Systemic Amyloid Research Articles

Early liver transplantation improves familial amyloidotic polyneuropathy patients' survival

Since the first liver transplantation for familial amyloidotic polyneuropathy was performed in 1990, it has become an accepted treatment for this systemic amyloid disorder. Liver transplantation halts the production of the mutated amyloidogenic transthyretin, and thereby amyloid formation, and also progression of the majority of symptoms. Improvement in survival from onset of disease in transplanted patients compared to non-transplanted subjects has of yet not been demonstrated, partly because of the natural relatively slow progression of the disease with an expected median survival of 13 years.In this retrospective study we compared the early initial series (n = 34) of transplantations, where severely malnourished patients were accepted, with a later series (n = 27) of transplants, as well as a control group (n = 19) consisting of non-transplanted patients.For transplanted patients with an modified body mass index (mBMI) above 600 an improved survival was noted compared with that of non-transplanted historical controls. So far no difference in survival between the early and late series has been found.Our previous recommendation of selection of patients primarily according to their nutritional status appears to be well justified, since it is now possible to demonstrate an increased survival for the transplanted group of patients with a preserved nutritional status (mBMI > 600) compared to the control group of non-transplanted patients.

CASE REPORT: Primary Biliary Cirrhosis and Systemic Amyloidosis, a New Association

Amyloidosis is a heterogeneous group of disorders characterized by the extracellular deposition of proteins in an abnormal fibrillar pattern with pathognomonic applegreen birefringence under polarized light when stained with Congo red (1). Historically, these have been classified as “primary” or “secondary” amyloidosis. Primary amyloidosis (AL) represents the most common form of systemic amyloid deposition in the Western world and is typically associated with immunocyte dyscrasias such as multiple myeloma, lymphomas, macroglobulinemia, and “benign” monoclonal gammopathies (2). Secondary amyloidosis (AA) is associated with longstanding infectious or noninfectious inflammatory disorders and, less frequently, neoplastic disorders. Associated disorders include adult rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Reiter’s syndrome, systemic lupus erythematosus, systemic sclerosis, tuberculosis, leprosy, Castleman’s disease, bronchiectasis, cystic fibrosis, osteomyelitis, heroin abuse, psoriasis, inflammatory bowel disease, and Whipple’s disease (1, 2). Despite a strong association with chronic inflammatory disorders and AA, an extensive literature review did not reveal a previously reported association between primary biliary cirrhosis (PBC) and AA. In this case review, we report the first association of these two entities.

Amyloidosis: Uncommon cause of dysphonia

Objectives: Case report of 3 cases of laryngeal amyloidosis Methods: Three cases of localized amyloidosis without systemic disease were identified at Centro Univerisitario de Otorrinolaringologia y Cirugia de Cabeza y Cuello at the Univerisity Hospital in Monterrey Mexico. In each patient the major site of involvement was glottic with small focus in the false vocal folds. Medical workup including full blood count, CSR, urea, electrolytes, ureanalysis, liver function test, chest x-ray, were performed. Physical examination ruled out systemic disease. Congo red staining confirmed the diagnosis in all surgical specimens. Results: Localized laryngeal amyloidosis was identified in 3 patients (2 males and 1 female) with ages ranging from 33 to 67 years. The presenting symptoms including hoarsness, throat soreness, voice breaks, and vocal fatigue. The duration of the symptoms before diagnosis varied from 3 to 12 years. Assesstment of the extent of laryngeal spread of disease included CT scan, complete voice analysis, and videolaryngostroboscopy in all patients. Material for biopsy was obtained by direct laryngoscopy, apple-green birefringence was seen with congo red stain establishing the histological diagnosis. The 3 patients underwent phonomicrosurgery for removal of the amyloid implantation using cold knife excision. Conclusion: Laryngeal amyloidosis is a rare disease with an 8 in 1,000,000 presentation rate. It is more common in males with 3:1 prevalence in the fifth decade. Once the diagnosis is confirmed by congo red staining, it is important to rule out systemic amyloid involvement. It is not necessary to do invasive approach on localized disease. Cold knife excision is still a good method to remove the deposition.

Primary central nervous system angiitis, amyloid angiopathy, and alzheimer's pathology presenting with balint's syndrome

We report a patient who presented with Balint's syndrome as a manifestation of primary central nervous system angiitis. Clinical findings included simultanagnosia, optic ataxia, and optic apraxia. Pathologic evaluation demonstrated amyloid angiopathy and Alzheimer's plaques. The presence of primary central nervous system angiitis along with amyloid angiopathy and Alzheimer's plaques may not be coincidental. Angiitis may be a foreign body reaction to A4 amyloid deposition.

The Classification and Typing of Amyloid Deposits

The diagnosis of amyloidosis, unlike many other diagnoses that fall on the shoulders of the pathologist, is based on a simple tinctorial property. Binding of the cotton wool dye Congo red, demonstrating green birefringence when viewed under polarized light, fulfills all diagnostic criteria for amyloid. Reporting amyloidosis in a pathologic specimen is reminiscent of a histologic diagnosis of “lymphoma.” The demonstration of amyloid in and of itself is not particularly helpful to the clinician, and an accurate determination of the type of amyloid is just as important as recognizing the presence of amyloid. The clinician will have many questions for the pathologist. Is the amyloid systemic or localized? Is the amyloidosis primary, secondary, or inherited? The former question is important because the majority of patients with localized disease do not require systemic therapy and the long-term prognosis is excellent. The latter question is important because the prognoses for the 3 forms of systemic amyloid and the treatment of the 3 disorders are vastly different. One often involves chemotherapy and stem cell transplantation; another might lead to liver transplantation. Accurate classification becomes imperative. Some forms of localized amyloid are light chain–derived, but the light chain production is local and not part of a systemic plasma cell dyscrasia.1 Localized forms of amyloid might be suspected because of the organ involved. When deposits of amyloid are found in the bladder, urethra, and ureter, it is virtually always a localized process. Most cases of amyloid in the skin and conjunctivae are localized. Amyloidosis of the larynx and tracheobronchial tree is not a systemic disorder, although it may cause troublesome complications. Amyloid deposits in the atria of the heart, pleura, and the articular cartilage generally are localized, and the diagnosis of systemic amyloidosis should not be made unless there is other evidence of visceral involvement. The majority of patients seen in the United States with systemic amyloid have immunoglobulin light chain amyloid (AL) or primary type. The origin of the fibril is an immunoglobulin light chain or immunoglobulin heavy chain fragment. Virtually all patients have a demonstrable clonal plasma cell dyscrasia, and this fact can be used to advantage in classifying the amyloid. These patients will have a detectable monoclonal light chain in the serum or urine shown by immunofixation or an elevation of the immunoglobulin free light chain level revealed by nephelometry.2 Bone marrow examination will demonstrate clonal plasma cells as the source of the light chain production.3 The finding of a monoclonal protein is helpful, but it is not sufficient to diagnose AL. Occasionally a patient will have an incidental monoclonal gammopathy of undetermined significance and a form of amyloid that is not immunoglobulin light chain in origin.4 Finding amyloid deposits on biopsy in the presence of monoclonal immunoglobulins is strong but not conclusive evidence of AL. Clinically, it is difficult to distinguish primary, secondary, familial, and senile forms of amyloid from one another. In the Mayo Clinic (Rochester, MN) experience, half of the patients with inherited amyloidosis do not have a positive family history. Patients with secondary amyloidosis typically have nephrotic syndrome. Renal biopsies demonstrate amyloid deposits. These patients also might have significant gastrointestinal involvement. Patients with hereditary systemic amyloidosis can have renal involvement

L’amyloïdose des vésicules séminales, une condition localisée sans répercussion systémique

Localised seminal vesicle amyloidosis is relatively infrequent and we present 9 additional cases. and methods: Those 9 cases were retrospectively retrieved from 803 radical prostatectomies performed between 1995 and 2000 for prostatic adenocarcinoma. In each case, the type of amyloidosis was characterised by immunohistochemistry. Information regarding a possible concurrent disease or prior hormone therapy has been obtained. The prevalence of amyloidosis of seminal vesicles is lower in our study (1.1%) than in unselected autopsy cases. The prevalence of amyloidosis in patients exposed to prior hormone therapy (LHRH agonist and anti-androgen) was 2% while it reached only 0.9% in those who received no hormone therapy (p>0.3). No patient had systemic amyloidosis and all cases were of non A-A type. Lactoferrin, a glycoprotein produced by normal seminal vesicles, was detected in more than a half of them (5/9). No association was found between the occurrence of seminal vesicle amyloidosis and occurrence of a prostatic adenocarcinoma, corcomitant systemic disease or exposure to prior hormone therapy. Seminal vesicle amyloidosis is a localised condition without systemic involvement and amyloid deposition is composed mostly of lactoferrin.

Classical and alternative pathway complement activation are not required for reactive systemic AA amyloid deposition in mice.

During induction of reactive systemic amyloid A protein (AA) amyloidosis in mice, either by chronic inflammation or by severe acute inflammation following injection of amyloid enhancing factor, the earliest deposits form in a perifollicular distribution in the spleen. Because the splenic follicular localization of immune complexes and of the scrapie agent are both complement dependent in mice, we investigated the possible complement dependence of AA amyloid deposition. In preliminary experiments, substantial depletion of circulating C3 by cobra venom factor had little effect on experimental amyloid deposition. More importantly, mice with targeted deletion of the genes for C1q or for both factor B and C2, and therefore unable to sustain activation, respectively, of either the classical complement pathway or both the classical and alternative pathways, showed amyloid deposition similar to wild type controls. Complement activation by either the classical or alternative pathways is thus not apparently necessary for the experimental induction of systemic AA amyloid in mice.

The systemic amyloidoses.

Clinical management of the amyloidoses has historically been the province of rheumatologists, because of the relation to long-standing inflammation in rheumatoid arthritis, ankylosing spondylitis, and juvenile chronic arthritis. Currently, nephrologists, hematologist-oncologists, neurologists, and transplant surgeons all have a diagnostic or therapeutic interest. Current advances, using the tools of physical biochemistry, cell biology, and genetics, have begun to impact the diagnosis and clinical management of these disorders and raise questions regarding our notions of protein conformation in vivo and how nonnatively folded proteins may produce disease. It appears that all amyloidogenic precursors undergo some degree of misfolding that allows them to populate an immediate precursor pool from which they rapidly aggregate. Depending on the particular protein, a variety of mechanisms appear operative, some of which involve nonphysiologic proteolysis, defective physiologic proteolysis, mutations involving changes in thermodynamic or kinetic properties, and pathways that are yet to be defined. Whatever the particular process, the result is a tendency toward oligomeric aggregation followed by the assembly of higher order structures that become insoluble under physiologic conditions. Detailed analyses have been described for transthyretin (senile systemic amyloidosis and familial amyloid polyneuropathy), immunoglobulin light chains (light-chain amyloid), beta2 microglobulin (dialysis-related amyloid), and apolipoprotein A1, and are in process for others. SUMMARY Therapies have been proposed based on precursor stabilization (transthyretin), elimination of the synthesizing cell (light-chain amyloid), fibril disruption and immunization to induce host-mediated aggregate clearance (Alzheimer disease, light-chain amyloid, prions), and aggressive therapy of a primary inflammatory process (amyloid A). During the next decade, the value of these therapies, and others, suggested by studies on the basic properties of cells and proteins, will become clear.

Polineuropatía amiloidótica familiar tipo I: Report of one case

Familial amyloidotic polyneuropathy type I is an autosomal dominant inherited disorder characterized by progressive peripheral and autonomic neuropathy, associated with neural and systemic amyloid deposits. The abnormality usually lies in the transthyretin (TTR) gene. We report a 25 years old man with 18 months history of dysesthesias and pain in the toes, abnormal micturition and sexual dysfunction. Neurophysiologically studies disclosed a sensory-motor axonal polyneuropathy. Autonomic tests showed sympathetic and parasympathetic involvement. An electron micrograph of sural nerve revealed amyloid fibrils in the endoneurium. His mother died after a clinical history suggestive, in retrospect, of familial amyloidotic polyneuropathy type I. The clinical and genetic analysis of this cause of polyneuropathy are discussed.

End-stage renal disease in familial amyloidosis ATTR Val30Met: a definitive indication to combined liver-kidney transplantation

AUTOSOMAL dominant amyloidoses characterized so far are most commonly associated with transthyretin (TTR), a plasma protein synthesized by the liver. The single gene for TTR is located on human chromosome 18; more than 70 TTR mutations have been documented. The most common type of hereditary amyloidosis is familial amyloid polyneuropathy type I (FAP, Portuguese type), a neuropathic form associated with a substitution of methionine for valine at position 30 of the TTR gene, TTR Val30Met. The largest number of patients and families with this mutation has been identified in Portugal, but now it has been recognized worldwide. FAP in Portugal usually begins in the third or fourth decade of life with death occuring about 11 years later. The clinical disease usually starts as a sensory neuropathy in the lower extremities, but autonomic and gastrointestinal features may occur early. Motor neuropathy usually manifests itself later with cardiac conduction disturbances frequently leading to the need for artificial pacing. Vitreous deposits of amyloid have been reported, most particularly in Swedish families. Cachexia has been described as a significant factor in mortality. Orthotopic liver transplantation (OLT) is widely recommended for patients affected by FAP; it is recognized as the only specific treatment for this disease. Virtually all TTR is produced by the liver, and, therefore, OLT halts the supply of variant amyloidogenic TTR (ATTR). Amyloid proteins have different organ specificity, leading to variations in clinical features. Classically, nephropathic and nonneuropathic autosomal dominant amyloidoses are associated with apolipoprotein A-I and A-II, fibrinogen A -chain, and lysozyme. Renal amyloidosis also has been described in FAP. In Portugal, approximately one third of FAP patients have clinical renal features with varying degrees of proteinuria and renal failure. The progression to end-stage renal disease (ESRD) occurs in 10% of Portuguese patients, more than 10 years after the onset of symptoms (Lobato et al, unpublished data). Although dialysis may prolong life, it does not prevent the progression of systemic amyloid involvement; death occurred, on average, at 22 months after renal replacement therapy. The cause was infection in one half of the patients (Lobato et al, unpublished data). The first successful renal transplantation in a patient with renal amyloidosis was reported in 1968, but until now this treatment has been associated with poor graft and patient survival. Most published series concerning renal transplantation in amyloidosis deal with familial Mediterranean fever or other forms of reactive amyloidosis (AA type). The results of kidney transplantation in ATTR have not been described. In patients with FAP undergoing dialysis, the potential advantages of simultaneous liver-kidney transplantation instead of isolated kidney transplantation are to avoid the progression of systemic manifestations and the recurrence of renal amyloidosis. The obstacles to renal transplantation

Systemic amyloidosis associated with pleomorphic sarcoma of the spleen and remission of nephrotic syndrome after removal of the tumor

We report a case of a 57-year-old woman who was diagnosed with a systemic AA amyloidosis associated with a pleomorphic sarcoma of the spleen. Although the association and causality between chronic inflammatory states and systemic AA amyloidosis have been well established, the evidence linking solid malignancies to reactive AA amyloidosis is scarce. Our patient had a significant systemic amyloid deposition including biopsy-proven renal and cardiac AA amyloidosis. Subsequent evaluation uncovered the presence of a large splenic mass, which was treated by splenectomy. Histologically the splenic tumor was classified as pleomorphic sarcoma. The removal of the tumor resulted in a marked decline in proteinuria, stable renal and cardiac functions, and symptomatic improvement at 1-year follow-up. Based on the noted improvements, we speculate that the pleomorphic sarcoma of the spleen caused secondary amyloidosis in our case. Stromal tumors, although rare, may be associated with and should be considered in the differential diagnosis of the cause of AA amyloidosis. © 2002 by the National Kidney Foundation, Inc.

Inflammation-Dependent Cerebral Deposition of Serum Amyloid A Protein in a Mouse Model of Amyloidosis

The major pathological hallmark of amyloid diseases is the presence of extracellular amyloid deposits. Serum amyloid A (SAA) is an apolipoprotein primarily produced in the liver. Serum protein levels can increase one thousandfold after inflammation. SAA is the precursor to the amyloid A protein found in deposits of systemic amyloid A amyloid (AA or reactive amyloid) in both mouse and human. To study the factors necessary for cerebral amyloid formation, we have created a transgenic mouse that expresses the amyloidogenic mouse Saa1 protein in the brain. Using the synapsin promoter to drive expression of theSaa1gene, the brains of transgenic mice expressed both RNA and protein. Under noninflammatory conditions, transgenic mice do not develop AA amyloid deposits in the brain; however, induction of a systemic acute-phase response in transgenic mice enhanced amyloid deposition. This deposition was preceded by an increase in cytokine levels in the brain, suggesting that systemic inflammation may be a contributing factor to the development of cerebral amyloid. The nonsteroidal anti-inflammatory agent indomethacin reduced inflammation and protected against the deposition of AA amyloid in the brain. These studies indicate that inflammation plays an important role in the process of amyloid deposition, and inhibition of inflammatory cascades may attenuate amyloidogenic processes, such as Alzheimer's disease.

Inflammation-dependent cerebral deposition of serum amyloid a protein in a mouse model of amyloidosis.

The major pathological hallmark of amyloid diseases is the presence of extracellular amyloid deposits. Serum amyloid A (SAA) is an apolipoprotein primarily produced in the liver. Serum protein levels can increase one thousandfold after inflammation. SAA is the precursor to the amyloid A protein found in deposits of systemic amyloid A amyloid (AA or reactive amyloid) in both mouse and human. To study the factors necessary for cerebral amyloid formation, we have created a transgenic mouse that expresses the amyloidogenic mouse Saa1 protein in the brain. Using the synapsin promoter to drive expression of the Saa1 gene, the brains of transgenic mice expressed both RNA and protein. Under noninflammatory conditions, transgenic mice do not develop AA amyloid deposits in the brain; however, induction of a systemic acute-phase response in transgenic mice enhanced amyloid deposition. This deposition was preceded by an increase in cytokine levels in the brain, suggesting that systemic inflammation may be a contributing factor to the development of cerebral amyloid. The nonsteroidal anti-inflammatory agent indomethacin reduced inflammation and protected against the deposition of AA amyloid in the brain. These studies indicate that inflammation plays an important role in the process of amyloid deposition, and inhibition of inflammatory cascades may attenuate amyloidogenic processes, such as Alzheimer's disease.

Misdiagnosis of Hereditary Amyloidosis as AL (Primary) Amyloidosis

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.

Familial British dementia (FBD): a cerebral amyloidosis with systemic amyloid deposition

Introduction: FBD is an autosomal dominant disease with neuropathological similarities to Alzheimer's disease (AD) as it is characterized by amyloid angiopathy, parenchymal amyloid plaque deposition and neurofibrillary degeneration. FBD is associated with a stop codon mutation in the BRI2 gene encoding a type II transmembrane protein, BriPP. Mutation results in an extended precursor protein, ABriPP, from which a C-terminal 34 amino acid peptide (ABri) is generated by furin-like proteolytic cleavage and deposited as amyloid and preamyloid in the central nervous system. Despite the morphological parallels with AD the sequences of the amyloidogenic peptides, ABri in FBD and Aβ in AD, are completely different. We examined systemic tissues in FBD for ABri deposition. Materials and methods: Immunohistochemistry using an ABri-specific antibody, Ab338, counterstained with Thioflavin S and Ab338 immuno-electron microscopy identified ABri deposits and determined whether these were amyloid or preamyloid in nature. Results: Amyloid bearing blood vessels stained positively for ABri in myocardium, uterus, bladder, spleen, pancreas, lung and skeletal muscle. ABri was also identified in either amyloid or preamyloid conformation in the parenchyma of myocardium, adrenal, pancreas and skeletal muscle. Conclusion: This study demonstrates that FBD is the first described cerebral amyloidosis with neurofibrillary pathology and dementia to be accompanied by systemic amyloid deposition.

Support for the multigenic hypothesis of amyloidosis: the binding stoichiometry of retinol-binding protein, vitamin A, and thyroid hormone influences transthyretin amyloidogenicity in vitro.

The amyloidoses are a large group of protein misfolding diseases. Genetic and biochemical evidence support the hypothesis that amyloid formation from wild-type or 1 of 80 sequence variants of transthyretin causes the human amyloid diseases senile systemic amyloidosis or familial amyloid polyneuropathy, respectively. The late onset and variable penetrance of these diseases has led to their designation as multigenic--implying that the expression levels and alleles of multiple gene products influence the course of pathology. Here we show that the binding stoichiometry of three interacting molecules, retinol-binding protein, vitamin A, and L-thyroxine, notably influenced transthyretin amyloidogenicity in vitro. At least 70 genes control retinol-binding protein, vitamin A, and L-thyroxine levels in plasma and have the potential to modulate the course of senile systemic amyloidosis or familial amyloid polyneuropathy.

Systemic amyloid deposits in familial British dementia.

Familial British dementia (FBD) is an early onset inherited disorder that, like familial Alzheimer's disease (FAD), is characterized by progressive dementia, amyloid deposition in the brain, and neurofibrillary degeneration of limbic neurons. The primary structure of the amyloid subunit (ABri) extracted from FBD brain tissues (Vidal, R., Frangione, B., Rostagno, A., Mead, S., Revesz, T., Plant, G., and Ghiso, J. (1999) Nature 399, 776-781) is entirely different and unrelated to any previously known amyloid protein. Patients with FBD have a single nucleotide substitution at codon 267 in the BRI2 gene, resulting in an arginine replacing the stop codon and a longer open reading frame of 277 amino acids instead of 266. The ABri peptide comprises the 34 C-terminal residues of the mutated precursor ABriPP-277 and is generated via furin-like proteolytic processing. Here we report that carriers of the Stop-to-Arg mutation have a soluble form of the amyloid peptide (sABri) in the circulation with an estimated concentration in the range of 20 ng/ml, several fold higher than that of soluble Abeta. In addition, ABri species identical to those identified in the brain were also found as fibrillar components of amyloid deposits predominantly in the blood vessels of several peripheral tissues, including pancreas and myocardium. We hypothesize that the high concentration of the soluble de novo created amyloidogenic peptide and/or the insufficient tissue clearance are the main causative factors for the formation of amyloid deposits outside the brain. Thus, FBD constitutes the first documented cerebral amyloidosis associated with neurodegeneration and dementia in which the amyloid deposition is also systemic.

Nodular Cutaneous Amyloid Tumors of the Eyelids in the Absence of Systemic Amyloidosis

A patient was referred with recurrent bilateral, slow-growing, painless, nodular tumors of the upper eyelid margins. The tumors were excised and the base of each lesion was ablated with the CO2 laser. Histological examination of the excised tissue revealed amyloid. Despite the fact that cutaneous, amyloid lesions of the eyelid have been previously described as essentially pathognomonic for systemic amyloid disease, no evidence of systemic amyloidosis was found in this patient. We believe that this represents only the second reported case of bilateral cutaneous amyloid of the eyelids without systemic involvement. We agree with previous authors that this lesion be added to the list of painless slow-growing bilateral eyelid tumors.

Acquired factor X deficiency in patients with amyloid light-chain amyloidosis: incidence, bleeding manifestations, and response to high-dose chemotherapy

Acquired deficiency of factor X occurs in patients with systemic amyloid light-chain (AL) amyloidosis, presumably due to adsorption of factor X to amyloid fibrils. Of 368 consecutive patients with systemic AL amyloidosis evaluated at Boston Medical Center, 32 patients (8.7%) had factor X levels below 50% of normal. Eighteen of these patients (56%) had bleeding complications, which were more frequent and severe in the 12 patients below 25% of normal; 2 episodes were fatal. Ten factor X-deficient patients received high-dose melphalan chemotherapy followed by autologous stem cell transplantation. Of 7 patients alive 1 year after treatment, 4 had a complete hematologic response, and all 4 experienced improvement in their factor X levels. One of 2 additional patients with partial hematologic responses had improvement in factor X. Thus, aggressive treatment of the underlying plasma cell dyscrasia in AL amyloidosis can lead to the amelioration of amyloid-related factor X deficiency.

Amyloid and Nonfibrillar Deposits in Mice Transgenic for Wild-Type Human Transthyretin: A Possible Model for Senile Systemic Amyloidosis

The human serum protein transthyretin (TTR) is highly fibrillogenic in vitro and is the fibril precursor in both autosomal dominant (familial amyloidotic polyneuropathy [FAP] and familial amyloidotic cardiomyopathy [FAC]) and sporadic (senile systemic amyloidosis [SSA]) forms of human cardiac amyloidosis. We have produced mouse strains transgenic for either wild-type or mutant (TTRLeu55Pro) human TTR genes. Eighty-four percent of C57Bl/6xDBA/2 mice older than 18 months, transgenic for the wild-type human TTR gene, develop TTR deposits that occur primarily in heart and kidney. In most of the animals, the deposits are nonfibrillar and non-Congophilic, but 20% of animals older than 18 months that bear the transgene have human TTR cardiac amyloid deposits identical to the lesions seen in SSA. Amino terminal amino acid sequence analysis and mass spectrometry of the major component extracted from amyloid and nonamyloid deposits revealed that both were intact human TTR monomers with no evidence of proteolysis or codeposition of murine TTR. This is the first instance in which the proteins from amyloid and nonfibrillar deposits in the same or syngeneic animals have been shown to be identical by sequence analysis. It is also the first time in any form of amyloidosis that nonfibrillar deposits have been shown to systematically occur temporally before the appearance of fibrils derived from the same precursor in the same tissues. These findings suggest, but do not prove, that the nonamyloid deposits represent a precursor of the fibril. The differences in the ultrastructure and binding properties of the deposits, despite the identical sizes and amino terminal amino acid sequences of the TTR and the dissociation of deposition and fibril formation, provide evidence that in vivo factors, perhaps associated with aging, impact on both systemic precursor deposition and amyloid fibril formation.