associated centronuclear myopathy.

  • 6.
    Cristea, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Karlsson Edlund, Patrick
    Lindblad, Joakim
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
    Qaisar, Rizwan
    Bengtsson, Ewert
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Effects of ageing and gender on the spatial organisation of nuclei in single human skeletal muscle cells2009In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 19, no 8, p. 605-606Article in journal (Refereed)
  • 7.
    Cristea, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Karlsson Edlund, Patrick
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
    Lindblad, Joakim
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis.
    Qaisar, Rizwan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Bengtsson, Ewert
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Effects of ageing and gender on the spatial organization of nuclei in single human skeletal muscle cells2009In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 19, p. 605-606Article in journal (Refereed)
  • 8.
    Feresiadou, Amalia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Oldfors, Carola Hedberg
    Univ Gothenburg, Inst Biomed, Dept Pathol & Genet, Gothenburg, Sweden..
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Oldfors, Anders
    Univ Gothenburg, Inst Biomed, Dept Pathol & Genet, Gothenburg, Sweden..
    Tubular aggregates in congenital myasthenic syndrome2018In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 28, no 2, p. 174-175Article in journal (Other academic)
  • 9. Hedberg, C.
    et al.
    Ohlsson, M.
    Bradvik, B.
    Lindberg, C.
    Tajsharghi, H.
    Danielsson, O.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Udd, B.
    Martinsson, T.
    Oldfors, A.
    Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin2012In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 22, no 9-10, p. 873-873Article in journal (Other academic)
    Abstract [en]

    Hereditary myopathy with early respiratory failure (HMERF) and extensive myofibrillar lesions have been described in sporadic and familial cases and linked to various chromosomal regions. We describe the clinical manifestations, muscle histopathology and genetics in eight individuals from three apparently unrelated families with clinical and pathological features of HMERF. All patients had 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.274375, T>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 699 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry of this novel and first disease-causing mutation in A-band titin associated with HMERF.

  • 10. Håkansson, Irene
    et al.
    Sandstedt, Anna
    Lundin, Fredrik
    Askmark, Håkan
    Pirskanen, Ritva
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Piehl, Fredrik
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Successful autologous haematopoietic stem cell transplantation for refractory myasthenia gravis - a case report2017In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 27, no 1, p. 90-93Article in journal (Refereed)
    Abstract [en]

    Myasthenia gravis (MG) is an autoimmune disease, with immune reactivity against the post-synaptic endplate of the neuromuscular junction. Apart from symptomatic treatment with choline esterase blockers, many patients also require immunomodulatory treatment. Despite existing treatment options, some patients are treatment refractory. We describe a patient with severe MG refractory to corticosteroids, four oral immunosuppressants, cyclophosphamide, rituximab and bortezomib who was treated with autologous haematopoietic stem cell transplantation. Two years after this, the patient has significantly improved in objective tests and in quality of life and leads an active life. Diplopia is her only remaining symptom and she is completely free of medication for MG. We believe that autologous haematopoietic stem cell transplantation can be an effective therapeutic option for carefully selected cases of severe, treatment refractory MG.

  • 11. Kollberg, Gittan
    et al.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Holme, Elisabeth
    Oldfors, Anders
    Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron-sulphur cluster deficiency myopathy2011In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 21, no 2, p. 115-120Article in journal (Refereed)
    Abstract [en]

    Myopathy with exercise intolerance and deficiency of iron sulphur cluster proteins is caused by an intronic IVS5+382 G > C mutation in ISCU, the gene encoding the iron sulphur cluster assembly protein (IscU). The mutation causes alternative splicing resulting in a truncated protein and severely reduced levels of IscU protein in muscle tissue. Disease manifestations include muscle fatigability, dyspnoea, cardiac palpitations and episodic myoglobinuria. Muscle tissue of these patients demonstrates marked histochemical succinate dehydrogenase deficiency and accumulation of iron in muscle fibres, which are morphological hallmarks of the disease. A biopsy specimen from a patient, two months after a severe attack of rhabdomyolysis, revealed regenerating muscle with normal succinate dehydrogenase activity and only minor iron accumulation, whereas another biopsy obtained nine years after the episode showed the typical hallmarks of the disease. The apparent explanation for the normal succinate dehydrogenase activity during regeneration was a markedly increased level of IscU protein in regenerating muscle tissue and an increase in normally spliced ISCU transcripts in the patient. The results have implications for diagnosis of the disease based on muscle biopsy findings and support the concept that an increase of normally spliced ISCU by RNA modulating therapy may be a therapeutic possibility for these patients.

  • 12.
    Li, Mingxin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lionikas, Arimantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Yu, F.
    Tajsharghi, H.
    Oldfors, A.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    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, p. 782-791Article 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.

  • 13.
    Lindqvist, Johan M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    The H40Y alpha-actin mutation differently affects limb and respiratory muscle contraction2012In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 22, no 9-10, p. 844-844Article in journal (Other academic)
    Abstract [en]

    Nemaline myopathy is the most common of the congenital non-dystrophic myopathies, with an estimated incidence of 1:50,000. The severe form of this disease is characterized by generalized weakness especially affecting limb and respiratory muscles. Questions that remain unanswered are (i) whether limb and respiratory muscles are affected to the same extent, and (ii) whether the underlying mechanisms are similar. The aim of the present study was to address these questions in a novel transgenic mouse model of severe nemaline myopathy. This model expresses the heterozygous amino acid substitution, H40Y, in skeletal α-actin. Hence, we dissected EDL and diaphragm muscles and evaluated the contraction mechanism. To our surprise, we observed muscle-specific defects that will be presented during the conference. These findings give valuable information for future potential therapeutic interventions.

  • 14.
    Melberg, Atle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Kretz, Christine
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wallgren-Pettersson, Carina
    Toussaint, Anne
    Böhm, Johann
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Laporte, Jocelyn
    Adult course in dynamin 2 dominant centronuclear myopathy with neonatal onset2010In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 20, no 1, p. 53-56Article in journal (Refereed)
    Abstract [en]

    We report a family with autosomal dominant centronuclear (myotubular) myopathy caused by a novel mutation, p.A618D, in dynamin 2 (DNM2). The 64-year-old mother and 26-year-old daughter had neonatal onset with hypotonia and weak suckling, followed by improvement, then slowly progressive muscle weakness and respiratory restriction. Muscle biopsy showed radial sarcoplasmic strands around the frequent central nuclei. Electrophysiology revealed predominantly myopathic patterns without peripheral nerve involvement. Centronuclear myopathy with neonatal onset caused by a DNM2 mutation in the C-terminal part of the pleckstrin homology domain may have a favorable prognosis and follow a course similar to adult-onset centronuclear myopathy. We advise respiratory follow-up in these patients.

  • 15.
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ca2+ sensitizers: An emerging class of agents for counterbalancing weakness in skeletal muscle diseases?2010In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 20, no 2, p. 98-101Article, review/survey (Refereed)
    Abstract [en]

    Ca(2+) ions are key regulators of skeletal muscle contraction. By binding to contractile proteins, they initiate a cascade of molecular events leading to cross-bridge formation and ultimately, muscle shortening and force production. The ability of contractile proteins to respond to Ca(2+) attachment, also known as Ca(2+) sensitivity, is often compromised in acquired and congenital skeletal muscle disorders. It constitutes, undoubtedly, a major physiological cause of weakness for patients. In this review, we discuss recent studies giving strong molecular and cellular evidence that pharmacological modulators of some of the contractile proteins, also termed Ca(2+) sensitizers, are efficient agents to improve Ca(2+) sensitivity and function in diseased skeletal muscle cells. In fact, they compensate for the impaired contractile proteins response to Ca(2+) binding. Currently, such Ca(2+) sensitizing compounds are successfully used for reducing problems in cardiac disorders. Therefore, in the future, under certain conditions, these agents may represent an emerging class of agents to enhance the quality of life of patients suffering from skeletal muscle weakness.

  • 16.
    Roos, S.
    et al.
    Department of Pathology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
    Lindgren, U.
    Department of Pathology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
    Ehrstedt, Christoffer
    Department of Women's and Children's Health, Uppsala University Children's Hospital, Sweden.
    Moslemi, A. R.
    Department of Pathology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
    Oldfors, A.
    epartment of Pathology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
    Mitochondrial DNA depletion in single fibers in a patient with novel TK2 mutations2014In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 24, no 8, p. 713-720Article in journal (Refereed)
    Abstract [en]

    The mitochondrial DNA (mtDNA) depletion syndrome is a genetically heterogeneous group of diseases caused by nuclear gene mutations and secondary reduction in mtDNA copy number. We describe a patient with progressive muscle weakness and increased creatine kinase and lactate levels. Muscle weakness was first noted at age 1.5 years and he died of respiratory failure and bronchopneumonia at age 3.5 years. The muscle biopsy showed dystrophic features with ragged red fibers and numerous cytochrome c oxidase (COX)-negative fibers. qPCR analysis demonstrated depletion of mtDNA and sequence analysis of the mitochondrial thymidine kinase 2 (TK2) gene revealed two novel heterozygous variants, c.332C > T, p.(T111I) and c.156 + 5G > C. Quantitative analysis of mtDNA in single muscle fibers demonstrated that COX-deficient fibers showed more pronounced depletion of mtDNA when compared with fibers with residual COX activity (P < 0.01, n = 25). There was no evidence of manifestations from other organs than skeletal muscle although there was an apparent reduction of mtDNA copy number also in liver. The patient showed a pronounced, albeit transient, improvement in muscle strength after onset of treatment with coenzyme Q10, asparaginase, and increased energy intake, suggesting that nutritional modulation may be a therapeutic option in myopathic mtDNA depletion syndrome.

  • 17. Roos, S.
    et al.
    Lindgren, U.
    Ehrstedt, Christoffer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Moslemi, A. R.
    Oldfors, A.
    Mitochondrial DNA depletion in single fibers in a patient with novel TK2 mutations2014In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 24, no 9-10, p. 865-865Article in journal (Other academic)
  • 18.
    Strang-Karlsson, Sonja
    et al.
    Univ Helsinki, Folkhaelsan Inst Genet, Folkhaelsan Dept Med Genet, Helsinki, Finland; Univ Helsinki, Dept Med & Clin Genet, Helsinki, Finland; Helsinki Univ Hosp, Childrens Hosp, Helsinki, Finland; Univ Helsinki, Helsinki, Finland.
    Johnson, Katherine
    Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Töpf, Ana
    Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Xu, Liwen
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA USA; Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Lek, Monkol
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA USA; Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    MacArthur, Daniel G.
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA USA; Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Williams, Maria
    Aland Cent Hosp, Mariehamn, Aland, Finland.
    Straub, Volker
    Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Wallgren-Pettersson, Carina
    Univ Helsinki, Folkhaelsan Inst Genet, Folkhaelsan Dept Med Genet, Helsinki, Finland; Univ Helsinki, Dept Med & Clin Genet, Helsinki, Finland.
    A novel compound heterozygous mutation in the POMK gene causing limb-girdle muscular dystrophy-dystroglycanopathy in a sib pair2018In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 28, no 7, p. 614-618Article in journal (Refereed)
    Abstract [en]

    We describe two Finnish siblings in whom an incidentally detected elevated creatine kinase activity eventually led to a diagnosis of limb-girdle muscular dystrophy-dystroglycanopathy (Type C12; MDDGC12). When diagnosed at age 10 and 13 years, they were mildly affected with a slow or non-progressive disease course. The main symptoms comprised infrequent hip cramps triggered by flexion, neck cramps triggered by yawning, transient growing pains, calf hypertrophy and mild proximal muscle weakness. Their cognitive and motor developments were unremarkable and they were physically active. Whole-exome sequencing revealed compound heterozygous mutations, both of which were novel, in the protein O-mannosyl kinase (POMK) gene in both siblings; a missense mutation, p.Pro322Leu (c.965C > T), and a nonsense mutation, p.Arg46Ter (c.136C > T). The results were confirmed by Sanger sequencing, showing that the parents were heterozygous carriers of one mutation each. This report adds to the literature by providing phenotype and genotype data on this ultra-rare POMK-related dystroglycanopathy.

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