| 21. |
- 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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| 22. |
- 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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| 23. |
- 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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| 24. |
- Kollberg, Gittan, 1963, et al.
(författare)
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Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron-sulphur cluster deficiency myopathy
- 2011
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 21:2, s. 115-120
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 25. |
- Kranendijk, Martijn, et al.
(författare)
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IDH2 Mutations in Patients with D-2-Hydroxyglutaric Aciduria.
- 2010
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 330:6002
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Tidskriftsartikel (refereegranskat)abstract
- Heterozygous somatic mutations in the genes encoding isocitrate dehydrogenase- 1 and -2 (IDH1 and IDH2) were recently discovered in human neoplastic disorders. These mutations disable the enzymes' normal ability to convert isocitrate to 2-ketoglutarate (2-KG) and confer on the enzymes a new function: the ability to convert 2-KG to d-2-hydroxyglutarate (D-2-HG). We have detected heterozygous germline mutations in IDH2 that alter enzyme residue R140 in 15 unrelated patients with d-2-hydroxyglutaric aciduria (D-2-HGA), a rare neurometabolic disorder characterized by supraphysiological levels of D-2-HG. These findings provide additional impetus for investigating the role of D-2-HG in the pathophysiology of metabolic disease and cancer.
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| 26. |
- Kyllerman, Mårten, 1941, et al.
(författare)
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Long-term follow-up, neurological outcome and survival rate in 28 Nordic patients with glutaric aciduria type 1.
- 2004
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Ingår i: European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. - 1090-3798. ; 8:3, s. 121-9
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Tidskriftsartikel (refereegranskat)abstract
- All 28 patients, 13 females and 15 males, with glutaric aciduria type 1 diagnosed between 1975 and 2001 in Denmark, Finland, Norway and Sweden were identified and studied retrospectively until 2001. Mass screening was not performed. Three were sibling cases. Prenatal enzymatic diagnosis performed in 11 pregnancies led to termination in one. The median follow-up time was 14 years. Six patients had died. At 10 years of age the cumulative survival rate was 89% and at 35 years 44%. The dominating neurological sign was dystonia in 20 and dyskinesia in 4. Three had only slight spastic signs and information was missing in one. The head circumference at birth was significantly larger than normal and increased significantly until 6 months of age. The onset was acute encephalopathic in 24 patients and insidious in 3. From the time of diagnosis, all patients but one were prescribed protein restriction and/or a diet low in lysine and tryptophan. Riboflavine and/or carnitine supplementation were given to 25. Neurological deficits did not improve on the offered treatment. Deterioration may have been averted by intense acute metabolic treatment in a few patients. Dystonia correlated significantly to absence of speech but not to cognitive function. Severe disability, including motor, cognitive and speech functions, correlated significantly with acute onset, dystonia and mortality, and weakly with a deteriorating course, but not with age at onset, diagnosis, or follow-up, nor to head size. Results from future population studies derived from mass screening will have to relate to clinical diagnostic series of the kind presented here.
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| 27. |
- Larochelle, Jean, et al.
(författare)
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Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec.
- 2012
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Ingår i: Molecular genetics and metabolism. - : Elsevier BV. - 1096-7206 .- 1096-7192. ; 107:1-2, s. 49-54
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Tidskriftsartikel (refereegranskat)abstract
- Hepatorenal tyrosinemia (HT1, fumarylacetoacetate hydrolase deficiency, MIM 276700) can cause severe hepatic, renal and peripheral nerve damage. In Québec, HT1 is frequent and neonatal HT1 screening is practiced. Nitisinone (NTBC, Orfadin ®) inhibits tyrosine degradation prior to the formation of toxic metabolites like succinylacetone and has been offered to HT1 patients in Québec since 1994.
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| 28. |
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| 29. |
- Moslemi, Ali-Reza, et al.
(författare)
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A novel mutation in the mitochondrial tRNA(Phe) gene associated with mitochondrial myopathy
- 2004
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Ingår i: Neuromuscul Disord. ; 14:1, s. 46-50
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Tidskriftsartikel (refereegranskat)abstract
- We report a novel heteroplasmic T-->C mutation at nt position 582 within the mitochondrial tRNA(Phe) gene of a 70-year-old woman with mitochondrial myopathy. No other family members were affected, suggesting that our patient was a sporadic case. The muscle showed frequent ragged red fibers and 43% cytochrome c oxidase deficient fibers. The mutation alters a conserved base pairing in the aminoacyl acceptor stem. The mutation load was 70% in muscle homogenate and varied from 0 to 95% in individual muscle fiber segments. Cytochrome c oxidase-negative fibers showed significantly higher levels of mutated mtDNA (>75%) than Cytochrome c oxidase-positive fibers (<55%). This mutation adds to the previously described four pathogenic mutations in the tRNA(Phe) gene.
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| 30. |
- Moslemi, Ali-Reza, et al.
(författare)
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Progressive encephalopathy and complex I deficiency associated with mutations in MTND1.
- 2008
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Ingår i: Neuropediatrics. - : Georg Thieme Verlag KG. - 0174-304X .- 1439-1899. ; 39:1, s. 24-8
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Tidskriftsartikel (refereegranskat)abstract
- Complex I of the oxidative phosphorylation system is composed of at least 45 subunits, seven of which are encoded by mitochondrial DNA (mtDNA). In this study we have investigated two children with complex I deficiency in muscle mitochondria. Patient 1 had cerebellar ataxia from early infancy and an abnormal MRI of the brain compatible with Leigh syndrome (LS). The course was rapidly progressive with frequent exacerbations and death at 2 years and 10 months of age. Patient 2 had a lactic acidosis in the newborn period and had a severe psychomotor developmental retardation. In her teens she developed hypertrophic cardiomyopathy and died at 26 years of age because of cardiac insufficiency. Sequencing analysis of mitochondrial encoded ND genes (MTND) showed two DE NOVO mutations in MTND1 in both patients. Patient 1 had a novel heteroplasmic G3890A mutation, R195Q. Patient 2 had a heteroplasmic G3481A mutation, E59K. The G3890A mutation in patient 1 is the first identified mutation in MTND1 in association with LS and complex I deficiency. The findings in this patient as well as in patient 2 demonstrate new clinical expressions of mutations in MTND1. The findings in patient 2 also illustrates that MTND mutations may be pathogenic even at a low percentage.
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