Familial Renal Amyloidosis Clinical Presentation

Patients with familial renal amyloidosis (FRA) typically present with proteinuria and/or hypertension followed by progressive renal failure. The latter may evolve extremely slowly, and patients with hereditary apolipoprotein AI and lysozyme amyloidosis may not develop end-stage renal failure for several decades. In contrast to AL amyloidosis, orthostatic hypotension is unusual, probably because autonomic involvement and amyloid cardiomyopathy are rare in FRA. ^{[26, 27]}

Many patients give a clear autosomal dominant family history of renal disease, but penetrance is variable. Individuals with the most common form of fibrinogen A alpha-chain amyloidosis, associated with the Glu526Val variant, frequently, or, perhaps even typically, are not aware of any such disease in their family. Patients with FRA who do not give a family history are readily misdiagnosed as having acquired AL amyloidosis.

With variant lysozyme amyloidosis, presentation may involve the following:

• This type of FRA usually results in substantial GI amyloid deposits that may cause poor gastric emptying, but these patients often remain asymptomatic until an acute crisis occurs

• The upper GI tract is perforated easily and has a tendency to bleed profusely should gastric erosions or peptic ulceration occur

• At presentation, most patients with this type of FRA have substantial amounts of amyloid in the kidneys, spleen, and liver, but the course of the disease tends to be remarkably slow.

• Even in the presence of massive hepatosplenomegaly, liver failure rarely occurs; however, spontaneous hepatic rupture has been reported in several cases.

• Cardiac amyloid and neuropathy are not features of lysozyme amyloidosis, but petechial rashes starting in childhood are associated with the lysozyme Ile56Thr variant.

The features of hereditary apolipoprotein AI amyloidosis vary significantly with different mutations, as follows:

• Patients with the most common amyloidogenic Gly26Arg variant usually present with hypertension and proteinuria and develop progressive renal impairment

• Many mutations are associated with extensive but clinically silent amyloid deposits in the liver and spleen

• Amyloid cardiomyopathy, gut involvement, and skin and laryngeal deposits occur occasionally, and a few patients with variant apolipoprotein AI Glu26Arg and Leu178His develop a progressive neuropathy resembling familial amyloid polyneuropathy, a disease that is usually associated with transthyretin mutations

Hereditary apolipoprotein AII amyloidosis appears to predominantly cause renal disease. Progression to end-stage renal failure occurs, and at least two patients have renal grafts that have functioned for more than a decade. There is one report of a patient with long-standing renal failure who subsequently developed evidence of amyloid cardiomyopathy.

Most patients diagnosed with fibrinogen A alpha-chain Glu526Val amyloidosis present in late middle age with proteinuria or hypertension and progress to end-stage renal failure during the following 5-10 years. Amyloid deposition occurs predominantly in the kidneys and also variably in the spleen, liver, and adrenal glands. ^[28] Clinically significant neuropathy or cardiac amyloid deposition does not seem to occur in patients with the Glu526Val variant, and liver failure is very rare.

The other three mutations that cause fibrinogen A alpha-chain amyloidosis have been identified in too few families to make generalizations, other than that these mutations are predominantly associated with renal disease.

Clinical features and their association with particular mutations are described in Pathophysiology. Physical examination findings include the following:

• Hypertension and edema occur in most patients diagnosed with FRA.

• Hepatosplenomegaly is quite common and is probably most common in patients with the apolipoprotein AI type.

• Heart failure resulting from restrictive amyloid cardiomyopathy occurs in some patients with variant apolipoprotein AI Leu60Arg and is the predominant feature in patients with the variants Arg173Pro and Leu174Ser.

• A symmetrical sensorimotor polyneuropathy occurs in some patients with the apolipoprotein AI Gly26Arg and Leu178His variants.

• Laryngeal and cutaneous deposits producing hoarseness, infiltrative plaques, and petechial rashes are associated with the apolipoprotein AI Arg173Pro, Ala175Pro, Leu90Pro, and Leu178His variants, and petechial rashes also occur in patients with lysozyme Ile56Thr.

Susceptibility to FRA is inherited in an autosomal dominant manner. In nearly all cases, the disease results from mutations in the genes encoding the following four plasma proteins:

• Lysozyme
• Apolipoprotein AI
• Apolipoprotein AII
• Fibrinogen A alpha-chain

In a small number of families, the cause has not yet been determined. Rare cases of renal amyloidosis associated with familial Mediterranean fever have been reported. ^{[29, 30]}

Lysozyme

Lysozyme is a ubiquitous bacteriolytic enzyme present in both external secretions and in leukocytes. Lysozyme mutations were identified as a cause of familial amyloidosis when, in 1993, amyloid fibrils in two British families were demonstrated to be derived from the lysozyme variants Asp67His and Ile56Thr, respectively. These represent the least common causes of FRA. The authors have identified a polymorphism encoding lysozyme Thr70Asn, which has an allele frequency of 5% in the British population and which has not been shown to be associated with amyloid deposition.

Apolipoprotein AI

Apolipoprotein AI is a major constituent of high-density lipoprotein (HDL) particles and participates in their central function of reverse cholesterol transport from the periphery to the liver. Approximately half of apolipoprotein AI is synthesized in the liver and half in the small intestine.

Variant forms of apolipoprotein AI are extremely rare in the general population and may be phenotypically silent or may affect lipid metabolism. In 1990, apolipoprotein AI Gly26Arg was identified as a cause of FRA. Since then, 12 other amyloidogenic apolipoprotein AI variants have been discovered. These are mostly other single amino acid substitutions but include deletions and deletion/insertions, not all of which are associated with clinical renal disease (see Pathophysiology). The amyloid fibril subunit protein has comprised the first 90 or so N-terminal residues of apolipoprotein AI in all cases that have been studied, even when the variant residue(s) has been more distal.

In contrast to lysozyme and fibrinogen A alpha-chain types, wild-type apolipoprotein AI is itself weakly amyloidogenic, and the various amyloidogenic variants are likely to render apolipoprotein AI less stable and/or more susceptible to enzymatic cleavage, promoting an abundance of a fibrillogenic N-terminal fragments.

Another potential mechanism could be reduced lipid binding, thereby increasing the amount of free (and therefore relatively less stable) apolipoprotein AI in the plasma.

Apolipoprotein AII

Apolipoprotein AII is the second major constituent of human HDL particles, accounting for approximately 20% of HDL protein. Like apolipoprotein AI, apolipoprotein AII is synthesized predominantly by the liver and the intestines.

In 2001, apolipoprotein AII stop78Gly was isolated from the amyloid fibrils of a patient who died of renal failure. ^[31] Since then, an additional three mutations (encoding two protein variants) have been described in association with hereditary renal amyloidosis (see Pathophysiology).

Unlike serum amyloid A protein (another apolipoprotein and the amyloid precursor in AA amyloidosis) or apolipoprotein AI, in apolipoprotein AII amyloidosis, the protein fibrils are not derived from a cleavage fragment of the native precursor but instead consist of the whole protein plus a 21 amino acid extension.

Fibrinogen

Fibrinogen is a multimeric 340-kd circulating glycoprotein composed of six peptide chains (two each of alpha, beta, and gamma types), all of which are synthesized in the liver. The alpha chains are the largest and are involved in cross-linking fibrin strands. Numerous alpha-chain variants have been recognized that are either silent or are associated with abnormal hemostasis.

Variant fibrinogen A alpha-chain Arg554Leu was first identified as an amyloid fibril protein in 1993. Since then, five other amyloidogenic mutations have been discovered (see the Table). All of these mutations are clustered within the carboxyl terminus of the gene in a relatively small portion of exon 5.

Two of these mutations result in frame shifts that terminate the protein prematurely at codon 548; one is a single nucleotide deletion in the third base of codon 524 and the other is a deletion at codon 522. A single-base transversion, resulting in the substitution of leucine for arginine at codon 554, has been reported in three families of Peruvian-Mexican, African American, and French Caucasian ethnic backgrounds. Residue 554 may be a mutational hot spot because other (nonamyloidogenic) mutations have also been identified at this position.

By far, the most common amyloidogenic variant is fibrinogen A alpha-chain Glu526Val, which has been found in numerous families of Irish, English, German, and Polish origin with FRA.

Genetic information is depicted in the images below.

Familial renal amyloidosis. An extended kindred with hereditary amyloidosis associated with fibrinogen A alpha-chain Glu526Val; disease penetrance is high in this particular family.

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Familial renal amyloidosis. Partial DNA sequence of the gene associated with fibrinogen A alpha-chain Glu526Val in a patient with familial renal amyloidosis, and a sequence from a healthy control. The mutation, which alters codon 526 from glutamic acid to valine, is marked with an arrow.

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