Serpinopathy with toxic serpin polymerization

Serpinopathy with toxic serpin polymerization refers to a group of rare conformational diseases caused by mutations in genes encoding serine protease inhibitors (serpins). These mutations destabilize the native protein structure, leading to aberrant polymerization of misfolded serpin molecules within the endoplasmic reticulum of producing cells. The accumulation of these toxic polymers causes cellular dysfunction and organ damage through a toxic gain-of-function mechanism, rather than simply through loss of protease inhibitory function. The most well-characterized serpinopathies involve alpha-1-antitrypsin (encoded by SERPINA1), antithrombin (SERPINC1), C1-inhibitor (SERPING1), and neuroserpin (SERPINI1), among others. The clinical manifestations depend on which serpin is affected and which organs primarily produce and accumulate the polymerized protein. For example, polymerization of alpha-1-antitrypsin in hepatocytes can lead to liver disease including cirrhosis and hepatocellular carcinoma, while the concurrent deficiency of circulating functional alpha-1-antitrypsin predisposes to early-onset emphysema. Neuroserpin polymerization in neurons causes familial encephalopathy with neuroserpin inclusion bodies (FENIB), characterized by progressive dementia and epilepsy. Antithrombin polymerization is associated with thrombotic disease. The body systems affected therefore span the hepatic, pulmonary, neurological, and vascular systems depending on the specific serpin involved. Treatment is largely supportive and directed at the specific organ manifestations. For alpha-1-antitrypsin deficiency-related lung disease, augmentation therapy with purified human alpha-1-antitrypsin is available. Liver transplantation may be required for severe hepatic disease. Research into small molecules that prevent serpin polymerization is ongoing and represents a promising therapeutic strategy, but no specific anti-polymerization therapies are currently approved for clinical use.

Inheritance

Variable

Can be inherited in different ways depending on the underlying gene

Age of Onset

Variable

Can begin at different ages, from infancy through adulthood

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Source: NORD Rare Disease Centers + NIH Undiagnosed Diseases Network (UDN) · centers verified active within last 12 months

Source: PubMed + NIH RePORTER + openFDA + clinical-journal RSS · last 30 days · disease-tagged at ingest by AI extraction with human QC

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