| 1. |
- Kimber, Eva, 1951, et al.
(författare)
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A mutation in the fast skeletal muscle troponin I gene causes myopathy and distal arthrogryposis
- 2006
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 1526-632X .- 0028-3878. ; 67:4, s. 597-601
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
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| 3. |
- Kollberg, Gittan, 1963, et al.
(författare)
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Cardiomyopathy and exercise intolerance in muscle glycogen storage disease 0.
- 2007
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Ingår i: The New England journal of medicine. - 1533-4406. ; 357:15, s. 1507-14
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Tidskriftsartikel (refereegranskat)abstract
- Storage of glycogen is essential for glucose homeostasis and for energy supply during bursts of activity and sustained muscle work. We describe three siblings with profound muscle and heart glycogen deficiency caused by a homozygous stop mutation (R462-->ter) in the muscle glycogen synthase gene. The oldest brother died from sudden cardiac arrest at the age of 10.5 years. Two years later, an 11-year-old brother showed muscle fatigability, hypertrophic cardiomyopathy, and an abnormal heart rate and blood pressure while exercising; a 2-year-old sister had no symptoms. In muscle-biopsy specimens obtained from the two younger siblings, there was lack of glycogen, predominance of oxidative fibers, and mitochondrial proliferation. Glucose tolerance was normal.
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| 4. |
- Kollberg, Gittan, 1963, et al.
(författare)
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POLG1 mutations associated with progressive encephalopathy in childhood.
- 2006
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Ingår i: Journal of neuropathology and experimental neurology. - : Oxford University Press (OUP). - 0022-3069 .- 1554-6578. ; 65:8, s. 758-68
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Tidskriftsartikel (refereegranskat)abstract
- We have identified compound heterozygous missense mutations in POLG1, encoding the mitochondrial DNA polymerase gamma (Pol gamma), in 7 children with progressive encephalopathy from 5 unrelated families. The clinical features in 6 of the children included psychomotor regression, refractory seizures, stroke-like episodes, hepatopathy, and ataxia compatible with Alpers-Huttenlocher syndrome. Three families harbored a previously reported A467T substitution, which was found in compound with the earlier described G848S or the W748S substitution or a novel R574W substitution. Two families harbored the W748S change in compound with either of 2 novel mutations predicted to give an R232H or M1163R substitution. Muscle morphology showed mitochondrial myopathy with cytochrome c oxidase (COX)-deficient fibers in 4 patients. mtDNA analyses in muscle tissue revealed mtDNA depletion in 3 of the children and mtDNA deletions in the 2 sibling pairs. Neuropathologic investigation in 3 children revealed widespread cortical degeneration with gliosis and subcortical neuronal loss, especially in the thalamus, whereas there were only subcortical neurodegenerative findings in another child. The results support the concept that deletions as well as depletion of mtDNA are involved in the pathogenesis of Alpers-Huttenlocher syndrome and add 3 new POLG1 mutations associated with an early-onset neurodegenerative disease.
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| 5. |
- Ochala, Julien, et al.
(författare)
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Effects of a R133W beta-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres
- 2007
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Ingår i: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 581:Pt 3, s. 1283-92
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Tidskriftsartikel (refereegranskat)abstract
- A novel R133W β-tropomyosin (β-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 β-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 β-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 β-Tm mutation. It is suggested that the R133W β-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.
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| 6. |
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| 7. |
- Tajsharghi, Homa, 1968, et al.
(författare)
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Distal arthrogryposis and muscle weakness associated with a beta-tropomyosin mutation
- 2007
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 1526-632X .- 0028-3878. ; 68:10, s. 772-5
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
- Tajsharghi, Homa, 1968, et al.
(författare)
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Embryonic myosin heavy-chain mutations cause distal arthrogryposis and developmental myosin myopathy that persists postnatally.
- 2008
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Ingår i: Archives of neurology. - : American Medical Association (AMA). - 1538-3687 .- 0003-9942. ; 65:8, s. 1083-90
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
- Bevilacqua, Jorge A, et al.
(författare)
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"Necklace" fibers, a new histological marker of late-onset MTM1-related centronuclear myopathy.
- 2009
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 117:3, s. 283-91
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the gene encoding the phosphoinositide phosphatase myotubularin 1 protein (MTM1) are usually associated with severe neonatal X-linked myotubular myopathy (XLMTM). However, mutations in MTM1 have also been recognized as the underlying cause of "atypical" forms of XLMTM in newborn boys, female infants, female manifesting carriers and adult men. We reviewed systematically the biopsies of a cohort of patients with an unclassified form of centronuclear myopathy (CNM) and identified four patients presenting a peculiar histological alteration in some muscle fibers that resembled a necklace ("necklace fibers"). We analyzed further the clinical and morphological features and performed a screening of the genes involved in CNM. Muscle biopsies in all four patients demonstrated 4-20% of fibers with internalized nuclei aligned in a basophilic ring (necklace) at 3 microm beneath the sarcolemma. Ultrastructurally, such necklaces consisted of myofibrils of smaller diameter, in oblique orientation, surrounded by mitochondria, sarcoplasmic reticulum and glycogen granules. In the four patients (three women and one man), myopathy developed in early childhood but was slowly progressive. All had mutations in the MTM1 gene. Two mutations have previously been reported (p.E404K and p.R241Q), while two are novel; a c.205_206delinsAACT frameshift change in exon 4 and a c.1234A>G mutation in exon 11 leading to an abnormal splicing and the deletion of nine amino acids in the catalytic domain of MTM1. Necklace fibers were seen neither in DNM2- or BIN1-related CNM nor in males with classical XLMTM. The presence of necklace fibers is useful as a marker to direct genetic analysis to MTM1 in CNM.
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| 10. |
- Darin, Niklas, 1964, et al.
(författare)
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Inflammation and response to steroid treatment in limb-girdle muscular dystrophy 2I
- 2007
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Ingår i: Eur J Paediatr Neurol. - : Elsevier BV. ; 11:6, s. 353-7
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Tidskriftsartikel (refereegranskat)abstract
- Limb-girdle muscular dystrophy (LGMD) type 2I, caused by mutations in the fukutin-related protein gene (FKRP), is one of the most common forms of LGMD in childhood. We describe two patients with LGMD2I and a Duchenne-like phenotype. In addition to the common L276I mutation, both patients had a new mutation in FKRP, L169P and P89L, respectively. Clinical onset was triggered by viral upper respiratory tract infections. In addition to the common dystrophic pattern with a weak immune histochemical staining for alpha-dystroglycan, muscle biopsy showed inflammatory changes. This was especially striking in one of the patients with up-regulation of MHC class 1 antigen, suggestive of myositis. Both patients showed a good clinical response to treatment with prednisolone, which was initiated at daily dosage of 0.35mg/kg/day. Our results provide evidence for an inflammatory involvement in the pathological expression of LGMD2I and open up the possibility that this disorder could be treatable with corticosteroids.
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| 11. |
- Darin, Niklas, 1964, et al.
(författare)
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Mitochondrial myopathy with exercise intolerance and retinal dystrophy in a sporadic patient with a G583A mutation in the mt tRNA(phe) gene
- 2006
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Ingår i: Neuromuscular disorders : NMD. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 16:8, s. 504-6
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Tidskriftsartikel (refereegranskat)abstract
- We describe a second patient with the 583G>A mutation in the tRNA(phe) gene of mitochondrial DNA (mtDNA). This 17-year-old girl had a mitochondrial myopathy with exercise intolerance and an asymptomatic retinopathy. Muscle investigations showed occasional ragged red fibers, 30% cytochrome c oxidase (COX)-negative fibers, and reduced activities of complex I+IV in the respiratory chain. The mutation was heteroplasmic (79%) in muscle but undetectable in other tissues. Analysis of single muscle fibers revealed a significantly higher level of mutated mtDNA in COX-negative fibers. Our study indicates that the 583G>A mutation is pathogenic and expands the clinical spectrum of this mutation.
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| 12. |
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| 13. |
- Horvath, Rita, et al.
(författare)
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Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.
- 2009
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 132:Pt 11, s. 3165-74
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Tidskriftsartikel (refereegranskat)abstract
- Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as 'benign cytochrome c oxidase deficiency myopathy' is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T>C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.
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| 14. |
- Kollberg, Gittan, 1963, et al.
(författare)
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A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion.
- 2009
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Ingår i: Neuromuscular disorders : NMD. - : Elsevier BV. - 0960-8966. ; 19:2, s. 147-50
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Tidskriftsartikel (refereegranskat)abstract
- This report describes two brothers, both deceased in infancy, with severe depletion of mitochondrial DNA (mtDNA) in muscle tissue. Both had feeding difficulties, failure to thrive, severe muscular hypotonia and lactic acidosis. One of the boys developed a renal proximal tubulopathy. A novel homozygous c.686 G-->T missense mutation in the RRM2B gene, encoding the p53-inducible ribonucleotide reductase subunit (p53R2), was identified. This is the third report on mutations in RRM2B associated with severe mtDNA depletion, which further highlights the importance of de novo synthesis of deoxyribonucleotides (dNTPs) for mtDNA maintenance.
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| 15. |
- Kollberg, Gittan, 1963, et al.
(författare)
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Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy
- 2009
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 132:8, s. 2170-2179
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Tidskriftsartikel (refereegranskat)abstract
- Myopathy with deficiency of succinate dehydrogenase and aconitase is a recessively inherited disorder characterized by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, severe metabolic acidosis and rhabdomyolysis may occur. The disease has so far only been identified in northern Sweden. The clinical, histochemical and biochemical phenotype is very homogenous and the patients are homozygous for a deep intronic IVS5 382GC splicing affecting mutation in ISCU, which encodes the differently spliced cytosolic and mitochondrial ironsulphur cluster assembly protein IscU. Ironsulphur cluster containing proteins are essential for iron homeostasis and respiratory chain function, with IscU being among the most conserved proteins in evolution. We identified a shared homozygous segment of only 405 000 base pair with the deep intronic mutation in eight patients with a phenotype consistent with the original description of the disease. Two other patients, two brothers, had an identical biochemical and histochemical phenotype which is probably pathognomonic for muscle ironsulphur cluster deficiency, but they presented with a disease where the clinical phenotype was characterized by early onset of a slowly progressive severe muscle weakness, severe exercise intolerance and cardiomyopathy. The brothers were compound heterozygous for the deep intronic mutation and had a c.149 GA missense mutation in exon 3 changing a completely conserved glycine residue to a glutamate. The missense mutation was inherited from their mother who was of Finnish descent. The intronic mutation affects mRNA splicing and results in inclusion of pseudoexons in most transcripts in muscle. The pseudoexon inclusion results in a change in the reading frame and appearance of a premature stop codon. In western blot analysis of protein extracts from fibroblasts, there was no pronounced reduction of IscU in any of the patients, but the analysis revealed that the species corresponding to mitochondrial IscU migrates slower than a species present only in whole cells. In protein extracted from isolated skeletal muscle mitochondria the western blot analysis revealed a severe deficiency of IscU in the homozygous patients and appearance of a faint new fraction that could represent a truncated protein. There was only a slight reduction of mitochondrial IscU in the compound heterozygotes, despite their severe phenotype, indicating that the IscU expressed in these patients is non-functional.
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| 16. |
- Kollberg, Gittan, 1963, et al.
(författare)
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Low frequency of mtDNA point mutations in patients with PEO associated with POLG1 mutations.
- 2005
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Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 13:4, s. 463-9
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial myopathy in progressive external ophthalmoplegia (PEO) has been associated with POLG1 mutations. POLG1 encodes the catalytic alpha subunit of polymerase gamma and is the only polymerase known to be involved in mtDNA replication. It has two functionally different domains, one polymerase domain and one exonuclease domain with proofreading activity. In this study we have investigated whether mtDNA point mutations are involved, directly or indirectly, in the pathogenesis of PEO. Muscle biopsy specimens from patients with POLG1 mutations, affecting either the exonuclease or the polymerase domain, were investigated. Single cytochrome c oxidase (COX)-deficient muscle fibers were dissected and screened for clonally expanded mtDNA point mutations using a sensitive denaturing gradient gel electrophoresis analysis, in which three different regions of mtDNA, including five different tRNA genes, were investigated. To screen for randomly distributed mtDNA point mutations in muscle, two regions of mtDNA including deletion breakpoints were investigated by high-fidelity PCR, followed by cloning and sequencing. Long-range PCR revealed multiple mtDNA deletions in all the patients but not the controls. No point mutations were identified in single COX-deficient muscle fibers. Cloning and sequencing of muscle homogenate identified randomly distributed point mutations at very low frequency in patients and controls (<1:50 000). We conclude that mtDNA point mutations do not appear to be directly or indirectly involved in the pathogenesis of mitochondrial disease in patients with different POLG1 mutations.
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| 17. |
- Kollberg, Gittan, 1963, et al.
(författare)
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Mitochondrial myopathy and rhabdomyolysis associated with a novel nonsense mutation in the gene encoding cytochrome c oxidase subunit I.
- 2005
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Ingår i: Journal of neuropathology and experimental neurology. - 0022-3069. ; 64:2, s. 123-8
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial DNA (mtDNA) mutations associated with rhabdomyolysis are rare but have been described in sporadic cases with mutations in the cytochrome b and cytochrome c oxidase (COX) genes and in 3 cases with tRNALeu mutation. We report a novel heteroplasmic G6708A nonsense mutation in the mtDNA COI gene encoding COX subunit I in a 30-year-old woman with muscle weakness, pain, fatigue, and one episode of rhabdomyolysis. Histochemical examination of muscle biopsy specimens revealed reduced COX activity in the majority of the muscle fibers (approximately 90%) and frequent ragged red fibers. Biochemical analysis showed a marked and isolated COX deficiency. Analysis of DNA extracted from single fibers revealed higher levels of the mutation in COX-deficient fibers (> 95%) compared with COX-positive fibers (1%-80%). The mutation was not detected in a skin biopsy, cultured myoblasts, or blood leukocytes. Nor was it identified in blood leukocytes from the asymptomatic mother, indicating a de novo mutation that arose after germ layer differentiation. Western blot analysis and immunohistochemical staining revealed that reduced levels of COX subunit I were accompanied by reduced levels of other mtDNA encoded subunits, as well as nuclear DNA encoded subunit IV, supporting the concept that COX subunit I is essential for the assembly of complex IV in the respiratory chain.
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| 18. |
- Kärppä, Mikko, et al.
(författare)
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Spectrum of myopathic findings in 50 patients with the 3243A>G mutation in mitochondrial DNA
- 2005
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 128:Pt 8, s. 1861-9
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Tidskriftsartikel (refereegranskat)abstract
- Myopathy is a typical clinical finding among patients with the 3243A>G mutation in mitochondrial DNA (mtDNA), but the variability in such findings has not been properly established. We have previously determined the prevalence of patients with 3243A>G in a defined population in northern Finland and characterized a group of patients who represent a good approximation to a population-based cohort. We report here on examinations performed on patients belonging to this cohort in order to determine the frequency of myopathy and to evaluate the clinical, histological, ultrastructural and single fibre mtDNA variability in muscle involvement. Fifty patients with 3243A>G underwent a thorough structured interview and clinical examination. Muscle histology, ultrastructure and single fibre analysis were examined in a subset of patients. A clinical diagnosis of myopathy was made in 50% of cases [95% confidence interval (CI), 36-64] and abnormalities in muscle histology were found in 72% (95% CI, 55-86). Moderate limb weakness leading to functional impairment was the most common myopathic sign, but mild weakness, ptosis and external ophthalmoplegia could also be found. The presence of intramitochondrial crystals and cytochrome c oxidase (COX)-negative fibres and variation in mitochondrial size and shape were more common in the muscles of the myopathic patients. Longitudinal variations in mutation heteroplasmy were examined in single muscle fibres from two severely affected patients. Although the total variation in mutation heteroplasmy along four ragged red fibres (RRFs) was small, the mutation heteroplasmy in five 10 microm segments was clearly lower (median 68%, range 64-74%) than that in the neighbouring segments. There were also segments with deviant mutation load in histologically normal fibres in one patient. The highest incidence of myopathy was in the fifth decade of life, but, apart from age, no other clinical variables such as gender, muscle heteroplasmy, physical inactivity or diabetes were associated with an increased risk of myopathy. The clinical presentation of myopathy is highly variable in patients with 3243A>G.
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| 19. |
- Li, Mingxin, et al.
(författare)
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Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys)
- 2006
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 16:11, s. 782-791
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 20. |
- Lindberg, Christopher, et al.
(författare)
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MELAS syndrome in a patient with a point mutation in MTTS1.
- 2008
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Ingår i: Acta neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 117:2, s. 128-32
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND, OBJECTIVE AND METHODS: We describe a female patient with a mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome. As a child, she developed epilepsy and stroke-like episodes giving cognitive impairment and ataxia but no hearing impairment. At the age of 44 years, she suffered a cerebral sinus thrombosis which was warfarin treated. One month later, she developed an episode of severe acidosis associated with encephalopathy and myelopathy. RESULTS: She was found to harbour a 7512T>C mutation in the mitochondrial encoded tRNA(Ser(UCN)) gene (MTTS1). The mutation load was 91% in muscle and 24% in blood. Enzyme histochemical analysis of the muscle tissue showed numerous cytochrome c oxidase (COX)-negative fibres. Restriction fragment length polymorphism (RFLP) analysis of single muscle fibres showed significantly higher level (median 97%, range: 94-99%) of the mutation in the COX-negative fibres compared with COX-positive fibres (median 36%, range: 12-91%), demonstrating the pathogenic effect of the mutation. Different levels of heteroplasmy (range 34-61%) were detected in hair shafts analysed by RFLP. CONCLUSION: This case adds to the spectrum of clinical presentations, i.e. sinus thrombosis, in patients having MTTS1 mutations.
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| 21. |
- Lindberg, Christopher, et al.
(författare)
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Raised troponin T in inclusion body myositis is common and serum levels are persistent over time
- 2006
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Ingår i: Neuromuscul Disord. - : Elsevier BV. ; 16:8, s. 495-7
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Tidskriftsartikel (refereegranskat)abstract
- Cardiac Troponin T (cTnT), creatine kinase (CK) and creatine kinase isoenzyme MB (CKMB) were measured in 42 consecutive patients with sporadic inclusion body myositis (s-IBM). 26 patients (62%) had a cTnT level >0.05mug/L, the cut off used in the diagnosis of myocardial infarction. The cTnT levels correlated somewhat more closely to CKMB (rho=0.83, p<0.0001) than to CK (rho=0.60, p<0.0001). Patients on immunosuppressive treatment had lower cTnT levels than untreated, while there were no significant differences according to age, disease duration or gender. Repeated samples in 26 patients showed that the cTnT levels were essentially unchanged over time up to 17 months. None of the patients had signs of myocardial damage or renal failure at time of sampling. It may be of value to analyse cTnT at some occasion(s) in s-IBM patients.
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| 22. |
- Maagaard, A., et al.
(författare)
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Mitochondrial (mt)DNA changes in tissue may not be reflected by depletion of mtDNA in peripheral blood mononuclear cells in HIV-infected patients
- 2006
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Ingår i: Antivir Ther. ; 11:5, s. 601-8
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Most data on mitochondrial toxicity have been derived from peripheral blood mononuclear cells (PBMCs). However, whether mitochondrial DNA (mtDNA) content in PBMCs reflects the mitochondrial state in tissues remains elusive. We report herein on mitochondrial toxicity in skeletal muscle in HIV-infected patients naive to antiretroviral treatment (ART [HIV+ART-naive]; n = 10) patients exposed to nucleoside reverse transcriptase inhibitors (NRTIs [HIV+NRTI+]; n = 24) and healthy controls (n = 11), and compare these tissue data with mtDNA in PBMCs. METHODS: Muscle biopsies were examined for (i) mtDNA and nuclear DNA (nDNA) content using TaqMan real-time PCR system, (ii) mtDNA deletions using long expand PCR with subsequent gel electrophoresis, and (iii) mitochondrial myopathy expressed as cytochrome c oxidase (COX)-deficient muscle fibres. RESULTS: The mt/n DNA ratio in muscle from HIV+NRTI+ patients was reduced compared with HIV-negative controls (P = 0.028). Moreover, mtDNA deletions were more frequent in HIV+NRTI+ patients than in both HIV-negative controls (P = 0.009) and HIV+ART-naive patients (P = 0.005). HIV+NRTI+ also tended to have more COX-deficient fibres than HIV-negative controls (P = 0.076). COX-deficient fibres were positively correlated with mtDNA deletions in HIV+NRTI+ patients (r = 0.83, P < 0.001). Patients with current use of didanosine (ddl) had more frequent mtDNA deletions and COX-deficient fibres than HIV+NRTI+ not on current treatment with ddl. It should be noted that mitochondrial alterations were not correlated with mtDNA/cell in PBMCs in any group. CONCLUSIONS: In skeletal muscle, HIV+NRTI+ had a reduced mt/n DNA ratio, more frequent mtDNA deletions and possibly more COX-deficient muscle fibres than HIV-negative controls. However, the mtDNA/cell in peripheral blood was decreased in both HIV+NRTI+ and HIV+ART-naive patients. Thus, mtDNA in peripheral blood may not be a relevant marker of mitochondrial toxicity in organ-specific tissue.
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| 23. |
- Mayr, J A, et al.
(författare)
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A novel sporadic mutation G14739A of the mitochondrial tRNA(Glu) in a girl with exercise intolerance
- 2006
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Ingår i: Neuromuscul Disord. - : Elsevier BV. ; 16:12, s. 874-7
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Tidskriftsartikel (refereegranskat)abstract
- We describe a 7-year-old girl who presented with loss of appetite, weakness and excercise intolerance. Enzyme investigation of the respiratory chain in muscle tissue revealed a combined complex I, III and IV deficiency. A novel heteroplasmic G-->A exchange at nucleotide position 14739 was found in the MTTE gene of the tRNA glutamic acid. The mutation load in muscle was 72%, urine sediment 38%, blood 31% and fibroblasts 29% and it correlated with COX-negative fibres. Our patient presented with a predominantly myopathic phenotype. The G14739A mutation is the third reported in the mitochondrial tRNA glutamic acid gene, and it occurred in a sporadic case.
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| 24. |
- Melberg, Atle, et al.
(författare)
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A patient with two mitochondrial DNA mutations causing PEO and LHON.
- 2009
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Ingår i: European journal of medical genetics. - : Elsevier BV. - 1878-0849 .- 1769-7212. ; 52:1, s. 47-8
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Tidskriftsartikel (refereegranskat)abstract
- We report a 22-year-old man with PEO and optic atrophy. PEO developed before the onset of optic atrophy. The patient showed mitochondrial myopathy with cytochrome c oxidase deficient fibers. In skeletal muscle the patient was homoplasmic for the mtDNA G11778A Leber hereditary optic neuropathy (LHON) mutation and heteroplasmic for the mtDNA 5 kb "common" deletion mutation. In blood only the homoplasmic LHON mutation was identified. The occurrence of two pathogenic mtDNA mutations is exceedingly rare. The clinical findings in this patient indicate that the combination of the two mtDNA mutations resulted in the expected combined phenotype since the mtDNA deletion mutation accounted for the PEO and the mtDNA G11778A point mutation for the optic atrophy.
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