Hereditary gelsolin amyloidosis (AGel amyloidosis) is a rare autosomal dominant systemic amyloidosis caused by mutations in the Gelsolin (GSN) gene encoding gelsolin. The condition is characterized by a triad of cranial nerve involvement, corneal lattice amyloidosis, and skin laxity, with a small proportion of cases involving the kidneys and heart. We report the first case of renal AGel amyloidosis associated with a c.487G > A mutation in the GSN gene, presenting as isolated proteinuria. A 55-year-old woman presented with proteinuria. She had a history of hypertension and diabetes but no family history of kidney disease. Physical examination revealed no abnormalities in the heart, eyes, nerves, or skin. Urinalysis showed moderate proteinuria (1975.5 mg/24h), and serum creatinine was normal (0.71 mg/dL). Renal biopsy revealed Congo red-positive glomeruli on light microscopy, with apple-green birefringence under polarized light. Electron microscopy showed randomly arranged fibrillar deposits in the glomeruli. Mass spectrometry analysis confirmed that the deposits were consistent with gelsolin protein. Genetic testing revealed a heterozygous missense mutation in the GSN gene (NM_198252.3; c.487G > A; p.Asp163Asn). The patient was diagnosed with AGel amyloidosis. Additionally, we compiled the phenotypic and genotypic characteristics of previously reported AGel amyloidosis cases. We report a novel mutation in AGel amyloidosis with renal involvement. This case highlights the importance of renal biopsy, mass spectrometry analysis, and genetic testing in establishing a definitive diagnosis. It expands the known spectrum of GSN gene mutations and further supports the heterogeneity of the AGel amyloidosis phenotype.

Amyloidosis is a group of disorders characterized by abnormal deposition of amyloid proteins in various tissues and organs, leading to progressive organ dysfunction. With over 40 precursor proteins linked to amyloid formation, identification of the amyloid type is critical to guide treatment. A man in his late 40s presenting with heart failure was diagnosed with cardiac amyloidosis based on an endomyocardial biopsy. Amyloid typing performed on the heart biopsy at Mayo Clinic Laboratories using differential laser microdissection and shotgun proteomics with mass spectrometry reported gelsolin amyloid (AGel) deposits exclusively in the vasculature and transthyretin amyloid deposits exclusively within the interstitium. Mutational analysis identified a novel p.Y474N in the gelsolin gene, establishing a diagnosis of hereditary AGel amyloidosis. Transthyretin gene mutations were absent, confirming a concurrent diagnosis of acquired transthyretin wild-type amyloidosis. The patient, who had been treated with guideline-directed medical therapy since his initial presentation, was subsequently started on tafamidis, with subsequent improvement of his ejection fraction after 6-7 months. Although rare, 2 different amyloid types may arise in the same anatomic site. Identification of all amyloid types is crucial for optimal patient management. In this case, the co-existence of 2 rare amyloid types (AGel with a novel mutation coupled with ATTRwt in a patient under 50 years of age) in mutually exclusive anatomic compartments in the same cardiac biopsy raises the possibility that an unknown systemic factor may play a role in amyloidogenesis in dual amyloid cases.

Advances in fibril typing by mass spectrometry have improved the accuracy of amyloidosis diagnosis. Dual amyloidogenic proteins have been reported in deposits in sole and multiple different organs. Five patients with dual amyloidoses were diagnosed between 1995 and 2022 by Congo red staining and fibril typing using the best available methods at the time of evaluation. Sequencing of TTR and GSN genes was performed. Literature search identified 46 additional cases. Three patients exhibited Waldenström macroglobulinemia-associated AL (n = 3) amyloidoses in conjunction with ATTRwt or AGel amyloidosis; two patients featured AL/ATTRwt and AA/ATTRwt amyloidoses. One patient demonstrated dual amyloidoses within one anatomical site; three patients featured two amyloidosis types at different anatomical sites; and one patient had dual amyloid deposits in a single anatomical site along with different sites. The time interval between diagnoses was 0-288 months, with the heart and kidneys being the most affected organs. Our findings underscore the complexity of clinical presentation in amyloidosis, as multiple amyloid types can co-exist in a single individual and affect various anatomical sites. Accurate assessment of the clinical phenotype and thorough amyloid fibril typing from the target organs are essential for precise diagnosis and tailored treatment. ClinicalTrials.gov Identifier: NCT00898235.

Aggregation of aberrant fragment of plasma gelsolin, AGelD187N, is a crucial event underlying the pathophysiology of Finnish gelsolin amyloidosis, an inherited form of systemic amyloidosis. The amyloidogenic gelsolin fragment AGelD187N does not play any physiological role in the body, unlike most aggregating proteins related to other protein misfolding diseases. However, no therapeutic agents that specifically and effectively target and neutralize AGelD187N exist. We used phage display technology to identify novel single-chain variable fragments that bind to different epitopes in the monomeric AGelD187N that were further maturated by variable domain shuffling and converted to antigen-binding fragment (Fab) antibodies. The generated antibody fragments had nanomolar binding affinity for full-length AGelD187N, as evaluated by biolayer interferometry. Importantly, all four Fabs selected for functional studies efficiently inhibited the amyloid formation of full-length AGelD187N as examined by thioflavin fluorescence assay and transmission electron microscopy. Two Fabs, neither of which bound to the previously proposed fibril-forming region of AGelD187N, completely blocked the amyloid formation of AGelD187N. Moreover, no small soluble aggregates, which are considered pathogenic species in protein misfolding diseases, were formed after successful inhibition of amyloid formation by the most promising aggregation inhibitor, as investigated by size-exclusion chromatography combined with multiangle light scattering. We conclude that all regions of the full-length AGelD187N are important in modulating its assembly into fibrils and that the discovered epitope-specific anti-AGelD187N antibody fragments provide a promising starting point for a disease-modifying therapy for gelsolin amyloidosis, which is currently lacking.