rs104894664 — TTR Ala45Thr (A25T)

Rare pathogenic TTR missense variant causing hereditary transthyretin amyloidosis with predominantly central nervous system and oculoleptomeningeal involvement

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TTR Ala45Thr — The Most Unstable Transthyretin Variant Known

Transthyretin (TTR) is a tetrameric transport protein produced mainly in the liver and choroid plexus that carries thyroxine and retinol-binding protein through the bloodstream and cerebrospinal fluid. In healthy individuals, four identical TTR subunits lock together into a stable tetramer. In hereditary TTR amyloidosis, single amino acid substitutions destabilize this structure — the tetramer dissociates into monomers that misfold and aggregate into amyloid fibrils that deposit in organs. TTR Ala45Thr (also called A25T, using mature-protein numbering after signal peptide cleavage) is extraordinary among the 120+ known pathogenic TTR variants: it is the most thermodynamically unstable TTR tetramer characterized to date11 it is the most thermodynamically unstable TTR tetramer characterized to date
Sekijima et al., Lab Invest 2003, yet its unusual combination of extreme instability and very low serum concentration results in a disease that strikes the central nervous system and meninges first — an atypical pattern that distinguishes it from the cardiac or peripheral nerve predominance seen in most other hATTR variants.

The Mechanism

TTR is encoded by the TTR gene on chromosome 18q12.1. The plus-strand GRCh38 reference at position 31,592,959 is G (encoding Ala45 in the precursor, Ala25 in the mature protein). The pathogenic A allele converts this to Thr (Ala→Thr; c.133G>A). Alanine-25 lies at a critical inter-subunit interface within the TTR [β-sandwich fold | a barrel-like protein architecture in which two four-stranded β-sheets pack face-to-face; the tetramer forms by pairing two such dimers across a weaker interface], where its methyl side-chain makes hydrophobic packing contacts that stabilize both the strong dimer interface and the weak dimer-dimer interface holding the tetramer together. The bulkier, hydroxyl-bearing threonine residue introduces steric clash and disrupts both interfaces simultaneously — a 19F-NMR dissociation study22 19F-NMR dissociation study
Sun et al., J Am Chem Soc 2024 showed the A25T mutation uniquely perturbs the tetramer at both quaternary contact points, not just one.

The result is a TTR variant that dissociates and misfolds far more readily than wild-type33 dissociates and misfolds far more readily than wild-type
Azevedo et al., Biochemistry 2011; 3 kcal/mol less stable than L55P-TTR, previously considered the most aggressive variant. Why, then, does disease appear in the fifth decade rather than earlier, and why does it strike the CNS rather than the heart? The answer lies in serum concentrations: the A25T protein is present at far lower levels in blood than wild-type TTR. Systemic amyloid deposition in peripheral nerves and heart requires high circulating TTR; leptomeningeal deposition instead exploits the choroid plexus's local TTR secretion directly into [cerebrospinal fluid | the fluid surrounding the brain and spinal cord, independent of serum TTR levels], where the concentrations are sufficient for local fibril formation even when systemic amyloid is minimal.

The Evidence

In vitro, A25T-TTR rapidly forms amyloid aggregates in cerebrospinal fluid conditions at body temperature within 15 days44 A25T-TTR rapidly forms amyloid aggregates in cerebrospinal fluid conditions at body temperature within 15 days
Azevedo et al., Biochemistry 2011. Proteomics of these aggregates identified 19 co-aggregating CSF proteins including clusterin, apolipoprotein E, complement components, and coagulation factors — all proteins already implicated in amyloid propagation and neuroinflammation, providing a plausible mechanism for the neurological damage seen in carriers.

In a mouse model, injection of A25T fibrils into the brain activated microglia to secrete TNF-α, IL-6, and nitric oxide55 injection of A25T fibrils into the brain activated microglia to secrete TNF-α, IL-6, and nitric oxide
Azevedo et al., Cell Death Dis 2013. Conditioned medium from these activated microglia caused synapse loss and neuronal apoptosis in culture. Importantly, minocycline — an antibiotic with known [microglial inhibitory effects | microglia are the brain's resident immune cells; minocycline suppresses their inflammatory activation] — prevented the memory deficits produced in vivo, pointing to neuroinflammation rather than direct fibril toxicity as the driver of CNS injury.

Clinically, the variant is vanishingly rare. Only a handful of patients with confirmed A25T pathology have been published, originating from Japan (initial case: CNS amyloid onset age 42, peripheral neuropathy age 44) and Europe (including a Spanish case of leptomeningeal amyloidosis and Polish patients with cardiac involvement). A 2024 Polish cohort study found p.Ala45Thr among several rare TTR variants associated with cardiac amyloidosis and noted diagnostic challenges given inconclusive nuclear scintigraphy in some carriers. This phenotypic heterogeneity — CNS-predominant in some patients, cardiac in others — remains incompletely explained but likely reflects modifier genes and environmental factors acting on top of the extreme baseline instability.

Disease-modifying therapies developed for the more common hATTR variants (Val30Met, V122I) are potentially applicable. The ATTR-ACT trial demonstrated that tafamidis, a TTR tetramer stabilizer, reduced all-cause mortality by 30% (HR 0.70) and cardiovascular hospitalizations by 32% over 30 months66 ATTR-ACT trial demonstrated that tafamidis, a TTR tetramer stabilizer, reduced all-cause mortality by 30% (HR 0.70) and cardiovascular hospitalizations by 32% over 30 months
Maurer et al., NEJM 2018 in patients with TTR cardiomyopathy. However, CNS-predominant hATTR presents an additional challenge: liver transplantation eliminates hepatic TTR production and is effective for systemic disease, but the choroid plexus continues to secrete TTR locally into the CNS regardless, which may explain why CNS progression sometimes continues after liver transplant in oculoleptomeningeal patients.

Practical Actions

Carriers require subspecialty evaluation from a center experienced in hereditary amyloidosis. Cardiac and neurological screening should run in parallel because the phenotype in any given carrier cannot be predicted in advance. TTR stabilizer therapy (tafamidis, acoramidis) is the current standard of care for TTR cardiomyopathy; RNA-silencing agents (patisiran, vutrisiran, inotersen, eplontersen) reduce circulating TTR production and are increasingly used for systemic disease, though CNS penetration of systemic TTR reduction may be incomplete due to local choroid plexus secretion. Genetic counseling for first-degree relatives is mandatory given autosomal dominant inheritance.

Interactions

TTR A25T shares biological consequences with other pathogenic TTR variants: rs28933979 (Val30Met/V30M), the most common hATTR variant worldwide, and rs76992529 (Val122Ile/V122I), the most common in individuals of West African descent. The mechanisms of TTR destabilization, amyloid formation, and response to TTR stabilizers are shared across all pathogenic TTR mutations, though clinical expression (cardiac vs. neuropathic vs. CNS-predominant) differs by variant. No compound heterozygosity data exist for A25T due to its extreme rarity, but double heterozygosity for two pathogenic TTR variants in the same individual would be expected to worsen disease expression based on known principles of additive tetramer destabilization.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

No TTR Ala45Thr variant detected — standard transthyretin function

You carry two copies of the reference G allele at rs104894664. Your TTR gene produces normal alanine at position 45 of the transthyretin precursor protein (position 25 in the mature protein), maintaining the stable tetrameric structure required for normal function. This is the overwhelmingly common genotype — the A25T pathogenic allele is absent from essentially all population databases. You do not carry this hereditary transthyretin amyloidosis variant.

AG hATTR Carrier High Risk

One copy of Ala45Thr — pathogenic TTR variant with high risk of CNS and systemic amyloidosis

Transthyretin amyloidosis caused by Ala45Thr is characterized by unusual biology. The TTR tetramer formed by A25T subunits is the most thermodynamically unstable yet characterized — it dissociates into amyloidogenic monomers faster than even L55P-TTR, previously considered the most aggressive variant. Yet because the A25T protein circulates at very low serum concentrations, systemic amyloid deposition (which requires high circulating TTR) is attenuated. Instead, local TTR secretion by the choroid plexus into cerebrospinal fluid allows fibril formation directly in the CNS — a route that is independent of serum levels.

Published cases have presented with: - Oculoleptomeningeal amyloidosis: amyloid deposits in the leptomeninges (brain-enveloping membranes) causing headache, cranial nerve palsies, vitreous opacities (amyloid "floaters"), and progressive neurological deterioration - Peripheral neuropathy: length-dependent sensorimotor neuropathy, as in other TTR variants - Cardiac involvement: restrictive cardiomyopathy with interventricular septal thickening (documented in European carriers, particularly Polish patients)

Disease onset typically occurs in the fifth decade (initial Japanese case: age 42). Inheritance is autosomal dominant — heterozygous carriers are affected, and each first-degree relative has a 50% chance of inheriting the variant. Homozygosity has not been documented due to extreme rarity but would be expected to produce earlier or more severe disease, as seen for other hATTR variants.

Current treatment options include TTR stabilizers (tafamidis, acoramidis) for cardiac involvement and RNA-silencing therapies (patisiran, inotersen, vutrisiran, eplontersen) for systemic disease. CNS-predominant disease presents additional challenges because liver transplantation eliminates hepatic TTR but not choroid plexus secretion, so CNS progression may continue post-transplant. No large trials have specifically enrolled A25T carriers given the variant's extreme rarity; treatment decisions are extrapolated from Val30Met and V122I trial data.

AA hATTR Homozygous High Risk

Two copies of Ala45Thr — homozygous TTR amyloidosis variant, expected to cause severe or early-onset disease

All TTR molecules in an A25T homozygous individual would carry the destabilizing substitution, with no wild-type TTR to form stable hybrid tetramers. Since even heterozygotes (who produce 50% wild-type TTR) develop amyloidosis in midlife, full homozygosity — producing no stabilizing TTR subunits — would be expected to cause earlier or more severe disease, though the extreme rarity of this scenario means no direct data exist.

For other hATTR variants: nine homozygous Val30Met patients showed similar age of onset to heterozygotes (suggesting some compensatory mechanism), but homozygous V122I carriers presented approximately a decade earlier (63 vs. 72 years median onset). A25T's unprecedented tetramer instability may produce a different pattern. Given uncertainty, all clinical management should proceed as for the most severe known hATTR presentations.