A missense mutation in the SAA1 protein causing hereditary amyloid A Amyloidosis

First author: Nelson Leung

Journal: Kidney International (2026), 110:255–259

PubMed link: https://pubmed.ncbi.nlm.nih.gov/41887599/

Summary by Prof. Sophie Georgin-Lavialle and Dr Rim Bourguiba

Key points

• Description of a familial form of AA amyloidosis due to a heterozygous SAA1 mutation.

• The presentation is unusual because there is no inflammatory syndrome and circulating SAA levels are normal or low.

• The p.D34V mutation markedly increases SAA1’s ability to form amyloid fibrils.

• This abnormality may not be detected by standard proteomic typing.

• A genetic cause should be considered in familial AA amyloidosis or AA amyloidosis without an obvious inflammatory cause.

Summary

This article reports a family affected by hereditary AA amyloidosis linked to an SAA1 mutation. The index case is a 37-year-old man investigated for significant proteinuria; kidney biopsy showed AA amyloid deposits. However, the presentation did not match “classic” AA amyloidosis: there was no inflammatory syndrome, no CRP elevation, and circulating SAA was below the detection threshold. The family history was highly suggestive, with several relatives affected by renal or systemic amyloidosis and early deaths, pointing toward autosomal dominant inheritance.

Whole-exome sequencing identified in affected individuals a heterozygous missense variant in SAA1, c.101A>T, leading to the p.D34V substitution. This variant was absent in the unaffected father and not present in population databases. Prior genetic investigations for an autoinflammatory disease were negative. The authors emphasize that this variant lies in a genomic region that can be masked in some standard analyses, creating a risk of missed diagnosis.

The work is also methodologically noteworthy. With conventional mass spectrometry, deposits were typed as AA amyloidosis with predominance of SAA1, but without detection of the mutant protein. In fact, the D34V substitution lies between two tryptic cleavage sites, making the mutant peptide difficult to detect with standard workflows. Using an alternative digestion with Asp-N enabled identification of the mutant peptide in amyloid deposits. Importantly, deposits preferentially contained the mutant form of SAA1, suggesting it aggregates much more readily than the wild-type protein.

Structural and functional analyses were consistent with this. The mutation replaces a negatively charged aspartic acid with a hydrophobic valine in a region important for fibrillogenesis. This change destabilizes the native structure of SAA1 and promotes its conversion into amyloid fibrils. Experiments with synthetic peptides showed a clear increase in aggregation of the mutant peptide, with higher Thioflavin T signal and abundant fibrils on electron microscopy, whereas the wild-type peptide aggregated little under the same conditions.

Overall, this work describes a new cause of hereditary AA amyloidosis, independent of chronic inflammation and driven by the intrinsic amyloidogenicity of mutant SAA1. Clinically, the message is important: in AA amyloidosis without an obvious inflammatory cause - especially in younger patients and/or in the presence of a family history - a genetic etiology should be considered and the SAA1 gene carefully analyzed. This observation also raises management questions, as usual AA amyloidosis treatments aimed at reducing SAA production (e.g., anti–IL-6 therapies) may have limited efficacy in this context.

Familial Mediterranean Fever: unexpected symptoms in some patients

Title in English: Non-canonical manifestations of FMF in homozygous M694V MEFV genotype: Insights from a large patient cohort

First author: Eitan Giat

Journal: Seminars in Arthritis and Rheumatism

Link to PubMed : https://pubmed.ncbi.nlm.nih.gov/40902213/

Summary by: Dr Catherine Grandpeix-Guyodo

Introduction:

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. Among the MEFV gene mutations associated with a classic FMF phenotype, homozygous M694V variants are classically associated with the most severe forms of the disease, with more frequent attacks, more frequent arthritis, lower limb pain during exercise, poorer quality of life, higher colchicine requirements, poorer treatment response, and increased risk of inflammatory amyloidosis, with half of AA amyloidosis cases in FMF patients being associated with a homozygous M694V genotype. This study examined clinical and biological manifestations other than those already known, associated with homozygous M694V mutations in a large cohort of patients in Israel.

Patients and methods:

This was a retrospective study of adults with FMF followed between 2010 and 2020 at an Israeli hospital center. Patients carrying the homozygous M694V mutation were compared to a control group of patients with a classic FMF phenotype and either homozygous MEFV mutations other than M694V, compound heterozygotes, or heterozygotes (known variants associated with classic FMF but also presence of variants of unknown significance (VUS) such as E148Q, K695R, P369S).

Results:

The cohort included 3,866 FMF patients, 47.6% male, and 517 (13.4%) homozygous M694V. Significant differences between the two groups were, in homozygous M694V: higher colchicine dosage (median 2 mg/day versus 1.5 mg/day) despite better compliance, greater number of colchicine failures requiring addition of biotherapy (anti-IL1 or anti-TNF) (30% versus 4.2%), higher number of associated pathologies (*ankylosing spondylitis (AS), Behçet's disease, congestive heart failure, deep vein thromboses, chronic renal failure, and hepatic dysfunctions*), more significant abnormalities in biological parameters (CRP, ESR, liver enzymes, bilirubin, creatinine, and uric acid), higher number of hospitalizations and emergency room visits, particularly due to FMF attacks.

The results are the same if patients with at least one M694V mutation are excluded from the control group. Moreover, comparison of a heterozygous M694V group to other controls shows no difference.

It should also be noted that homozygous M694V patients on biotherapies had more AS, Behçet's disease, chronic renal failure, hepatic cytolysis, hyperuricemia, emergency room visits, and hospitalizations. However, there was no difference in terms of cardiovascular pathologies between homozygotes on biotherapies and those on colchicine alone.

Discussion:

In addition to what is described in the literature (more severe phenotype, more attacks, specific locations of FMF flares, poorer response to colchicine, more associations with inflammatory diseases, more AA amyloidosis and chronic renal failure), this study shows in FMF patients with homozygous M694V mutation the use of higher colchicine dosages, more frequent use of biotherapies, no increase in ischemic cardiovascular pathologies despite greater inflammation (possibly due to the action of anti-IL1). The study did find a higher rate of congestive heart failure which could be attributed to greater systemic inflammation, as has been shown in rheumatoid arthritis, Crohn's disease, and ulcerative colitis. The same applies to the higher frequency of deep vein thromboses.

Hepatic dysfunctions and hepatic cytolysis were more frequent in homozygous M694V FMF patients and could also be attributed to systemic inflammation that would generate hepatic steatosis.

To better understand the pathophysiological mechanisms, more studies seem necessary.

Conclusion:

In addition to the more severe and complicated presentations of classic FMF associated with the homozygous M694V genotype of MEFV, higher colchicine requirements or even recourse to biotherapies are observed, more frequent associated pathologies such as inflammatory diseases (AS, Behçet), increased frequency of congestive heart failure, deep vein thromboses, chronic renal failure, and liver diseases. Increased biannual monitoring of homozygous M694V patients seems essential.

Renal amyloidosis in Norway: how the disease has evolved over 30 years

English title: Epidemiology and clinical presentation of kidney amyloidosis have changed over the past three decades: a nationwide population-based study

First author: Hilde J. Vasstrand

Journal : BMC Nephrology

Reference : BMC Nephrol. 2025 Jun 2;26(1):272.

PubMed link : https://pubmed.ncbi.nlm.nih.gov/40457206/

Article summarized by: Dr Catherine Grandpeix-Guyodo

Introduction:

Amyloidoses are diseases related to protein deposits in the form of amyloid fibrils. Protein typing helps understand the presentation of the disease, its progression, prognosis, and allows treatment adaptation. Early diagnosis of kidney amyloidosis is essential for treatment optimization and prognosis improvement. This Norwegian nationwide study conducted over 30 years explores changes in the epidemiology and clinical presentation of kidney amyloidosis to raise awareness about these conditions.

Patients and methods: Over a 30-year period, 479 patients with amyloidosis on kidney biopsy were identified in the registries, including 209 AA amyloidoses (SAA protein deposits) and 270 non-AA amyloidoses (mainly AL amyloidoses from immunoglobulin light chain deposits). Patient records were studied and cases were separated into AA amyloidosis and non-AA amyloidosis.

Results:

The frequency of renal amyloidosis was stable over time (4% of kidney biopsies), but AL amyloidosis became the predominant form of non-AA amyloidoses with a frequency increasing from 1.9% to 2.8% of kidney biopsies (p = 0.014). In parallel, the proportion of AA amyloidosis decreased from 2.6% to 1.3% (p < 0.001), due to the reduction in amyloidoses secondary to inflammatory rheumatic diseases, partly offset by AA amyloidoses secondary to drug injections.

Advances in typing amyloid deposits significantly reduced undetermined amyloidoses (p < 0.001) and led to more precise diagnoses. Clinical presentations were varied, but proteinuria was present in 94% of patients. Nephrotic syndrome was noted more frequently in patients with non-AA amyloidosis (70%) than in those with AA amyloidosis (51%). Kidney function was better preserved in non-AA amyloidoses (median GFR 53 ml/min/1.73 m²) than in AA amyloidoses (median GFR 27 ml/min/1.73 m²). Patients with AA amyloidosis were younger (p < 0.001) and more often hypertensive (53% versus 38%, p < 0.001).

Regarding patients developing AA amyloidosis following drug injection, they were younger, more often male, and presented more advanced kidney disease with half in end-stage kidney disease.

Recently, the authors noted that patients with non-AA amyloidosis had better albumin, hemoglobin, and ESR levels (p < 0.05). Additionally, the proportion of non-AA amyloidosis with end-stage kidney disease dropped from 26.8% to 8.7% (p = 0.005), which could indicate earlier diagnoses.

Conclusion:

There have been changes in the epidemiology of kidney amyloidosis in Norway over the past 30 years. The rate of non-AA amyloidosis in biopsies has increased, and certain indicators suggest that diagnosis is made earlier. Amyloid typing has improved, which is reflected in more precise diagnoses with a decrease in undetermined forms. AA amyloidoses related to inflammatory rheumatic diseases have significantly decreased, but the increase in AA amyloidoses in patients who inject drugs is becoming a growing problem.

Awareness of amyloidoses remains necessary, especially during this period when epidemiology is changing with, as a consequence, the possibility of changes in clinical presentation and therapeutic needs.