Amyloid deposits regress when the supply of fibril precursor proteins is sufficiently reduced, indicating that amyloid fibrils are degradable in vivo. Serum amyloid P component (SAP), a universal constituent of amyloid deposits, efficiently protects amyloid fibrils from proteolysis in vitro, and may contribute to persistence of amyloid in vivo. Drugs that prevent binding of SAP to amyloid fibrils in vivo should therefore promote regression of amyloid and we are actively seeking such agents. A complementary strategy is identification of critical molecular processes in fibrillogenesis as targets for pharmacological intervention. All amyloidogenic variants of apolipoprotein AI contain an additional positive charge in the N-terminal fibrillogenic region of the protein. This is unlikely to be a coincidence and should be informative about amyloidogenesis by this protein. The two amyloidogenic variants of human lysozyme, caused by the first natural mutations found in its gene, provide a particularly powerful model system because both the crystal structure and folding pathways of wild-type lysozyme are so well characterized. The amyloidogenic variant lysozymes have similar 3D crystal structures to the wild type, but are notably less thermostable. They unfold on heating, lose enzymic activity, and aggregate to form amyloid fibrils in vitro.

BACKGROUND:Beta2-Microglobulin (beta2M) amyloidosis occurs in patients with end-stage renal failure (ESRF) who undergo long-term continuous ambulatory peritoneal dialysis (CAPD), but its prevalence in patients treated exclusively by CAPD is unknown. In addition, its features may differ from those of haemodialysis-associated beta2M amyloidosis because CAPD is more biocompatible.METHODS:We performed serum amyloid P component (SAP) scintigraphy, a specific technique for imaging amyloid deposits, in 13 consecutive patients with ESRF who had been dialysed for >5 years, at least 80% of the time by CAPD. Clinical and radiological features of beta2M amyloidosis were sought and compared with the results of SAP scintigraphy.RESULTS:SAP scans showed articular amyloid deposits in seven patients, all of whom had evidence of carpal tunnel syndrome and four of whom had arthralgia characteristic of dialysis amyloidosis. Typical radiographic bone cysts were present in only one case who had been dialysed for >17 years. The remaining six patients had no clinical, radiological or scintigraphic evidence of beta2M amyloidosis.CONCLUSIONS:The prevalence of beta2M amyloidosis in this study was comparable with that in reported haemodialysis populations. Many of the amyloid deposits demonstrated by SAP scintigraphy were not associated with symptoms, but larger and longer term studies are required to determine whether CAPD favourably influences their clinical expression.

AIMS/BACKGROUND: Primary localised amyloidosis is rarely encountered in the orbit. The typical clinical and radiological appearances have not been clearly established, in particular the single site deposition of amyloid has never been proved. METHODS: Six cases were reviewed in detail and their clinical and radiological characteristics are described here. Four patients had scintigraphy with 123I serum amyloid P component and one patient had typing of the amyloid fibrils. RESULTS: All the patients had a firm mass in the upper orbit with a predilection for the region of the lacrimal gland. Computed tomography showed a homogeneous mass with thickening and irregularity of the adjacent bone and/or calcification within the mass. None was associated with systemic disease. Scintigraphy with 123I serum amyloid P component demonstrated that the amyloid was confined to the orbit. In one patient the amyloid fibrils were derived from an IgG4 heavy chain constant domain. The lesions were partially excised with subsequent clinical stability over 6 months to 18 years in all but one patient who had continued enlargement of the lesion. CONCLUSION: There is a characteristic clinical and radiological pattern for primary localised amyloidosis of the orbit. The disease process is truly local and not part of a systemic process. A majority respond to simple debulking with subsequent observation.

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.

We report the five year outcome of nine patients with dialysis-related amyloid (DRA) who underwent successful renal transplantation (RT) and six patients who remained on hemodialysis (HD). Amyloid bone cysts, a radiologic feature of DRA, and scintigraphy with 123I-labeled serum amyloid P component (SAP), a specific technique for evaluating amyloid deposits in vivo, were monitored and compared with clinical features. In all HD patients there was clinical, scintigraphic and/or radiologic evidence that DRA progressed. In contrast, eight of the RT patients experienced profound early relief of DRA symptoms following transplantation that persisted throughout follow-up, despite the reduction or withdrawal of corticosteroids. Amyloid bone cysts improved in four patients and SAP scans demonstrated regression of articular amyloid in eight out of nine cases. The modest radiographic improvement suggests that amyloid is mobilized more slowly in bone cysts than elsewhere or that cystic bone is remodeled poorly. This is the first objective evidence that DRA regresses following renal transplantation, and suggests that this may contribute to the long-term relief of DRA symptoms in transplant recipients who discontinue corticosteroids.

Conference Abstract| February 01 1996 Scintigraphic Imaging of Amyloid Deposits Using Technetium-Labelled Serum Amyloid P Component W L Hutchinson; W L Hutchinson 1Immunological Medicine Unit, RPMS, Hammersmith Hospital, and Department of Nuclear Medicine, St Bartholomew's Hospital, London, England Search for other works by this author on: This Site PubMed Google Scholar S J Mather; S J Mather 1Immunological Medicine Unit, RPMS, Hammersmith Hospital, and Department of Nuclear Medicine, St Bartholomew's Hospital, London, England Search for other works by this author on: This Site PubMed Google Scholar M Staltieri; M Staltieri 1Immunological Medicine Unit, RPMS, Hammersmith Hospital, and Department of Nuclear Medicine, St Bartholomew's Hospital, London, England Search for other works by this author on: This Site PubMed Google Scholar G E Noble; G E Noble 1Immunological Medicine Unit, RPMS, Hammersmith Hospital, and Department of Nuclear Medicine, St Bartholomew's Hospital, London, England Search for other works by this author on: This Site PubMed Google Scholar D M Vigushin; D M Vigushin 1Immunological Medicine Unit, RPMS, Hammersmith Hospital, and Department of Nuclear Medicine, St Bartholomew's Hospital, London, England Search for other works by this author on: This Site PubMed Google Scholar S Y Tan; S Y Tan 1Immunological Medicine Unit, RPMS, Hammersmith Hospital, and Department of Nuclear Medicine, St Bartholomew's Hospital, London, England Search for other works by this author on: This Site PubMed Google Scholar A Seymour; A Seymour 1Immunological Medicine Unit, RPMS, Hammersmith Hospital, and Department of Nuclear Medicine, St Bartholomew's Hospital, London, England Search for other works by this author on: This Site PubMed Google Scholar P N Hawkins; P N Hawkins 1Immunological Medicine Unit, RPMS, Hammersmith Hospital, and Department of Nuclear Medicine, St Bartholomew's Hospital, London, England Search for other works by this author on: This Site PubMed Google Scholar M B Pepys M B Pepys 1Immunological Medicine Unit, RPMS, Hammersmith Hospital, and Department of Nuclear Medicine, St Bartholomew's Hospital, London, England Search for other works by this author on: This Site PubMed Google Scholar Clin Sci (Lond) (1996) 90 (s34): 18P. https://doi.org/10.1042/cs090018P Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation W L Hutchinson, S J Mather, M Staltieri, G E Noble, D M Vigushin, S Y Tan, A Seymour, P N Hawkins, M B Pepys; Scintigraphic Imaging of Amyloid Deposits Using Technetium-Labelled Serum Amyloid P Component. Clin Sci (Lond) 1 February 1996; 90 (s34): 18P. doi: https://doi.org/10.1042/cs090018P Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 1996 The Biochemical Society and the Medical Research Society1996 Article PDF first page preview Close Modal You do not currently have access to this content.

BACKGROUND:Amyloidosis is a disorder of protein metabolism characterized by extracellular accumulation of abnormal protein fibrils. Different proteins form the fibrils in different forms of the disease, and the condition can be acquired or hereditary. Involvement of the heart is quite common, producing a serious and usually fatal cardiomyopathy. Cardiac amyloidosis is often diagnosed late, and cardiac biopsy together with proper histological examination is essential. Contrary to previous perceptions, there is much recent evidence of effective treatment for several different types of systemic and cardiac amyloidosis, including the most common hereditary form caused by mutations in the transthyretin gene. Chemical and genetic typing of amyloid is therefore of considerable clinical importance.METHODS AND RESULTS:Seven members in two generations of an Italian family presented with cardiac disease inherited as an autosomal dominant and were found to have systemic amyloidosis. Angina pectoris-like pain, an unusual feature in cardiac amyloidosis, was a prominent symptom, possibly related to partial obliteration of the distal coronary arteries by amyloid infiltration. There were also cases of sudden cardiac death. Peripheral and autonomic neuropathy, which are the usual features of hereditary amyloidosis, were present in only two cases, and a diagnosis of acquired, immunoglobulin light chain (AL type) amyloidosis was suspected in the index case before the family history emerged. In fact, the amyloid fibrils were composed of transthyretin, and the two affected individuals from whom DNA was available were both heterozygotes for a single base change in exon 3 of the transthyretin gene, encoding substitution of Lys for the wild-type Thr residue at position 59 in the mature protein. This mutation has not previously been reported.CONCLUSIONS:We have identified a novel mutation in the transthyretin gene encoding 59Thr-->Lys associated with autosomal dominant hereditary systemic amyloidosis in an Italian kindred in whom cardiac involvement was the major feature. This family illustrates the difficulty in diagnosis of cardiac amyloid, the variable clinical phenotype in hereditary amyloidosis even within a family, and the importance of precise fibril typing for correct management in this condition.

Amyloidosis is the extracellular deposition of normally soluble autologous protein in a characteristic abnormal fibrillar form. Systemic amyloidosis and some local forms are progressive, cause major morbidity, and are often fatal. No treatment specifically causes the resolution of amyloid deposits, but therapy that reduces the supply of amyloid fibril precursor proteins can improve survival and preserve organ function. Major regression of amyloid occurs in at least a proportion of such cases, suggesting that the clinical improvement reflects mobilization of amyloid. The clearest evidence for regression of amyloid has been obtained in juvenile rheumatoid arthritis patients with AA amyloidosis treated with chlorambucil. This drug suppresses the acute phase production of serum amyloid A protein, the precursor of AA amyloid fibrils, and is associated with remission of proteinuria and greatly improved survival. In many such patients, scintigraphy with serum amyloid P component shows major regression of amyloid over 12 to 36 months and frequently reveals a discrepancy between the local amyloid load and organ dysfunction. Measurement of target organ function is therefore not an adequate method for monitoring treatment aimed at promoting the resolution of amyloid. In monoclonal immunoglobulin light chain (AL) amyloidosis the aim of treatment is to suppress the underlying B-cell clone and, therefore, production of the amyloid fibril precursor protein. This can be difficult to achieve or sustain and, since the prognosis is so poor, many patients die before benefits of therapy are realized. A recent development has been the introduction of liver transplantation as treatment for familial amyloid polyneuropathy caused by transthyretin gene mutations. This leads to the disappearance of variant transthyretin from the plasma and halts progression of the neurologic disease. Features of autonomic neuropathy frequently ameliorate, and improvement in peripheral motor nerve function has been recently reported. Serum amyloid P component scans show regression of associated visceral amyloidosis. This surgical form of gene therapy holds much promise for patients with familial amyloid polyneuropathy and has been widely adopted. The only other form of amyloidosis in which the supply of the fibril precursor protein can be sharply reduced is beta 2M amyloidosis in long-term hemodialysis patients. Renal transplantation lowers the plasma concentration of beta 2M to normal levels and is associated with rapid improvement of the osteoarticular symptoms. Preliminary observations suggest that the beta 2M amyloid deposits also can regress in some patients.(ABSTRACT TRUNCATED AT 400 WORDS)

A man with hereditary non-neuropathic systemic amyloidosis had amyloid fibril protein subunits consisting of N-terminal fragments (residues 1-86, 1-92 and 1-93) of a previously unknown variant of apolipoprotein Al, Trp50Arg, encoded by a thymine-cytosine transition. This is the third reported amyloidogenic apoAl variant. All involve substitutions of single neutral amino acids by the cationic residue arginine, suggesting a common mechanism of amyloidogenesis. However, the phenotypic expression of these mutations varies both within and between the seven known families with hereditary apoAl amyloidosis. These findings should facilitate analysis of the molecular basis of fibrillogenesis and of factors that modulate amyloid deposition and its consequences in vivo.

1. Primary orbital amyloidosis is a rare form of localized amyloidosis in which the precursor protein has not previously been identified. We report here the first extraction of amyloid fibrils from a tissue biopsy containing orbital amyloid, and characterization of the fibril protein. 2. The N-terminal nine residues were identical with residues 278-286 and 275-283 of the third constant (CH3) domains of IgG1 and IgG4 gamma heavy chains, respectively. The mass of the fibril subunit protein was 6125Da by time-of-flight mass spectrometry, compared with the expected masses of 6169.9Da and 6214.9Da for the CH3 domains of gamma 1 from residue 278 and gamma 4 from residue 275, respectively. The fibril protein thus appeared to consist exclusively of an immunoglobulin heavy chain constant domain. 3. Only two examples of immunoglobulin heavy chain derived amyloid have been reported previously and both of these, as well as all published cases of the usual immunoglobulin light chain derived amyloid, contained variable domain sequence. The present case therefore represents a form of local, presumably clonal, B-cell/plasma-cell disorder characterized uniquely by deposition of an amyloidogenic immunoglobulin heavy chain constant domain fragment.