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ABSTRACT: Apolipoprotein E (apoE) is present in the amyloid deposits in Alzheimer's disease (AD) and in acquired and hereditary systemic amyloidosis, and apoE genotype is an important risk factor for late onset AD. In order to determine whether it is also a risk factor for developing reactive systemic amyloid A protein (AA) amyloidosis or transthyretin (TTR) Met 30 familial amyloid polyneuropathy (FAP), apoE genotype was determined in 32 patients with AA amyloid and 31 patients with FAP. Prevalence of the apoE ε4 allele was not significantly different than in a normal population. There was also no correlation between apoE genotype and either the time from presentation of the underlying disease to the diagnosis of AA amyloid or the age of onset of symptoms in FAP. These results suggest that apoE genotype does not affect susceptibility to or expression of AA amyloidosis or TTR Met 30 FAP.
07/2009; 2(3):163-166.
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ABSTRACT: Identification of factors that cause susceptibility to, and clinical expression of, variant Creutzfeldt-Jakob disease (vCJD) is essential for future management of the disease. We established MHC genotypes of 76 individuals with vCJD and 131 controls, and analysed MHC phenotypes in relation to age of onset of vCJD and its duration from presentation to death. There were no significant differences between vCJD and control populations in frequencies of any MHC types, nor were there associations between MHC type and age of onset or duration of vCJD disease. Our results do not support the idea of an association between MHC types and either susceptibility to, or expression of, vCJD.
The Lancet 03/2003; 361(9356):487-9. · 38.28 Impact Factor
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ABSTRACT: The majority of patients with familial Mediterranean fever (FMF) have identifiable mutations in both alleles of the MEFV gene, while some individuals with paired MEFV mutations do not have clinical symptoms of the disease. During family studies we identified nine such individuals from six kindreds, most of whom either subsequently developed FMF or had other clinically significant inflammatory disease; one case benefiting substantially from colchicine therapy. Four individuals remained asymptomatic. Two further asymptomatic subjects with paired MEFV mutations were identified among 49 healthy controls from western Turkey, of whom a further 18.4 per cent were simple heterozygotes. This carrier rate was higher than would be expected from prevalence of FMF in this region, suggesting that penetrance of paired recognised pathogenic MEFV mutations may frequently be incomplete. MEFV genotyping results must be interpreted with due caution, and follow-up of apparently asymptomatic subjects with paired mutations is advisable.
European Journal of HumanGenetics 01/2003; 10(12):786-9. · 4.40 Impact Factor
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Ebun Aganna,
Fabio Martinon,
Philip N Hawkins,
John B Ross,
Daniel C Swan, David R Booth,
Helen J Lachmann,
Alison Bybee,
Roxanne Gaudet,
Patricia Woo,
Conleth Feighery,
Finbarr E Cotter,
Margot Thome,
Graham A Hitman,
Jürg Tschopp,
Michael F McDermott
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ABSTRACT: Familial cold urticaria (FCU) and Muckle-Wells syndrome (MWS) are dominantly inherited autoinflammatory disorders that cause rashes, fever, arthralgia, and in some subjects, AA amyloidosis, and have been mapped to chromosome 1q44. Sensorineural deafness in MWS, and provocation of symptoms by cold in FCU, are distinctive features. This study was undertaken to characterize the genetic basis of FCU, MWS, and an overlapping disorder in French Canadian, British, and Indian families, respectively.
Mutations in the candidate gene NALP3, which has also been named CIAS1 and PYPAF1, were sought in the study families, in a British/Spanish patient with apparent sporadic MWS, and in matched population controls. Identified variants were sought in 50 European subjects with uncharacterized, apparently sporadic periodic fever syndromes, 48 subjects with rheumatoid arthritis (RA), and 19 subjects with juvenile idiopathic arthritis (JIA).
Point mutations, encoding putative protein variants R262W and L307P, were present in all affected members of the Indian and French Canadian families, respectively, but not in controls. The R262W variant was also present in the subject with sporadic MWS. The V200M variant was present in all affected members of the British family with MWS, in 2 of the 50 subjects with uncharacterized periodic fevers, and in 1 of 130 Caucasian and 2 of 48 Indian healthy controls. No mutations were identified among the subjects with RA or JIA.
These findings confirm that mutations in the NALP3/CIAS1/PYPAF1 gene are associated with FCU and MWS, and that disease severity and clinical features may differ substantially within and between families. Analysis of this gene will improve classification of patients with inherited or apparently sporadic periodic fever syndromes.
Arthritis & Rheumatism 10/2002; 46(9):2445-52. · 7.87 Impact Factor
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ABSTRACT: Hereditary, autosomal dominant amyloidosis, caused by mutations in the genes encoding transthyretin, fibrinogen A alpha-chain, lysozyme, or apolipoprotein A-I, is thought to be extremely rare and is not routinely included in the differential diagnosis of systemic amyloidosis unless there is a family history.
We studied 350 patients with systemic amyloidosis, in whom a diagnosis of the light-chain (AL) type of the disorder had been suggested by clinical and laboratory findings and by the absence of a family history, to assess whether they had amyloidogenic mutations.
Amyloidogenic mutations were present in 34 of the 350 patients (9.7 percent), most often in the genes encoding fibrinogen A alpha-chain (18 patients) and transthyretin (13 patients). In all 34 of these patients, the diagnosis of hereditary amyloidosis was confirmed by additional investigations. A low-grade monoclonal gammopathy was detected in 8 of the 34 patients (24 percent).
A genetic cause should be sought in all patients with amyloidosis that is not the reactive systemic amyloid A type and in whom confirmation of the AL type cannot be obtained.
New England Journal of Medicine 07/2002; 346(23):1786-91. · 53.30 Impact Factor
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ABSTRACT: To investigate genetic susceptibility to recurrent fevers, generalized severe myalgia, and migratory erythema in an Israeli Arab child with no family history of similar disease.
DNA sequencing of exons 1-6 of the TNFRSF1A gene (formerly TNFR1) was performed in the patient and his parents to determine the presence of the autosomal-dominant tumor necrosis factor receptor-associated periodic syndrome (TRAPS); informative markers spanning the TNFRSF1A locus were used to genotype all available members of the patient's family. The TNFRSF1A gene was subsequently screened in 69 healthy Arab controls and 96 Caucasian controls. Formal forensic paternity testing was performed on the child.
We found a de novo missense mutation in exon 3 of the TNFRSF1A gene, involving a novel C-->T transition encoding a Cys70Arg (C70R) variant, in the Israeli Arab patient. Eight of the common familial Mediterranean fever (FMF) gene MEFV mutations were excluded. This mutation was not present in the parents or siblings, or among the 69 healthy Arab controls. However, another TNFRSF1A variant, Pro46Lys (P46L), was present in 1 of the Arab controls.
We have identified a TNFRSF1A mutation associated with periodic fever in an Arab patient, and a TNFRSF1A variant, which is variably pathogenic in Caucasians, in an Arab control. This is the first report of a de novo mutation in periodic fevers in general, and also of TRAPS in the Arab population. These findings demonstrate the need to include TRAPS in the differential diagnosis of recurrent fevers in this population.
Arthritis & Rheumatism 01/2002; 46(1):245-9. · 7.87 Impact Factor
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David R Booth,
Si-Yen Tan,
Sussanne E. Booth,
Glenys A Tennent,
Winston L Hutchinson,
J. Justin Hsuan,
Nicholas F. Totty,
Oanh Truong,
Anne K. Soutar,
Philip N Hawkins,
Miquel Bruguera Cortada,
Joan Caballería Rovira,
Manel Solé,
Josep Ma. Campistol Plana,
Mark B Pepys
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ABSTRACT: We report a Spanish family with autosomal-dominant non-neuropathic hereditary amyloidosis with a unique hepatic presentation and death from liver failure, usually by the sixth decade. The disease is caused by a previously unreported deletion/insertion mutation in exon 4 of the apolipoprotein AI (apoAI) gene encoding loss of residues 60-71 of normal mature apoAI and insertion at that position of two new residues, ValThr. Affected individuals are heterozygous for this mutation and have both normal apoAI and variant molecules bearing one extra positive charge, as predicted from the DNA sequence. The amyloid fibrils are composed exclusively of NH2-terminal fragments of the variant, ending mainly at positions corresponding to residues 83 and 92 in the mature wild-type sequence. Amyloid fibrils derived from the other three known amyloidogenic apoAI variants are also composed of similar NH2-terminal fragments. All known amyloidogenic apoAI variants carry one extra positive charge in this region, suggesting that it may be responsible for their enhanced amyloidogenicity. In addition to causing a new phenotype, this is the first deletion mutation to be described in association with hereditary amyloidosis and it significantly extends the value of the apoAI model for investigation of molecular mechanisms of amyloid fibrillogenesis.
