Objective
AA amyloidosis is a life‐threatening complication of the hereditary periodic fever syndromes (HPFS), which are otherwise often compatible with normal life expectancy. This study was ...undertaken to determine the characteristics, presentation, natural history, and response to treatment in 46 patients who had been referred for evaluation at the UK National Amyloidosis Centre.
Methods
Disease activity was monitored by serial measurement of serum amyloid A. Renal function was assessed by measurement of serum creatinine and albumin levels, the estimated glomerular filtration rate, and proteinuria from 24‐hour urine collections. The amyloid load was measured by serum amyloid P scintigraphy.
Results
Twenty‐four patients had familial Mediterranean fever, 12 patients had tumor necrosis factor receptor–associated periodic syndrome, 6 patients had cryopyrin‐associated periodic syndromes, and 4 patients had mevalonate kinase deficiency. The median age at onset of HPFS was 5 years; median age at presentation with AA amyloidosis was 38 years. Diagnosis of an HPFS had not been considered prior to presentation with AA amyloidosis in 23 patients (50%). Eleven patients (24%) had end‐stage renal failure (ESRF) at presentation; of these, 3 had received transplants prior to referral. A further 13 patients developed ESRF over the followup period, with 10 undergoing renal transplantation. The median time to progression to ESRF from onset of AA amyloidosis was 3.3 years (interquartile range IQR 2–8), with a median time to transplant of 4 years (IQR 3–6). Eleven patients (24%) died. The median survival in the entire cohort was 19 years from diagnosis of AA amyloidosis. Of the 37 patients who were treated successfully, or in whom at least partial suppression of the underlying HPFS was achieved, 17 (46%) showed amyloid regression, 14 (38%) showed a stable amyloid load, and 2 (5%) showed increased amyloid deposition over the followup period.
Conclusion
AA amyloidosis remains a challenging and serious late complication of HPFS; however, outcomes are excellent when HPFS is diagnosed early enough to allow effective treatment, thus preventing or retarding further amyloid deposition and organ damage.
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.
The genetic diagnosis of inherited anaemias is an important aspect of the diagnostic pathway for patients with haematological disorders, allowing discrimination between conditions of overlapping ...phenotypes therefore enabling more effective clinical treatment. Next Generation sequencing platforms are now in widespread use in diagnostic settings and are facilitating more rapid, accurate and cost-effective molecular diagnosis. The Red Cell Gene Panel developed by the Viapath Molecular Pathology laboratory based at King's College Hospital, London has harnessed this technology with the aim of identifying genetic diagnoses of rare inherited causes of anaemia. Although originally setup to diagnose inherited red cell disorders, clinical demand has led to the inclusion of inherited bone marrow failure syndromes and other related conditions such that the panel now consists of 194 genes, divided into 16 subpanels (see table 1).
Here we present the data from the first 1000 diagnostic cases reported under the following referral groups: 462 cases of unexplained anaemia (including haemolytic anaemia, sideroblastic anaemia, congenital dyserythropoietic anaemia, Diamond-Blackfan Anaemia), 232 cases of inherited bone marrow failure syndromes (including thrombocytopenia and neutropenia), 163 cases of congenital erythrocytosis and 143 other cases (including but not limited to iron regulation, haemophagocytic lymphohistiocytosis (HLH) and Criggler-Najjar ). Of these 1000 cases, we have achieved an overall diagnostic yield of approximately 25%. A diagnosed case is defined here as one in which a clear pathogenic or likely pathogenic variant that explains the phenotype has been detected. The unexplained anaemia cases have achieved the highest percentage of cases diagnosed with 47% diagnostic yield and data will be presented outlining the gene-by-gene breakdown of diagnoses made.
Our bespoke bioinformatics pipeline has also allowed the detection of novel disease-causing structural variants in 20 cases, contributing 2% of our diagnostic yield. These are detected using three different methods; read-depth analysis, split-read mapping and discordant insert-size analysis. All reported structural variants have been confirmed with a second method, either breakpoint mapping or dosage-sensitive PCR.
A significant proportion of cases (28%) have been reported with variants of uncertain clinical significance, highlighting the need for family studies and functional characterisation to be able to accurately ascertain the significance of these variants. Future developments of the service include functional characterisation of membrane disorders using next generation ektacytometry and preliminary data from this work will be presented here.
Display omitted
Kulasekararaj:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Pagliuca:Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
Abstract
The clinical features of hereditary gelsolin (AGel) amyloidosis include corneal lattice dystrophy, distal sensorimotor, cranial neuropathy and cutis laxa. To date, four mutations of the ...gelsolin (GSN) gene encoding the following variants have been identified as the cause of this malady; p.D214N, p.D214Y, p.G194R and p.N211K (this nomenclature includes the 27-residue signal peptide). Interestingly, the latter two variants are associated exclusively with a renal amyloidosis phenotype. Here we report the clinical features in 10 patients with AGel amyloidosis associated with the p.D214N mutation, all of whom underwent whole body 123I-SAP scintigraphy and were followed up in a single UK Centre for a prolonged period. Two patients, from the same kindred presented with proteinuria; eight subjects had a characteristic AGel amyloidosis phenotype including cranial neuropathy and/or corneal lattice dystrophy. 123I-SAP scintigraphy revealed substantial renal amyloid deposits in all 10 patients, including those with preserved renal function, and usually without tracer uptake into other visceral organs. 123I-SAP scintigraphy is a non-invasive technique that aids early diagnosis of patients with this rare disease, especially those who lack a family history and/or present with an unusual clinical phenotype.
Summary
Human serum amyloid P component (SAP) binds avidly to DNA, chromatin and apoptotic cells in vitro and in vivo. 129\Sv × C57BL\6 mice with targeted deletion of the SAP gene spontaneously ...develop antinuclear autoantibodies and immune complex glomerulonephritis. SAP‐deficient animals, created by backcrossing the 129\Sv SAP gene deletion into pure line C57BL\6 mice and studied here for the first time, also spontaneously developed broad spectrum antinuclear autoimmunity and proliferative immune complex glomerulonephritis but without proteinuria, renal failure, or increased morbidity or mortality. Mice hemizygous for the SAP gene deletion had an intermediate autoimmune phenotype. Injected apoptotic cells and isolated chromatin were more immunogenic in SAP–\– mice than in wild‐type mice. In contrast, SAP‐deficient pure line 129\Sv mice did not produce significant autoantibodies either spontaneously or when immunized with extrinsic chromatin or apoptotic cells, indicating that loss of tolerance is markedly strain dependent. However, SAP deficiency in C57BL\6 mice only marginally affected plasma clearance of exogenous chromatin and had no effect on distribution of exogenous nucleosomes between the liver and kidneys, which were the only tissue sites of catabolism. Furthermore, transgenic expression of human SAP in the C57BL\6 SAP knockout mice did not abrogate the autoimmune phenotype. This may reflect the different binding affinities of mouse and human SAP for nuclear autoantigens and\or the heterologous nature of transgenic human SAP in the mouse. Alternatively, the autoimmunity may be independent of SAP deficiency and caused by expression of 129\Sv chromosome 1 genes in the C57BL\6 background.
Hereditary amyloidosis in early childhood associated with a novel insertion-deletion (indel) in the fibrinogen Aα chain gene.
Systemic amyloidosis occurring in early childhood is extremely rare, and ...is usually of AA type complicating chronic inflammatory diseases. We report the molecular basis of amyloidosis in a Korean girl who presented at 7 years of age with asymptomatic proteinuria and developed amyloid hepatomegaly and end-stage renal failure within 2 years.
Renal biopsy showed enlarged glomeruli virtually replaced by amyloid, but without interstitial or vascular involvement. The histologic appearance was identical to that seen in patients with hereditary fibrinogen Aα chain Glu526Val amyloidosis, and the amyloid deposits stained specifically with antibodies to fibrinogen. Mutations were sought in the genes of the amyloidogenic proteins, transthyretin, apolipoprotein AI, lysozyme and fibrinogen Aα chain genes by polymerase chain reaction (PCR) and sequencing.
A unique frameshift insertion-deletion (indel) mutation was identified in one allele of her fibrinogen Aα chain gene, which encodes a partly novel peptide and a premature stop signal, similar to the two previously reported amyloidogenic point deletions at codons 522 and 524 in this molecule. The mutation was absent in samples verified to be from her parents, indicating that it had occurred de novo.
This is the first description of hereditary fibrinogen Aα chain amyloidosis in an Asian individual, and the distinctive renal histology offered a strong clue to the diagnosis. The disease is potentially curable by combined hepatorenal transplantation.
Background. Systemic amyloidosis occurring in early childhood is extremely rare, and is usually of AA type complicating chronic inflammatory diseases. We report the molecular basis of amyloidosis in ...a Korean girl who presented at 7 years of age with asymptomatic proteinuria and developed amyloid hepatomegaly and end-stage renal failure within 2 years. Methods. Renal biopsy showed enlarged glomeruli virtually replaced by amyloid, but without interstitial or vascular involvement. The histologic appearance was identical to that seen in patients with hereditary fibrinogen A alpha chain Glu526Val amyloidosis, and the amyloid deposits stained specifically with antibodies to fibrinogen. Mutations were sought in the genes of the amyloidogenic proteins, transthyretin, apolipoprotein AI, lysozyme and fibrinogen A alpha chain genes by polymerase chain reaction (PCR) and sequencing. Results. A unique frameshift insertion-deletion (indel) mutation was identified in one allele of her fibrinogen A alpha chain gene, which encodes a partly novel peptide and a premature stop signal, similar to the two previously reported amyloidogenic point deletions at codons 522 and 524 in this molecule. The mutation was absent in samples verified to be from her parents, indicating that it had occurred de novo. Conclusion. This is the first description of hereditary fibrinogen A alpha chain amyloidosis in an Asian individual, and the distinctive renal histology offered a strong clue to the diagnosis. The disease is potentially curable by combined hepatorenal transplantation.
Systemic amyloidosis occurring in early childhood is extremely rare, and is usually of AA type complicating chronic inflammatory diseases. We report the molecular basis of amyloidosis in a Korean ...girl who presented at 7 years of age with asymptomatic proteinuria and developed amyloid hepatomegaly and end-stage renal failure within 2 years.
Renal biopsy showed enlarged glomeruli virtually replaced by amyloid, but without interstitial or vascular involvement. The histologic appearance was identical to that seen in patients with hereditary fibrinogen Aalpha chain Glu526Val amyloidosis, and the amyloid deposits stained specifically with antibodies to fibrinogen. Mutations were sought in the genes of the amyloidogenic proteins, transthyretin, apolipoprotein AI, lysozyme and fibrinogen Aalpha chain genes by polymerase chain reaction (PCR) and sequencing.
A unique frameshift insertion-deletion (indel) mutation was identified in one allele of her fibrinogen Aalpha chain gene, which encodes a partly novel peptide and a premature stop signal, similar to the two previously reported amyloidogenic point deletions at codons 522 and 524 in this molecule. The mutation was absent in samples verified to be from her parents, indicating that it had occurred de novo.
This is the first description of hereditary fibrinogen Aalpha chain amyloidosis in an Asian individual, and the distinctive renal histology offered a strong clue to the diagnosis. The disease is potentially curable by combined hepatorenal transplantation.
Systemic amyloidosis occurring in early childhood is extremely rare, and is usually of AA type complicating chronic inflammatory diseases. We report the molecular basis of amyloidosis in a Korean ...girl who presented at 7 years of age with asymptomatic proteinuria and developed amyloid hepatomegaly and end-stage renal failure within 2 years. Renal biopsy showed enlarged glomeruli virtually replaced by amyloid, but without interstitial or vascular involvement. The histologic appearance was identical to that seen in patients with hereditary fibrinogen Aalpha chain Glu526Val amyloidosis, and the amyloid deposits stained specifically with antibodies to fibrinogen. Mutations were sought in the genes of the amyloidogenic proteins, transthyretin, apolipoprotein AI, lysozyme and fibrinogen Aalpha chain genes by polymerase chain reaction (PCR) and sequencing. A unique frameshift insertion-deletion (indel) mutation was identified in one allele of her fibrinogen Aalpha chain gene, which encodes a partly novel peptide and a premature stop signal, similar to the two previously reported amyloidogenic point deletions at codons 522 and 524 in this molecule. The mutation was absent in samples verified to be from her parents, indicating that it had occurred de novo. This is the first description of hereditary fibrinogen Aalpha chain amyloidosis in an Asian individual, and the distinctive renal histology offered a strong clue to the diagnosis. The disease is potentially curable by combined hepatorenal transplantation.
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.
PDF
