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| 3. |
- Donkervoort, S., et al.
(författare)
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Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores
- 2020
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 107:6, s. 1078-1095
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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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| 4. |
- Eggens, Veerle Rc, et al.
(författare)
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EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations.
- 2014
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Ingår i: Orphanet journal of rare diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1.
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| 5. |
- Heard, J. M., et al.
(författare)
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Availability, accessibility and delivery to patients of the 28 orphan medicines approved by the European Medicine Agency for hereditary metabolic diseases in the MetabERN network
- 2020
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Background The European Medicine Agency granted marketing approval to 164 orphan medicinal products for rare diseases, among which 28 products intended for the treatment of hereditary metabolic diseases. Taking advantage of its privileged connection with 69 healthcare centres of excellence in this field, MetabERN, the European Reference Network for hereditary metabolic diseases, performed a survey asking health care providers from 18 European countries whether these products are available on the market, reimbursed and therefore accessible for prescription, and actually delivered in their centre. Results Responses received from 52 centres (75%) concerned the design of treatment plans, the access to marketed products, and the barriers to delivery. Treatment options are always discussed with patients, who are often involved in their treatment plan. Most products (26/28) are available in most countries (15/18). Among the 15 broadly accessible products (88.5% of the centres), 9 are delivered to most patients (mean 70.1%), and the others to only few (16.5%). Among the 10 less accessible products (40.2% of the centres), 6 are delivered to many patients (66.7%), and 4 are rarely used (6.3%). Information was missing for 3 products. Delay between prescription and delivery is on average one month. Beside the lack of availability or accessibility, the most frequent reasons for not prescribing a treatment are patients' clinical status, characteristic, and personal choice. Conclusions Data collected from health care providers in the MetabERN network indicate that two-third of the orphan medicines approved by EMA for the treatment of hereditary metabolic diseases are accessible to treating patients, although often less than one-half of the patients with the relevant conditions actually received the approved product to treat their disease. Thus, in spite of the remarkable achievement of many products, patients concerned by EMA-approved orphan medicinal products have persistent unmet needs, which deserve consideration. The enormous investments made by the companies to develop products, and the high financial burden for the Member States to purchase these products emphasize the importance of a scrupulous appreciation of treatment value involving all stakeholders at early stage of development, before marketing authorization, and during follow up.
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| 6. |
- Hikmat, O., et al.
(författare)
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Expanding the phenotypic spectrum of BCS1L-related mitochondrial disease
- 2021
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Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 8:11, s. 2155-2165
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To delineate the full phenotypic spectrum of BCS1L-related disease, provide better understanding of the genotype-phenotype correlations and identify reliable prognostic disease markers. Methods: We performed a retrospective multinational cohort study of previously unpublished patients followed in 15 centres from 10 countries. Patients with confirmed biallelic pathogenic BCS1L variants were considered eligible. Clinical, laboratory, neuroimaging and genetic data were analysed. Patients were stratified into different groups based on the age of disease onset, whether homozygous or compound heterozygous for the c.232A>G (p.Ser78Gly) variant, and those with other pathogenic BCS1L variants. Results: Thirty-three patients were included. We found that growth failure, lactic acidosis, tubulopathy, hepatopathy and early death were more frequent in those with disease onset within the first month of life. In those with onset after 1 month, neurological features including movement disorders and seizures were more frequent. Novel phenotypes, particularly involving movement disorder, were identified in this group. The presence of the c.232A>G (p.Ser78Gly) variant was associated with significantly worse survival and exclusively found in those with disease onset within the first month of life, whilst other pathogenic BCS1L variants were more frequent in those with later symptom onset. Interpretation: The phenotypic spectrum of BCS1L-related disease comprises a continuum of clinical features rather than a set of separate syndromic clinical identities. Age of onset defines BCS1L-related disease clinically and early presentation is associated with poor prognosis. Genotype correlates with phenotype in the presence of the c.232A>G (p.Ser78Gly) variant.
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| 7. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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| 8. |
- Baumann, I., et al.
(författare)
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Do cognitively stimulating activities affect the association between retirement timing and cognitive functioning in old age?
- 2022
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Ingår i: Ageing & Society. - : Cambridge University Press. - 0144-686X .- 1469-1779. ; 42:2, s. 306-330
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Tidskriftsartikel (refereegranskat)abstract
- In response to the rising financial pressure on old-age pension systems in industrialised economies, many European countries plan to increase the eligibility age for retirement pensions. We used data from Sweden to examine whether (and if so, how) retirement after age 65 - the eligibility age for basic pension - compared to retiring earlier affects older adults' (between ages 70 and 85) cognitive functioning. Using a propensity score matching (PSM) approach, we addressed the selection bias potentially introduced by non-random selection into either early or late retirement. We also examined average and heterogeneous treatment effects (HTEs). HTEs were evaluated for different levels of cognitive stimulation from occupational activities before retirement and from leisure activities after retirement. We drew from a rich longitudinal data-set linking two nationally representative Swedish surveys with a register data-set and found that, on average, individuals who retire after age 65 do not have a higher level of cognitive functioning than those who retire earlier. Similarly, we did not observe HTEs from occupational activities. With respect to leisure activities, we found no systematic effects on cognitive functioning among those working beyond age 65. We conclude that, in general, retirement age does not seem to affect cognitive functioning in old age. Yet, the rising retirement age may put substantial pressure on individuals who suffer from poor health at the end of their occupational career, potentially exacerbating social- and health-related inequalities among older people.
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| 11. |
- Bergström, T, et al.
(författare)
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[Gene amplification in viral CNS infections. Rapid diagnostic identification of herpesviruses]. : Genamplifiering vid virala CNS-infektioner. Snabb diagnostik av herpesgruppens virus.
- 1995
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Ingår i: Lakartidningen. - 0023-7205. ; 92:5, s. 427-32
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Tidskriftsartikel (refereegranskat)abstract
- DNA amplification with the polymerase chain reaction (PCR) technique was used as a diagnostic test on cerebrospinal fluid samples in cases where herpesvirus infection of the central nervous system (CNS) was suspected. During the period, 1992-93, 47 (8.9%) of 528 patients tested were positive for one or another of the following herpesviruses: herpes simplex virus type 1 (n = 16) or type 2 (n = 9), cytomegalovirus (n = 16), varicella-zoster virus (n = 4), or Epstein-Barr virus (n = 2). The study showed PCR to be a rapid and useful diagnostic method in clinical routine, enabling early antiviral intervention in several cases with an atypical clinical picture. Moreover, cytomegalovirus was found to be an important CNS pathogen in addition to herpes simplex virus, especially during childhood.
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| 12. |
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| 13. |
- Bomfim, I L, et al.
(författare)
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The immunogenetics of narcolepsy associated with A(H1N1)pdm09 vaccination (Pandemrix) supports a potent gene-environment interaction.
- 2017
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Ingår i: Genes and immunity. - : Springer Science and Business Media LLC. - 1476-5470 .- 1466-4879. ; 18, s. 75-81
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Tidskriftsartikel (refereegranskat)abstract
- The influenza A(H1N1)pdm09 vaccination campaign from 2009 to 2010 was associated with a sudden increase in the incidence of narcolepsy in several countries. Narcolepsy with cataplexy is strongly associated with the human leukocyte antigen (HLA) class II DQB1*06:02 allele, and protective associations with the DQB1*06:03 allele have been reported. Several non-HLA gene loci are also associated, such as common variants of the T-cell receptor-α (TRA), the purinergic receptor P2RY11, cathepsin H (CTSH) and TNFSF4/OX40L/CD252. In this retrospective multicenter study, we investigated if these predisposing gene loci were also involved in vaccination-associated narcolepsy. We compared HLA- along with single-nucleotide polymorphism genotypes for non-HLA regions between 42 Pandemrix-vaccinated narcolepsy cases and 1990 population-based controls. The class II gene loci associations supported previous findings. Nominal association (P-value<0.05) with TRA as well as suggestive (P-value<0.1) associations with P2RY11 and CTSH were found. These associations suggest a very strong gene-environment interaction, in which the influenza A(H1N1)pdm09 strain or Pandemrix vaccine can act as potent environmental triggers.Genes and Immunity advance online publication, 23 March 2017; doi:10.1038/gene.2017.1.
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| 16. |
- Krebs, Frederik C, et al.
(författare)
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A round robin study of flexible large-area roll-to-roll processed polymer solar cell modules
- 2009
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Ingår i: SOLAR ENERGY MATERIALS AND SOLAR CELLS. - : Elsevier BV. - 0927-0248. ; 93:11, s. 1968-1977
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Tidskriftsartikel (refereegranskat)abstract
- A round robin for the performance of roll-to-roll coated flexible large-area polymer solar-cell modules involving 18 different laboratories in Northern America, Europe and Middle East is presented. The study involved the performance measurement of the devices at one location (Riso DTU) followed by transportation to a participating laboratory for performance measurement and return to the starting location (Riso DTU) for re-measurement of the performance. It was found possible to package polymer solar-cell modules using a flexible plastic barrier material in such a manner that degradation of the devices played a relatively small role in the experiment that has taken place over 4 months. The method of transportation followed both air-mail and surface-mail paths.
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| 17. |
- Ohlsson, M., et al.
(författare)
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Follow-up of nemaline myopathy in two patients with novel mutations in the skeletal muscle alpha-actin gene (ACTA1)
- 2004
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Ingår i: Neuromuscular Disorders. - : Institute of Information Science. - 0960-8966 .- 1873-2364. ; 14:8-9, s. 471-475
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Tidskriftsartikel (refereegranskat)abstract
- Nemaline myopathy has been associated with mutations in five different genes, which all encode protein components of the sarcomeric thin filaments. We report follow-up studies in two children with mutations not previously described in skeletal muscle alpha-actin (ACTA1). Case 1 was a male patient who after birth suffered from pronounced muscle weakness and hypotonia. Muscle biopsy showed small fibers with numerous rods. He failed to achieve any motor milestones. At the age of 17 he required 24 h ventilator support. He could not lift his arms against gravity, but he could use his hands to control his electric wheelchair. The muscle biopsy showed marked replacement of muscle tissue by fat and connective tissue. Only few fibers showed nemaline rods. He had a de novo, heterozygous mutation, G268D in ACTA1. Case 2 was a female patient with feeding difficulties and mild hypotonia in the neonatal period. Muscle biopsy showed hypoplastic muscle fibers and numerous rods. At 11 years of age she walked and moved unhindered and could run fairly well. She had a de novo, heterozygous mutation, K373E, in ACTA1. These two patients illustrate the marked variability in the clinical features of nemaline myopathy in spite of similar muscle pathology in early childhood. The severe muscle atrophy with replacement of fat and connective tissue in case 1 demonstrates the progressive nature of nemaline myopathy in some cases. The described two mutations add to the previously reported mutations in ACTA1 associated with nemaline myopathy.
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| 18. |
- Ohlsson, M., et al.
(författare)
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New morphologic and genetic findings in cap disease associated with beta-tropomyosin (TPM2) mutations
- 2008
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Ingår i: Neurology. - : American Academy of Neurology. - 0028-3878 .- 1526-632X. ; 71:23, s. 1896-1901
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Mutations in the beta-tropomyosin gene (TPM2) are a rare cause of congenital myopathies with features of nemaline myopathy and cap disease and may also cause distal arthrogryposis syndromes without major muscle pathology. We describe the muscle biopsy findings in three patients with cap disease and novel heterozygous mutations in TPM2.METHODS: Three unrelated patients with congenital myopathy were investigated by muscle biopsy and genetic analysis.RESULTS: All three patients had early-onset muscle weakness of variable severity and distribution. Muscle biopsy demonstrated in all three patients near uniformity of type 1 fibers and an unusual irregular and coarse-meshed intermyofibrillar network. By electron microscopy, the myofibrils were broad and partly split, and the Z lines appeared jagged. In one of the patients caps structures were identified only by electron microscopy, and in one patient they were identified only in a second biopsy at adulthood. Three novel, de novo, heterozygous mutations in TPM2 were identified: a three-base pair deletion in-frame (p.Lys49del), a three-base pair duplication in-frame (p.Gly52dup), and a missense mutation (p.Asn202Lys).CONCLUSIONS: Mutations in TPM2 seem to be a frequent cause of cap disease. Because cap structures may be sparse, other prominent features, such as a coarse-meshed intermyofibrillar network and jagged Z lines, may be clues to correct diagnosis and also indicate that the pathogenesis involves defective assembly of myofilaments.
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| 19. |
- Parasyri, M., et al.
(författare)
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Renal Phenotype in Mitochondrial Diseases: A Multicenter Study
- 2022
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Ingår i: Kidney Diseases. - : S. Karger AG. - 2296-9381 .- 2296-9357. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- Aims: This study aimed to investigate associations between renal and extrarenal manifestations of mitochondrial diseases and their natural history as well as predictors of renal disease severity and overall disease outcome. The secondary aim was to generate a protocol of presymptomatic assessment and monitoring of renal function in patients with a defined mitochondrial disease. Methods: A multicenter, retrospective cohort study was performed by the Mitochondrial Clinical and Research Network (MCRN). Patients of any age with renal manifestations associated with a genetically verified mitochondrial disease were included from 8 expert European centers specializing in mitochondrial diseases: Gothenburg, Oulu, Copenhagen, Bergen, Helsinki, Stockholm, Rotterdam, and Barcelona. Results: Of the 36 patients included, two-thirds had mitochondrial DNA-associated disease. Renal manifestations were the first sign of mitochondrial disease in 19%, and renal involvement was first identified by laboratory tests in 57% of patients. Acute kidney injury occurred in 19% of patients and was the first sign of renal disease in the majority of these. The most common renal manifestation was chronic kidney disease (75% with stage 2 or greater), followed by tubulopathy (44.4%), the latter seen mostly among patients with single large-scale mitochondrial DNA deletions. Acute kidney injury and tubulopathy correlated with worse survival outcome. The most common findings on renal imaging were increased echogenicity and renal dysplasia/hypoplasia. Renal histology revealed focal segmental glomerulosclerosis, nephrocalcinosis, and nephronophthisis. Conclusion: Acute kidney injury is a distinct renal phenotype in patients with mitochondrial disease. Our results highlight the importance to recognize renal disease as a sign of an underlying mitochondrial disease. Acute kidney injury and tubulopathy are 2 distinct indicators of poor survival in patients with mitochondrial diseases.
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| 21. |
- Schwantje, M., et al.
(författare)
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Thermo-sensitive mitochondrial trifunctional protein deficiency presenting with episodic myopathy
- 2022
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Ingår i: Journal of Inherited Metabolic Disease. - : Wiley. - 0141-8955 .- 1573-2665. ; 45:4, s. 819-831
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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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| 22. |
- Vogel, G. F., et al.
(författare)
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Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants
- 2023
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 25:6
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. Methods: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. Results: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. Conclusion: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.
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