LYZ – ALys Amyloidosis

Hereditary lysozyme amyloidosis (ALys) is an autosomal dominant systemic amyloidosis caused by missense variants in the lysozyme gene LYZ, leading to deposition of insoluble fibrils in multiple organs, predominantly the gastrointestinal tract MONDO:0019732. Early diagnosis impacts management, as ALys must be distinguished from immunoglobulin light chain (AL) amyloidosis to guide appropriate therapy.

Clinical validity for the LYZ–ALys association is Strong. More than 7 unrelated families have been reported with segregating missense alleles, including a pedigree of 9 affected individuals carrying p.Trp82Arg, with complete cosegregation and amyloid confirmed by histology in all carriers (PMID:16523055; PMID:25217048).

Genetic evidence is Strong: ALys follows autosomal dominant inheritance with full penetrance in adulthood. Case series encompass at least 7 unrelated families, with p.Trp82Arg recurring in Piedmont kindreds and additional variants p.Leu102Ser and the compound p.Phe21Leu/p.Thr88Asn reported in independent pedigrees, all leading to amyloidogenic missense substitutions [PMID:28049649]; segregation of p.Trp82Arg in 9 affected relatives confirms pathogenicity (PMID:25217048).

Functional evidence is Moderate: Biophysical and cellular assays demonstrate that amyloidogenic lysozyme variants (e.g., I56T, F57I, W64R, D67H) destabilize native folding, accumulate in the endoplasmic reticulum, and activate the unfolded protein response via IRE1α, recapitulating key pathogenetic mechanisms of intracellular aggregation (PMID:25659958). Proteomic analyses confirm mutant lysozyme within patient deposits.

No credible conflicting reports have emerged. The consistency of clinical, genetic, and experimental data across multiple cohorts supports a causative role of LYZ variants in ALys.

Integrated evidence indicates that pathogenic LYZ missense alleles drive a toxic gain-of-function via protein misfolding and fibrillogenesis, resulting in systemic amyloid deposition with predominant gastrointestinal and occasional multi-organ involvement. ALys should be suspected in familial chronic gastroenteritis, bleeding, inflammatory bowel-like symptoms, or organ dysfunction with non-immunoglobulin amyloid. Genetic testing of LYZ can confirm diagnosis and inform family screening.

Key Take-home: Autosomal dominant missense variants in LYZ, notably p.Trp82Arg, cause systemic ALys amyloidosis characterized by gastrointestinal involvement and amyloid fibril deposition, with strong clinical and functional evidence supporting genetic testing for definitive diagnosis.

References

• BMC gastroenterology • 2014 • A new family with hereditary lysozyme amyloidosis with gastritis and inflammatory bowel disease as prevailing symptoms. PMID:25217048
• Medicine • 2006 • Lysozyme amyloidosis: report of 4 cases and a review of the literature. PMID:16523055
• Journal of the American Society of Nephrology : JASN • 2017 • Hereditary Lysozyme Amyloidosis Variant p.Leu102Ser Associates with Unique Phenotype. PMID:28049649
• Biochimica et biophysica acta • 2015 • Amyloidogenic lysozymes accumulate in the endoplasmic reticulum accompanied by the augmentation of ER stress signals. PMID:25659958

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