TTR – Transthyretin-related Familial Amyloid Neuropathy

Familial amyloid polyneuropathy (FAP) is an autosomal dominant disorder caused by pathogenic missense variants in the TTR gene, leading to extracellular deposition of misfolded transthyretin as amyloid fibrils predominantly in peripheral nerves and other organs. The condition, also known as familial amyloid neuropathy, presents with progressive sensorimotor and autonomic neuropathy often accompanied by cardiomyopathy and other systemic features.

Extensive genetic studies have identified over 120 distinct missense variants in TTR across more than 260 pedigrees worldwide. A global case series reported 542 symptomatic ATTR-PN cases, encompassing 65 different genotypes and broad geographic representation (PMID:30736835). A European cohort study of 99 patients from 64 families further confirmed the predominance of missense alleles in FAP (PMID:7655883). Variants cluster in the tetramer interface and include recurrent founder alleles such as c.148G>A (p.Val50Met).

Segregation analyses corroborate autosomal dominant transmission, with multiple families demonstrating co-segregation of TTR variants and disease. For example, the Gly47Glu variant was identified in five affected members over three generations in an Italian kindred (PMID:12000196). Across published pedigrees, at least 19 additional affected relatives with segregating variants have been documented.

Functional assessments reveal that pathogenic TTR variants destabilize the native tetramer, promoting dissociation into amyloid-prone monomers under physiologic conditions. In vitro studies show that the Leu55Pro variant markedly reduces tetramer stability and accelerates fibril formation at mildly acidic pH (PMID:8218290). Conversely, the protective Thr119Met variant enhances tetramer stability, restoring resistance to amyloidogenesis (PMID:11243784).

Non-amyloidogenic variants such as Gly121Ser exhibit increased tetramer stability and lower fibril-forming propensity, underscoring the mechanistic link between tetramer stability and pathogenicity (PMID:29607936).

Collectively, these robust genetic and experimental data establish a Definitive association between TTR variants and familial amyloid neuropathy, supporting the use of targeted genetic testing for early diagnosis and guiding therapeutic strategies, including tetramer stabilizers and gene-targeted therapies. Key take-home: TTR variant analysis is clinically essential for accurate diagnosis and management of familial amyloid polyneuropathy.

References

• Orphanet Journal of Rare Diseases • 2019 • Epidemiological and clinical characteristics of symptomatic hereditary transthyretin amyloid polyneuropathy: a global case series. PMID:30736835
• Brain : a journal of neurology • 1995 • Transthyretin gene analysis in European patients with suspected familial amyloid polyneuropathy. PMID:7655883
• Amyloid : the international journal of experimental and clinical investigation • 2002 • Familial amyloid polyneuropathy with genetic anticipation associated to a gly47glu transthyretin variant in an Italian kindred. PMID:12000196
• Biochemistry • 1993 • Transthyretin mutation Leu-55-Pro significantly alters tetramer stability and increases amyloidogenicity. PMID:8218290
• Journal of Molecular Biology • 2001 • Transthyretin stability as a key factor in amyloidogenesis: X-ray analysis at atomic resolution. PMID:11243784
• Biological & Pharmaceutical Bulletin • 2018 • Characterization of Non-amyloidogenic G101S Transthyretin. PMID:29607936

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