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Sökning: WFRF:(Hedberg Carola 1969)

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1.
  • Darin, Niklas, 1964, et al. (författare)
  • Functional analysis of a novel POL gamma A mutation associated with a severe perinatal mitochondrial encephalomyopathy
  • 2021
  • Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 31:4, s. 348-358
  • Tidskriftsartikel (refereegranskat)abstract
    • Mutations in the mitochondrial DNA polymerase gamma catalytic subunit (POL. A) compromise the stability of mitochondrial DNA (mtDNA) by leading to mutations, deletions and depletions in mtDNA. Patients with mutations in POL gamma A often differ remarkably in disease severity and age of onset. In this work we have studied the functional consequence of POL gamma A mutations in a patient with an uncommon and a very severe disease phenotype characterized by prenatal onset with intrauterine growth restriction, lactic acidosis from birth, encephalopathy, hepatopathy, myopathy, and early death. Muscle biopsy identified scattered COX-deficient muscle fibers, respiratory chain dysfunction and mtDNA depletion. We identified a novel POL.A mutation (p.His1134Tyr) in trans with the previously identified p.Thr251Ile/Pro587Leu double mutant. Biochemical characterization of the purified recombinant POL gamma A variants showed that the p.His1134Tyr mutation caused severe polymerase dysfunction. The p.Thr251Ile/Pro587Leu mutation caused reduced polymerase function in conditions of low dNTP concentration that mimic postmitotic tissues. Critically, when p.His1134Tyr and p.Thr251Ile/Pro587Leu were combined under these conditions, mtDNA replication was severely diminished and featured prominent stalling. Our data provide a molecular explanation for the patients mtDNA depletion and clinical features, particularly in tissues such as brain and muscle that have low dNTP concentration. (c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
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2.
  • Hedberg, Carola, 1969, et al. (författare)
  • Hereditary myopathy with early respiratory failure is associated with misfolding of the titin fibronectin III 119 subdomain
  • 2014
  • Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 24:5, s. 373-379
  • Tidskriftsartikel (refereegranskat)abstract
    • Hereditary myopathy with early respiratory failure is a rare disease with muscle weakness and respiratory failure as early symptoms. Muscle pathology is characterized by the presence of multiple cytoplasmic bodies and other protein aggregates in muscle fibers. The disease is associated with mutations in the titin gene (TTN). All patients harbor mutations located in exon 343 in the TTN gene that codes for the fibronectin III domain 119 (FN3 119) in the 10th motif of the 11-element motif A-band super-repeat. We investigated how such disease-causing mutations affect the biochemical behavior of this titin domain. All five disease-causing amino acid changes analyzed by us (p.P30068R, p.C30071R, p.W30088R, p.W30088C and p.P30091L) resulted in impaired FN3 119 domain solubility. In contrast, amino acid changes associated with common SNPs (p.V30076I, p.R30107C and p.S30125F) did not have this effect. In silica analyses further support the notion that disease-causing mutations impair proper folding of the FN3 119 domain. The results suggest that hereditary myopathy with early respiratory failure is caused by defective protein folding. (C) 2014 Elsevier B.V. All rights reserved.
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3.
  • Lindgren, Ulrika, et al. (författare)
  • Inclusion body myositis with early onset: a population-based study
  • 2023
  • Ingår i: Journal of Neurology. - 0340-5354. ; :270, s. 5483-5492
  • Tidskriftsartikel (refereegranskat)abstract
    • IntroductionInclusion body myositis (IBM), an inflammatory myopathy with progressive weakness without efficient treatment, typically presents after 45 years of age and younger patients are sparsely studied.MethodsIn a population-based study during a 33-year period, 142 patients with IBM were identified in western Sweden. Six patients fell outside the European Neuromuscular Centre 2011 criteria for IBM due to young age at symptom onset, verified by a muscle biopsy < 50 years of age. These were defined as early-onset IBM and included in this study. Medical records, muscle strength, comorbidities, muscle biopsies, and nuclear- and mitochondrial DNA were examined and compared with patients with IBM and age matched controls from the same population.ResultsThe median age at symptom onset was 36 (range 34-45) years and at diagnosis 43 (range 38-58) years. Four patients were deceased at a median age of 59 (range 50-75) years. The median survival from diagnosis was 14 (range 10-18) years. The prevalence December 31 2017 was 1.2 per million inhabitants and the mean incidence 0.12 patients per million inhabitants and year. The mean decline in quadriceps strength & PLUSMN; 1 standard deviation was 1.21 & PLUSMN; 0.2 Newton or 0.91 & PLUSMN; 0.2% per month and correlated to time from diagnosis (p < 0.001). Five patients had swallowing difficulties. All patients displayed mitochondrial changes in muscle including cytochrome c oxidase deficiency and the mitochondrial DNA mutation load was high.ConclusionsEarly-onset IBM is a severe disease, causing progressive muscle weakness, high muscle mitochondrial DNA mutation load and a reduced cumulative survival in young and middle-aged individuals.
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4.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Deep sequencing of mitochondrial DNA and characterization of a novel POLG mutation in a patient with arPEO.
  • 2020
  • Ingår i: Neurology. Genetics. - 2376-7839. ; 6:1
  • Tidskriftsartikel (refereegranskat)abstract
    • To determine the pathogenicity of a novel POLG mutation in a man with late-onset autosomal recessive progressive external ophthalmoplegia using clinical, molecular, and biochemical analyses.A multipronged approach with detailed neurologic examinations, muscle biopsy analyses, molecular genetic studies, and in vitro biochemical characterization.The patient had slowly progressive bilateral ptosis and severely reduced horizontal and vertical gaze. Muscle biopsy showed slight variability in muscle fiber size, scattered ragged red fibers, and partial cytochrome c oxidase deficiency. Biallelic mutations were identified in the POLG gene encoding the catalytic A subunit of POLγ. One allele carried a novel mutation in the exonuclease domain (c.590T>C; p.F197S), and the other had a previously characterized null mutation in the polymerase domain (c.2740A>C; p.T914P). Biochemical characterization revealed that the novel F197S mutant protein had reduced exonuclease and DNA polymerase activities and confirmed that T914P was inactive. By deep sequencing of mitochondrial DNA (mtDNA) extracted from muscle, multiple large-scale rearrangements were mapped and quantified.The patient's phenotype was caused by biallelic POLG mutations, resulting in one inactive POLγA protein (T914P) and one with decreased polymerase and exonuclease activity (F197S). The reduction in polymerase activity explains the presence of multiple pathogenic large-scale deletions in the patient's mtDNA.
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5.
  • Ávila-Polo, R., et al. (författare)
  • Loss of Sarcomeric Scaffolding as a Common Baseline Histopathologic Lesion in Titin-Related Myopathies
  • 2018
  • Ingår i: Journal of Neuropathology and Experimental Neurology. - : Oxford University Press (OUP). - 1554-6578 .- 0022-3069. ; 77:12, s. 1101-1114
  • Tidskriftsartikel (refereegranskat)abstract
    • Titin-related myopathies are heterogeneous clinical conditions associated with mutations in TTN. To define their histopathologic boundaries and try to overcome the difficulty in assessing the pathogenic role of TTN variants, we performed a thorough morphological skeletal muscle analysis including light and electron microscopy in 23 patients with different clinical phenotypes presenting pathogenic autosomal dominant or autosomal recessive (AR) mutations located in different TTN domains. We identified a consistent pattern characterized by diverse defects in oxidative staining with prominent nuclear internalization in congenital phenotypes (AR-CM) (n=10), ±necrotic/regenerative fibers, associated with endomysial fibrosis and rimmed vacuoles (RVs) in AR early-onset Emery-Dreifuss-like (AR-ED) (n=4) and AR adult-onset distal myopathies (n=4), and cytoplasmic bodies (CBs) as predominant finding in hereditary myopathy with early respiratory failure (HMERF) patients (n=5). Ultrastructurally, the most significant abnormalities, particularly in AR-CM, were multiple narrow core lesions and/or clear small areas of disorganizations affecting one or a few sarcomeres with M-band and sometimes A-band disruption and loss of thick filaments. CBs were noted in some AR-CM and associated with RVs in HMERF and some AR-ED cases. As a whole, we described recognizable histopathological patterns and structural alterations that could point toward considering the pathogenicity of TTN mutations.
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6.
  • Basu, Swaraj, et al. (författare)
  • Accurate mapping of mitochondrial DNA deletions and duplications using deep sequencing
  • 2020
  • Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Deletions and duplications in mitochondrial DNA (mtDNA) cause mitochondrial disease and accumulate in conditions such as cancer and age-related disorders, but validated high-throughput methodology that can readily detect and discriminate between these two types of events is lacking. Here we establish a computational method, MitoSAlt, for accurate identification, quantification and visualization of mtDNA deletions and duplications from genomic sequencing data. Our method was tested on simulated sequencing reads and human patient samples with single deletions and duplications to verify its accuracy. Application to mouse models of mtDNA maintenance disease demonstrated the ability to detect deletions and duplications even at low levels of heteroplasmy. Author summary Deletions in the mitochondrial genome cause a wide variety of rare disorders, but are also linked to more common conditions such as neurodegeneration, diabetes type 2, and the normal ageing process. There is also a growing awareness that mtDNA duplications, which are also relevant for human disease, may be more common than previously thought. Despite their clinical importance, our current knowledge about the abundance, characteristics and diversity of mtDNA deletions and duplications is fragmented, and based to large extent on a limited view provided by traditional low-throughput analyses. Here, we describe a bioinformatics method, MitoSAlt, that can accurately map and classify mtDNA deletions and duplications using high-throughput sequencing. Application of this methodology to mouse models of mitochondrial deficiencies revealed a large number of duplications, suggesting that these may previously have been underestimated.
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7.
  • Casar-Borota, Olivera, et al. (författare)
  • A novel dynamin-2 gene mutation associated with a late-onset centronuclear myopathy with necklace fibres
  • 2015
  • Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 25:4, s. 345-348
  • Tidskriftsartikel (refereegranskat)abstract
    • 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. (C) 2015 Elsevier B.V. All rights reserved.
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8.
  • Darin, Niklas, 1964, et al. (författare)
  • Benign mitochondrial myopathy with exercise intolerance in a large multigeneration family due to a homoplasmic m.3250T>C mutation in MTTL1.
  • 2017
  • Ingår i: European journal of neurology. - : Wiley. - 1468-1331 .- 1351-5101. ; 24:4, s. 587-593
  • Tidskriftsartikel (refereegranskat)abstract
    • Most mitochondrial disorders with onset in early childhood are progressive and involve multiple organs. The m.3250T>C mutation in MTTL1 has previously been described in a few individuals with a possibly riboflavin-responsive myopathy and an association with sudden infant death syndrome was suspected. We describe a large family with this mutation and evaluate the effect of riboflavin treatment.Medical data were collected with the help of a standardized data collection form. Sanger sequencing was used to screen for variants in mitochondrial DNA and the proportion of the mutation was analyzed in different tissues. Biochemical and muscle morphological investigations of muscle tissue were performed in two individuals. The effect of riboflavin treatment was evaluated in two individuals.Thirteen family members experienced exercise intolerance with fatigue and weakness. Inheritance was maternal with 100% penetrance. The course was either static or showed improvement over time. There was no evidence of other organ involvement except for a possible mild transient cardiac enlargement in one child. Muscle investigations showed isolated complex I deficiency and mitochondrial proliferation. The level of m.3250T>C was apparently 100%, i.e. homoplasmic, in all examined tissues. Riboflavin treatment showed no effect in any treated family member and there have been no cases of sudden infant death in this family.This study illustrates the importance of considering mitochondrial disorders in the work-up of individuals with exercise intolerance and provides a better understanding of the phenotype associated with the m.3250T>C mutation in MTTL1.
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9.
  • Donkervoort, S., et al. (författare)
  • Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores
  • 2020
  • Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 107:6, s. 1078-1095
  • Tidskriftsartikel (refereegranskat)abstract
    • The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.
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10.
  • Falck, Eva, et al. (författare)
  • SKY analysis revealed recurrent numerical and structural chromosome changes in BDII rat endometrial carcinomas
  • 2011
  • Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Genomic alterations are common features of cancer cells, and some of these changes are proven to be neoplastic-specific. Such alterations may serve as valuable tools for diagnosis and classification of tumors, prediction of clinical outcome, disease monitoring, and choice of therapy as well as for providing clues to the location of crucial cancer-related genes. Endometrial carcinoma (EC) is the most frequently diagnosed malignancy of the female genital tract, ranking fourth among all invasive tumors affecting women. Cytogenetic studies of human ECs have not produced very conclusive data, since many of these studies are based on karyotyping of limited number of cases and no really specific karyotypic changes have yet been identified. As the majority of the genes are conserved among mammals, the use of inbred animal model systems may serve as a tool for identification of underlying genes and pathways involved in tumorigenesis in humans. In the present work we used spectral karyotyping (SKY) to identify cancer-related aberrations in a well-characterized experimental model for spontaneous endometrial carcinoma in the BDII rat tumor model. Results: Analysis of 21 experimental ECs revealed specific nonrandom numerical and structural chromosomal changes. The most recurrent numerical alterations were gains in rat chromosome 4 (RNO4) and losses in RNO15. The most commonly structural changes were mainly in form of chromosomal translocations and were detected in RNO3, RNO6, RNO10, RNO11, RNO12, and RNO20. Unbalanced chromosomal translocations involving RNO3p was the most commonly observed structural changes in this material followed by RNO11p and RNO10 translocations. Conclusion: The non-random nature of these events, as documented by their high frequencies of incidence, is suggesting for dynamic selection of these changes during experimental EC tumorigenesis and therefore for their potential contribution into development of this malignancy. Comparative molecular analysis of the identified genetic changes in this tumor model with those reported in the human ECs may provide new insights into underlying genetic changes involved in EC development and tumorigenesis.
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11.
  • Hedberg, Carola, 1969, et al. (författare)
  • Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation
  • 2012
  • Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 20:9, s. 984-985
  • Tidskriftsartikel (refereegranskat)abstract
    • Using exome sequencing we searched for the genetic cause of autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy (ARVC) in a Swedish family. A heterozygous C-to-T transition, c.1255C>T, p.Pro419Ser in the desmin gene on chromosome 2q35, was identified. Previous studies had demonstrated linkage to chromosome 10q22.3, but no causative mutation had been found in that region. Sanger sequencing of DNA from 17 family members confirmed the heterozygous c.1255C>T desmin mutation in seven out of ten family members that had been classified as affected in the previous study. Our new results demonstrate the usefulness of next-generation sequencing, and the diagnostic difficulties with some forms of dominantly inherited muscle diseases as they can display a wide clinical and morphological variability even within a given family. European Journal of Human Genetics (2012) 20, 984-985; doi:10.1038/ejhg.2012.39; published online 7 March 2012
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12.
  • Hedberg, Carola, 1969, et al. (författare)
  • B3GALNT2 is a gene associated with congenital muscular dystrophy with brain malformations.
  • 2014
  • Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 22:5, s. 707-710
  • Tidskriftsartikel (refereegranskat)abstract
    • Congenital muscular dystrophies associated with brain malformations are a group of disorders frequently associated with aberrant glycosylation of α-dystroglycan. They include disease entities such a Walker-Warburg syndrome, muscle-eye-brain disease and various other clinical phenotypes. Different genes involved in glycosylation of α-dystroglycan are associated with these dystroglycanopathies. We describe a 5-year-old girl with psychomotor retardation, ataxia, spasticity, muscle weakness and increased serum creatine kinase levels. Immunhistochemistry of skeletal muscle revealed reduced glycosylated α-dystroglycan. Magnetic resonance imaging of the brain at 3.5 years of age showed increased T2 signal from supratentorial and infratentorial white matter, a hypoplastic pons and subcortical cerebellar cysts. By whole exome sequencing, the patient was identified to be compound heterozygous for a one-base duplication and a missense mutation in the gene B3GALNT2 (β-1,3-N-acetylgalactosaminyltransferase 2; B3GalNAc-T2). This patient showed a milder phenotype than previously described patients with mutations in the B3GALNT2 gene.European Journal of Human Genetics advance online publication, 2 October 2013; doi:10.1038/ejhg.2013.223.
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13.
  • Hedberg, Carola, 1969, et al. (författare)
  • Childhood onset tubular aggregate myopathy associated with de novo STIM1 mutations
  • 2014
  • Ingår i: Journal of Neurology. - : Springer. - 0340-5354 .- 1432-1459. ; 261:5, s. 870-876
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated three unrelated patients with tubular-aggregate myopathy and slowly progressive muscle weakness manifesting in the first years of life. All patients showed type 1 muscle fiber predominance and hypotrophy of type 2 fibers. Tubular aggregates were abundant. In all three patients mutations were identified in the gene STIM1, and the mutations were found to be de novo in all patients. In one of the patients the mutation was identified by exome sequencing. Two patients harbored the previously described mutation c.326A > G p.(His109Arg), while the third patient had a novel mutation c.343A > T p.(Ile115Phe). Taking our series together with previously published cases, the c.326A > G p.(His109Arg) seems to be a hotspot mutation that is characteristically related to early onset muscle weakness.
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14.
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15.
  • Hedberg, Carola, 1969, et al. (författare)
  • Myopathy in a woman and her daughter associated with a novel splice site MTM1 mutation.
  • 2012
  • Ingår i: Neuromuscular disorders : NMD. - : Elsevier BV. - 1873-2364 .- 0960-8966. ; 22:3, s. 244-51
  • Tidskriftsartikel (refereegranskat)abstract
    • We have investigated a woman and her daughter with an early onset, slowly progressive myopathy. Muscle biopsy showed in both cases severe atrophy with marked fatty replacement. Frequent fibers with internalized nuclei were present but no typical features of centronuclear myopathy. There were also many fibers with deep invaginations of the plasma membrane. The presence of necklace fibers provided clue to correct genetic diagnosis. Both patients had a novel heterozygous splice site mutation in the myotubularin gene, MTM1 (c.867+1G>T). Analysis of MTM1 cDNA revealed that the mutation resulted in aberrant splicing with variable exon skipping. The expression of normal transcripts was markedly reduced and there was reduced expression of myotubularin protein. Although the expression of the allele without the mutation was reduced we did not obtain evidence of skewed X-chromosome inactivation. Other factors than skewed X-inactivation may cause allele inactivation and manifestation of severe myopathy in heterozygous carriers of pathogenic MTM1 mutations.
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16.
  • Hedberg, Carola, 1969 (författare)
  • Novel Tumor Suppressor Gene Candidates in Experimental Endometrial Carcinoma - From Cytogenetic to Molecular Analysis
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Endometrial carcinoma (EC) is the most common form of gynecological malignancy, ranking fourth in incidence among tumors diagnosed in women. As is the case with other complex diseases, detailed analyses of the underlying mechanisms of cancer are difficult, due mainly to the genetic heterogeneity of the human population and differences in the environment and lifestyle of individuals. In this sense, analysis in animal models may serve as a valuable complement. The inbred BDII rat strain is genetically prone to spontaneous hormone-related EC and it has been used as a powerful model to investigate molecular alterations in this tumor type. BDII female rats were crossed with males from two non-susceptible rat strains and tumors were developed in a significant fraction of the progeny. We subjected a subset of BDII rat tumors to detailed analysis based on the molecular data used for the classification of human ECs. Our analysis revealed that this tumor model can be related to higher grade human type I ECs, i.e. a subgroup of ECs that constitutes more than 80% of this tumor type in humans. Earlier work using comparative genome hybridization (CGH) revealed that rat chromosome 10 (RNO10) was frequently involved in cytogenetic aberrations in BDII rat tumors. To identify the potential target region(s)/gene(s) for these changes, we subjected a panel of rat ECs to allelic imbalance (AI) analysis. Four distinct regions of recurrent AI were identified. By deriving evolutionary tree models based on AI data, we demonstrated that one of these AI regions (located adjacent to Tp53) was close to the root in the derived onco-tree models, indicating that this segment might harbor early important events. In combined FISH, chromosome paint, gene expression and gene sequencing analyses, we found that, instead of Tp53, the main selection target was a region close and distal to Tp53. We developed a detailed deletion map of this area and substantially narrowed down the size of the candidate region. We then subjected all 19 genes located within this segment to qPCR analysis, followed by statistical analysis of the results, and thus identified the Hic1, Skip and Myo1c genes as potential target(s). By subjecting these genes to DNA sequencing, analysis of protein expression and of epigenetic silencing, we ruled out Hic1 and confirmed Skip and Myo1c as the candidates. Interestingly, it appears that Skip and Myo1c perform overlapping roles in PI 3-kinase/Akt signaling, which is known to have implications for the survival and growth of cancer cells. In conclusion, starting from cytogenetic findings and applying a candidate gene approach, we introduced two attractive candidate genes within the independent region of tumor suppressor activity distal to Tp53.
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17.
  • Hedberg, Carola, 1969, et al. (författare)
  • Reply to Brodehl et al.
  • 2013
  • Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 21:6
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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18.
  • Jennions, Elizabeth, et al. (författare)
  • TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism
  • 2019
  • Ingår i: Journal of Inherited Metabolic Disease. - : Wiley. - 0141-8955 .- 1573-2665. ; 42:5, s. 898-908
  • Tidskriftsartikel (refereegranskat)abstract
    • Exome sequencing has recently identified mutations in the gene TANGO2 (transport and Golgi organization 2) as a cause of developmental delay associated with recurrent crises involving rhabdomyolysis, cardiac arrhythmias, and metabolic derangements. The disease is not well understood, in part as the cellular function and subcellular localization of the TANGO2 protein remain unknown. Furthermore, the clinical syndrome with its heterogeneity of symptoms, signs, and laboratory findings is still being defined. Here, we describe 11 new cases of TANGO2-related disease, confirming and further expanding the previously described clinical phenotype. Patients were homozygous or compound heterozygous for previously described exonic deletions or new frameshift, splice site, and missense mutations. All patients showed developmental delay with ataxia, dysarthria, intellectual disability, or signs of spastic diplegia. Of importance, we identify two subjects (aged 12 and 17 years) who have never experienced any overt episode of the catabolism-induced metabolic crises typical for the disease. Mitochondrial complex II activity was mildly reduced in patients investigated in association with crises but normal in other patients. In one deceased patient, post-mortem autopsy revealed heterotopic neurons in the cerebral white matter, indicating a possible role for TANGO2 in neuronal migration. Furthermore, we have addressed the subcellular localization of several alternative isoforms of TANGO2, none of which were mitochondrial but instead appeared to have a primarily cytoplasmic localization. Previously described aberrations in Golgi morphology were not observed in cultured skin fibroblasts.
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19.
  • Laforet, P., et al. (författare)
  • Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment
  • 2019
  • Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene. In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large nonmembrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model. In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples. These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.
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20.
  • Lindgren, Ulrika, et al. (författare)
  • Mitochondrial pathology in inclusion body myositis
  • 2015
  • Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 25:4, s. 281-288
  • Tidskriftsartikel (refereegranskat)abstract
    • Inclusion body myositis (IBM) is usually associated with a large number of cytochrome c oxidase (COX)-deficient muscle fibers and acquired mitochondrial DNA (mtDNA) deletions. We studied the number of COX-deficient fibers and the amount of mtDNA deletions, and if variants in nuclear genes involved in mtDNA maintenance may contribute to the occurrence of mtDNA deletions in IBM muscle. Twenty-six IBM patients were included. COX-deficient fibers were assayed by morphometry and mtDNA deletions by qPCR. POLG was analyzed in all patients by Sanger sequencing and C10orf2 (Twinkle), DNA2, MGME1, OPA1, POLG2, RRM2B, SLC25A4 and TYMP in six patients by next generation sequencing. Patients with many COX-deficient muscle fibers had a significantly higher proportion of mtDNA deletions than patients with few COX-deficient fibers. We found previously unreported variants in POLG and C10orf2 and IBM patients had a significantly higher frequency of an RRM2B variant than controls. POLG variants appeared more common in IBM patients with many COX-deficient fibers, but the difference was not statistically significant. We conclude that COX-deficient fibers in inclusion body myositis are associated with multiple mtDNA deletions. In IBM patients we found novel and also previously reported variants in genes of importance for mtDNA maintenance that warrants further studies. (C) 2014 Elsevier B.V. All rights reserved.
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21.
  • Luo, S. S., et al. (författare)
  • Muscle pathology and whole-body MRI in a polyglucosan myopathy associated with a novel glycogenin-1 mutation
  • 2015
  • Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 25:10, s. 780-785
  • Tidskriftsartikel (refereegranskat)abstract
    • We report a 46-year-old female with late-onset skeletal myopathy affecting proximal limb muscles. Muscle biopsy revealed a polyglucosan myopathy with PAS-positive inclusions predominantly in glycogen-depleted fibers, which were demonstrated as type I fibers by ATPase staining. Whole-body magnetic imaging disclosed that the paravertebral, scapular, and pelvic girdle muscles, the anterior compartment of the arms, and the posterior compartment of the thighs were preferentially involved. Genetic analysis revealed a homozygous novel mutation in exon 6 of the glycogenin-1 gene (GYG1) (c.634C>T, p.His212Tyr). Protein, analysis revealed normal levels of glycogenin-1 even before alpha-amylase digestion indicating preserved protein expression but impaired glucosylation. In vitro functional assay demonstrated that this variant impaired the autoglucosylating ability resulting in a non-functional protein. We report a glycogenin-1 related myopathy with a distinct histopathology and unique muscle imaging pattern. (C) 2015 Elsevier B.V. All rights reserved.
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22.
  • Malfatti, Edoardo, et al. (författare)
  • A New Muscle Glycogen Storage Disease Associated with Glycogenin-1 Deficiency
  • 2014
  • Ingår i: Annals of Neurology. - : Wiley. - 0364-5134. ; 76:6, s. 891-898
  • Tidskriftsartikel (refereegranskat)abstract
    • We describe a slowly progressive myopathy in 7 unrelated adult patients with storage of polyglucosan in muscle fibers. Genetic investigation revealed homozygous or compound heterozygous deleterious variants in the glycogenin-1 gene (GYG1). Most patients showed depletion of glycogenin-1 in skeletal muscle, whereas 1 showed presence of glycogenin-1 lacking the C-terminal that normally binds glycogen synthase. Our results indicate that either depletion of glycogenin-1 or impaired interaction with glycogen synthase underlies this new form of glycogen storage disease that differs from a previously reported patient with GYG1 mutations who showed profound glycogen depletion in skeletal muscle and accumulation of glycogenin-1. Ann Neurol 2014;76:891-898
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23.
  • Malfatti, E., et al. (författare)
  • A novel neuromuscular form of glycogen storage disease type IV with arthrogryposis, spinal stiffness and rare polyglucosan bodies in muscle
  • 2016
  • Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 26:10, s. 681-687
  • Tidskriftsartikel (refereegranskat)abstract
    • Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder causing polyglucosan storage in various tissues. Neuromuscular forms present with fetal akinesia deformation sequence, lethal myopathy, or mild hypotonia and weakness. A 3-year-old boy presented with arthrogryposis, motor developmental delay, weakness, and rigid spine. Whole body MRI revealed fibroadipose muscle replacement but sparing of the sartorius, gracilis, adductor longus and vastus intermedialis muscles. Polyglucosan bodies were identified in muscle, and GBE1 gene analysis revealed two pathogenic variants. We describe a novel neuromuscular GSD IV phenotype and confirm the importance of muscle morphological studies in early onset neuromuscular disorders. © 2016
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24.
  • Meinert, Monika, et al. (författare)
  • Danon disease presenting with early onset of hypertrophic cardiomyopathy and peripheral pigmentary retinal dystrophy in a female with a de novo novel mosaic mutation in the LAMP2 gene
  • 2019
  • Ingår i: Ophthalmic Genetics. - : Informa UK Limited. - 1381-6810 .- 1744-5094. ; 40:3, s. 227-236
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: To describe the phenotype and genotype in a young woman with Danon disease. Methods: The patient underwent an ophthalmic examination including best corrected visual acuity (BCVA), fundus photography and fundus autofluorescence (FAF), full-field electroretinography (full-field ERG), multifocal ERG, optical coherence tomography (OCT) and SAP-Humphrey 30-2 at the ages of 20 and 25. Electrooculography, fluorescein angiography (FA), indocyanine angiography and OCT angiography were performed only once. Genetic testing using a Next-Generation Sequencing panel and immunohistochemical analysis of LAMP2 protein expression were performed in the patient's explanted heart, and the patient's cardiologic and ophthalmologic records were retrospectively reviewed. Results: A de novo, novel, mosaic mutation, c.135dupA; p.(Trp46Metfs*10) was identified in exon 2 of the LAMP2 gene. Immunohistochemical investigation of the myocardium in the explanted heart revealed pronounced deficiency of LAMP2 protein in cardiomyocytes. The color photographs, FAF images and FA revealed more extensive peripheral pigmentary retinal dystrophy (PPRD) at the 5-year follow-up examination. No changes were observed in BCVA, OCT, SAP-Humphrey 30-2 or multifocal ERG findings at follow-up. Full-field ERG showed an asymmetric interocular reduction in ERG response at follow-up: the b-wave amplitude of the rod response had decreased by 29% in the right eye, but by only 6 % in the left eye. The a-wave amplitude of single-flash response had decreased by 9 % in the left eye, while it had increased by 3% in the right eye. Conclusions: Although PPRD progressed slowly, it was an important clue in the diagnosis of the life-threatening condition of Danon disease.
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25.
  • Michael, Eva, et al. (författare)
  • Long-term follow-up and characteristic pathological findings in severe nemaline myopathy due to LMOD3 mutations
  • 2019
  • Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 29:2, s. 108-113
  • Tidskriftsartikel (refereegranskat)abstract
    • We describe the long-term follow-up of a patient with severe nemaline myopathy due to a novel homozygous mutation in the Leiomodin 3 (LMOD3) gene and describe the histopathological characteristics of the disease. The patient presented at birth with hydrops fetalis, multiple joint contractures, severe generalized muscle weakness, no movement, and respiratory insufficiency. At eight years of age, she had bilateral ophthalmoplegia, visual impairment, multiple contractures, and scoliosis, and is dependent on a home mechanical ventilator and gastrostomy. Except for slight head nodding, she has no voluntary movements. Whole-exome sequencing revealed a homozygous one-base duplication in the LMOD3 gene (c.882dupA, p.Asp295Argfs*2), which would result in a truncated protein. Muscle biopsy in the girl and an unrelated patient homozygous for LMOD3 p.G1u357* showed characteristic morphology of the nemaline rods. Many rods appeared as fragments of thickened Z-discs, frequently in pairs, which were interconnected by short thin filaments. Although not specific, this may be a morphological hallmark of LMOD3-associated nemaline myopathy.
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26.
  • Ohlsson, Monica, et al. (författare)
  • Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin
  • 2012
  • Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 135:6, s. 1682-1694
  • Tidskriftsartikel (refereegranskat)abstract
    • Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T > C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.
  •  
27.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency.
  • 2016
  • Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 24:12, s. 1771-1777
  • Tidskriftsartikel (refereegranskat)abstract
    • We describe a new early-onset neuromuscular disorder due to a homozygous loss-of-function variant in the kyphoscoliosis peptidase gene (KY). A 7.5-year-old girl with walking difficulties from 2 years of age presented with generalized muscle weakness; mild contractures in the shoulders, hips and feet; cavus feet; and lordosis but no scoliosis. She had previously been operated with Achilles tendon elongation. Whole-body MRI showed atrophy and fatty infiltration in the calf muscles. Biopsy of the vastus lateralis muscle showed variability in fiber size, with some internalized nuclei and numerous very small fibers with variable expression of developmental myosin heavy chain isoforms. Some small fibers showed abnormal sarcomeres with thickened Z-discs and small nemaline rods. Whole-exome sequencing revealed a homozygous one-base deletion (c.1071delG, p.(Thr358Leufs*3)) in KY, predicted to result in a truncated protein. Analysis of an RNA panel showed that KY is predominantly expressed in skeletal muscle in humans. A recessive variant in the murine ortholog Ky was previously described in a spontaneously generated mouse mutant with kyphoscoliosis, which developed postnatally and was caused by dystrophy of postural muscles. The abnormal distribution of Xin and Ky-binding partner filamin C in the muscle fibers of our patient was highly similar to their altered localization in ky/ky mouse muscle fibers. We describe the first human case of disease associated with KY inactivation. As in the mouse model, the affected child showed a neuromuscular disorder - but in contrast, no kyphoscoliosis.
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28.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Analysis of an independent tumor suppressor locus telomeric to Tp53 suggested Inpp5k and Myo1c as novel tumor suppressor gene candidates in this region
  • 2015
  • Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 16:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Several reports indicate a commonly deleted chromosomal region independent from, and distal to the TP53 locus in a variety of human tumors. In a previous study, we reported a similar finding in a rat tumor model for endometrial carcinoma (EC) and through developing a deletion map, narrowed the candidate region to 700 kb, harboring 19 genes. In the present work real-time qPCR analysis, Western blot, semi-quantitative qPCR, sequencing, promoter methylation analysis, and epigenetic gene expression restoration analyses (5-aza-2'-deoxycytidine and/or trichostatin A treatments) were used to analyze the 19 genes located within the candidate region in a panel of experimental tumors compared to control samples. Results: Real-time qPCR analysis suggested Hic1 (hypermethylated in cancer 1), Inpp5k (inositol polyphosphate-5-phosphatase K; a.k.a. Skip, skeletal muscle and kidney enriched inositol phosphatase) and Myo1c (myosin 1c) as the best targets for the observed deletions. No mutation in coding sequences of these genes was detected, hence the observed low expression levels suggest a haploinsufficient mode of function for these potential tumor suppressor genes. Both Inpp5k and Myo1c were down regulated at mRNA and/or protein levels, which could be rescued in gene expression restoration assays. This could not be shown for Hic1. Conclusion:Innp5k and Myo1c were identified as the best targets for the deletions in the region. INPP5K and MYO1C are located adjacent to each other within the reported independent region of tumor suppressor activity located at chromosome arm 17p distal to TP53 in human tumors. There is no earlier report on the potential tumor suppressor activity of INPP5K and MYO1C, however, overlapping roles in phosphoinositide (PI) 3-kinase/Akt signaling, known to be vital for the cell growth and survival, are reported for both. Moreover, there are reports on tumor suppressor activity of other members of the gene families that INPP5K and MYO1C belong to. Functional significance of these two candidate tumor suppressor genes in cancerogenesis pathways remains to be investigated.
  •  
29.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Cardiomyopathy as presenting sign of glycogenin-1 deficiency-report of three cases and review of the literature.
  • 2017
  • Ingår i: Journal of inherited metabolic disease. - : Wiley. - 1573-2665 .- 0141-8955. ; 40:1, s. 139-149
  • Tidskriftsartikel (refereegranskat)abstract
    • We describe a new type of cardiomyopathy caused by a mutation in the glycogenin-1 gene (GYG1). Three unrelated male patients aged 34 to 52years with cardiomyopathy and abnormal glycogen storage on endomyocardial biopsy were homozygous for the missense mutation p.Asp102His in GYG1. The mutated glycogenin-1 protein was expressed in cardiac tissue but had lost its ability to autoglucosylate as demonstrated by an in vitro assay and western blot analysis. It was therefore unable to form the primer for normal glycogen synthesis. Two of the patients showed similar patterns of heart dilatation, reduced ejection fraction and extensive late gadolinium enhancement on cardiac magnetic resonance imaging. These two patients were severely affected, necessitating cardiac transplantation. The cardiomyocyte storage material was characterized by large inclusions of periodic acid and Schiff positive material that was partly resistant to alpha-amylase treatment consistent with polyglucosan. The storage material had, unlike normal glycogen, a partly fibrillar structure by electron microscopy. None of the patients showed signs or symptoms of muscle weakness but a skeletal muscle biopsy in one case revealed muscle fibres with abnormal glycogen storage. Glycogenin-1 deficiency is known as a rare cause of skeletal muscle glycogen storage disease, usually without cardiomyopathy. We demonstrate that it may also be the cause of severe cardiomyopathy and cardiac failure without skeletal muscle weakness. GYG1 should be included in cardiomyopathy gene panels.
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30.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24
  • 2019
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 28:11, s. 1919-1929
  • Tidskriftsartikel (refereegranskat)abstract
    • Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown. Here, we show that mutations in KLHL24 cause HCM in humans. Using genome-wide linkage analysis and exome sequencing, we identified homozygous mutations in KLHL24 in two consanguineous families with HCM. Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure. KLHL24 is a member of the Kelch-like protein family, which acts as substrate-specific adaptors to Cullin E3 ubiquitin ligases. Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments. Knock-down of the zebrafish homologue klhl24a results in heart defects similar to that described for other HCM-linked genes providing additional support for KLHL24 as a HCM-associated gene. Our findings reveal a crucial role for KLHL24 in cardiac development and function.
  •  
31.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Carey-Fineman-Ziter syndrome with mutations in the myomaker gene and muscle fiber hypertrophy
  • 2018
  • Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective To describe the long-term clinical follow-up in 3 siblings with Carey-Fineman-Ziter syndrome (CFZS), a form of congenital myopathy with a novel mutation in the myomaker gene (MYMK). We performed clinical investigations, repeat muscle biopsy in 2 of the siblings at ages ranging from 11 months to 18 years, and whole-genome sequencing. All the siblings had a marked and characteristic facial weakness and variable dysmorphic features affecting the face, hands, and feet, and short stature. They had experienced muscle hypotonia and generalized muscle weakness since early childhood. The muscle biopsies revealed, as the only major abnormality at all ages, a marked hypertrophy of both type 1 and type 2 fibers with more than twice the diameter of that in age-matched controls. Genetic analysis revealed biallelic mutations in the MYMK gene, a novel c.235T>C; p.(Trp79Arg), and the previously described c.271C>A; p.(Pro91Thr). Our study expands the genetic and clinical spectrum of MYMK mutations and CFZS. The marked muscle fiber hypertrophy identified from early childhood, despite apparently normal muscle bulk, indicates that defective fusion of myoblasts during embryonic muscle development results in a reduced number of muscle fibers with compensatory hypertrophy and muscle weakness.
  •  
32.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • COX deficiency and leukoencephalopathy due to a novel homozygous APOPT1/COA8 mutation
  • 2020
  • Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 6:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective To describe the long-term follow-up and pathogenesis in a child with leukoencephalopathy and cytochrome c oxidase (COX) deficiency due to a novel homozygous nonsense mutation in APOPT1/COA8. Methods The patient was clinically investigated at 3, 5, 9, and 25 years of age. Brain MRI, repeat muscle biopsies with biochemical, morphologic, and protein expression analyses were performed, and whole-genome sequencing was used for genetic analysis. Results Clinical investigation revealed dysarthria, dysphagia, and muscle weakness following pneumonia at age 3 years. There was clinical regression leading to severe loss of ambulation, speech, swallowing, hearing, and vision. The clinical course stabilized after 2.5 years and improved over time. The MRI pattern in the patient demonstrated cavitating leukoencephalopathy, and muscle mitochondrial investigations showed COX deficiency with loss of complex IV subunits and ultrastructural abnormalities. Genetic analysis revealed a novel homozygous mutation in the APOPT1/COA8 gene, c.310T>C; p.(Gln104*). Conclusions We describe a novel nonsense mutation in APOPT1/COA8 and provide additional experimental evidence for a COX assembly defect in human muscle causing the complex IV deficiency. The long-term outcome of the disease seems in general to be favorable, and the characteristic MRI pattern with cavitating leukoencephalopathy in combination with COX deficiency should prompt for testing of the APOPT1/COA8 gene.
  •  
33.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Dominantly inherited myosin IIa myopathy caused by aberrant splicing of MYH2
  • 2022
  • Ingår i: BMC Neurology. - : Springer Science and Business Media LLC. - 1471-2377. ; 22:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Myosin heavy chain (MyHC) isoforms define the three major muscle fiber types in human extremity muscles. Slow beta/cardiac MyHC (MYH7) is expressed in type 1 muscle fibers. MyHC IIa (MYH2) and MyHC IIx (MYH1) are expressed in type 2A and 2B fibers, respectively. Whereas recessive MyHC IIa myopathy has been described in many cases, myopathy caused by dominant MYH2 variants is rare and has been described with clinical manifestations and muscle pathology in only one family and two sporadic cases. Methods We investigated three patients from one family with a dominantly inherited myopathy by clinical investigation, whole-genome sequencing, muscle biopsy, and magnetic resonance imaging (MRI). Results Three siblings, one woman and two men now 54, 56 and 66 years old, had experienced muscle weakness initially affecting the lower limbs from young adulthood. They have now generalized proximal muscle weakness affecting ambulation, but no ophthalmoplegia. Whole-genome sequencing identified a heterozygous MYH2 variant, segregating with the disease in the three affected individuals: c.5673 + 1G > C. Analysis of cDNA confirmed the predicted splicing defect with skipping of exon 39 and loss of residues 1860-1891 in the distal tail of the MyHC IIa, largely overlapping with the filament assembly region (aa1877-1905). Muscle biopsy in two of the affected individuals showed prominent type 1 muscle fiber predominance with only a few very small, scattered type 2A fibers and no type 2B fibers. The small type 2A fibers were frequently hybrid fibers with either slow MyHC or embryonic MyHC expression. The type 1 fibers showed variation in fiber size, internal nuclei and some structural alterations. There was fatty infiltration, which was also demonstrated by MRI. Conclusion Dominantly inherited MyHC IIa myopathy due to a splice defect causing loss of amino acids 1860-1891 in the distal tail of the MyHC IIa protein including part of the assembly competence domain. The myopathy is manifesting with slowly progressive muscle weakness without overt ophthalmoplegia and markedly reduced number and size of type 2 fibers.
  •  
34.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Early onset cardiomyopathy in females with Danon disease
  • 2015
  • Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 25:6, s. 493-501
  • Tidskriftsartikel (refereegranskat)abstract
    • Danon disease is caused by mutations in the lysosome-associated membrane protein-2 gene, LAMP2, located on the X chromosome. Female carriers with LAMP2 mutations most often present with late onset cardiomyopathy and slow disease progress; however, there are unusual cases that emerge early and show a more severe disease course. We investigated the explanted heart and skeletal muscle biopsies in two girls, aged ten and thirteen years, who underwent cardiac transplantation because of hypertrophic cardiomyopathy secondary to LAMP2 mutations and a 41-year old female with late-onset familial LAMP2 cardiomyopathy with more typical clinical phenotype. The two girls in contrast had clinical features that mimicked severe primary hypertrophic cardiomyopathy caused by mutations in genes encoding sarcomeric proteins. Immunohistochemistry in cardiac muscles showed a remarkable pattern with lack of LAMP2 protein in large regions including thousands of cardiomyocytes that also showed myocyte hypertrophy, lysosomial enlargement and disarray. In other equally large regions there were preserved LAMP2 expression and nearly normal histology. The skeletal muscle biopsy revealed no pathological changes. An uneven distribution of LAMP2 protein may cause deleterious effects depending on which regions of the myocardium are lacking LAMP2 protein in spite of an overall moderate reduction of LAMP2 protein. This may be a more common mechanism behind early aggressive disease in females than an overall skewed X-chromosome inactivation in the tissue. (C) 2015 Elsevier B.V. All rights reserved.
  •  
35.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Functional characterization of GYG1 variants in two patients with myopathy and glycogenin-1 deficiency
  • 2019
  • Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 29:12, s. 951-960
  • Tidskriftsartikel (refereegranskat)abstract
    • Glycogen storage disease XV is caused by variants in the glycogenin-1 gene, GYG1, and presents as a predominant skeletal myopathy or cardiomyopathy. We describe two patients with late-onset myopathy anti biallelic GYG1 variants. In patient 1, the novel c.144-2A>G splice acceptor variant and the novel frameshift variant c.631delG (p.Va1211Cysfs(star)30) were identified, and in patient 2, the previously described c.304G>C (p.Asp102His) and c.487deLG (p.Asp163Thrfs(star)5) variants were found. Protein analysis showed total absence of glycogenin-1 expression in patient 1, whereas in patient 2 there was reduced expression of glycogenin-1, with the residual protein being non-functional. Both patients showed glycogen and polyglucosan storage in their muscle fibers, as revealed by PAS staining and electron microscopy. Age at onset of the myopathy phenotype was 53 years and 70 years respectively, with the selective pattern of muscle involvement on MRI corroborating the pattern of weakness. Cardiac evaluation of patient 1 and 2 did not show any specific abnormalities linked to the glycogenin-1 deficiency. In patient 2, who was shown to express the p.Asp102His mutated glycogenin-1, cardiac evaluation was still normal at age 77 years. This contrasts with the association of the p.Asp102His variant in homozygosity with a severe cardiomyopathy in several cases with an onset age between 30 and 50 years. This finding might indicate that the level of p.Asp102His mutated glycogenin-1 determines if a patient will develop a cardiomyopathy. (C) 2019 Elsevier B.V. All rights reserved.
  •  
36.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Grand paternal inheritance of X-linked myotubular myopathy due to mosaicism, and identification of necklace fibers in an asymptomatic male.
  • 2017
  • Ingår i: Neuromuscular disorders : NMD. - : Elsevier BV. - 1873-2364 .- 0960-8966. ; 27:9, s. 843-847
  • Tidskriftsartikel (refereegranskat)abstract
    • X-linked recessive myotubular myopathy (XLMTM) is a disorder associated with mutations in the myotubularin gene (MTM1) that usually affects boys, with transmission of the mutated allele from the mother. Here we describe a family with unexpected grand paternal transmission of a novel mutation in MTM1 (c.646_648dupGTT; p.Val216dup) identified in a severely affected infant boy with a centronuclear myopathy. We confirmed the carrier status of the mother, but surprisingly we found that her father was a carrier of the mutated MTM1 gene together with wild-type MTM1. A muscle biopsy from the grandfather revealed occasional typical necklace fibers with internalized nucleus, which is typically found in MTM1-associated myopathies. Further analysis of the grandfather revealed equal amounts of DNA with the wild-type sequence and DNA with the c.646_648dupGTT variant in five different tissues examined. In the presence of a normal karyotype (46,XY) in the grandfather and no evidence of intragenic duplication of MTM1, the result was interpreted as postzygotic mosaicism and the mutation had probably occurred at the first mitosis of the zygote. This study demonstrates the importance of considering the possibility of paternal transmission in families with severe X-linked disorders. The muscle biopsy with the finding of typical necklace fibers was important to further establish the pathogenicity of the novel MTM1 mutation.
  •  
37.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles
  • 2020
  • Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:8, s. 2406-2420
  • Tidskriftsartikel (refereegranskat)abstract
    • The muscle specific isoform of the supervillin protein (SV2), encoded by the SVIL gene, is a large sarcolemmal myosin II- and F-actin-binding protein. Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines. Despite its important role in muscle cell physiology suggested by various in vitro studies, there are so far no reports of any human disease caused by SVIL mutations. We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. All patients showed increased levels of serum creatine kinase but no or minor muscle weakness. Mild cardiac manifestations were observed. Muscle biopsies showed complete loss of large supervillin isoforms in muscle fibres by western blot and immunohistochemical analyses. Light and electron microscopic investigations revealed a structural myopathy with numerous lobulated muscle fibres and considerable myofibrillar alterations with a coarse and irregular intermyofibrillar network. Autophagic vacuoles, as well as frequent and extensive deposits of lipoproteins, including immature lipofuscin, were observed. Several sarcolemma-associated proteins, including dystrophin and sarcoglycans, were partially mis-localized. The results demonstrate the importance of the supervillin (SV2) protein for the structural integrity of muscle fibres in humans and show that recessive loss-of-function mutations in SVIL cause a distinctive and novel myopathy
  •  
38.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Mitochondrial DNA variants in inclusion body myositis characterized by deep sequencing
  • 2021
  • Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 31:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Muscle pathology in inclusion body myositis (IBM) typically includes inflammatory cell infiltration, muscle fibers with rimmed vacuoles and cytochrome c oxidase (COX)-deficient fibers. Previous studies have revealed clonal expansion of large mitochondrial DNA (mtDNA) deletions in the COX-deficient muscle fibers. Technical limitations have prevented complete investigations of the mtDNA deletions and other mtDNA variants. Detailed characterization by deep sequencing of mtDNA in muscle samples from 21 IBM patients and 10 age-matched controls was performed after whole genome sequencing with a mean depth of mtDNA coverage of 46,000x. Multiple large mtDNA deletions and duplications were identified in all IBM and control muscle samples. In general, the IBM muscles demonstrated a larger number of deletions and duplications with a mean heteroplasmy level of 10% (range 1%-35%) compared to controls (1%, range 0.2%-3%). There was also a small increase in the number of somatic single nucleotide variants in IBM muscle. More than 200 rearrangements were recurrent in at least two or more IBM muscles while 26 were found in both IBM and control muscles. The deletions and duplications, with a high recurrence rate, were mainly observed in three mtDNA regions, m.534-4429, m.6330-13993, and m.8636-16072, where some were flanked by repetitive sequences. The mtDNA copy number in IBM muscle was reduced to 42% of controls. Immunohistochemical and western blot analyses of IBM muscle revealed combined complex I and complex IV deficiency affecting the COX-deficient fibers. In conclusion, deep sequencing and quantitation of mtDNA variants revealed that IBM muscles had markedly increased levels of large deletions and duplications, and there were also indications of increased somatic single nucleotide variants and reduced mtDNA copy numbers compared to age-matched controls. The distribution and type of variants were similar in IBM muscle and controls indicating an accelerated aging process in IBM muscle, possibly associated with chronic inflammation.
  •  
39.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Muscle pathology in Vici syndrome-A case study with a novel mutation in EPG5 and a summary of the literature.
  • 2017
  • Ingår i: Neuromuscular disorders : NMD. - : Elsevier BV. - 1873-2364 .- 0960-8966. ; 27:8, s. 771-776
  • Tidskriftsartikel (refereegranskat)abstract
    • Vici syndrome is a disorder characterized by myopathy, cardiomyopathy, agenesis of the corpus callosum, immunodeficiency, cataracts, hypopigmentation, microcephaly, gross developmental delay and failure to thrive. It is caused by mutations in EPG5, which encodes a protein involved in the autophagy pathway. Although myopathy is part of the syndrome, few publications have described the muscle pathology. We present a detailed morphological analysis in a boy with Vici syndrome due to a novel homozygous one-base deletion in EPG5 (c.784delA), and we review the histopathological findings from previous reports. Muscle biopsy was performed at three months of age and demonstrated small vacuolated fibers, frequently with internal nuclei, and expressing developmental and fast myosin isoforms. There was an increase in acid phosphatase activity in the small fibers, which also showed LAMP-2 upregulation, glycogen accumulation and contained numerous p62-positive inclusions and some lipid droplets. Electron microscopy demonstrated hypoplastic fibers with massive glycogen accumulation and extensive disorganization of the myofibrils. This study expands the muscle pathological features of Vici syndrome and demonstrates a pattern of vacuolar myopathy with glycogen storage and immature, hypoplastic and atrophic muscle fibers. Increased lysosomes and accumulation of p62 are in line with a disturbance of the autophagic pathway as an essential part of the pathogenesis.
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40.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Polyglucosan myopathy and functional characterization of a novel GYG1 mutation
  • 2018
  • Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314. ; 137:3, s. 308-315
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: Disorders of glycogen metabolism include rare hereditary muscle glycogen storage diseases with polyglucosan, which are characterized by storage of abnormally structured glycogen in muscle in addition to exercise intolerance or muscle weakness. In this study, we investigated the etiology and pathogenesis of a late-onset myopathy associated with glycogenin-1 deficiency. Materials and methods: A family with two affected siblings, 64- and 66-year-olds, was studied. Clinical examination and whole-body MRI revealed weakness and wasting in the hip girdle and proximal leg muscles affecting ambulation in the brother. The sister had weakness and atrophy of hands and slight foot dorsiflexion difficulties. Muscle biopsy and whole-exome sequencing were performed in both cases to identify and characterize the pathogenesis including the functional effects of identified mutations. Results: Both siblings demonstrated storage of glycogen that was partly resistant to alpha-amylase digestion. Both were heterozygous for two mutations in GYG1, one truncating 1-base deletion (c.484delG; p.Asp163Thrfs*5) and one novel missense mutation (c.403G>A; p.Gly135Arg). The mutations caused reduced expression of glycogenin-1 protein, and the missense mutation abolished the enzymatic function as analyzed by an in vitro autoglucosylation assay. Conclusion: We present functional evidence for the pathogenicity of a novel GYG1 missense mutation located in the substrate binding domain. Our results also demonstrate that glycogenin-1 deficiency may present with highly variable distribution of weakness and wasting also in the same family.
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41.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Polyglucosan storage myopathies
  • 2015
  • Ingår i: Molecular Aspects of Medicine. - : Elsevier BV. - 0098-2997. ; 46, s. 85-100
  • Tidskriftsartikel (refereegranskat)abstract
    • Polyglucosan is an amylopectin-like polysaccharide associated with defective glycogen metabolism and, unlike normal glycogen, it is to some extent resistant to α-amylase digestion. It also has a characteristic fibrillar appearance under the electron microscope. Polyglucosan may aggregate into dense inclusions known as polyglucosan bodies. Its accumulation can be found in various tissues to some degree in normal ageing, but it is also the hallmark of some diseases associated with defects in glycogen metabolism. These diseases frequently involve both skeletal and cardiac muscle tissue, causing myopathy with muscle weakness and wasting, and cardiomyopathy with arrhythmia, conduction block, and cardiac failure. Mutations in eight human genes are known to be associated with polyglucosan storage involving muscle, namely GYG1, GBE1, RBCK1 (HOIL-1), PFKM, EPM2A, EPM2B (NHLRC1), PRDM8, and PRKAG2. There is also a common equine polysaccharide storage myopathy belonging to this group of diseases involving the GYS1 gene. The pathogenic mechanisms that cause the abnormal glycogen accumulation appearing as polyglucosan have been studied in some of these diseases. In most cases the pathogenesis is largely unknown. In this review, we summarize the polyglucosan storage diseases from a clinical, morphological, and genetic standpoint. We also identify some important similarities and differences regarding the morphological appearance of polyglucosan accumulation and discuss pathogenic pathways. © 2015 Elsevier Ltd.
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42.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Respiratory chain dysfunction in perifascicular muscle fibres in patients with dermatomyositis is associated with mitochondrial DNA depletion
  • 2022
  • Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 48:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims Patients with dermatomyositis (DM) suffer from reduced aerobic metabolism contributing to impaired muscle function, which has been linked to cytochrome c oxidase (COX) deficiency in muscle tissue. This mitochondrial respiratory chain dysfunction is typically seen in perifascicular regions, which also show the most intense inflammatory reaction along with capillary loss and muscle fibre atrophy. The objective of this study was to investigate the pathobiology of the oxidative phosphorylation deficiency in DM. Methods Muscle biopsy specimens with perifascicular COX deficiency from five juveniles and seven adults with DM were investigated. We combined immunohistochemical analyses of subunits in the respiratory chain including complex I (subunit NDUFB8), complex II (succinate dehydrogenase, subunit SDHB) and complex IV (COX, subunit MTCO1) with in situ hybridisation, next generation deep sequencing and quantitative polymerase chain reaction (PCR). Results There was a profound deficiency of complexes I and IV in the perifascicular regions with enzyme histochemical COX deficiency, whereas succinate dehydrogenase activity and complex II were preserved. In situ hybridisation of mitochondrial RNA showed depletion of mitochondrial DNA (mtDNA) transcripts in the perifascicular regions. Analysis of mtDNA by next generation deep sequencing and quantitative PCR in affected muscle regions showed an overall reduction of mtDNA copy number particularly in the perifascicular regions. Conclusion The respiratory chain dysfunction in DM muscle is associated with mtDNA depletion causing deficiency of complexes I and IV, which are partially encoded by mtDNA, whereas complex II, which is entirely encoded by nuclear DNA, is preserved. The depletion of mtDNA indicates a perturbed replication of mtDNA explaining the muscle pathology and the disturbed aerobic metabolism.
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43.
  • Oldfors Hedberg, Carola, 1969, et al. (författare)
  • Ribonuclease inhibitor 1 (RNH1) deficiency cause congenital cataracts and global developmental delay with infection-induced psychomotor regression and anemia
  • 2023
  • Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438.
  • Tidskriftsartikel (refereegranskat)abstract
    • Ribonuclease inhibitor 1, also known as angiogenin inhibitor 1, encoded by RNH1, is a ubiquitously expressed leucine-rich repeat protein, which is highly conserved in mammalian species. Inactivation of rnh1 in mice causes an embryonically lethal anemia, but the exact biological function of RNH1 in humans remains unknown and no human genetic disease has so far been associated with RNH1. Here, we describe a family with two out of seven siblings affected by a disease characterized by congenital cataract, global developmental delay, myopathy and psychomotor deterioration, seizures and periodic anemia associated with upper respiratory tract infections. A homozygous splice-site variant (c.615-2A > C) in RNH1 segregated with the disease. Sequencing of RNA derived from patient fibroblasts and cDNA analysis of skeletal muscle mRNA showed aberrant splicing with skipping of exon 7. Western blot analysis revealed a total lack of the RNH1 protein. Functional analysis revealed that patient fibroblasts were more sensitive to RNase A exposure, and this phenotype was reversed by transduction with a lentivirus expressing RNH1 to complement patient cells. Our results demonstrate that loss-of-function of RNH1 in humans is associated with a multiorgan developmental disease with recessive inheritance. It may be speculated that the infection-induced deterioration resulted from an increased susceptibility toward extracellular RNases and/or other inflammatory responses normally kept in place by the RNase inhibitor RNH1.
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44.
  • Palmio, Johanna, et al. (författare)
  • Hereditary myopathy with early respiratory failure: occurrence in various populations
  • 2014
  • Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 85:3, s. 345-353
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Several families with characteristic features of hereditary myopathy with early respiratory failure (HMERF) have remained without genetic cause. This international study was initiated to clarify epidemiology and the genetic underlying cause in these families, and to characterise the phenotype in our large cohort. Methods DNA samples of all currently known families with HMERF without molecular genetic cause were obtained from 12 families in seven different countries. Clinical, histopathological and muscle imaging data were collected and five biopsy samples made available for further immunohistochemical studies. Genotyping, exome sequencing and Sanger sequencing were used to identify and confirm sequence variations. Results All patients with clinical diagnosis of HMERF were genetically solved by five different titin mutations identified. One mutation has been reported while four are novel, all located exclusively in the FN3 119 domain (A150) of A-band titin. One of the new mutations showed semirecessive inheritance pattern with subclinical myopathy in the heterozygous parents. Typical clinical features were respiratory failure at mid-adulthood in an ambulant patient with very variable degree of muscle weakness. Cytoplasmic bodies were retrospectively observed in all muscle biopsy samples and these were reactive for myofibrillar proteins but not for titin. Conclusions We report an extensive collection of families with HMERF with five different mutations in exon 343 of TTN, which establishes this exon as the primary target for molecular diagnosis of HMERF. Our relatively large number of new families and mutations directly implies that HMERF is not extremely rare, not restricted to Northern Europe and should be considered in undetermined myogenic respiratory failure.
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45.
  •  
46.
  • Roos, Sara, 1979, et al. (författare)
  • Expression pattern of mitochondrial respiratory chain enzymes in skeletal muscle of patients with mitochondrial myopathy associated with the homoplasmic m.14674T>C variant
  • 2022
  • Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 32:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Two homoplasmic variants in tRNA(Glu) (m.14674T>C/G) are associated with reversible infantile respiratory chain deficiency. This study sought to further characterize the expression of the individual mitochondrial respiratory chain complexes and to describe the natural history of the disease. Seven patients from four families with mitochondrial myopathy associated with the homoplasmic m.14674T>C variant were investigated. All patients underwent skeletal muscle biopsy and mtDNA sequencing. Whole-genome sequencing was performed in one family. Western blot and immunohistochemical analyses were used to characterize the expression of the individual respiratory chain complexes. Patients presented with hypotonia and feeding difficulties within the first weeks or months of life, except for one patient who first showed symptoms at 4 years of age. Histopathological findings in muscle included lipid accumulation, numerous COX-deficient fibers, and mitochondrial proliferation. Ultrastructural abnormalities included enlarged mitochondria with concentric cristae and dense mitochondrial matrix. The m.14674T>C variant in MT-TE was identified in all patients. Immunohistochemistry and immunoblotting demonstrated pronounced deficiency of the complex I subunit NDUFB8. The expression of MTCO1, a complex IV subunit, was also decreased, but not to the same extent as NDUFB8. Longitudinal follow-up data demonstrated that not all features of the disorder are entirely transient, that the disease may be progressive, and that signs and symptoms of myopathy may develop during childhood. This study sheds new light on the involvement of complex I in reversible infantile respiratory chain deficiency, it shows that the disorder may be progressive, and that myopathy can develop without an infantile episode.
  •  
47.
  • Roos, Sara, 1979, et al. (författare)
  • Mitochondrial complex IV deficiency caused by a novel frameshift variant in MT-CO2 associated with myopathy and perturbed acylcarnitine profile
  • 2019
  • Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 27:2, s. 331-335
  • Tidskriftsartikel (refereegranskat)abstract
    • Mitochondrial myopathies are a heterogeneous group of disorders associated with a wide range of clinical phenotypes. We present a 16-year-old girl with a history of exercise intolerance since childhood. Acylcarnitine species suggestive of multiple acyl-CoA dehydrogenase deficiency were found in serum, however genetic analysis did not reveal variants in genes associated with this disorder. Biochemical analyses of skeletal muscle mitochondria revealed an isolated and extremely low activity of cytochrome c oxidase (COX). This finding was confirmed by enzyme histochemistry, which demonstrated an almost complete absence of fibers with normal COX activity. Whole-exome sequencing revealed a single base-pair deletion (m.8088delT) in MT-CO2, which encodes subunit 2 of COX, resulting in a premature stop codon. Restriction fragment length polymorphism-analysis confirmed mtDNA heteroplasmy with high mutant load in skeletal muscle, the only clinically affected tissue, but low levels in other investigated tissues. Single muscle fiber analysis showed segregation of the mutant genotype with respiratory chain dysfunction. Immuno-histochemical studies indicated that the truncating variant in COX2 has an inhibitory effect on the assembly of the COX holoenzyme.
  •  
48.
  • Rosenstein, Igal, 1984, et al. (författare)
  • Four Swedish cases of CSF1R-related leukoencephalopathy: Visualization of clinical phenotypes
  • 2022
  • Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 145:5, s. 599-609
  • Tidskriftsartikel (refereegranskat)abstract
    • Colony stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is a rare, genetic disease caused by heterozygous mutations in the CSF1R gene with rapidly progressive neurodegeneration, behavioral, cognitive, motor disturbances. Objective: To describe four cases of CSF1R-related leukoencephalopathy from three families with two different pathogenic mutations in the tyrosine kinase domain of CSF1R and to develop an integrated presentation of inter-individual diversity of clinical presentations. Methods: This is an observational study of a case series. Patients diagnosed with CSF1R encephalopathy were evaluated with standardized functional estimation scores and subject to analysis of cerebrospinal fluid biomarkers. Brain computed tomography (CT) and magnetic resonance imaging (MRI) were evaluated. We performed a functional phosphorylation assay to confirm the dysfunction of mutated CSF1R protein. Results: Two heterozygous missense mutations in the CSF1R gene were identified, c.2344C>T; p.Arg777Trp and c.2329C>T; p.Arg782Cys. A phosphorylation assay in vitro showed markedly reduced autophosphorylation in cells expressing mutations. According to ACMG criteria, both mutations were pathogenic. A radiological investigation revealed typical white matter lesions in all cases. There was inter-individual diversity in the loss of cognitive, motor-neuronal, and extrapyramidal functions. Conclusions: Including the present cases, currently three CSF1R mutations are known in Sweden. We present a visualization tool to describe the clinical diversity, with potential use for longitudinal follow-up for this and other leukoencephalopathies.
  •  
49.
  • Samuelson, Emma, 1974, et al. (författare)
  • Molecular classification of spontaneous endometrial adenocarcinomas in BDII rats.
  • 2009
  • Ingår i: Endocrine-related cancer. - 1351-0088 .- 1479-6821. ; 16:1, s. 99-111
  • Tidskriftsartikel (refereegranskat)abstract
    • Female rats of the BDII/Han inbred strain are prone to spontaneously develop endometrial carcinomas (EC) that in cell biology and pathogenesis are very similar to those of human. Human EC are classified into two major groups: Type I displays endometroid histology, is hormone-dependent, and characterized by frequent microsatellite instability and PTEN, K-RAS, and CTNNB1 (beta-Catenin) mutations; Type II shows non-endometrioid histology, is hormone-unrelated, displays recurrent TP53 mutation, CDKN2A (P16) inactivation, over-expression of ERBB2 (Her2/neu), and reduced CDH1 (Cadherin 1 or E-Cadherin) expression. However, many human EC have overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II. The EC developed in BDII rats can be related to type I tumors, since they are hormone-related and histologically from endometrioid type. Here, we combined gene sequencing (Pten, Ifr1, and Ctnnb1) and real-time gene expression analysis (Pten, Cdh1, P16, Erbb2, Ctnnb1, Tp53, and Irf1) to further characterize molecular alterations in this tumor model with respect to different subtypes of EC in humans. No mutation in Pten and Ctnnb1 was detected, whereas three tumors displayed sequence aberrations of the Irf1 gene. Significant down regulation of Pten, Cdh1, p16, Erbb2, and Ctnnb1 gene products was found in the tumors. In conclusion, our data suggest that molecular features of spontaneous EC in BDII rats can be related to higher-grade human type I tumors and thus, this model represents an excellent experimental tool for research on this malignancy in human.
  •  
50.
  • Schwantje, M., et al. (författare)
  • Thermo-sensitive mitochondrial trifunctional protein deficiency presenting with episodic myopathy
  • 2022
  • Ingår i: Journal of Inherited Metabolic Disease. - : Wiley. - 0141-8955 .- 1573-2665. ; 45:4, s. 819-831
  • Tidskriftsartikel (refereegranskat)abstract
    • Mitochondrial trifunctional protein (MTP) is involved in long-chain fatty acid beta-oxidation (lcFAO). Deficiency of one or more of the enzyme activities as catalyzed by MTP causes generalized MTP deficiency (MTPD), long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), or long-chain ketoacyl-CoA thiolase deficiency (LCKATD). When genetic variants result in thermo-sensitive enzymes, increased body temperature (e.g. fever) can reduce enzyme activity and be a risk factor for clinical decompensation. This is the first description of five patients with a thermo-sensitive MTP deficiency. Clinical and genetic information was obtained from clinical files. Measurement of LCHAD and LCKAT activities, lcFAO-flux studies and palmitate loading tests were performed in skin fibroblasts cultured at 37 degrees C and 40 degrees C. In all patients (four MTPD, one LCKATD), disease manifested during childhood (manifestation age: 2-10 years) with myopathic symptoms triggered by fever or exercise. In four patients, signs of retinopathy or neuropathy were present. Plasma long-chain acylcarnitines were normal or slightly increased. HADHB variants were identified (at age: 6-18 years) by whole exome sequencing or gene panel analyses. At 37 degrees C, LCHAD and LCKAT activities were mildly impaired and lcFAO-fluxes were normal. Remarkably, enzyme activities and lcFAO-fluxes were markedly diminished at 40 degrees C. Preventive (dietary) measures improved symptoms for most. In conclusion, all patients with thermo-sensitive MTP deficiency had a long diagnostic trajectory and both genetic and enzymatic testing were required for diagnosis. The frequent absence of characteristic acylcarnitine abnormalities poses a risk for a diagnostic delay. Given the positive treatment effects, upfront genetic screening may be beneficial to enhance early recognition.
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