Familial Renal Amyloidosis

Updated: Aug 21, 2015
  • Author: Helen J Lachmann, MD, MRCP; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Overview

Background

Amyloidosis is a disorder of protein folding in which normally soluble proteins undergo a conformational change and are deposited in the extracellular space in an abnormal fibrillar form, as shown below. Accumulation of these fibrils causes progressive disruption of the structure and function of tissues and organs, and the systemic (generalized) forms of amyloidosis are frequently fatal. The conditions that underlie amyloid deposition may be either acquired or hereditary, and at least 20 different proteins can form amyloid fibrils in vivo. See the image below.

Proposed mechanism for amyloid fibril formation. T Proposed mechanism for amyloid fibril formation. The drawing depicts a generic amyloid fibril precursor protein (I) in equilibrium with a partially unfolded, molten, globulelike form of the protein (II) and its completely denatured state (III). Autoaggregation through the beta domains initiates fibril formation (IV), providing a template for ongoing deposition of precursor proteins and for the development of the stable, mainly beta-sheet, core structure of the fibril. The amyloidogenic precursor proteins in patients with familial renal amyloidosis are thought to be less stable than their wild-type counterparts, causing them to populate intermediate, molten, globulelike states more readily.

Renal dysfunction is one of the most common presenting features of patients with systemic amyloidosis, and amyloid accumulation is the major pathological finding in approximately 2.5% of all native renal biopsies. Most such patients have either reactive systemic (AA) amyloidosis or monoclonal immunoglobulin light-chain (AL) amyloidosis, but in the few remaining cases, the disease is hereditary.

The syndrome of familial systemic amyloidosis with predominant nephropathy is inherited in an autosomal dominant manner and was first described in a German family by Ostertag in 1932. [1] Research has shown that almost all patients with familial renal amyloidoses (FRA) are heterozygous for mutations in the genes for lysozyme, apolipoprotein AI, apolipoprotein AII, or fibrinogen A alpha-chain and that the amyloid fibrils in this condition are derived from the respective variant proteins. Both penetrance and the clinical phenotype can vary substantially among different families with the same mutation, even within individual kindreds.

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Pathophysiology

The pathogenesis of amyloid centers around off-pathway folding of the various amyloid fibril precursor proteins. These proteins can exist as two radically different stable structures: the normal soluble form and a highly abnormal fibrillar conformation.

All amyloid fibrils share a common core structure in which the subunit proteins are arranged in a stack of twisted, antiparallel, beta-pleated sheets lying with their long axes perpendicular to the fibril long axis. Proteins that can form amyloid transiently populate partly unfolded intermediate molecular states that expose the beta-sheet domain, enabling them to interact with similar molecules in a highly ordered fashion.

Propagation of the resulting low molecular weight aggregates into mature amyloid fibrils is probably a self-perpetuating process that depends only on a sustained supply of the fibril precursor protein. In some cases, the precursors undergo partial proteolytic cleavage; however, whether this occurs before, during, or after the formation of amyloid fibrils remains unknown.

Studies on hereditary amyloidosis have provided unique and valuable insights into the general pathogenesis of amyloid. Most of the variant proteins associated with hereditary amyloidosis differ from their wild-type counterparts by just a single amino acid substitution, although deletions and insertions also occur (see the Table).

 

Table. Recognized Genotypes and Their Associated Phenotypes in Familial Renal Amyloidosis (Open Table in a new window)

Amyloid Fibril Precursor Protein Organs/Tissues Predominantly Affected by Amyloid and Common Clinical Features Ethnic Origin of Affected Kindreds
Lysozyme Ile56Thr Renal - Proteinuria and renal failure



Skin - Petechial rashes



Liver and spleen - Organomegaly (usually well-preserved function)



2 British families



(possibly related)



Lysozyme Asp67His Renal - Proteinuria and renal failure



GI tract - Bleeding and perforation



Liver and spleen - Organomegaly and hepatic hemorrhage



Salivary glands – Sicca syndrome



Single British family
Lysozyme Try64Arg Renal - Proteinuria and renal failure



GI tract - Bleeding and perforation



Salivary glands – Sicca syndrome



Single French family
Apolipoprotein AI



wild type



Amyloid deposits in human aortic atherosclerotic plaques 20-30% of elderly individuals at autopsy
Apolipoprotein AI



Gly26Arg



Renal - Proteinuria and renal failure



Gastric mucosa - Peptic ulcers



Peripheral nerves - Progressive neuropathy



Liver and spleen - Organomegaly (usually well-preserved function)



Multiple families



(mostly of northern European extraction)



Apolipoprotein AI



Trp50Arg



Renal - Proteinuria and renal failure



Liver and spleen - Organomegaly and liver failure



Single Ashkenazi family
Apolipoprotein AI



Leu60Arg



Renal - Proteinuria and renal failure



Liver and spleen - Organomegaly (usually well-preserved function)



Cardiac (rarely) - Heart failure



British and



Irish kindreds



Apolipoprotein AI



deletion 60-71



insertion 60-61



Liver - Liver failure Single Spanish family
Apolipoprotein AI



Leu64Pro



Renal - Proteinuria and renal failure



Liver and spleen - Organomegaly



Single Canadian-Italian family
Apolipoprotein AI



deletion 70-72



Renal - Proteinuria and renal failure



Liver and spleen - Organomegaly (usually well-preserved function)



Retina - Central scotoma



Single family of British origin
Apolipoprotein AI



Leu75Pro



Renal - Proteinuria and



renal failure



Liver and spleen - Organomegaly



Italy – Variable penetrance
Apolipoprotein AI



Leu90Pro



Cardiac - Heart failure



Larynx - Dysphonia



Skin – Infiltrated yellowish plaques



Single French family
Apolipoprotein AI



deletion Lys107



Aortic intima - Aggressive early-onset ischemic heart disease Single Swedish patient at autopsy
Apolipoprotein AI



Arg173Pro



Cardiac - Heart failure



Larynx - Dysphonia



Skin - Acanthosis nigricans-like plaques



British and American families
Apolipoprotein AI



Leu174Ser



Cardiac - Heart failure Single Italian family
Apolipoprotein AI



Ala175Pro



Larynx - Dysphonia



Testicular - Infertility



Single British family
Apolipoprotein AILeu178His Cardiac - Heart failure



Larynx – Dysphonia



Skin - Infiltrated plaques



Peripheral nerves – Neuropathy



Single French family
Apolipoprotein AII



Stop78Gly



Renal - Proteinuria and renal failure American family
Apolipoprotein AIIStop78Ser Renal - Proteinuria and renal failure American family
Apolipoprotein AIIStop78Arg Renal - Proteinuria and renal failure Russian family, Spanish family(different nucleotide substitutions in the two kindreds)
Fibrinogen A alpha-chain Arg554Leu Renal - Proteinuria and renal failure Peruvian,



African American and



French families



Fibrinogen A alpha-chain



frame shift at codon 522



Renal - Proteinuria and renal failure Single French family
Fibrinogen A alpha-chain



frame shift at codon 524



Renal - Proteinuria and renal failure Single American family
Fibrinogen A alpha-chain Glu526Val Renal - Proteinuria and renal failure



Late-onset liver (rarely) - Organomegaly and liver failure



Multiple families



(northern European extraction,



variable penetrance)



Fibrinogen A alpha-chain Gly540Val Renal - Proteinuria and renal failure Single German family
Fibrinogen A alpha-chain Indel 517-522 Renal - Proteinuria and renal failure Single Korean child

Investigation of the variant amyloidogenic forms of lysozyme has been exceptionally informative because wild-type lysozyme is not associated with amyloidosis and has been thoroughly characterized. The amyloidogenic mutations give rise to amino acid substitutions that subtly destabilize the native fold so that, under physiological conditions, these variants readily visit partly unfolded states, promoting their spontaneous aggregation into amyloid fibrils.

The whole process of lysozyme amyloid fibril formation can be reversed. A soluble functional variant lysozyme has been recovered in vitro from preparations of isolated ex vivo amyloid fibrils that had been denatured and permitted to refold in the normal conformation. Wild-type apolipoprotein AI is inherently moderately amyloidogenic, and small amyloid deposits derived from it occur in aortic atherosclerotic plaques in 20-30% of middle-aged and elderly individuals.

Amyloid deposits in all different forms of the disease, both in humans and in nonhuman animals, contain the nonfibrillar glycoprotein amyloid P component (AP). AP is identical to and derived from the normal circulating plasma protein, serum amyloid P component (SAP), a member of the pentraxin protein family that includes C-reactive protein.

SAP consists of five identical subunits, each with a molecular mass of 25.462 d, which are noncovalently associated in a pentameric disklike ring. The SAP molecule is highly resistant to proteolysis, and, although not itself a proteinase inhibitor, its reversible binding to amyloid fibrils in vitro protects them against proteolysis. In contrast to its normal rapid clearance from the plasma, SAP persists for very prolonged periods within amyloid deposits. The possibility that SAP may contribute to the pathogenesis and/or persistence of amyloid deposits in vivo has been confirmed in studies on SAP knockout mice. [2]

Amyloid deposits accumulate in the extracellular space, progressively disrupting the normal tissue architecture and consequently impairing organ function. Amyloid deposits can also produce space-occupying effects at both microscopic and macroscopic levels. Although amyloid is inert in the sense that it does not stimulate either a local or systemic inflammatory response, some evidence suggests that the deposits exert cytotoxic effects and possibly promote apoptosis.

Strong clinical impressions exist that suggest the rate of accumulation of amyloid has a major bearing on organ function, which can be preserved for very long periods in the presence of an extensive but stable amyloid load. This may reflect adaptation to gradual amyloid accumulation or may relate to toxic properties of newly formed amyloid material.

Prospective studies with serial SAP scintigraphy, a specific and semiquantitative nuclear medicine technique for imaging amyloid deposits, have confirmed that amyloid deposits are turned over constantly, albeit at a relatively low and variable rate. Therefore, the course of a particular patient's amyloid disease depends on the relative rates of amyloid deposition versus turnover. Amyloid deposits often regress when the supply of the respective fibril precursor protein is reduced, and, under favorable circumstances, this is accompanied by stabilization or recovery of organ function.

Many questions about amyloid deposition remain unanswered. Why only a small number of unrelated proteins form amyloid in vivo remains unclear, and, as yet, little is known about the genetic or environmental factors that determine individual susceptibility to amyloid or factors that govern its anatomical distribution and clinical effects. Hereditary amyloid deposition starts in the first or second decade in some patients, but possibly not until much later in life in other patients. In addition, the mechanism by which amyloid deposits are cleared and why the rate of this varies so substantially among patients are not understood.

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Epidemiology

Frequency

International

No systematic data address the frequency of FRA, but the condition is not as rare as previously thought. The lack of awareness of the condition and the frequent absence of a family history (owing to its variable penetrance) have contributed to substantial underdiagnosis.

Since the authors introduced routine DNA screening into their investigations of patients with systemic amyloidosis at their facility in the United Kingdom, approximately 5% of patients with presumed AL primary amyloidosis have been diagnosed with hereditary lysozyme, apolipoprotein AI, or fibrinogen A alpha-chain amyloid. The amyloidosis is associated with the fibrinogen A alpha-chain variant Glu526Val in more than 80% of these patients. [3]

Mortality/Morbidity

The natural history of familial renal amyloidosis is a relentless gradual progression, leading to renal and sometimes other organ failure and, eventually, death. Amyloid deposits can ultimately affect many organ systems, but they may be widespread and very extensive without causing symptoms.

The rate of progression and course of disease are extremely variable. Some patients with clinically overt involvement of multiple organs survive for many years or decades. Overall, the prognosis of patients with FRA is much better than that of those with acquired AA and AL amyloidosis.

Histological localization of amyloid deposits determines overall survival in patients with renal amyloidosis. In a study of 35 patients, the glomerulus was the most common and most severely affected renal compartment. Compared with patients without glomerular amyloid deposits, those with severe glomerular amyloidosis advanced more quickly towards end-stage renal disease and premature death. [4]

Race-, Sex-, and Age-related Demographics

Most patients are of northern European Caucasian ancestry, but fibrinogen A alpha-chain amyloidosis has been reported in Peruvian-Mexican, Korean, and African American families, and the authors are presently investigating a northern Indian family with uncharacterized FRA.

Gene carriage and the incidence of clinical disease are equal between men and women.

FRA may manifest any time from the first decade to old age but most typically in mid adult life. The age at presentation, like other clinical features, varies among mutations and even within individual kindreds.

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