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.

The effect of IL-1 blockers on exertional leg pain in Familial Mediterranean Fever patients: an exploratory study

• First author: Amit Druyan1

• Journal: Rheumatology

• Reference: Rheumatology (Oxford). 2026;65:keag160

• PubMed link: https://pubmed.ncbi.nlm.nih.gov/42024667/

• Abstracted by: Dr. Catherine Grandpeix-Guyodo

Key points:

- Exertional/orthostatic leg pain is a frequent complaint in FMF patients with severe phenotypes.

- This lower-limb pain impacts quality of life.

- Interleukin‑1 inhibitors seem effective in at least about half of patients.

Introduction

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide and is associated with mutations in the MEFV gene. The classic presentation combines febrile attacks and serositis. Patients also frequently report leg pain typically triggered by walking or prolonged standing, lasting for several hours despite rest and often associated with swelling and sometimes redness. This symptom responds less well to colchicine than other manifestations and is associated with severe FMF phenotypes, persistent inflammation, homozygosity for the MEFV M694V variant, and an increased risk of AA amyloidosis. This study evaluated the efficacy of anti‑interleukin‑1 therapy (anti‑IL‑1) on leg pain in FMF.

Patients and methods

This retrospective, single‑center Turkish study included adult FMF patients resistant to colchicine, treated with anti‑IL‑1 for at least 3 months and with colchicine at the maximum tolerated dose, and who had leg pain that pre‑dated the start of anti‑IL‑1. The control group was a historical cohort of FMF patients with leg pain who had not received anti‑IL‑1. Variables assessed included demographics, homozygosity for the M694V variant, leg pain, and quality of life.

Results

A total of 27 long‑term anti‑IL‑1–treated patients with leg pain (23 canakinumab, 4 anakinra) were compared with 99 patients from the historical cohort. These anti‑IL‑1 patients had more severe disease, with more frequent attacks prior to anti‑IL‑1 (50/year), homozygous MEFV M694V in 55%, lower‑limb arthritis during FMF flares in 85%, a higher mean colchicine dose (2.6 mg/day), and AA amyloidosis in 11%. Leg pain was bilateral, triggered by prolonged standing or walking, and resolved after several hours of lying down. Under anti‑IL‑1, attack frequency decreased to a mean of 9/year and inter‑critical CRP normalized in 50% of patients. Improvement in leg pain was reported in 52% of patients. An association between quality of life and leg pain was observed only in anti‑IL‑1–treated patients, likely because the symptom had previously been masked by inflammatory attacks.

Discussion

Leg pain improved in only about half of patients, but the cohort had particularly severe FMF. In the literature, MRI studies have shown signs of spondyloarthritis or occult enthesitis in some patients with leg pain. The mediators of these conditions are TNF‑α and IL‑17 more than IL‑1, which may explain lack of efficacy in some. Limitations include the retrospective design, small sample size, and missing data. Canakinumab is very expensive and should not be prescribed as first‑line therapy.

Therapeutic Outcomes in VEXAS Syndrome: A Multicenter Comparative Cohort of Allogeneic Hematopoietic Stem Cell Transplantation and Hypomethylating Agents

First author: Saubia Fathima

Journal: American Journal of Hematology, 2026

Link to the article: https://pubmed.ncbi.nlm.nih.gov/42260942/

Authors of the abstract: Pr Sophie Georgin-Lavialle et Pr Olivier Kosmider

Key points

- In this multicenter cohort of 66 patients with VEXAS syndrome, allogeneic hematopoietic stem cell transplantation (allo-HSCT) was associated with better overall survival than hypomethylating agents (HMAs).

- Allo-HSCT achieved molecular remission in all evaluable patients, compared with 22% under HMAs.

- Corticosteroid withdrawal was markedly more frequent after transplantation than with HMAs.

- HMAs -mainly azacitidine- remained active in some patients, but with a high rate of discontinuation due to toxicity or lack of efficacy.

- These findings support allo-HSCT as a potentially curative strategy in selected patients.

Summary

VEXAS syndrome is an acquired hematoinflammatory disease caused by somatic mutations in the UBA1 gene, affecting mainly men over 50 years of age. It combines systemic autoinflammatory manifestations, cytopenias, and sometimes an associated myelodysplastic syndrome. Management remains challenging, with frequent corticosteroid dependence and often limited effectiveness of steroid-sparing treatments. In this context, this retrospective multicenter U.S. study compared outcomes of two approaches targeting the pathological clone: hypomethylating agents and allogeneic hematopoietic stem cell transplantation.

Sixty-six patients with confirmed VEXAS were included between 2019 and 2025, including 31 treated with allo-HSCT and 35 with an HMA, mainly azacitidine. Indications for therapy were glucocorticoid-refractory inflammation, progressive bone marrow failure or associated myeloid neoplasia, or combinations of these manifestations. The two groups were broadly comparable clinically and biologically, except for older age in the HMA group.

After a median follow-up of 18 months, 14 deaths were observed 3 in the transplant group and 11 in the HMA group. Allo-HSCT was associated with a significant improvement in overall survival, with median survival not reached versus 29.6 months with HMAs, including after adjustment for age and comorbidities. This superiority persisted across several sensitivity analyses, strengthening the robustness of the signal despite methodological limitations inherent to the retrospective design.

Beyond survival, allo-HSCT was associated with major clinical and biological benefit. All evaluable patients achieved molecular remission, with no re-emergence of the UBA1 clone at last follow-up. Corticosteroid discontinuation was also far more frequent after transplantation, with steroid cessation in 58% of patients, versus only 6% with HMAs. By contrast, HMAs showed real but more modest activity, with molecular remission in 22% of evaluable patients and a high treatment discontinuation rate. Nearly one in two patients stopped treatment, mainly due to infections, prolonged cytopenias, toxicity, or lack of response.

Overall, this North American study suggests that allo-HSCT is currently, as expected, the most effective and potentially curative option for eligible patients with VEXAS, particularly in severe disease, steroid dependence, or bone marrow involvement. HMAs may still have a role in patients not immediately eligible for transplant, as bridging therapy or a step toward transplantation, but in this study their benefit appeared more modest and less durable.