TTR – Hereditary Systemic Amyloidosis 1

Hereditary transthyretin amyloidosis (ATTRv; MONDO:0971004) is an autosomal dominant systemic disorder caused by misfolded transthyretin (TTR; HGNC:12405) amyloid fibril deposition in peripheral nerves, heart, gastrointestinal tract, and eyes. Affected individuals typically present in mid-to-late adulthood with progressive sensorimotor polyneuropathy, restrictive cardiomyopathy, autonomic dysfunction, and vitreous opacities. Penetrance varies by variant and ancestry, and ~3% of individuals of African descent carry the common c.424G>A (p.Val142Ile) allele associated primarily with cardiomyopathy (PMID:25819286).

Genetic studies have identified >120 TTR missense variants across multiple families and populations. Initial case reports include a French pedigree harboring c.391C>A (p.Leu131Met), presenting with peripheral neuropathy, diarrhea, orthostatic hypotension, and vitreous floaters in two generations with heterozygous segregation to two of five children (PMID:8095302). An Italian family with c.161G>C (p.Arg54Thr) exhibited late-onset neuropathy and restrictive cardiomyopathy (PMID:9605286). Multiple subsequent case series have described variants such as Asp38Ala, Ala36Pro, Leu12Pro, and Gly87Arg segregating with mixed neuropathic, cardiac, and ocular phenotypes.

A single-institution cohort of 266 patients with ATTR reported 206 pathogenic alleles, with Thr60Ala (25%), Val122Ile (12%), and Ser97Tyr among the most prevalent. Median age at diagnosis was 63.3 y, with median survival of 56.8 months; peripheral neuropathy and weight loss conferred increased risk of mortality (PMID:26017327). Population screening revealed founder effects for Ala97Ser in Taiwan (>90% allelic share) and for Glu89Gln in Romania. Exome sequencing in 134 753 individuals identified 0.12% prevalence of P/LP TTR variants, predominantly V122I in African-ancestry participants, with heart failure and increased septal thickness detected in >14% of older carriers without prior amyloidosis diagnosis (PMID:34746851).

The TTR variant spectrum is exclusively missense, including splice-region changes (e.g., c.421GTC[1] (p.Val142del)). Recurrent founder alleles demonstrate geographic clustering (e.g., Val30Met in Portugal, Ala36Pro in China). Phenotypic heterogeneity spans early-onset neuropathy (Ala36Pro), ophthalmic-predominant disease (Gly103Arg), leptomeningeal amyloidosis (Ile127Met), and cardiomyopathy-predominant forms (Val142Ile, Thr119Met). Carrier frequency and penetrance estimates vary by variant and age, underscoring the need for genetic testing in multi-organ presentations.

Functional and structural analyses demonstrate that pathogenic TTR variants destabilize the native tetramer, promoting dissociation into amyloidogenic monomers under mildly acidic conditions. Leu55Pro tetramers exhibit markedly reduced stability and elevated fibrillogenesis in thioflavin T assays (PMID:8218290). Conversely, the non-pathogenic Thr119Met substitution enhances intersubunit contacts (Ser117-Ser117, Met119-Tyr114), increases tetramer stability and T4 affinity, and mitigates Met30 amyloidogenicity (PMID:11243784). Cryo-EM and X-ray crystallography confirm variant-specific conformational shifts correlating with clinical severity.

Collectively, robust genetic, segregation, biochemical, and structural data support a definitive TTR–ATTRv association. The autosomal dominant inheritance with >500 affected individuals across >100 families, consistent functional concordance, and presence of multiple founder variants underscore the causal role of TTR missense mutations in systemic amyloidosis. Early genetic diagnosis enables prompt initiation of disease-modifying therapy (e.g., tafamidis, patisiran) and cascade testing. Key Take-home: Genetic screening of TTR in patients with unexplained neuropathy, cardiomyopathy, or ocular involvement significantly improves diagnostic accuracy and informs targeted treatment.

References

• Journal of medical genetics • 1993 • A transthyretin variant (alanine 71) associated with familial amyloidotic polyneuropathy in a French family. PMID:8095302
• American journal of medical genetics • 1998 • Novel transthyretin missense mutation (Thr34) in an Italian family with hereditary amyloidosis. PMID:9605286
• Neuromuscular disorders : NMD • 2015 • Transthyretin V122I amyloidosis with clinical and histological evidence of amyloid neuropathy and myopathy. PMID:25819286
• Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis • 2015 • Hereditary transthyretin amyloidosis: a single-institution experience with 266 patients. PMID:26017327
• JACC. CardioOncology • 2021 • Genomic Screening for Pathogenic Transthyretin Variants Finds Evidence of Underdiagnosed Amyloid Cardiomyopathy From Health Records. PMID:34746851
• 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

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