| 1. |
- Björck, Martin, et al.
(författare)
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Nya behandlingsmöjligheter vid vaskulärt Ehlers : Danlos syndrom
- 2013
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Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 110:29-31, s. 1354-1355
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Vaskulärt Ehlers–Danlos syndrom (VED) är en mycket ovanlig, autosomalt dominant nedärvd, sjukdom. Endast ca 50 individer i Sverige har en molekylärgenetiskt verifierad diagnos.En randomiserad studie visar att betablockeraren celiprolol kan förebygga kärlkatastrofer vid vaskulärt Ehlers–Danlos syndrom.Vid kärlkomplikationer är konservativ behandling första val, men det kan vara riskabelt att avstå från öppen eller endovaskulär kärlkirurgi.Behandling behöver ofta inledas omgående, men kontakt bör tas med ett center med erfarenhet av att behandla detta farliga och ovanliga tillstånd.
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| 2. |
- Dahlqvist, Johanna, et al.
(författare)
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Congenital ichthyosis : mutations in ichthyin are associated with specific structural abnormalities in the granular layer of epidermis
- 2007
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 44:10, s. 615-620
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Tidskriftsartikel (refereegranskat)abstract
- Background: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin disorders. Several mutant genes have been identified in ARCI, but the association between genotype and phenotype is poorly understood. Methods: To investigate genotype–phenotype correlations in ARCI, we selected 27 patients from 18 families with specific ultrastructural features of the epidermis. The characteristic findings using electron microscopy (EM) were abnormal lamellar bodies and elongated membranes in the stratum granulosum, classified as ARCI EM type III. DNA samples from a subset of affected individuals were screened for homozygous genomic regions, and a candidate gene region was identified on chromosome 5q33. The region coincides with the ichthyin gene, previously reported as mutated in ARCI. Results: Mutation screening of ichthyin revealed missense or splice-site mutations in affected members from 16 of 18 (89%) families with characteristics of ARCI EM type III. In a control group of 18 patients with ARCI without EM findings consistent with type III, we identified one patient homozygous for a missense mutation in ichthyin. Discussion: Our findings indicate a strong association between ultrastructural abnormalities in the granular layer of epidermis and ichthyin mutations. The results also suggest that EM provides a tool for specific diagnosis in a genetically homogenous subgroup of patients with ARCI.
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| 3. |
- Gudmundsson, Sanna, et al.
(författare)
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Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26
- 2017
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Ingår i: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 26:6, s. 1070-1077
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Tidskriftsartikel (refereegranskat)abstract
- Revertant mosaicism(RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c. 148G>A, p. Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultradeep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p. Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p. Asp50Asn mutation. To our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.
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| 4. |
- Hotz, Alrun, et al.
(författare)
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Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients
- 2021
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Ingår i: Genes. - : MDPI. - 2073-4425. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. To date mutations in ten genes have been identified to cause ARCI: TGM1, ALOX12B, ALOXE3, NIPAL4, CYP4F22, ABCA12, PNPLA1, CERS3, SDR9C7, and SULT2B1. The main focus of this report is the mutational spectrum of the genes ALOX12B and ALOXE3, which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in ALOX12B and 27 pathogenic mutations in ALOXE3 have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in ALOX12B and 25 novel mutations in ALOXE3. We investigated the spectrum of mutations in ALOX12B and ALOXE3 in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations.
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| 5. |
- Norlin, Maria, et al.
(författare)
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Drug-mediated gene regulation of vitamin D3 metabolism in primary human dermal fibroblasts
- 2017
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 120:1, s. 59-63
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin D metabolism was studied in primary human dermal fibroblasts with focus on drug-mediated gene regulation related to adverse side effects of antiretroviral drugs used in HIV therapy. The fibroblasts expressed mRNA for cytochrome P450 (CYP) enzymes catalysing bioactivating (CYP2R1, CYP27A1 and CYP27B1) and catabolic reactions (CYP24A1). The cells produced both 25-hydroxyvitamin D3 and 1a,25-dihydroxyvitamin D3. The results demonstrate that primary dermal fibroblasts have an active vitamin D3 metabolising system. High incidence of low bone mineral density is a concern for HIV-infected patients treated with antiretroviral drugs. Osteomalacia and severe vitamin D deficiency have been reported. We investigated whether drug-mediated gene regulation could be a possible mechanism behind these adverse drug effects. Fibroblasts were treated with different drugs used in HIV therapy and the 1a,25-dihydroxyvitamin D3 levels and relative mRNA-levels for crucial enzymes were determined. Efavirenz, stavudine and ritonavir significantly downregulated the bioactivating CYP2R1 and upregulated the catabolic CYP24A1. The drugs reduced bioactivating enzyme activities and cellular levels of 1a,25-dihydroxyvitamin D3. The current results indicate that effects on gene expression may lead to disturbed vitamin D-metabolism and decreased cellular levels of active vitamin D3. The data are consistent with the impaired bone health in patients treated with certain antiretroviral drugs.
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| 6. |
- Rajpopat, Shefali, et al.
(författare)
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Harlequin Ichthyosis A Review of Clinical and Molecular Findings in 45 Cases
- 2011
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Ingår i: Archives of Dermatology. - : American Medical Association (AMA). - 0003-987X. ; 147:6, s. 681-686
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Forskningsöversikt (refereegranskat)abstract
- Objective: To assess the clinical outcomes of 45 cases of harlequin ichthyosis and review the underlying ABCA12 gene mutations in these patients. Design: Multicenter, retrospective, questionnaire-based survey. Setting: Dermatology research institute. Participants: Patients with harlequin ichthyosis for whom we had performed ABCA12 mutation analysis. Main Outcome Measures: Referring physicians were asked to complete a questionnaire using the patients' notes, detailing the clinical outcome of the affected child. In each case, the causative ABCA12 mutation was identified using standard polymerase chain reaction and sequencing techniques. Results: Of the 45 cases, the ages of the survivors ranged from 10 months to 25 years, with an overall survival rate of 56%. Death usually occurred in the first 3 months and was attributed to sepsis and/or respiratory failure in 75% of cases. The early introduction of oral retinoids may improve survival, since 83% of those treated survived, whereas 76% who were not given retinoids died. Recurrent skin infections in infancy affected one-third of patients. Problems maintaining weight affected 44%. Three children developed an inflammatory arthritis, and developmental delay was reported in 32%. Mutation analysis revealed that 52% of survivors had compound heterozygous mutations, whereas all deaths were associated with homozygous mutations. Conclusions: Harlequin ichthyosis should be regarded as a severe chronic disease that is not invariably fatal. With improved neonatal care and probably the early introduction of oral retinoids, the number of survivors is increasing. Compound heterozygotes appear to have a survival advantage.
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| 7. |
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| 8. |
- Vahlquist, Anders, et al.
(författare)
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Genotypic and clinical spectrum of self-improving collodion ichthyosis : ALOX12B, ALOXE3, and TGM1 mutations in Scandinavian patients
- 2010
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 130:2, s. 438-443
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Tidskriftsartikel (refereegranskat)abstract
- Infants born with autosomal recessive congenital ichthyosis (ARCI) are often encapsulated in a collodion membrane, which shows a lamellar or erythrodermic type of ichthyosis upon shedding. However, some babies show a nearly normal underlying skin after several weeks, a phenotype called "self-healing collodion baby" (SHCB). Mutations in two genes, TGM1 and ALOX12B, have previously been implicated in the etiology of SHCB, but the full genotypic spectrum remains to be determined. DNA sequencing in 11 Swedish and 4 Danish SHCB patients showed ALOX12B mutations in eight cases, ALOXE3 mutations in three cases, and TGM1 mutations in one case. In three patients, we could not find mutations in any of the known ARCI genes. In all cases, a spontaneous shedding of the collodion membrane occurred 2-4 weeks after birth. When re-examined at 2-37 years of age, the patients showed skin xerosis, a mild or focal scaling, palmar hyperlinearity with keratoderma, and a frequent appearance of red cheeks and anhidrosis. Thus, we propose replacing SHCB with the term "self-improving collodion ichthyosis" (SICI). In conclusion, ALOX12B mutations are the leading cause of SICI in Scandinavia, followed by ALOXE3 mutations, which have not been previously associated with this variant of ARCI.
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| 9. |
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| 10. |
- Zhao, Linshu, et al.
(författare)
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Palmoplantar Keratoderma of the Gamborg-Nielsen Type is Caused by Mutations in the SLURP1 Gene and Represents a Variant of Mal de Meleda
- 2014
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Ingår i: Acta Dermato-Venereologica. - : Medical Journals Limited. - 0001-5555 .- 1651-2057. ; 94:6, s. 707-710
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Tidskriftsartikel (refereegranskat)abstract
- Palmoplantar keratoderma of the Gamborg-Nielsen type (PPK-GN) is a rare autosomal recessive skin disorder described in patients from Sweden. Mal de Meleda (MDM) is also a rare autosomal recessive inherited PPK first reported in 5 families from the island of Meleda. The 2 conditions phenotypically overlap and are characterised by palmoplantar erythematous hyperkeratotic plaques. The genetic background giving rise to PPK-GN has hitherto been unknown, whereas MDM is known to be caused by mutations in the gene encoding secreted Ly-6/uPAR-related protein 1, SLURP-1. In the present study we scrutinised individuals affected by PPK-GN for mutations in the SLURP1 gene and identified 2 different mutations. Fourteen Swedish patients were homozygous for a previously described mutation, c.43T>C, while one individual was a compound heterozygote with one copy of a novel mutation, c.280T>A, in addition to one copy of the c.43T>C mutation. Hereby we confirm that PPK-GN is an allelic variant of MDM.
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