Hereditary transthyretin amyloidosis

ATTRv amyloidosis is a progressive multisystem disorder characterized by sensorimotor and/or autonomic neuropathy, with possible cardiac, leptomeningeal, ocular, and renal involvement. Sensory neuropathy typically begins in the lower extremities with paraesthesia (e.g., burning or tingling sensations) or hypoaesthesia of the feet; temperature and pain sensation are impaired earlier than vibration and position sense, with motor neuropathy emerging within a few years. Age of onset is highly variable and is influenced by TTR genotype and geographic background: early onset (third to fourth decade) predominates in endemic Portuguese and Japanese clusters carrying p.Val50Met, whereas late onset is more common in non-endemic populations, including northern European, Swedish, French, and African-descent groups and in association with other TTR variants. Carpal tunnel syndrome may be an early manifestation of transthyretin amyloidosis, particularly in wild-type ATTR amyloidosis and in association with certain TTR variants. Cardiac involvement frequently develops after age 50 and includes atrioventricular block, sick sinus syndrome, atrial fibrillation, and progressive restrictive cardiomyopathy with heart failure. Leptomeningeal amyloidosis may produce transient focal neurological episodes and intracerebral or subarachnoid haemorrhage; ophthalmopathy (vitreous opacities, glaucoma) and nephropathy are also frequently observed. Sensorimotor and autonomic neuropathy progress over ten to twenty years, with cachexia common at late stages.

ATTRv amyloidosis is a rare disease for which precise overall prevalence estimates are not well defined and vary depending on geographic region and underlying TTR variant. The estimated prevalence of p.Val50Met-associated ATTRv amyloidosis in individuals of northern European origin in the United States is approximately 1/100,000. Prevalence is markedly higher in endemic foci, including approximately 1/538 in northern Portugal for this variant. The p.Val142Ile variant shows a heterozygote frequency of 3.0–3.9 % among African Americans.

ATTRv amyloidosis is typically caused by heterozygous germline pathogenic variants in a single gene, TTR (18q12.1).1 Almost all reported pathogenic variants to date are missense changes within exons 2, 3, or 4. The molecular mechanism is gain-of-function: pathogenic variants reduce the stability of the circulating transthyretin tetramer, generating pro-amyloidogenic monomers that polymerise into amyloid fibrils deposited in peripheral nerves, autonomic ganglia, heart, eyes, kidneys, and the leptomeninges.

ATTRv amyloidosis is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the TTR pathogenic variant.

The diagnosis is established in an individual with characteristic clinical and laboratory findings and identification of a heterozygous germline pathogenic variant in TTR. Early diagnosis is important in the context of a multisystem disease. Tissue biopsy (subcutaneous abdominal fat, skin, gastric or rectal mucosa, sural nerve, endocardium, or peritendinous fat from carpal tunnel surgery) with Congo red staining shows yellow-green birefringence under polarised light, and immunohistochemistry with anti-transthyretin antibodies identifies TTR-type amyloid deposits. Echocardiography may show left or biventricular thickening with speckled myocardium; bone scintigraphy with 99mTc-DPD, 99mTc-PYP, or 99mTc-HMDP detects cardiac amyloid, and nerve conduction studies document sensorimotor neuropathy.

Main differential diagnoses include:

• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): peripheral neuropathy without cardiomyopathy; most common misdiagnosis in simplex ATTRv cases; acquired condition (no associated gene).
• Immunoglobulin light chain (AL) amyloidosis: polyneuropathy, autonomic neuropathy in approximately one-third of affected individuals, cardiomyopathy, and kidney failure; distinguished by positive serum and/or urine monoclonal protein and negative myocardial 99mTc-PYP scintigraphy; acquired condition (no associated gene).
• Wild-type ATTR amyloidosis (senile systemic amyloidosis): cardiomyopathy and carpal tunnel syndrome predominantly in older adults, with severe peripheral neuropathy rare; identical TTR amyloid deposition pathology without an inherited pathogenic variant; TTR.
• In selected cases, other hereditary amyloidoses, hereditary multisystem disorders, or acquired conditions affecting commonly involved organs (e.g., heart, peripheral nerves, kidneys or eyes) may also be considered.

• Establishing the diagnosis through identification of the underlying pathogenic variant.
• Enabling specific and individualised surveillance and thereby supporting personalised medical care, planned and implemented by the treating physicians in consultation with the affected individual.
• Allowing predictive testing of at-risk family members once the familial pathogenic variant has been identified.

• Sekijima Y, Nakamura K. Hereditary Transthyretin Amyloidosis. GeneReviews. 2001 Nov 5 [Updated 2024 May 30]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20301373. Available from:
• Delgado D, Dabbous F, Shivappa N, Mazhar F, Wittbrodt E, Shridharmurthy D, et al. Epidemiology of transthyretin (ATTR) amyloidosis: a systematic literature review. Orphanet Journal of Rare Diseases. 2025;20(1):29. PMID: .
• Pinto MV, França MC Jr, Gonçalves MVM, Machado-Costa MC, Freitas MRG, Gondim FAA, et al. Brazilian consensus for diagnosis, management and treatment of hereditary transthyretin amyloidosis with peripheral neuropathy: second edition. Arquivos de Neuro-Psiquiatria. 2023;81(3):308-321. PMID: .
• Gillmore JD, Hahn K, Smith JG, Conceição I, Tian Z, Grogan M, et al. Rationale and Design of ANTHOLOGY: An ATTR Amyloidosis Real-World Evidence Program Aiming to Address Gaps in Amyloidosis Care. Cardiology and Therapy. 2025;14(3):477-490. PMID: .