| 1. |
- Darin, Niklas, 1964, et al.
(author)
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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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In: Neuromuscular disorders : NMD. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 16:8, s. 504-6
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Journal article (peer-reviewed)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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| 2. |
- Horvath, Rita, et al.
(author)
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Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.
- 2009
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 132:Pt 11, s. 3165-74
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Journal article (peer-reviewed)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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| 3. |
- Kollberg, Gittan, 1963, et al.
(author)
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A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion.
- 2009
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In: Neuromuscular disorders : NMD. - : Elsevier BV. - 0960-8966. ; 19:2, s. 147-50
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Journal article (peer-reviewed)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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| 4. |
- Kollberg, Gittan, 1963, et al.
(author)
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Antisense oligonucleotide therapeutics for iron-sulphur cluster deficiency myopathy.
- 2009
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In: Neuromuscular disorders : NMD. - : Elsevier BV. - 1873-2364 .- 0960-8966. ; 19:12, s. 833-6
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Journal article (peer-reviewed)abstract
- Iron-sulphur cluster deficiency myopathy is caused by a deep intronic mutation in ISCU resulting in inclusion of a cryptic exon in the mature mRNA. ISCU encodes the iron-sulphur cluster assembly protein IscU. Iron-sulphur clusters are essential for most basic redox transformations including the respiratory-chain function. Most patients are homozygous for the mutation with a phenotype characterized by a non-progressive myopathy with childhood onset of early fatigue, dyspnoea and palpitation on trivial exercise. A more severe phenotype with early onset of a slowly progressive severe muscle weakness, severe exercise intolerance and cardiomyopathy is caused by a missense mutation in compound with the intronic mutation. Treatment of cultured fibroblasts derived from three homozygous patients with an antisense phosphorodiamidate morpholino oligonucleotide for 48 h resulted in 100% restoration of the normal splicing pattern. The restoration was stable and after 21 days the correctly spliced mRNA still was the dominating RNA species.
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| 5. |
- Kollberg, Gittan, 1963, et al.
(author)
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Cardiomyopathy and exercise intolerance in muscle glycogen storage disease 0.
- 2007
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In: The New England journal of medicine. - 1533-4406. ; 357:15, s. 1507-14
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Journal article (peer-reviewed)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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| 6. |
- Kollberg, Gittan, 1963, et al.
(author)
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Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy
- 2009
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 132:8, s. 2170-2179
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Journal article (peer-reviewed)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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| 7. |
- Kollberg, Gittan, 1963
(author)
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Crisis in Energy Metabolism - Mitochondrial Defects and a New Disease Entity
- 2006
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Doctoral thesis (other academic/artistic)abstract
- Impairment of energy metabolism may be associated with severe implications for affected individuals since all fundamental cell functions are energy-dependent. Disorders of energy metabolism are often genetic and associated with defects in the oxidative phosphorylation in mitochondria. This thesis addresses the pathogenesis in some mitochondrial disorders and a new disease entity associated with defects in the glycogen metabolism. In paper I we report on a primary mutation in mitochondrial DNA. We identified a T?C mutation at position 582 in the gene for tRNAPhe in a case of mitochondrial myopathy. The mutation alters a conserved base pairing in the aminoacyl stem of the tRNA. By analysis of single muscle fibers we showed that the level of heteroplasmy (proportion of mutant mtDNA) was higher in muscle fibers with defective cytochrome c oxidase (COX) activity compared to normal muscle fibers. Based on these findings we conclude that this mutation was responsible for the disease. In paper II we investigated a 30-year-old woman, who presented with an attack of acute rhabdomyolysis. We found an isolated deficiency of COX and a novel nonsense mutation in mtDNA in the gene encoding COX subunit I. In addition to its catalytic function, our data clearly indicates an important function of subunit I for the assembly of COX. The mutation was restricted to the patient?s muscle, but was not detectable in myoblasts, cultured from satellite cells isolated from affected muscle tissue. This result may have interesting implications for the natural evolution of the disease and perhaps therapy, since regenerating muscle occurs by proliferation of satellite cells. In paper III we investigated patients with mitochondrial diseases (progressive external ophthalmoplegia, PEO) due to primary mutations in POLG1 encoding mtDNA polymerase gamma (Pol?) and secondary multiple mtDNA deletions. The results show that it is very unlikely that mtDNA point mutations contribute to the pathogenesis in PEO patients with primary POLG1 mutations, and that the mechanism by which mutant Pol? cause mtDNA deletions does not involve mtDNA point mutations as an intermediate step, as has been previously proposed. In paper IV mtDNA alterations and pathology of muscle, brain and liver was investigated in children with Alpers-Huttenlocher syndrome (AHS), a fatal neurodegenerative disease associated with liver failure. All children had compound heterozygous missense mutations in POLG1. We provide evidence that AHS is a mitochondrial disease by demonstrating mtDNA alterations (reduced mtDNA copy number and multiple mtDNA deletions). Liver disease was triggered by valproate treatment in several cases possibly due to severe respiratory chain deficiency, which was demonstrated in liver tissue in one case. In paper V we report on a new disease entity ?Muscle glycogen storage disease type zero? due to a homozygous stop mutation in the muscle glycogen synthase gene (GYS1). We performed investigations on a family where one child suffered sudden cardiac death at the age of 10 and his younger brother showed muscle fatigability and hypertrophic cardiomyopathy. In muscle there was a profound glycogen deficiency and an almost total predominance of oxidative muscle fibers.
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| 8. |
- Kollberg, Gittan, 1963, et al.
(author)
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Low frequency of mtDNA point mutations in patients with PEO associated with POLG1 mutations.
- 2005
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In: 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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Journal article (peer-reviewed)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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| 9. |
- Kollberg, Gittan, 1963, et al.
(author)
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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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In: Journal of neuropathology and experimental neurology. - 0022-3069. ; 64:2, s. 123-8
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Journal article (peer-reviewed)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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| 10. |
- Kollberg, Gittan, 1963, et al.
(author)
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POLG1 mutations associated with progressive encephalopathy in childhood.
- 2006
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In: Journal of neuropathology and experimental neurology. - : Oxford University Press (OUP). - 0022-3069 .- 1554-6578. ; 65:8, s. 758-68
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Journal article (peer-reviewed)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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