Hereditary Transthyretin Amyloidosis (ATTRv)

Literature and regulatory information updated: 6 October 2026.

Familial amyloid polyneuropathy (Corino de Andrade disease, “paramyloidosis”) and variant transthyretin amyloid cardiomyopathy

0. Initial Reference Table

1. Introduction

Hereditary transthyretin amyloidosis is the most frequent systemic hereditary amyloidosis and a paradigmatic example of a genetic disease in which understanding the molecular mechanism led, over seven decades, from a clinical description of an invariably fatal course to a range of gene- and protein-targeted therapies [2, 26]. The disease results from extracellular deposition in multiple organs of amyloid fibrils formed from transthyretin (TTR) carrying an amino acid substitution; peripheral and autonomic nerves, heart, eye, kidney and leptomeninges are the main sites of deposition [2].

The history of the disease is inseparable from Portugal. In the late 1930s, the neurologist Mário Corino da Costa Andrade (Corino de Andrade, 1906–2005), in Porto, began observing patients with sensory-motor and autonomic neuropathy that local people called “doença dos pezinhos” (“disease of the little feet”). Observation of dozens of similar cases concentrated in fishing families from Póvoa de Varzim and neighbouring municipalities led to publication of the foundational article in Brain in 1952: “A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves” [35]. In that series, 54 of 64 patients (25 families) came from Póvoa de Varzim or surrounding parishes; Andrade described ascending neuropathy with sensory-motor loss and severe autonomic dysfunction, beginning between 25 and 35 years in both sexes, with familial transmission and histological demonstration of amyloid in nerves [9, 35, 36]. A preliminary note had been published in 1951 in Acta Psychiatrica et Neurologica Scandinavica [37].

Subsequent molecular milestones were also achieved largely by Portuguese researchers. In 1978, Pinho e Costa, Figueira and Bravo demonstrated that the amyloid fibril protein from FAP patients shared antigenic determinants with plasma prealbumin (13,745 Da subunit), excluding AL and AA proteins [38]. In 1984, Saraiva, Birken, Costa and Goodman identified, by peptide mapping and microsequencing, the substitution of valine by methionine at position 30 of the mature protein (Val30Met), the first amyloidogenic TTR variant described [39]. The classic “Val30Met” designation numbered the residues of the mature protein after removal of the 20-amino-acid signal peptide; current HGVS nomenclature, numbering from the initiation methionine, designates the same variant as NM_000371.4:c.148G>A p.(Val50Met) [2, 3].

The Swedish focus (described in 1968, with later onset and vitreous opacities) and Japanese foci (Arao in Kumamoto and Ogawa in Nagano) confirmed the variant's worldwide distribution, and foci were subsequently described in Majorca (Balearic Islands) and Brazil [2, 29, 36]. In parallel, discovery that p.Val142Ile (Val122Ile), present in 3–4% of African Americans, explained part of the higher frequency of isolated cardiac amyloidosis in older Black people [40] consolidated the current concept that FAP and familial amyloid cardiomyopathy represent extremes of the same phenotypic spectrum [3].

Therapeutically, the disease has passed through four phases: exclusively symptomatic treatment (1952–1990); orthotopic liver transplantation, introduced in Sweden in 1990 and rapidly adopted in Portugal, replacing the main source of variant TTR [41, 42]; the tetramer stabiliser era, beginning with European tafamidis approval in 2011 [17]; and the gene silencer era (small interfering RNAs and antisense oligonucleotides), from 2018 [43, 44]. In vivo CRISPR-Cas9 gene editing (NTLA-2001) is in phase 3 trials [19, 45]. This article addresses ATTRv across its entire phenotypic range — predominantly Portuguese polyneuropathy (p.Val50Met) and predominantly African-ancestry (p.Val142Ile) and Irish (p.Thr80Ala) cardiomyopathy — and indicates, where relevant, differences from wild-type transthyretin amyloidosis (ATTRwt), which is not hereditary.

2. Molecular Genetics and Pathophysiology

2.1. The TTR gene and transthyretin protein

The TTR gene is located at 18q12.1, has four exons and encodes a 147-amino-acid prepeptide, from which a 20-residue signal peptide is cleaved, yielding the mature 127-amino-acid monomer [2, 3]. Transthyretin is synthesised predominantly by the liver and, in smaller amounts, by the choroid plexuses and retinal pigment epithelium; it circulates in plasma and cerebrospinal fluid as a homotetramer [2, 3]. The name “prealbumin” derives from its electrophoretic migration ahead of albumin [3]. “Transthyretin” summarises its physiological functions: transport of thyroxine (binding approximately 15% of serum thyroxine) and retinol, the latter through its complex with retinol-binding protein (RBP4) [2, 3]. This function explains the reduction in serum vitamin A levels observed with silencing drugs (section 7) [14].

2.2. Variant spectrum

More than 130 amyloidogenic variants have been described, almost all missense and located in exons 2, 3 and 4 [2, 25]. Virtually every amino acid of the small TTR protein can be substituted by amyloidosis-associated variants, except for a benign polymorphism at codon 6 of the mature protein (Gly6Ser, historical numbering, = NM_000371.4:c.76G>A p.(Gly26Ser)) [3]. No pathogenic intragenic deletions or duplications have been described, consistent with the gain-of-function mechanism; deletion/duplication analysis is therefore not indicated, and TTR sequencing has an analytical sensitivity approaching 100% [2]. The following table summarises the variants of greatest clinical and population relevance.

Other variants with a predominantly cardiac phenotype include p.Asp38Asn, p.Val40Ile, p.Pro44Ser, p.Ala65Ser, p.Ala65Thr, p.His76Arg, p.Gly77Arg, p.Ile88Leu, p.Ala101Thr, p.Ala101Val, p.His108Arg, p.Glu112Lys, p.Arg123Ser and p.Leu131Met; in these cases, peripheral and autonomic neuropathy is absent or mild [2].

In France, a non-endemic area, the most frequent variant is also c.148G>A p.(Val50Met), followed by NM_000371.4:c.290C>A p.(Ser97Tyr) (Ser77Tyr), c.290C>T p.(Ser97Phe) (Ser77Phe) and c.379A>G p.(Ile127Val) (Ile107Val); the French national protocol stresses that all known amyloidogenic variants are missense and refers to an international database of TTR variants (amyloidosismutations.com), which also lists non-pathogenic polymorphisms [10].

2.3. Molecular mechanism of amyloidogenesis

Amyloidogenesis occurs in two stages: dissociation of the soluble tetramer into pro-amyloidogenic monomers, and polymerisation of these monomers into amyloid fibrils in particular tissues [2]. Pathogenic variants cause conformational changes that reduce the tetramer's thermodynamic and kinetic stability; tetramers containing variant subunits dissociate more readily than wild-type tetramers [2]. In vitro amyloidogenicity correlates with protein instability, but the relationship is not linear: extremely destabilised variants are degraded by hepatic endoplasmic reticulum quality control before secretion, so serum concentrations are low and they do not cause severe systemic amyloidosis. The clinically most severe variant, p.Leu75Pro, is the most destabilised variant still secreted at levels comparable to wild-type protein. Variants associated with central nervous system amyloidosis are the least stable, and the choroid plexus secretes highly destabilised TTR more efficiently than hepatocytes, explaining selective leptomeningeal deposition [2].

All forms of amyloidosis share a common mechanism: misfolded, insoluble proteins aggregate into fibrils that accumulate in the extracellular space. Conditions favouring misfolding — destabilising variants, oxidative stress, production of monoclonal light chains at high concentration — facilitate the initiation and propagation of the process, and, once an amyloid nucleus is established, deposition tends to progress even after removal of the initial cause: after liver transplantation, which eliminates the source of the variant protein, disease frequently progresses through deposition of wild-type TTR on pre-existing amyloid [3]. The mechanisms of tissue tropism (why some variants affect nerves at young ages and others the heart at advanced ages) remain largely unknown [3]. In preclinical research, induced pluripotent stem cells (iPS cells) from patients with ATTRv have been differentiated into hepatic, neuronal and cardiac lineages, reproducing the three main tissue types involved; in this model (variant p.Leu75Pro, Leu55Pro in historical numbering), variant TTR secreted by iPS-derived hepatocytes reduced the survival of iPS-derived cardiomyocytes, which makes these models useful for studying the interaction between the protein-producing organ and the target organs [47].

Fibril composition contributes to this heterogeneity. Early-onset p.Val50Met patients have type B fibrils, composed exclusively of full-length TTR, whereas late-onset patients have type A fibrils, composed of full-length TTR and C-terminal fragments; this difference coincides with the observation that bone scintigraphy is negative in young p.Val50Met patients (section 5) [2].

2.4. Genetic observations with therapeutic implications

The tetramer stabilisation strategy arose from a genetic observation: rare compound heterozygotes for p.Val50Met and the stabilising variant p.Thr139Met (Thr119Met) have much later onset and milder disease than carriers of p.Val50Met alone; in vitro, increasing the proportion of stabilising monomers proportionally improves tetramer stability [2, 3]. This “experiment of nature” underpinned development of molecules occupying thyroxine-binding sites and pharmacologically reproducing the protective variant's effect (section 7) [3].

2.5. Tissue pathophysiology

In peripheral nerves, amyloid deposition in the endoneurium, around vessels and in sensory and sympathetic ganglia causes a length-dependent axonal neuropathy initially affecting small-calibre fibres (unmyelinated and thinly myelinated), responsible for temperature and pain sensation and autonomic function; large-calibre and motor fibres are affected later [2]. Deposition in the digestive tract wall and its nerve plexuses explains the severity of gastrointestinal manifestations [2].

In the heart, amyloid accumulation in the myocardial extracellular matrix increases wall thickness without myocyte hypertrophy, causing diastolic dysfunction and progressively restrictive cardiomyopathy [3]. As the left ventricular cavity shrinks, stroke volume decreases despite preserved ejection fraction, and cardiac output becomes directly proportional to heart rate: high rates are poorly tolerated because of ventricular stiffness, but bradycardia worsens heart failure. In late stages, ejection fraction decreases, with relative apical sparing [3]. Conduction system infiltration and diffuse fibrosis explain sinus node dysfunction, chronotropic incompetence, bundle branch blocks and atrioventricular blocks [3]. Myocardial ischaemia without obstructive epicardial coronary disease results from microvascular dysfunction due to perivascular and intramyocardial arterial intima–media deposition: in a prospective study using vasodilator stress positron emission tomography (PET), 21 patients with cardiac amyloidosis had regional perfusion defects and reduced resting and stress myocardial blood flow and coronary reserve, even after adjustment for wall thickness, unlike 10 patients with hypertensive heart disease [3].

Central nervous system amyloidosis results from TTR produced by the choroid plexuses, unaffected by liver transplantation or current drugs (which act on hepatic TTR); prolonged survival of treated patients is making late leptomeningeal and ocular manifestations more frequent [2]. Likewise, TTR produced by retinal pigment epithelium explains progression of vitreous opacities and glaucoma after liver transplantation [2, 36].

2.6. Population genetics, penetrance and anticipation

ATTRv penetrance is incomplete and varies with the variant, geographical region and ethnicity [2]. For p.Val50Met, the cumulative risk of disease in Portugal was estimated at 80% by 50 years and 91% by 70 years, whereas in French heterozygotes it is 14% by 50 years and 50% by 70 years [2, 48]. The French national protocol gives different values, taken from later reviews: overall penetrance of 73% in French p.Val50Met carriers and of about 95% for the other variants, a risk of 18% by 50 years and of 86% by 80 years in the French population, and overall penetrance of 91% in Portuguese carriers, with 26% by 30 years and 80% by 50 years [10]. The differences between the French estimates reflect different cohorts, periods and methods of correcting for ascertainment bias; in counselling, the range and its source should be presented rather than a single value. In Sweden, where 1.5% of the population of the north of the country is heterozygous for p.Val50Met, penetrance is much lower: 1.7% at 30 years, 5% at 40, 11% at 50, 22% at 60, 36% at 70, 52% at 80 and 69% at 90 years [2, 49]. Penetrance is higher in endemic foci than outside them; some p.Val50Met homozygotes remain asymptomatic [2].

Anticipation — progressively earlier onset in successive generations — was attributed for decades to ascertainment bias. Analysis of 926 parent–offspring pairs from 284 Portuguese families followed at Porto's Unidade Clínica de Paramiloidose over 70 years demonstrated a real biological phenomenon: 291 pairs showed marked anticipation (≥ 10 years), and in 203 of these the transmitting parent was the mother; mother–son pairs showed the greatest anticipation (mean 10.43 years), and father–daughter pairs only residual anticipation (1.23 years) [6]. Women have later onset than men (daughters 33.70 vs. sons 29.43 years; mothers 39.57 vs. fathers 35.62 years), and parents with onset ≤ 40 years never had offspring with onset ≥ 50 years. Anticipation persisted after exclusion of the proband, pairs with simultaneous onset and offspring born after 1960 [6]. Unlike repeat-expansion diseases, the molecular basis of this parent-of-origin effect remains unclear.

Proposed modifiers include the haplotype of origin (the Japanese founder is probably independent of the Portuguese founder), variants in cis and trans (such as p.Thr139Met), and unknown environmental factors, which might explain later onset and milder disease in Sweden with the same variant [2, 3].

3. Clinical Spectrum and Manifestations by System

3.1. Overview and frequency of manifestations

ATTRv presents as a multisystem disease whose dominant phenotype depends on variant, age at onset and geographical origin. The following table summarises manifestation frequencies in three genotypic groups [2].

Source: GeneReviews (data from Gentile et al., 2023) [2].

3.2. Age at onset

Onset is earlier in endemic foci. In Portuguese patients with p.Val50Met, mean age at onset is 33.5 ± 9.4 years (range 17–78); 87% of the 1233 patients in the Centro de Estudos de Paramiloidose series developed symptoms before 40 years, and in the Póvoa de Varzim/Vila do Conde area the mean was 31.1 ± 6.7 years, with no onset after 57 years [9]. In Japanese patients from the Ogawa and Arao foci, the mean is 40.1 ± 12.8 years (22–74), whereas in Japanese p.Val50Met patients without links to endemic foci it is 62.7 ± 6.6 years (52–80) [2]. Onset is considerably later in Swedish, French or British patients [2]. The distinction between early (< 50 years) and late (≥ 50 years) onset has clinical and prognostic value: in a Portuguese series of 86 patients (43 in each group), late-onset cases less frequently had a family history and autonomic dysfunction but more frequently had other organ involvement and severe neuropathic pain [50]. In the Portuguese national study, 28.7% of incident cases between 2010 and 2016 had late onset, a higher proportion than in historical series [8].

In France, late-onset forms (> 50 years) account for about 75% of cases, frequently without a family history and with a mean diagnostic delay of 3 years after the first manifestations [10]. Early-onset forms (< 50 years), seen mainly in patients aged 25 to 35 years of Portuguese origin with a family history, begin with sensory symptoms (paraesthesiae of the feet in 40%, neuropathic pain in 5%, plantar perforating ulcer), autonomic symptoms (erectile dysfunction, diarrhoea, constipation, vomiting) or with unexplained weight loss, the presenting feature in 16% [10]. Late-onset forms are distinguished by a sensory-motor deficit with early gait disturbance, involvement of all sensory modalities (proprioceptive and thermal-pain), more frequent pain and less frequent dysautonomia; among French patients, ataxic forms (26%) and forms beginning in the upper limbs (22%) together account for about half of cases, and there are exceptional purely motor forms [10]. The initial presentation may also be gastrointestinal (alternating diarrhoea and constipation, vomiting), ophthalmological (presenting vitreous opacities) or cardiac (conduction disturbances with syncope, arrhythmia, ventricular hypertrophy, heart failure) [10]. These proportions refer to patients diagnosed in France and cannot be transposed to endemic foci.

3.3. Peripheral sensory-motor neuropathy

Neuropathy is typically axonal, symmetrical and length-dependent. Initial symptoms are paraesthesias (burning sensation, lancinating pain) or foot hypoaesthesia; temperature and pain sensation are affected before vibration and position sense — a dissociation reflecting preferential small-fibre involvement [2]. By the time sensory disturbance reaches the knees, the hands are usually involved, and neuropathy eventually acquires a “glove-and-stocking” distribution [2]. Motor neuropathy (atrophy and weakness) follows within a few years, with foot drop, wrist drop and functional hand disability [2]. Sensory loss predisposes to trophic lower-limb ulcers, painless burns and neuropathic arthropathy [2]. In late-onset forms and non-Val50Met variants, neuropathy may begin with bilateral carpal tunnel syndrome, predominantly affect motor or large fibres and progress more rapidly; 12.7% of patients may meet electrodiagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) [2, 25].

Coutinho and colleagues described the natural history of neuropathy from 483 Portuguese patients in three locomotor stages (stage 1: unaided walking; stage 2: assisted walking; stage 3: wheelchair-dependent or bedridden), with mean durations of 5.6 ± 2.8, 4.8 ± 3.6 and 2.3 ± 3.1 years, respectively, in early-onset p.Val50Met; in late-onset forms and other variants, stages are shorter (2–4, 2–3 and 1–2 years) [25, 51]. Staging is detailed in section 5.

3.4. Autonomic neuropathy

Autonomic dysfunction may be the initial manifestation, particularly in early-onset cases, and is frequently the main cause of morbidity [2]. It includes orthostatic hypotension, constipation alternating with diarrhoea, episodes of nausea and vomiting, delayed gastric emptying, erectile dysfunction, anhidrosis, urinary retention or incontinence and weight loss [2, 25]. Amyloid deposition in the digestive tract wall, involving intestinal autonomic nerves, is frequent [2]. Unexplained weight loss and cachexia (reflected by a reduced modified body mass index, mBMI = BMI × serum albumin in g/L) are major prognostic markers [2, 42].

3.5. Cardiac involvement

Most patients develop cardiac manifestations after 50 years [2]. These include arrhythmias — atrioventricular block, sinus node disease and atrial fibrillation — and progressive restrictive cardiomyopathy with heart failure, in which diastolic dysfunction precedes systolic dysfunction; in some patients cardiomyopathy is the predominant manifestation and there is no peripheral neuropathy [2]. Cardiac involvement is usually asymptomatic at diagnosis of the neuropathic form but has been detected by imaging in up to 72% of patients, and 55% (33 of 60) of patients with late-onset p.Val50Met have septal thickness > 12 mm at presentation, particularly men [25]. In neuropathic forms, cardiac involvement manifests predominantly as right heart failure, conduction blocks or supraventricular arrhythmias [52]. The French protocol describes an infiltrative cardiomyopathy without electrical hypertrophy or arterial hypertension, which progresses from heart failure with preserved ejection fraction to refractory failure with reduced ejection fraction, frequently preceded by very early sympathetic or parasympathetic cardiac denervation, whose value is mainly prognostic; it also estimates that the prevalence of atrial fibrillation, as a percentage, approximates the patient's age minus 10 (about 60% at 70 years), and notes that the atrial standstill of advanced forms allows atrial thrombi in sinus rhythm [10].

The French PNDS (French National Diagnosis and Care Protocol) on cardiac amyloidoses (reference centre for cardiac amyloidoses, CARDIOGEN network, 2021), which covers the AL, ATTRwt and ATTRv forms together, brings together frequency estimates that show the underdiagnosis of the TTR form: hereditary forms would account for more than 5% of hypertrophic cardiomyopathies, and ATTR as a whole for 8% of hypertrophic cardiomyopathies, 13% of cases of heart failure with preserved ejection fraction and 16–22% of aortic stenoses; these values come from selected hospital series and are not population prevalences [34]. The prevalence of ATTRv is unknown; an analysis of the French national health data system (ePACT study) estimated at 4815 the number of patients with ATTR cardiomyopathy (all forms) diagnosed in France between 2011 and 2017 [34]. In France, p.(Val142Ile) is the most frequent variant in cardiac forms, with a carrier frequency of about 3.6% in people of African, African American or French Caribbean origin and unknown penetrance, followed by p.(Val50Met), which outside Portuguese families causes a mixed cardiac and neurological phenotype with onset at around 70 years; in variants with cardiac tropism, disease usually begins after 50 years, with a mean age at diagnosis of 72 years in France, but there are early-onset exceptions, such as NM_000371.4:c.391C>A p.(Leu131Met) (Leu111Met) in Denmark and c.220G>C p.(Glu74Gln) (Glu54Gln) in Romania [34]. The same protocol reports an association between p.(Val142Ile) carrier status and atrial fibrillation and ischaemic stroke in African Americans, independent of the presence of amyloid cardiomyopathy [34]. Diagnostic wandering is explained by the fact that cardiac amyloidosis mimics several syndromes: hypertrophic cardiomyopathy, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction and thick walls, left ventricular hypertrophy with sinoatrial block, 2nd- or 3rd-degree atrioventricular block, atrial fibrillation or flutter, and calcific aortic stenosis with hypertrophy or with low flow and low gradient [34].

Clinical manifestations of cardiac amyloidosis include congestive heart failure (oedema, dyspnoea, ascites), low output during systolic dysfunction, hypotension or orthostatic symptoms (from systolic and autonomic dysfunction), angina without obstructive coronary disease, frequent ventricular ectopy — rarely progressing to ventricular tachycardia — and atrial fibrillation, the most frequent tachyarrhythmia [3]. Cardiac thromboembolism may occur even in sinus rhythm: in an autopsy series, intracardiac thrombi were found in up to 33% of amyloidotic hearts, mainly atrial, with similar prevalence in patients with and without documented atrial fibrillation, attributed to atrial electromechanical dissociation, endothelial dysfunction or hypercoagulability [3]. The main clinical and paraclinical signs (“amyloid” phenotype) are organised in the following table [3].

Macroglossia and periorbital purpura are characteristic of AL amyloidosis and rare in ATTR, providing clues to the differential diagnosis.

p.Val142Ile cardiomyopathy

The p.Val142Ile variant causes late-onset cardiomyopathy (mean ≈ 70 years), clinically similar to ATTRwt, with reduced, age-dependent penetrance [3, 46]. At autopsy, all carriers over 65 years had cardiac TTR deposits, but clinical penetrance varies, and the allele was found in 10% of African Americans over 65 years with severe congestive heart failure [46]. Homozygosity occurs; in a cohort of 13 homozygotes and review of 11 published cases, initial symptoms appeared approximately 10 years earlier than in heterozygotes, although severity was similar [3]. Bilateral carpal tunnel syndrome frequently precedes cardiomyopathy by several years, and neuropathy, when present, is mild.

p.Thr80Ala (Thr60Ala) phenotype

In a contemporary Irish cohort of 24 patients (12 women), median age at diagnosis was 65 years; carpal tunnel syndrome was the initial manifestation in 46%, and the phenotype was mixed, with autonomic (75%), small-fibre (58%) and large-fibre (46%) neuropathy generally preceding cardiomyopathy (heart failure 63%, atrial arrhythmia 42%, bradycardia 13%) [7].

3.6. Ocular involvement

Ocular involvement is frequent and occurs in most p.Val50Met patients: vitreous opacities (≈ 20% of ATTRv patients), glaucoma, dry eye, abnormal conjunctival vessels, pupillary irregularities and ocular amyloid angiopathy [2]. In a Japanese study, 4 of 43 p.Val50Met patients had vitreous amyloidosis as their first manifestation, and there are cases in which vitreous opacification was the only evidence of disease [2]. In Portugal, vitreous opacities were rare in the natural history, but prolonged survival after liver transplantation significantly increased their prevalence, because retinal production of variant TTR persists [36]. According to the French protocol, ATTRv is the only systemic amyloidosis with vitreous involvement; the prevalence of vitreous deposits ranges from 0 to 30% depending on the series and increases with disease duration. In order of frequency, the ocular manifestations are keratoconjunctivitis sicca, vitreous deposits, secondary glaucoma and retinal angiopathy; glaucoma is silent and can cause blindness, and amyloid deposits on the pupillary margin or a scalloped pupil predict amyloid glaucoma, which may appear months or years later [10].

3.7. Leptomeningeal and central nervous system involvement

The most frequent manifestation is transient focal neurological episodes (TFNE): brief, self-limiting episodes of focal cortical dysfunction (hemiparesis, hemisensory deficit, motor aphasia), common in p.Val50Met patients with longstanding disease [2]. Following TFNE, dementia and intracranial haemorrhage may develop approximately 20 years after disease onset [2]. Amyloid is deposited in the pia mater, arachnoid and vessel walls of the subarachnoid space; myelopathy rarely occurs [2]. In leptomeningeal variants, the presentation includes dementia, psychosis, visual loss, headache, seizures, motor paresis, ataxia, hydrocephalus and intracerebral or subarachnoid haemorrhage. Cerebrospinal fluid protein is usually elevated, and gadolinium-enhanced magnetic resonance imaging shows extensive enhancement of the brain surface, ventricles and spinal cord; amyloid PET with Pittsburgh compound B (PiB) detects central nervous system deposition [2].

3.8. Renal and haematological involvement

The kidney is consistently involved in post mortem studies [2]. Nephropathy is preceded by proteinuria and occurs mainly in advanced stages; renal failure develops in about one-third of Portuguese patients with early-onset p.Val50Met but rarely in late-onset forms [2]. Anaemia with low erythropoietin has been described in 25% of patients [2]. Renal involvement has been described with about fifteen variants, including p.Val50Met, mainly in the early-onset form; it is predominantly glomerular, but vascular or tubulointerstitial lesions may coexist or occur in isolation, and microalbuminuria precedes renal failure by about 5 years, which justifies systematic screening for it [10].

3.9. Other manifestations

Nodular cutaneous amyloidosis and diffuse pulmonary involvement with dyspnoea have been described [2]. Carpal tunnel syndrome is common to almost all genotypes and frequently precedes other manifestations by several years [2, 7].

4. Clinical Recognition and Red Flags

Diagnostic delay is the main avoidable determinant of poor prognosis because all available treatments are more effective in early stages [25]. In non-endemic regions, 52–77% of cases have no known family history, ATTRv is suspected in only 26–38% of initial assessments, and 20–40% of patients receive successive incorrect diagnoses before the correct diagnosis [25].

The international expert consensus proposes an index of suspicion differentiated by epidemiological context [25]. In endemic countries (Portugal, Japan, Sweden, Brazil), ATTRv with polyneuropathy should be suspected in any patient with length-dependent small-fibre polyneuropathy with autonomic dysfunction and a family history, unexplained weight loss, cardiac rhythm disturbances, vitreous opacities or renal abnormalities. In non-endemic countries, the disease may present as rapidly progressive idiopathic axonal sensory-motor neuropathy or as atypical CIDP, with any of the preceding signs or with bilateral carpal tunnel syndrome, gait disturbance or cardiac hypertrophy [25]. In people with a known family history, any length-dependent axonal polyneuropathy with predominant thermal-pain involvement, autonomic dysfunction or cardiac arrhythmia requires targeted assessment [25]. The concept of “red-flag clusters” proposes suspecting ATTRv when progressive neuropathy is associated with at least one sign of multisystem involvement [53]. The French protocol summarises suspicion for the attending physician: a progressive sensory or sensory-motor polyneuropathy, particularly if associated with dysautonomia (erectile dysfunction, diarrhoea, orthostatic hypotension), weight loss greater than 10% or infiltrative or arrhythmic cardiomyopathy, should prompt contact with a neurology team specialising in rare peripheral neuropathies [10].

Source: expert consensus (Adams et al., 2021) [25]; in simplex case series, 18 of 90 patients without a family history and 7 of 15 simplex cases had initially been diagnosed as CIDP [2].

Cardiological red flags include: left ventricular hypertrophy on echocardiography or magnetic resonance imaging with normal or low electrocardiographic voltage (voltage–mass discordance); heart failure with preserved ejection fraction in older people, particularly those of African descent; intolerance of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or beta blockers; a pseudoinfarction pattern; conduction blocks or unexplained pacemaker requirements; bilateral carpal tunnel syndrome, lumbar spinal stenosis or biceps tendon rupture; and disproportionately and persistently elevated NT-proBNP or troponin [3, 27, 28]. Amyloidosis is the most frequent cause of restrictive cardiomyopathy in Western countries and should be excluded in any restrictive phenotype or unexplained “hypertrophy” [54]. Family history may include rapidly progressive polyneuropathy of unknown cause, heart failure, sudden death or arrhythmia; its absence does not exclude the diagnosis [2].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criterion

ATTRv is diagnosed in a proband with suggestive manifestations (including imaging or histopathological findings of amyloidosis) and a heterozygous pathogenic or likely pathogenic TTR variant identified by molecular genetic testing [2]. Under American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards, pathogenic and likely pathogenic variants are equivalent for clinical decision-making; a variant of uncertain significance neither establishes nor excludes the diagnosis [2]. Diagnosis therefore rests on two complementary categories of tools: TTR sequencing and demonstration of amyloid deposits (biopsy or bone scintigraphy) [25]. An asymptomatic carrier of a pathogenic variant does not thereby have the disease: disease diagnosis requires clinical manifestations and/or evidence of amyloid.

For a positive diagnosis, the French protocol requires both components — an amyloidogenic TTR variant and amyloid deposits with anti-TTR immunostaining — and considers that the absence of an amyloidogenic variant formally excludes ATTRv; it accepts, however, that in the absence of monoclonal gammopathy, cardiac uptake on bone scintigraphy (DPD or HMDP) may replace histology when the latter is negative, and that a patient with clinical signs, an amyloidogenic variant and positive scintigraphy may start treatment without histological proof [10]. For conversion from carrier to patient, the same protocol considers disease to have begun when there are at least two of three abnormalities — symptoms reported by the carrier, clinical changes relative to the baseline assessment and cardiac changes (low voltage, pseudo-infarct pattern, conduction block) — together with histological demonstration of amyloid, with the same exception for positive scintigraphy [10].

5.2. Genetic testing

The approach may be gene-targeted or genomic [2]. Sequencing of the four TTR exons detects missense, nonsense and splicing variants and small deletions/insertions; in endemic foci, c.148G>A p.(Val50Met) may be tested first. Multigene neuropathy or cardiomyopathy panels including TTR (for example, NM_000371.3 in cardiomyopathy panels) are useful when the differential is broad, and exome or genome sequencing detects coding variants in atypical phenotypes [2, 55]. Deletion/duplication analysis is not indicated [2]. In confirmed TTR cardiac amyloidosis, genetic testing is mandatory to distinguish ATTRv from ATTRwt, even in older people, because the absence of a family history does not exclude the hereditary form and the result has implications for relatives [3, 27]. Fibril mass spectrometry may identify variant peptides but does not replace genotyping [3]. In France, testing requires informed consent and is performed in an authorised laboratory on DNA from peripheral blood (EDTA tube, 10 mL) or saliva, shipped at room temperature within 24–48 hours or stored at 4 °C until shipment, and consists of sequencing the four coding exons; the result is communicated to the patient by the prescribing physician [10].

Genetic test limitations and report content

Test coverage should be read in the report. Sequencing the four exons and exon–intron junctions detects virtually all known amyloidogenic variants, which are coding missense variants; pathogenic intragenic deletions or duplications have not been described, so absence of CNV analysis is not a relevant limitation in this disease [2]. However, deep intronic and regulatory regions lie outside the scope of most panels and exomes, and low-level somatic mosaicism may be undetected; disease is not caused by repeat expansions, so those methods are not indicated [2]. Genotyping targeted only to c.148G>A p.(Val50Met), useful in endemic foci, does not exclude another variant: with a convincing phenotype and a negative result, the complete gene should be sequenced [2]. High analytical sequencing sensitivity (the proportion of detectable coding variants) should not be confused with clinical sensitivity: in confirmed TTR cardiac amyloidosis, negative complete sequencing classifies disease as ATTRwt rather than “undetected ATTRv” [2, 3].

The report should state the gene, versioned reference transcript — the MANE Select transcript is NM_000371.4 (NP_000362.1), although older panels cite NM_000371.3 [4, 55] —, HGVS c. and p. nomenclature, zygosity (homozygosity and compound heterozygosity, for example p.Val50Met with the protective variant p.Thr139Met, alter counselling), classification under ACMG/AMP criteria and technical limitations. Clinical literature uses historical numbering of the mature protein (without the 20-amino-acid signal peptide), which should be given in parentheses without replacing normalised nomenclature: p.(Val50Met) corresponds to Val30Met, p.(Val142Ile) to Val122Ile and p.(Thr80Ala) to Thr60Ala [2, 3]. In ClinVar (consulted 6 October 2026), c.148G>A p.(Val50Met) is classified as pathogenic (VCV000013417; multiple submitters, no conflicts), c.424G>A p.(Val142Ile) and c.238A>G p.(Thr80Ala) as pathogenic/likely pathogenic (VCV000013426 and VCV000013421), c.416C>T p.(Thr139Met) has conflicting classifications (VCV000013434), consistent with a non-amyloidogenic variant, and c.224T>C p.(Leu75Pro), although clinically severe in the literature, has a single older submission without classification criteria (VCV000013438) [4]. Classification should therefore be performed by the laboratory using ACMG/AMP criteria, rather than imported unreviewed from literature or databases.

A variant of uncertain significance does not become pathogenic because a patient responds to a stabiliser or silencer, or because of partial segregation in a small family; segregation studies and detection of the variant peptide by mass spectrometry in fibrils are described as additional investigation that may support formal reclassification but does not replace it [2, 3]. Finally, an asymptomatic carrier's report should explicitly state that the variant confers risk, with penetrance dependent on variant, population and age, and does not predict age at onset or severity (sections 2.6 and 8.2) [2].

5.3. Histological demonstration of amyloid

Congo red staining, with yellow-green (“apple-green”) birefringence under polarised light, confirms the presence of amyloid fibrils [2, 25]. Suitable tissues include abdominal wall subcutaneous fat (aspiration or biopsy), skin, labial salivary gland, gastric, duodenal or rectal mucosa, sural nerve, endomyocardium and peritendinous tissue obtained during carpal tunnel surgery [2]. The sensitivity of endoscopic gastrointestinal mucosal biopsy is about 85%; sural nerve biopsy is less sensitive because deposition is focal [2]. The expert consensus recommends that, if the first biopsy is negative, another be performed, preferably minimally invasive (skin, labial salivary gland, abdominal fat), and that a negative result should not exclude the diagnosis [25]. Amyloid typing (immunohistochemistry with anti-TTR antibodies or, preferably, liquid chromatography mass spectrometry) is indispensable to distinguish ATTR from AL amyloidosis, particularly because immunohistochemistry of an endomyocardial biopsy may be simultaneously positive for light chains and TTR [2, 3]. Typing is also the step that identifies the hereditary forms not mediated by transthyretin: fibrinogen A alpha chain (FGA), apolipoprotein A-I (APOA1), apolipoprotein A-II (APOA2), lysozyme (LYZ), gelsolin (GSN) and β2-microglobulin (B2M). An amyloid deposit whose precursor protein is not transthyretin and which corresponds neither to a plasma cell dyscrasia nor to chronic inflammation requires these entities to be considered, because immunohistochemistry with restricted panels may not cover them and only mass spectrometry identifies them unequivocally.

The French protocol places minor salivary gland biopsy first-line and prefers the least invasive samples (salivary gland, skin punch biopsy, abdominal subcutaneous fat); nerve, muscle, kidney, heart and, more rarely, vitreous are alternatives. A negative biopsy leads to repeat sampling at other sites, preferably clinically affected ones, and gastric biopsy may be positive in patients with upper gastrointestinal symptoms or weight loss. Typing combines anti-TTR immunostaining with immunofluorescence for κ and λ light chains; when typing fails, proteomics by mass spectrometry, of more restricted access, increases the diagnostic yield [10].

5.4. Non-invasive diagnosis of TTR amyloid cardiomyopathy

The most relevant advance of the last decade was validation of bone scintigraphy with technetium-99m-labelled tracers — 3,3-diphosphono-1,2-propanedicarboxylic acid (99mTc-DPD), pyrophosphate (99mTc-PYP) or hydroxymethylene diphosphonate (99mTc-HMDP) — for diagnosis without biopsy [3, 11]. In a multicentre study of 1217 patients with suspected cardiac amyloidosis (857 with histologically confirmed amyloid and 360 with non-amyloid cardiomyopathies), myocardial uptake had sensitivity > 99% and specificity 86% for cardiac ATTR, with false positives almost exclusively due to AL amyloidosis; combining grade 2 or 3 uptake with absence of monoclonal protein in serum and urine had specificity and positive predictive value of 100% (positive predictive value confidence interval 98.0–100%) [11]. These criteria were adopted by the 2021 European Society of Cardiology (ESC) position statement and the 2023 American College of Cardiology (ACC) decision pathway [27, 28]. Quantification may use the heart-to-contralateral-rib uptake ratio: the cardiogenetics chapter gives a ratio above 2.0 as diagnostic, and uptake extent, not merely its presence, helps distinguish ATTR from AL [3]. Expert consensus notes that a heart-to-whole-body ratio above 7.5 is associated with the highest event rate [25]. Single-photon emission computed tomography (SPECT) should confirm that uptake is myocardial rather than from intracavitary blood.

The algorithm is sequential [3, 11, 27]:

1. Clinical suspicion (red flags, compatible echocardiography or magnetic resonance imaging).
2. Mandatory investigation for plasma cell dyscrasia: serum and urine electrophoresis and immunofixation and serum free light chain measurement (κ, λ and κ/λ ratio).
3. Without monoclonal protein and with grade 2–3 scintigraphy: diagnosis of cardiac ATTR without biopsy → TTR sequencing to distinguish ATTRv from ATTRwt.
4. With monoclonal protein (or grade 1 scintigraphy, or negative scintigraphy with persistent suspicion): tissue biopsy (abdominal fat, bone marrow or endomyocardium) with mass spectrometry typing.

Two limitations are particularly relevant to the geneticist: bone scintigraphy is negative in young p.Val50Met patients (type B fibrils), so a negative examination does not exclude ATTRv in this group; and positive scintigraphy does not distinguish ATTRwt from ATTRv [2]. Absence of cardiac lesions on scintigraphy in an early-onset p.Val50Met patient should therefore be interpreted alongside echocardiography, electrocardiography, biomarkers and magnetic resonance imaging.

The PNDS on cardiac amyloidoses points out that a monoclonal gammopathy of undetermined significance accompanies 10–20% of ATTRwt cardiac amyloidoses, owing to its frequency in older people; therefore, in the presence of abnormal free light chains, positive scintigraphy is not sufficient and histological proof with typing is required, first in an extracardiac biopsy and, if this is inconclusive, in an endomyocardial biopsy or another affected organ [34]. Genetic testing is performed at any age, with no upper limit, because cardiac forms of ATTRv are frequently diagnosed after 60 years; the absence of a variant on sequencing of the four coding exons rules out ATTRv [34]. The protocol also systematises the causes of false results on bone scintigraphy, summarised in the following table.

Table 5.4a. False positives and false negatives of cardiac uptake on bone scintigraphy (99mTc-DPD or 99mTc-HMDP) [34]

The correspondence between the historical and HGVS numbering of the variants in the table was confirmed in ClinVar (NM_000371.4:c.250T>C p.(Phe84Leu), VCV000013453, pathogenic). Among the criteria for suspicion, the PNDS highlights unexplained wall thickness ≥ 12 mm associated with grade ≥ 2 diastolic dysfunction, mitral annular velocities on tissue Doppler (s′ or e′) < 5 cm/s or global longitudinal strain with an absolute value < 15% with an apex-to-base gradient; on magnetic resonance, subendocardial, transmural or heterogeneous late enhancement, increased native T1 and ECV > 40%; and incidental cardiac uptake on bone scintigraphy requested for another reason, which in about 10% of cases corresponds to AL amyloidosis [34].

5.5. Supplementary cardiac investigations

Electrocardiography shows low limb-lead voltage in approximately 50–60% of AL amyloidosis patients but only approximately 30% of familial forms and 40% of ATTRwt; discordance between imaging “hypertrophy” and absence of ECG hypertrophy criteria is more important than the formal low-voltage criterion [3, 54]. Other findings include atrioventricular blocks, atrial fibrillation, a pseudoinfarction pattern (Q waves in DII, DIII, aVF and V1–V3, QS pattern in right precordial leads) and intraventricular conduction delays [2, 3].

Echocardiography reveals diffuse, usually symmetrical left ventricular wall thickening that may involve the right ventricle, interatrial septum and valves; a “granular sparkling” myocardial appearance is suggestive but has low sensitivity and specificity [2, 3]. Diastolic dysfunction may be the first and only sign; advanced stages show a restrictive pattern, biatrial dilatation, pericardial effusion (rarely with tamponade) and intracardiac thrombi [3]. Longitudinal strain by speckle tracking or tissue Doppler is reduced early, predominantly affecting basal and mid segments with “apical sparing”, a pattern with high sensitivity and specificity [3].

Cardiac magnetic resonance imaging assesses morphology and function with higher spatial resolution; late gadolinium enhancement is diffuse, subendocardial or transmural, with difficulty “nulling” myocardial signal (determining the optimal inversion time) [3]. Native T1 mapping is increased, and estimated extracellular volume (ECV) above 40% is highly predictive of cardiac amyloidosis [3]. Gadolinium should be used cautiously in patients with amyloid nephropathy because of nephrogenic systemic fibrosis risk [2].

5.6. Neurological assessment

Initial assessment includes a complete neurological examination and nerve conduction studies showing axonal sensory-motor neuropathy; small fibres are assessed by quantitative sensory testing, skin biopsy with intraepidermal fibre density and autonomic testing (heart rate variation with deep breathing, sympathetic skin response, sudomotor tests) [2, 25]. Scales used in assessment and trials include the Neuropathy Impairment Score (NIS) and mNIS+7, polyneuropathy disability score (PND), 6-minute or 10-metre walk test, Composite Autonomic Symptom Score (COMPASS-31) questionnaire, Rasch-built Overall Disability Scale (R-ODS) and Norfolk QoL-DN quality-of-life scale [2, 26].

The French protocol reproduces in its annexes the instruments of neurological assessment: the Small Fibre Neuropathy Symptom Inventory Questionnaire SFN-SIQ (15 items scored from 0 to 3; positive screening with a score ≥ 2/15 and a score out of 45 to follow symptom frequency), the NIS items (with conversion of MRC strength: 5 = 0, 4+ = 1, 4 = 2, 4− = 3, 3 = 3.25, 2 = 3.5, 1 = 3.75 and 0 = 4), grip strength measured with a Jamar dynamometer, the PND and FAP stages, the R-ODS (24 activities scored from 0 to 2) and the Compound Autonomic Dysfunction Test (CADT), which grades from 4 (normal) to 0 orthostatic hypotension, upper and lower gastrointestinal symptoms, micturition disturbances and erectile dysfunction (normal maximum of 16 in women and 20 in men) [10]. These are complemented by electroneuromyography, R-R interval variability, sympathetic skin response and, where available, intraepidermal nerve fibre density, electrochemical skin conductance (Sudoscan®), laser-evoked potentials and quantitative thermal testing [10].

5.7. Staging

Neurological staging

Source: Coutinho et al. (1980) and expert consensus (Adams et al., 2021) [25, 51]. European regulatory indications for silencers refer to stage 1 or 2 polyneuropathy, and tafamidis 20 mg to symptomatic stage 1 [17].

Cardiac staging

The United Kingdom National Amyloidosis Centre system, applicable to ATTRwt and ATTRv, uses two universal biomarkers: stage I, NT-proBNP ≤ 3000 ng/L and estimated glomerular filtration rate (eGFR) ≥ 45 mL/min; stage III, NT-proBNP > 3000 ng/L and eGFR < 45 mL/min; stage II, remaining combinations [56]. In 869 patients (553 ATTRwt, 316 ATTRv), median survival was 69.2 months in stage I, 46.7 months in stage II and 24.1 months in stage III; age-adjusted mortality hazard ratios were 2.05 (95% CI 1.54–2.72) and 3.80 (2.73–5.28) for stages II and III versus I, independently of genotype [56]. New York Heart Association (NYHA) functional class complements staging and determines therapeutic eligibility.

In addition to the National Amyloidosis Centre stage (validated in ATTRwt and ATTRv, with hazard ratios of 2.1 and 3.8 for stages II and III), the PNDS on cardiac amyloidoses presents the Mayo Clinic score for ATTRwt (troponin T > 0.05 ng/mL or high-sensitivity troponin T ≥ 65 ng/L, and NT-proBNP > 3000 pg/mL; hazard ratios of 1.4 and 3.6 for stages II and III), which has not been validated in the hereditary form and therefore does not apply to ATTRv [34, 56].

5.8. Assessment after diagnosis

6. Differential Diagnosis

The differential diagnosis depends on the dominant presentation. Among amyloidoses, 35 amyloidogenic proteins have been identified in humans, and ATTRv is the most prevalent hereditary amyloidosis [2]. Nomenclature uses the letter A followed by the precursor protein abbreviation [1, 3].

ATTRv is distinguished from ATTRwt exclusively by genetic testing; distinguishing ATTR from AL requires monoclonal protein testing and, when present, histological typing — misclassification has serious therapeutic consequences because untreated cardiac AL amyloidosis has median survival of approximately 7 months [3].

When the patient has demonstrated systemic amyloidosis and TTR sequencing reveals no variant, the differential diagnosis continues with the other hereditary amyloidoses: fibrinogen A alpha chain amyloidosis (AFib, FGA, OMIM 105200, ORPHA:93562), apolipoprotein A-I amyloidosis (AApoAI, APOA1, OMIM 620657, ORPHA:93560), apolipoprotein A-II amyloidosis (AApoAII, APOA2, no phenotype MIM number, ORPHA:238269), lysozyme amyloidosis (ALys, LYZ, OMIM 620658, ORPHA:93561), gelsolin amyloidosis (AGel, GSN, OMIM 105120, ORPHA:85448) and β2-microglobulin amyloidosis (Aβ2M, B2M, OMIM 620659, ORPHA:314652); the Orphanet parent entity for the class is ORPHA:85450. All are autosomal dominant, with homozygosity described for GSN, and none responds to tetramer stabilisers or TTR silencers, so identification of the precursor protein precedes any therapeutic decision.

7. Treatments and Risk Management Strategies

7.1. General principles

Therapy has two components: cause-directed treatment, aiming to reduce available amyloidogenic TTR (silencers) or prevent tetramer dissociation (stabilisers), and treatment of manifestations [2, 3]. Pharmacotherapy is first-line for all ATTRv patients; liver transplantation is no longer first-line and has a limited indication [2, 26]. ISA guidelines and GeneReviews propose the following phenotype-based approach [2, 26]: in pure neuropathy, second-generation silencers (vutrisiran or eplontersen) or stabilisers (tafamidis), with second-generation silencers superior to first-generation agents (patisiran, inotersen) in safety and convenience; in isolated cardiomyopathy, tafamidis (NYHA classes I–III), joined by acoramidis and vutrisiran, approved for ATTR cardiomyopathy (sections 7.3 and 7.4); in mixed phenotype (neuropathy with cardiomyopathy, defined by end-diastolic septal thickness > 12 mm), tafamidis or silencers with demonstrated cardiac efficacy. Treatment should begin as early as possible after symptom onset [17, 25].

The most recent recommendations diverge on first choice in polyneuropathy. ISA guidelines (2022) accept stabilisers or silencers [26]; the US expert panel (2024) recommends silencers as first-line and acknowledges no consensus on what constitutes progression during treatment [30]; and the German DGAK/DGN consensus (2026) recommends a second-generation silencer (vutrisiran or eplontersen) for most symptomatic ATTRv-PN patients and immediate switching to a silencer for even mild signs of progression on a stabiliser, noting limited evidence on switching between silencers or combinations and that no approved drug sufficiently crosses the blood–brain barrier [33]. These are expert consensus recommendations based on trials with different comparators (section 7.9), rather than direct drug comparisons. In cardiomyopathy, the Sociedade Portuguesa de Cardiologia published recommendations in 2025 on suspicion, referral, diagnosis and treatment of ATTR-CM and, with national paramyloidosis reference centres, a consensus on targeted therapy in ATTRv patients with cardiac involvement after liver transplantation [31, 57].

The French national protocol (PNDS of the Haute Autorité de Santé, 2022) sets as objectives to offer, whenever possible, an anti-amyloid treatment, to treat organ manifestations, to prevent and treat organ failure and to prevent new cases in the family through genetic counselling, taking into account tolerability, social and occupational impact and the patient's expectations [10]. Targeted treatments are indicated only in symptomatic disease; the choice depends on the phenotype, stage and cardiac involvement, and difficult cases are discussed with the reference centre or in a national multidisciplinary team meeting [10]. The PNDS algorithm, which predates the European authorisation of vutrisiran, eplontersen, acoramidis and Attrogy®, proposes tafamidis 20 mg, patisiran or inotersen at stage 1 (walking unaided), with liver transplantation in selected cases, and patisiran or inotersen at stage 2 (walking with assistance). In the opinions of the HAS Transparency Committee reproduced in the protocol, patisiran (March 2019; important actual medical benefit, moderate improvement in actual medical benefit, level III, with public health interest) is first-line treatment at stages 1 and 2; inotersen (March 2019; minor improvement, level IV) is second-line for those who cannot receive patisiran; tafamidis 20 mg (April 2012; minor improvement, level IV) has a place at stage 1, while awaiting liver transplantation or when this is contraindicated; and tafamidis 61 mg (October 2020; important improvement, level II, with public health interest) is first-line in ATTR cardiomyopathy [10]. It is also recommended that each patient carry a card stating the disease, treatments (including pacemaker) and the reference physicians to contact [10].

7.2. Summary table of targeted drugs

Abbreviations: CM, cardiomyopathy; GalNAc, N-acetylgalactosamine (targets the molecule to the hepatocyte asialoglycoprotein receptor); IV, intravenous; PN, polyneuropathy; SC, subcutaneous. A generic tafamidis medicine (Tafamidis Accord) was also authorised in the EU by decision dated 18 September 2026 (CHMP opinion 23 July 2026), with an indication restricted to hereditary ATTR cardiomyopathy (ATTRh-CM) in adults, excluding wild-type disease and polyneuropathy [17]. In the USA, Drugs@FDA lists the tafamidis meglumine 20 mg capsule (Vyndaqel®, NDA 211996) as discontinued, with Vyndamax® 61 mg remaining, although the joint label still describes the 80 mg dosage [12, 59].

7.3. Tetramer stabilisers

Tafamidis. Designed to reproduce diflunisal's stabilising effect without its non-steroidal anti-inflammatory properties [3]. In the phase 2/3 Fx-005 trial, patients with early-stage p.Val50Met polyneuropathy received 20 mg/day or placebo for 18 months; coprimary endpoints were not met in the intention-to-treat population (NIS-LL responders 45.3% vs. 29.5%; p = 0.068), partly because withdrawals for liver transplantation exceeded expectations; in the efficacy-evaluable population, there were more responders with tafamidis (60.0% vs. 38.1%; p = 0.041) and better preservation of quality of life, and TTR was stabilised in 98% of treated patients [65]. Based on this trial, the EMA authorised tafamidis 20 mg in 2011 for stage 1 polyneuropathy — approval the FDA did not grant for this indication [12, 17].

In ATTR-ACT, 441 patients with ATTR cardiomyopathy (24% ATTRv, 76% ATTRwt; mean age 74 years) were randomised (2:1:2) to tafamidis meglumine 80 mg, 20 mg or placebo for 30 months [12, 66]. Hierarchical analysis of all-cause mortality and cardiovascular hospitalisations favoured tafamidis (p < 0.001); all-cause mortality was 29.5% vs. 42.9% (hazard ratio 0.70; 95% CI 0.51–0.96), and cardiovascular hospitalisation rates were lower (0.48 vs. 0.70 per year; risk ratio 0.68), with less decline in 6-minute walk distance and KCCQ-OS (Kansas City Cardiomyopathy Questionnaire – Overall Summary) score [66]. Adverse-effect incidence was similar to placebo [3, 66]. Benefit was not demonstrated in NYHA class IV [2]. Approved dosage is Vyndaqel® 80 mg (four 20 mg capsules) or Vyndamax® 61 mg once daily; capsules should be swallowed whole, and a missed dose should not be doubled [12]. In the EU, the cardiomyopathy dose is one Vyndaqel® 61 mg capsule daily, and the summary of product characteristics requires confirmation of ATTR-CM diagnosis and exclusion of AL amyloidosis before initiation, with TTR genotyping [58]. Women of childbearing potential should use contraception during treatment and for one month after discontinuation, and the drug is not recommended in pregnancy or breastfeeding [58].

The French PNDS adds practical rules for tafamidis 20 mg: it requires symptomatic disease, an amyloidogenic variant and amyloid deposits on biopsy; it is taken daily, at the same time; the most frequently reported adverse effects are diarrhoea, urinary tract infections and vaginitis, and, in the event of severe gastrointestinal intolerance (diarrhoea several times a day or faecal incontinence), usually in the first weeks, it recommends stopping for 15 days and reintroducing, with definitive discontinuation if it recurs [10]. In the long-term evidence summarised by the protocol, about one-third of patients respond, one-third respond partially and one-third do not respond, and the p.Val50Met variant of Portuguese origin, female sex and early start of treatment predict a better response; disability progresses in 55% of p.Val50Met patients with late onset or advanced stage, a phase 2 study in non-Val50Met variants showed clinical worsening after 1 year, and in the 5-year follow-up of early-onset p.Val50Met patients the disease stabilised with a baseline NIS < 10 but progressed with a baseline NIS of 14 [10]. In France, tafamidis 20 mg is prescribed by a neurologist and renewed every 6 months after clinical assessment and NT-proBNP measurement, and clinically significant progression requires stopping the drug and changing treatment; tafamidis 61 mg has an initial hospital prescription restricted to cardiologists, with unrestricted renewal, and switching from 20 mg to 61 mg in a patient with ATTRv-PN should be discussed at the national multidisciplinary meeting [10]. In its reading of ATTR-ACT, the protocol stresses that the benefit was more marked in NYHA class II than in class III and in ATTRwt than in ATTRv, and that the long-term extension suggests superiority of the 80 mg dose (bioequivalent to 61 mg) over the 20 mg dose, with similar tolerability [10].

Acoramidis. A high-affinity stabiliser identified by chemical screening (initial designation AG10), achieving over 90% stabilisation throughout the dosing interval [3, 67]. In phase 3 ATTRibute-CM, 632 patients with ATTR cardiomyopathy were randomised (2:1) to acoramidis or placebo for 30 months; a four-step hierarchical analysis (all-cause death, cardiovascular hospitalisation, change in NT-proBNP and walking distance) favoured acoramidis (p < 0.001; win ratio 1.8; 95% CI 1.4–2.2) [67]. According to the label, all-cause mortality was 19% vs. 26% and cardiovascular hospitalisations 27% vs. 43%, with a 35.5% reduction in risk of the composite of death or first cardiovascular hospitalisation (HR 0.645; 95% CI 0.500–0.832) and differences of 40 m in the walk test and 10 KCCQ-OS points at 30 months [13]. Dosage is 712 mg (two 356 mg tablets) twice daily, with or without food, swallowed whole [13, 60]. The most frequent adverse effects were diarrhoea (11.6% vs. 7.6%), upper abdominal pain (5.5% vs. 1.4%) and gout (11.2%), mostly non-serious [13, 60]. There are no efficacy data in NYHA class IV [60].

Diflunisal. A non-steroidal anti-inflammatory drug whose capacity to stabilise TTR was recognised late [3]. In a randomised, double-blind trial of 130 patients with polyneuropathy, diflunisal 250 mg twice daily for 2 years reduced NIS+7 progression (increase of 8.7 vs. 25.0 points; difference 16.3 points) and preserved quality of life [64]. Based mainly on this trial, the European Commission authorised diflunisal as Attrogy® on 17 July 2025 for adults with ATTRv and stage 1 or 2 polyneuropathy; the EMA public summary reports a mean increase in mNIS+7 at 24 months of 8.2 points with diflunisal and 26.2 with placebo and acknowledges the high number of withdrawals for liver transplantation as a limitation [18]. The SmPC recommends 250 mg twice daily, preferably with food, without adjustment in older people or in mild to moderate renal or hepatic impairment, and contraindicates the drug in active gastrointestinal bleeding, severe heart failure, GFR ≤ 30 mL/min, severe hepatic impairment (Child-Pugh C), the third trimester of pregnancy and breastfeeding [18]. In the USA, diflunisal has no indication for ATTR, and its use is off-label. In any jurisdiction it requires monitoring of renal function, fluid retention and gastrointestinal bleeding and is problematic in heart failure, which limits its place in disease with cardiac involvement [2, 3, 18]. In 2022, the French PNDS cited a reduction of about 60% in the progression of NIS+7 and NIS at 2 years and recorded that diflunisal was not available in France (but was in the USA, Italy and Sweden); this information predates the European authorisation of Attrogy® [10, 18]. Tolcapone, a catechol-O-methyltransferase inhibitor developed for Parkinson disease, binds to the tetramer and stabilises it in plasma, but the severe hepatotoxicity described with this drug requires close liver monitoring, and its use in ATTR remains experimental [3].

7.4. Transthyretin silencers

Silencers reduce hepatic synthesis of TTR (variant and wild-type), with median serum reductions of the order of 80% [3]. They do not act on TTR produced by the choroid plexuses and the retina [2, 3]. All reduce serum vitamin A levels: supplementation at the recommended daily allowance is advised (in the EU, in adults, about 2500 IU/day with patisiran, with no maximum dose defined in the SmPC outside pregnancy; 2500–3000 IU/day, not exceeding 3000 IU, with eplontersen), without attempting to normalise serum levels, which do not reflect body stores, and with referral to ophthalmology if symptoms suggestive of deficiency (night blindness) develop [15, 16, 63, 68]. In pregnancy, vitamin A is essential for fetal development: with eplontersen, it is recommended to stop the drug and supplementation before conception and to confirm normalisation of vitamin A levels, and, in an unplanned pregnancy, not to exceed 3000 IU/day in the first trimester [63]; with patisiran, supplementation is stopped in the first trimester, unless there are clinical signs of deficiency, in which case it should not exceed 2500 IU/day, and is resumed at 2500 IU/day in the second and third trimesters if levels have not normalised [68].

Patisiran (Onpattro®). The first small interfering RNA drug approved. In the APOLLO trial, 225 patients with ATTRv polyneuropathy were randomised (2:1) to patisiran 0.3 mg/kg IV every 3 weeks or placebo for 18 months; mNIS+7 changed by −6.0 vs. +28.0 points (difference −34.0; p < 0.001), with benefit also in Norfolk QoL-DN (−21.1 points), walking speed and mBMI [14, 43]. The dose, in adults, is 0.3 mg/kg every 3 weeks, with a maximum recommended dose of 30 mg in patients weighing ≥ 100 kg [68], infused over about 80 minutes, with mandatory premedication at least 60 minutes beforehand (IV corticosteroid, for example dexamethasone 10 mg; oral paracetamol 500 mg; IV H1 and H2 antagonists) [14]. Infusion reactions occurred in 19% vs. 9% (placebo); upper respiratory tract infections were also more frequent [14]. In the APOLLO-B trial, in 360 patients with ATTR cardiomyopathy (wt or variant), patisiran reduced the decline in 6-minute walk distance at 12 months (median difference 14.69 m) and improved KCCQ-OS (3.7 points), without significant benefit in the composite of events [69]; the cardiac indication was not approved [2, 14].

The French PNDS describes the administration of patisiran in detail. The first infusions are given in hospital; the drug (0.3 mg/kg, with a maximum of 30 mg from 100 kg, according to the SmPC) is prepared with a 0.45 µm filter, diluted in 250 mL of normal saline and administered with di(2-ethylhexyl) phthalate (DEHP)-free equipment and a 1.2 µm polyethersulfone in-line filter, over about 80 minutes (≈ 1 mL/min for the first 15 minutes and ≈ 3 mL/min thereafter), which may be prolonged if a reaction occurs. Premedication, 1 hour beforehand, includes oral paracetamol 500 mg, a corticosteroid (oral prednisone 60, 45 or 30 mg, or IV dexamethasone 10, 7.5 or 5 mg, depending on the step), an H2 antagonist (oral famotidine 20 mg or cimetidine 200 mg) and an H1 antagonist (oral cetirizine 10 mg or IV dexchlorpheniramine 5 mg); it may be switched to the oral route and the corticosteroid may be reduced in steps of 25% and then 50%, down to half of the initial dose, in the absence of reaction [10]. The European SmPC provides for IV premedication (dexamethasone 10 mg or equivalent, an H1 antagonist, for example diphenhydramine 50 mg, an H2 antagonist, for example famotidine 20 mg) with oral paracetamol 500 mg, oral equivalents when the IV route is not available or not tolerated, and reduction of the corticosteroid in steps of no more than 2.5 mg down to a minimum of 5 mg of dexamethasone, after at least 3 consecutive infusions without reaction [68]. The risk of extravasation was below 0.5% in the trials and is prevented by monitoring the puncture site and using a cannula of adequate gauge; oral vitamin A supplementation (2500 IU/day) is maintained in the long term, and the French preparations listed in the protocol are taken weekly or daily [10]. In APOLLO, 56% of treated patients improved their mNIS+7, compared with 4% on placebo, with benefit in quality of life, walking speed and COMPASS-31, confirmed in the open-label extension [10, 43].

Vutrisiran (Amvuttra®). GalNAc-conjugated siRNA, administered subcutaneously every 3 months. In HELIOS-A (164 polyneuropathy patients; 3:1 randomisation to vutrisiran 25 mg every 3 months or reference patisiran), vutrisiran met the primary endpoint of mNIS+7 change at 9 months versus the APOLLO external placebo group (difference −17.0 points) and all secondary endpoints, with TTR reduction non-inferior to patisiran, without drug-related discontinuations or deaths [15, 70]. In HELIOS-B, 655 ATTR cardiomyopathy patients (88% ATTRwt; 40% receiving tafamidis at enrolment) were randomised to vutrisiran 25 mg or placebo every 12 weeks for up to 36 months: vutrisiran reduced the composite of all-cause death and recurrent cardiovascular events (HR 0.72; 95% CI 0.56–0.93 overall; HR 0.67; 0.49–0.93 in the monotherapy population) and all-cause mortality through 42 months (HR 0.65; 0.46–0.90), with less decline in 6-minute walking distance (26.5 m) and KCCQ-OS (5.8 points) [71]. Based on these results, the FDA approved the cardiac indication on 20 March 2025 to reduce cardiovascular mortality, cardiovascular hospitalisations and urgent heart failure visits, and the European Commission extended the indication to adults with wild-type or hereditary ATTR cardiomyopathy on 5 June 2025 (CHMP opinion 25 April 2025) [15, 59, 61]. Vutrisiran is thus the first drug simultaneously indicated for ATTRv polyneuropathy and ATTR cardiomyopathy. Dose is 25 mg SC every 3 months, administered by a healthcare professional in the abdomen, thighs or arms; a missed dose should be administered as soon as possible, restarting the 3-month interval from that date [15]. The most frequent adverse effects (≥ 5%) were pain in the extremities, arthralgia, dyspnoea and reduced vitamin A [15].

Inotersen (Tegsedi®). A 2'-O-methoxyethyl antisense oligonucleotide. In NEURO-TTR (172 patients with stage 1 or 2 polyneuropathy; weekly inotersen 300 mg inotersen sodium, equivalent to 284 mg inotersen, or placebo, for 15 months), mNIS+7 and Norfolk QoL-DN improved (differences −19.7 and −11.7 points), independently of stage, variant and cardiomyopathy presence [44]. Glomerulonephritis (3%) and severe thrombocytopenia (3%) occurred, with one death associated with grade 4 thrombocytopenia, prompting enhanced monitoring [44]. In the EU, dose is 284 mg SC weekly, contraindicated with platelets < 100 × 10⁹/L, urine protein/creatinine ratio ≥ 113 mg/mmol (1 g/g), eGFR < 45 mL/min/1.73 m² or severe hepatic impairment; platelet counts are monitored every 2 weeks, reducing to 284 mg every 2 weeks if 75–100 × 10⁹/L and interrupting if < 75 × 10⁹/L, and urine protein/creatinine ratio and eGFR are monitored for glomerulonephritis risk, requiring permanent discontinuation if confirmed [62]. In the USA, Tegsedi® is listed as discontinued [59].

According to the PNDS, in NEURO-TTR 36% of patients treated with inotersen had stable or improved mNIS+7, compared with 19% on placebo [10]. In the trial publication, the 36% refers only to patients who completed the intervention period (no increase in mNIS+7 from baseline), in an additional analysis whose placebo group values appear in the supplementary appendix; the primary result, in all 172 treated patients, is the difference of −19.7 points in mNIS+7 [44]. The PNDS organises treatment on an outpatient basis: prior assessment of bleeding risk (full blood count with platelets, renal function, proteinuria); first injection in hospital and subsequent ones at home (by a nurse, the patient or the caregiver), with the pre-filled syringe left at room temperature for at least 30 minutes and rotation of injection sites; platelets every 15 days and creatinine with eGFR and urinary protein/creatinine ratio every 3 months; long-term vitamin A supplementation; and medical validation of each administration according to the platelet count, as set out in the following table, which reproduces the scheme of the European SmPC [10, 62]. The protocol includes pregnancy and breastfeeding among the contraindications [10].

Source: PNDS NAH-TTR, annex 6, and European SmPC of Tegsedi® [10, 62].

Eplontersen (Wainua®/Wainzua®). A GalNAc-conjugated antisense oligonucleotide with greater potency and lower dose than inotersen. In open-label NEURO-TTRansform (168 patients with Coutinho stage 1 or 2 polyneuropathy; eplontersen 45 mg every 4 weeks compared with the NEURO-TTR historical placebo group), adjusted mean serum TTR reduction at 65 weeks was 81.7% (vs. 11.2%), and mNIS+7 changes (0.3 vs. 25.1; difference −24.8) and Norfolk QoL-DN (−5.5 vs. 14.2) favoured eplontersen [72]. Dose is 45 mg SC once monthly in the abdomen or thigh (or back of the upper arm if administered by another person); the most frequent adverse effects (≥ 9%) were reduced vitamin A and vomiting [16, 63]. In phase 3 CARDIO-TTRansform, published in 2026, 1432 ATTR cardiomyopathy patients received eplontersen 45 mg or placebo every 4 weeks through 140 weeks: the primary endpoint (cumulative composite of cardiovascular death and recurrent cardiovascular events) did not differ significantly (29.4% vs. 32.2% of patients with events; rate ratio 0.89; 95% CI 0.73–1.09; p = 0.28) [73]. In a statement on 9 July 2026 (a preliminary result, not superseded by the publication on this point), the sponsor reported that 57% of patients in each arm received a stabiliser at baseline and another 24% started one during the trial, and that, in a prespecified subgroup analysis, eplontersen monotherapy patients had a nominally significant hazard ratio of 0.71 for the composite, without effect in patients receiving a stabiliser [74]; as a subgroup analysis of a negative trial, this finding generates hypotheses and does not support an indication. Eplontersen therefore retains only the neurological indication.

The 2022 PNDS did not recommend combinations of tafamidis, patisiran and inotersen, owing to lack of data; after liver transplantation, tafamidis was sometimes used without specific studies, and patisiran and inotersen had been administered for one year, in a phase 2 study with few patients who were worsening after transplantation, with good tolerability and efficacy [10]. The protocol identified as lines of research new siRNA and antisense oligonucleotide formulations, trials focused on cardiac involvement in ATTRv, new therapeutic targets and biomarkers such as plasma neurofilament light chain [10].

7.5. Liver transplantation

Orthotopic liver transplantation, introduced in 1990, rapidly replaces plasma variant TTR with donor wild-type TTR; in the first Swedish patients, neurological deterioration stopped and visceral deposits regressed on serum amyloid P component scintigraphy, although neuropathy showed little objective improvement [41]. In the worldwide registry (Familial Amyloidotic Polyneuropathy World Transplant Registry), with 1940 patients from 77 centres (1990–2010), 20-year survival was 55.3%; mBMI, early onset (< 50 years), disease duration before transplantation and p.Val50Met were independent survival factors — early-onset patients had 38% of the expected mortality of late-onset patients, and each pretransplant disease year increased expected mortality by 11% [42]. At a centre with 86 transplanted patients, 5-year survival increased from 66.7% (1990–1995) to 92.3% (1996–2005); age ≥ 40 years, duration ≥ 7 years and mBMI < 600 were poor prognostic factors [75]. Cardiovascular death is more frequent than after transplantation for end-stage liver disease because cardiomyopathy may progress through wild-type TTR deposition, particularly in non-Val50Met variants and patients with previous cardiac involvement [3, 42, 52]. p.Thr80Ala is usually associated with severe multiorgan involvement, and most programmes refuse isolated liver transplantation in these patients; 5-year survival after liver or combined liver–heart transplantation ranges from 62% to 82% in larger series, depending on variant and previous clinical status, and patients with cardiac involvement have better prognosis after combined than isolated liver transplantation [3]. Transplantation does not halt leptomeningeal or ocular amyloidosis [2]. It is currently considered in p.Val50Met patients aged < 60 years, with disease duration < 5 years, polyneuropathy limited to the lower limbs or isolated autonomic neuropathy, and no significant cardiac or renal dysfunction [2]. The explanted, structurally normal liver may be used for sequential (“domino”) transplantation in selected recipients, with acquired ATTR risk years later [2]. Isolated heart transplantation has a limited role in advanced-age ATTRwt and is not indicated as treatment of the protein source [3].

The French PNDS is more restrictive regarding liver transplantation. More than 2000 patients have been transplanted worldwide for this indication, but the disease may progress after transplantation, through deposition of wild-type TTR and through variant TTR produced in the eye and brain: 25% of patients need a pacemaker at a median of 11 years, 29% develop heart failure, and central manifestations due to meningeal angiopathy appear more than 10 years later [10]. General contraindications are age over 50 years, neoplasia or other comorbidities, an unstable psychosocial situation, advanced respiratory or neurological disease and incurable chronic infection; factors of poor prognosis after transplantation are the need for walking assistance (PND > II), orthostatic hypotension and significant cardiac involvement (NYHA dyspnoea > I, QRS > 120 ms, interventricular septal thickening, with no threshold defined in the protocol), and a survival calculator estimating 5-year mortality above 50% should lead to consideration of combined liver–heart transplantation or inclusion in a trial [10]. In 2022, liver transplantation was reserved for young patients (< 50 years) with p.Val50Met and short disease duration, as second-line treatment after failure of oral tafamidis; in these patients, each year of waiting increases post-transplant mortality by about 20%, which requires close monitoring [10]. With cardiac involvement or end-stage renal failure, isolated liver transplantation is contraindicated and combined liver–heart or liver–kidney transplantation is discussed at a medical-surgical meeting; kidney transplantation is added when GFR is below 40 mL/min or there is nephrotic syndrome [10]. During follow-up, in addition to neurological, cardiological and ophthalmological surveillance, the hepatologist adjusts immunosuppression (close appointments for 5 years, then annually), monitors liver function, blood glucose and renal function and performs control liver biopsies at 1, 2 and 5 years to exclude rejection [10].

7.6. Treatment of manifestations

In amyloid heart failure, conventional neurohormonal therapy has not demonstrated benefit: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers worsen (orthostatic) hypotension because the amyloid heart does not increase stroke volume in response to vasodilatation, and beta blockers may be harmful because cardiac output depends on rate with a relatively fixed stroke volume [3, 52]. Some patients may tolerate digoxin with close renal function and serum level monitoring [3]. Atrial fibrillation is difficult to control because drugs slowing atrioventricular conduction are poorly tolerated; thromboembolic risk is high even in sinus rhythm, but benefit from prophylactic anticoagulation without atrial fibrillation is unknown [3]. Regarding implantable cardioverter-defibrillators, in a retrospective series of 45 patients, 27% received at least one appropriate therapy in 17 months, but transplant-free survival was only 60% over the same period; data do not support generalised primary-prevention use [3]. The ESC Heart Failure Association clinical consensus document on non-specific ATTR-CM treatment (2025, published in 2026) systematises volume and diuretic management, individualised neurohormonal modulation, heart transplantation and mechanical circulatory support in advanced stages, and advises transcatheter aortic valve implantation (TAVI) as the preferred treatment for associated aortic stenosis; the authors themselves emphasise that recommendations rest mainly on expert opinion and retrospective studies because randomised trials are lacking [32].

The PNDS also includes psychological support (individual consultations, discussion groups, therapeutic education workshops), intended to prevent the patient from reducing their identity to a gene or identifying with the affected parent and to maintain life plans, and social services (administrative procedures, liaison with disability support structures, vocational guidance, human and technical assistance at home, specialised accommodation) [10]. Caregivers should know the patient associations and networks, be listened to given the risk of burnout and benefit, if necessary, from respite stays [10].

The PNDS on cardiac amyloidoses details the cardiological management common to the ATTR forms, applicable to the cardiomyopathy of ATTRv; the recommendations are based on expert opinion and observational series [34].

Table 7.6a. Cardiological management according to the PNDS on cardiac amyloidoses (HAS, 2021) [34]

7.7. Risk management in asymptomatic carriers

Asymptomatic carrier management aims to detect disease onset for early treatment. GeneReviews and ISA guidelines recommend [2, 26]: annual abdominal wall fat aspiration or gastrointestinal biopsy (stomach, duodenum or rectum) with Congo red, if possible; systematic neurological assessment at least annually (NIS, PND, 6- or 10-metre walking, COMPASS-31, R-ODS) and annual nerve conduction studies; clinical cardiac assessment and BNP/NT-proBNP annually or at every consultation, ECG and echocardiography at least annually and 99mTc-PYP scintigraphy every 3–5 years; annual assessment for central nervous system involvement; ophthalmological examination with glaucoma assessment at least annually; annual renal function; mBMI. Surveillance initiation should consider familial age at onset, which, because of anticipation, may be 10 or more years earlier than the parent's, particularly in maternal transmission to sons [6]. Carriers should avoid local heating devices (hot-water bottles) because of painless burn risk [2].

The French PNDS, supported by the European ATTReuNET network, proposes for carriers an assessment in five domains (history, clinical examination, sensory-motor functions, dysautonomia, cardiac and renal assessment), avoiding invasive examinations and limiting the number of annual examinations; the schedule is adapted to age, variant, age at onset in the family and sex of the transmitting parent (anticipation with maternal transmission) and becomes annual from 10 years before the age at onset of the index case — from the third decade in early-onset p.Val50Met families and later in late-onset families [10]. Unlike GeneReviews and the ISA guidelines, the French protocol does not recommend routine biopsies during surveillance and reserves them for confirming disease onset (criterion in section 5.1) [2, 10, 26]. The carrier should know the initial symptoms and is referred to a specialised centre close to home [10].

No targeted drug is authorised in the USA or EU for asymptomatic carriers: all indications require disease (symptomatic polyneuropathy or cardiomyopathy), and treating a carrier without demonstrated disease would be off-label, without trial support [12–18]. This question is under investigation in phase 3 ACT-EARLY (NCT06563895), randomising approximately 587 carriers aged 18–75 years, with a pathogenic or likely pathogenic variant and age within 10 years before or after predicted age of disease onset (PADO), without ATTR-CM or ATTR-PN, to acoramidis or placebo; the primary endpoint is time to development of ATTR (cardiac or neurological, centrally adjudicated), with estimated primary completion in October 2031, and an open-label extension is registered for participants developing ATTR-CM [24]. For cardiac surveillance, a European multicentre study of 159 at-risk relatives (10 centres) assessed the 2021 ESC position statement screening recommendations: 25% (40/159) already had ATTRv-CM at first assessment, the screening indication (≤ 10 years before predicted onset and absence of extracardiac amyloidosis) had negative predictive value 97%, 13% of relatives with ATTRv-CM lacked signs on first-line tests (ECG, echocardiography and blood tests), and reassessment every 3 years (41 relatives) detected new cases in 9.4%; the authors recommend repeating bone scintigraphy at 3 years [77]. These data come from relatives assessed at cardiac reference centres and do not apply directly to young p.Val50Met carriers, in whom scintigraphy may be negative (section 5.4).

The PNDS on cardiac amyloidoses adds rules for variants with cardiac tropism. Genetic counselling of relatives is offered only to those over 18 years, frequently between 40 and 50, and at least 10 years before the age at onset of the youngest affected relative; for p.(Val142Ile) it is recommended before 50 years, for a first cardiological assessment around that age, and for p.(Val50Met) in families of Portuguese origin from adulthood, because of early neurological onset [34]. The carrier's baseline assessment includes ECG, echocardiography, cardiac magnetic resonance, bone scintigraphy, NT-proBNP and troponin (a rise in troponin may be the first biological sign of infiltration), neurological assessment (symptoms, electromyography, Sudoscan®) and screening for vascular dysautonomia (orthostatic hypotension and, depending on the centre, MIBG scintigraphy, atropine test and sinus rate variability) [34]. With a normal assessment, the carrier is reviewed every 2–3 years until the expected age at onset and annually thereafter. In cardiac variants (p.(Val142Ile)), reassessment includes a cardiology appointment, ECG, echocardiography with strain, NT-proBNP and troponin, with bone scintigraphy and then magnetic resonance whenever there is any doubt, and skin or salivary gland biopsy to confirm onset. In neurological or mixed variants (p.(Val50Met), p.(Ser97Tyr), p.(Ile127Val)), cardiology and neurology appointments are combined, and magnetic resonance and scintigraphy are requested only in the event of cardiac suspicion, bearing in mind that negative scintigraphy may not exclude infiltration in these variants (table 5.4a) [34].

7.8. Investigational therapies

Gene editing — NTLA-2001 (nexiguran ziclumeran, nex-z). A single-dose CRISPR-Cas9-based therapy, consisting of a lipid nanoparticle encapsulating Cas9 messenger RNA and a guide RNA targeting TTR in the hepatocyte [45]. In the phase 1 trial, in six patients with ATTRv polyneuropathy, the mean reduction in serum TTR at day 28 was 52% (0.1 mg/kg) and 87% (0.3 mg/kg), with mild adverse effects [45]. Two phase 3 trials are ongoing: MAGNITUDE (NCT06128629; ATTR cardiomyopathy, ≈ 1200 patients, estimated primary completion in December 2027) and MAGNITUDE-2 (NCT06672237; ATTRv polyneuropathy, ≈ 60 patients) [20]. On 29 October 2025, the FDA suspended both trials (clinical hold) following a grade 4 transaminase elevation with increased total bilirubin in a MAGNITUDE participant, who died on 5 November 2025 of septic shock secondary to a perforated duodenal ulcer, during a clinical course that included acute liver injury treated with corticosteroids [19]. The hold was lifted in January 2026 (MAGNITUDE-2) and March 2026 (MAGNITUDE), and recruitment resumed; in August 2026, a genomic analysis of more than 600 samples from the trials identified that the greatest transaminase elevations occurred in carriers of a specific HLA allele, with HLA genotyping subsequently communicated to investigators and participants [19]. The sponsor expects to complete MAGNITUDE-2 recruitment in the second half of 2026 [19]. Information on the hold, the death and the HLA analysis comes from the sponsor's regulatory documents (form 10-Q), rather than a peer-reviewed publication. There is no regulatory approval.

Next-generation silencer — nucresiran. A next-generation siRNA from the same sponsor as patisiran and vutrisiran, under development for six-monthly administration. According to the sponsor, in a phase 1 trial in healthy volunteers, 300 mg reduced serum TTR by more than 90% at day 15, with the effect maintained for six months (a result reported by the sponsor, unpublished in a peer-reviewed journal at the time of consultation) [78]. TRITON-CM (NCT07052903; phase 3, randomised, double-blind, placebo-controlled; wt or hereditary ATTR cardiomyopathy, allowing background stabilisers; target expanded from 1250 to approximately 1750 patients; primary composite endpoint of all-cause mortality and recurrent cardiovascular events; estimated primary completion in May 2030) and TRITON-PN (NCT07223203; open-label phase 3, 125 patients with ATTRv-PN, nucresiran 300 mg or vutrisiran followed by nucresiran; primary endpoint: change in mNIS+7 at 9 months compared with the external APOLLO placebo group) are ongoing [22, 78]. No marketing authorisation application has been submitted.

Amyloid-depleting antibodies. Stabilisers and silencers halt the formation of new amyloid but do not remove existing deposits [3]. ALXN2220 (NI006, cliramitug), an antibody targeting the amyloid conformations of wild-type and variant TTR, showed a reduction in imaging markers of cardiac amyloid burden in the phase 1 trial [21] and is in a phase 3 trial (DepleTTR-CM, NCT06183931; active, not recruiting, estimated primary completion in December 2027) [79]. NNC6019-0001 (formerly PRX004, coramitug), targeting misfolded forms, was evaluated in a published phase 2 trial (NCT05442047): 104 patients with ATTR cardiomyopathy (median age 77 years; 93% men; 13% ATTRv; 90% receiving disease-modifying therapy, mainly tafamidis) received coramitug 10 or 60 mg/kg or placebo every 4 weeks for 52 weeks; the 60 mg/kg dose reduced NT-proBNP relative to placebo (−48%; 95% CI −65% to −22%; p = 0.0017), with no significant difference in the 6-minute walk test, which was the other primary endpoint [79, 80]. A biomarker is not a clinical endpoint, and the phase 3 CLEOPATTRA trial (NCT07207811; approximately 1280 patients with ATTR-CM, approximately 15% of whom have ATTRv; primary composite endpoint of cardiovascular death and recurrent cardiovascular events; estimated primary completion in June 2029) is recruiting [23]. A phase 2b trial of ALXN2220 in combination with eplontersen (ATTRiumph, NCT07608354; primary endpoint: peak oxygen consumption at 52 weeks) and a long-term open-label extension are registered [23]. The anti-serum amyloid P component strategy (CPHPC followed by an anti-SAP antibody) has also been explored [3].

Four levels of evidence, which are not equivalent, are distinguished: results published in peer-reviewed journals (phase 1 of NTLA-2001, phase 1 of NI006, phase 2 of coramitug); sponsor-reported results (phase 1 of nucresiran; CARDIO-TTRansform subgroup analysis); records of ongoing trials, which describe designs rather than results; and regulatory decisions. In the sources consulted (the EMA medicines data file and sponsors' SEC documents), none of these products had a CHMP opinion or an announced marketing authorisation application at the date of this update; this check does not exclude undisclosed applications [17, 19, 78].

7.9. Pivotal trials and limitations of comparisons between drugs

These trials do not allow drugs to be ranked through indirect comparison. Primary endpoints differ (NIS-LL responders, NIS+7, different versions of mNIS+7, Finkelstein–Schoenfeld hierarchical analyses, win ratio, recurrent-event composites), as do populations (early-stage p.Val50Met in Fx-005, ATTRwt in 76% of ATTR-ACT and 88% of HELIOS-B patients), eras and background treatment: in HELIOS-B, 40%, and in CARDIO-TTRansform, more than half of patients were already receiving a stabiliser, reducing the event rate in the placebo group and the detectable incremental effect [66, 71, 73, 74]. Three polyneuropathy trials (HELIOS-A, NEURO-TTRansform and the ongoing TRITON-PN) use external or historical placebo groups, with risks of bias that propensity-score weighting attenuates but does not eliminate [22, 70, 72]. Relative reductions (for example, HR 0.70 for mortality with tafamidis) must be read alongside the residual absolute rates (29.5% mortality at 30 months in the treated group), and a difference in medians (APOLLO-B) is not equivalent to a difference in means. Negative or partially negative trials — Fx-005 in the intention-to-treat population, APOLLO-B in the event composite, CARDIO-TTRansform and walking in the coramitug trial — form part of the evidence and justify differences in indication between drugs of the same class.

7.10. Comparative regulatory status: United States and European Union

A favourable CHMP opinion is not authorisation: the latter results from a European Commission decision, usually approximately two months later (as with vutrisiran, from 25/04 to 05/06/2025, and Tafamidis Accord, from 23/07 to 18/09/2026) [17, 61]. In turn, authorisation does not guarantee marketing, reimbursement or access in each country: in Portugal, access depends on INFARMED assessment and, in Brazil, on ANVISA registration and incorporation into the Unified Health System following CONITEC assessment; the 2023 Brazilian consensus refers to at least three drugs approved in the country but does not replace consultation of current decisions [29]. Evidence extrapolation must also be distinguished from off-label use. Treating polyneuropathy with tafamidis 20 mg in the USA, an asymptomatic carrier in any jurisdiction, a child or adolescent (no label includes patients under 18 years, and the disease has adult onset) or stage 3 polyneuropathy in the EU, where silencer labels are limited to stages 1 and 2, is off-label use, which depends on the wording of the label, age and jurisdiction [12–17]. By contrast, using vutrisiran or acoramidis for hereditary ATTR-CM caused by a rare variant poorly represented in trials is not off-label use, because the labels cover hereditary ATTR-CM, but is extrapolation of evidence obtained predominantly in ATTRwt and p.Val142Ile; the same applies to women, under-represented in cardiomyopathy trials (section 9.5). In pregnancy, Attrogy® is contraindicated in the third trimester and during breastfeeding, tafamidis is not recommended, and eplontersen should be discontinued before conception (section 8.4) [18, 58, 63].

7.11. French national protocol (PNDS 2022): divergences from other sources

The PNDS on hereditary transthyretin amyloid neuropathy was written by the national reference centre for rare peripheral neuropathies (Bicêtre Hospital, Paris), with a text dated April 2022 published by the HAS in July 2022; it has the status of an expert consensus and predates the European authorisation of vutrisiran (September 2022), acoramidis, eplontersen and Attrogy® [10, 17]. For doses, the guideline is the reference and the label serves for comparison. The following table summarises the divergences from the other sources of this article.

7.12. French protocol on cardiac amyloidoses (PNDS 2021): divergences

The PNDS on cardiac amyloidoses was written by the reference centre for cardiac amyloidoses (Henri Mondor Hospital, Créteil) within the CARDIOGEN network (text of August 2021, summary for the attending physician of April 2021, publication by the HAS in December 2021); it covers AL, ATTRwt and ATTRv together and predates HELIOS-B, CARDIO-TTRansform, the authorisation of acoramidis and the cardiac extension of vutrisiran [34]. For doses, the guideline is the reference and the label serves for comparison.

8. Reproductive Options and Family Counselling

8.1. Mode of transmission and risks

ATTRv is inherited in an autosomal dominant manner: each child of a heterozygote has a 50% probability of inheriting the variant, and all children of a homozygote or compound heterozygote inherit a pathogenic variant [2]. Siblings of a proband with a heterozygous parent have a 50% risk; if both parents are heterozygous, the risk is 50% for one variant and 25% for two [2]. The proportion of de novo variants is unknown; if the variant is not detected in either parent, the recurrence risk for siblings is estimated at approximately 1% (germline mosaicism) [2]. An apparently negative family history may result from reduced penetrance, early parental death or late onset, particularly for late-onset variants and paternal transmission — as illustrated by the clinical case in section 10 [2, 36]. Even within a family, age at onset may vary by 10 to 20 or more years [2]. Homozygotes generally have earlier onset and greater penetrance than heterozygotes in the same family, although p.Val50Met and p.Val142Ile homozygotes in non-endemic areas may have an age at onset similar to that of heterozygotes [2, 3].

Counselling should incorporate information on variant- and population-specific penetrance (section 2.6) and on anticipation and the effect of the transmitting parent's sex in Portuguese p.Val50Met families: children of affected mothers, particularly males, tend to develop disease earlier, and a parent with onset ≤ 40 years rarely has offspring with late onset [6].

8.2. Predictive testing

Predictive testing of at-risk relatives is possible once the familial variant has been identified; it does not predict age at onset, severity, symptom type or rate of progression [2]. The consequences (psychological, socioeconomic, insurance and employment) and the need for long-term surveillance should be discussed in a formal genetic counselling consultation, using a protocol similar to those for adult-onset neurodegenerative diseases [2]. Unlike Huntington disease, ATTRv is now a treatable disease, reinforcing the benefit of knowing carrier status: identifying carriers early allows treatment to begin at conversion to disease [2, 25]. Genetic testing of first-degree relatives should be offered at the ages when the familial variant usually manifests, or earlier if desired for family planning [3]. Predictive testing in asymptomatic minors is generally not recommended, because there is no therapeutic benefit at that age; in symptomatic relatives, testing is appropriate at any age [2]. For variants with a cardiac phenotype, the 2021 ESC position statement proposes starting cardiological screening of carriers approximately 10 years before the expected age at onset in the family; in a European multicentre assessment of this rule, the indication for screening had a negative predictive value of 97% (section 7.7) [27, 77]. In Japan, where liver transplantation from a related living donor was frequent, donor candidates are always tested [2].

In France, predictive testing is governed by the bioethics laws: it is open to any adult who requests it individually and voluntarily, in a multidisciplinary consultation with a geneticist, mandatory psychological support and two blood samples; the PNDS recommends it because of the severity of the disease, the existence of treatments effective at onset, the implications for offspring and the possibility of medically assisted reproduction, systematically proposes the family enquiry, and the transmission of information to relatives follows specific legal rules (decree no. 2013-527 of 20 June 2013) [10]. Disclosure of the diagnosis to the patient is twofold — that of a serious chronic disease and that of its genetic origin — and takes place in a dedicated consultation, with active listening, support from a psychologist and, when possible, therapeutic education [10].

8.3. Prenatal diagnosis and preimplantation genetic testing

Once the familial variant has been identified, prenatal diagnosis and preimplantation genetic testing (PGT-M; preimplantation genetic testing) are technically possible [2]. PGT-M for FAP was successfully performed in Portugal in 2005, with the birth of healthy twin girls following blastomere biopsy and single-cell fluorescent PCR for the p.Val50Met region [84]. In a Portuguese series of PGT-M cycles in p.Val50Met carriers (including patients who had undergone transplantation or were receiving tafamidis), the live-birth rate per treatment cycle was 48%, with no evidence of impaired gamete reproductive capacity [85]. In a survey of Portuguese carriers followed at the northern surveillance unit, 75.4% knew about PGT-M; the main reasons for using it were to avoid offspring suffering (48.9%) and to raise a healthy child (39.4%), and the main reasons for not using it were cost (29.6%), technical distrust (29.1%) and time to pregnancy (17.3%) [86]. For high-penetrance variants (p.Val50Met in endemic foci, p.Thr80Ala), the dilemmas surrounding PGT-M are more relevant than for late-onset low-penetrance variants such as p.Val142Ile [3]. Perspectives on prenatal diagnosis and PGT-M may differ between professionals and families, and the decision is personal [2]. The ideal time for discussion is before pregnancy, and counselling should be offered to affected or at-risk young adults [2].

In France, prenatal diagnosis is performed only in one of the 48 multidisciplinary prenatal diagnosis centres, after a genetics clinic appointment and discussion at a multidisciplinary meeting: chorionic villus sampling between 11 and 14 weeks of gestation or amniocentesis from 15 weeks, with a risk of fetal loss of about 0.5%; chorionic villus sampling allows, if the couple so wishes, termination of pregnancy for medical reasons by aspiration before 14 completed weeks, whereas after 15 weeks termination is performed vaginally [10]. PGT-M is performed in one of the 5 authorised French centres, with about 18 months between the request and the procedure; it requires adequate ovarian reserve and a feasibility study by the laboratory, analyses one or two cells from each embryo and transfers one or, at most, two non-carrier embryos. Enrolling women over 37 years is not recommended, the success rate, understood as the probability of having a healthy child, is about 30%, and health insurance covers four attempts [10]. This French rate, without an explicit denominator, and the Portuguese rate of 48% live births per treatment cycle are not directly comparable [10, 85].

8.4. Pregnancy

The onset of AL amyloidosis and of most forms of ATTR is usually postmenopausal in women, who tend to manifest the disease later than men [3]. In early-onset forms (p.Val50Met), neurological rather than cardiac involvement predominates, so pregnancy does not appear to impose an increased risk of heart failure; there are no trials or published cases of women with heart failure due to cardiac amyloidosis during pregnancy [3]. Treatment should be planned: tafamidis is not recommended in pregnancy and requires contraception until one month after discontinuation [58]; silencers reduce vitamin A, which is essential for fetal development, and should be discontinued before conception, with prior normalisation of vitamin A levels [63]. Diflunisal (Attrogy®) is contraindicated in the third trimester and during breastfeeding; from 20 weeks it may cause oligohydramnios due to fetal renal dysfunction, so in the first and second trimesters it should be used only if necessary [18]. The French PNDS adds that, in asymptomatic carriers, pregnancy proceeds normally and that, in symptomatic patients, there are no data suggesting worsening of the disease by pregnancy; in liver or kidney transplant recipients, pregnancy is possible with adapted follow-up, taking into account the teratogenicity of some immunosuppressants [10]. It recommends stopping tafamidis when pregnancy is desired (teratogenicity in animals) and not breastfeeding on tafamidis, which passes into breast milk; it considers silencers contraindicated in pregnancy, because of the malformation risk linked to variations in vitamin A, and advises against breastfeeding on a silencer [10]. The European SmPC of patisiran does not formally contraindicate it, but advises against use in pregnancy unless clinically necessary and leaves breastfeeding to an individual decision, with the same practical consequence (section 7.11) [68]. The PNDS on cardiac amyloidoses requests a cardiological opinion before conception in any cardiac amyloidosis, because some cardiological drugs are teratogenic and because the severity of cardiac involvement may require enhanced surveillance or contraindicate pregnancy; on specific treatment, the reference centre should be consulted [34].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Portugal: the largest focus worldwide

Portugal contains the largest focus of ATTRv worldwide, associated almost exclusively with the p.Val50Met variant [9, 36]. The genetic epidemiology study in Póvoa de Varzim and Vila do Conde, based on 1233 patients from 489 families diagnosed at the Porto Centre for the Study of Paramyloidosis, estimated a crude prevalence in 1991 of 90.3 per 100,000 inhabitants (one in 1108) and a carrier frequency of 186 per 100,000 (one in 538), of whom 48.4% had already developed symptoms [9]. In that population, 432 patients belonged to 140 families originating from the area, and mean age at onset was 31.1 ± 6.7 years [9]. The study also observed high fertility among patients (a mean of 3.7 children), higher in affected women, who had longer reproductive periods — a factor that, alongside the founder effect, contributed to maintaining the allele frequency [9].

The national study of 2010–2016 estimated a mean incidence of 0.87 per 100,000 adults per year (71 new patients/year), with a 31% reduction over the last 7 years, and a crude prevalence in 2016 of 22.93 per 100,000 adults (95% CI 21.90–23.99), corresponding to 1865 patients (45.8% men; mean age 52.3 ± 15.4 years) [8]. The region with the highest prevalence recorded a 16% increase over 25 years, and the proportion of late-onset cases increased [8]. The decline in incidence is compatible with the effect of genetic counselling and PGT-M, and the increase in prevalence with the prolonged survival conferred by transplantation and drugs. Beyond Póvoa de Varzim and Vila do Conde, there are families from other regions and late-onset cases without a family history, such as that described in section 10 [8, 9, 36].

Portuguese experience rests on dedicated structures established from Porto — the Centre for the Study of Paramyloidosis and the Clinical Paramyloidosis Unit, whose registry encompasses more than 70 years of observation — with carrier surveillance, predictive testing and PGT-M programmes [6, 9, 85, 86].

9.2. Sweden, Japan, Majorca and Brazil

In Sweden, 1.5% of the population of the north of the country carries p.Val50Met, but penetrance is low and age at onset is later (penetrance of 11% at 50 years and 69% at 90 years) [2, 49]. In Japan, the Arao (Kumamoto) and Ogawa (Nagano) foci have a mean onset at 40 years, whereas p.Val50Met cases unrelated to the endemic foci develop disease at a mean age of 62.7 years [2]. Majorca (Balearic Islands) is another p.Val50Met focus [36]. In Brazil, ATTRv with polyneuropathy is predominantly associated with p.Val50Met introduced by Portuguese emigration; the Brazilian consensus (2nd edition, 2023) describes a disease leading to death in approximately 10 years if untreated, with more than 130 known variants and at least three drugs approved in the country [29]. No population-based studies estimating Brazilian national prevalence were identified; the available data come from referral centres.

9.3. People of African ancestry and the p.Val142Ile variant

The p.Val142Ile variant results from a G>A transition at a CpG dinucleotide and has an allele frequency of 0.0173 in African Americans, corresponding to 3.5% carriers in the community (3.0–3.9% across series) [2, 46, 87]. In Africa, the highest allele frequency (0.0253) is found in the adjoining West African countries — Sierra Leone, Guinea, Côte d'Ivoire, Burkina Faso, Ghana and Nigeria — with a mean of 0.011 in the remaining countries, consistent with a small number of founders in southern West Africa and the geography of the slave trade to North America [46, 87]. In the USA, isolated cardiac amyloidosis after 60 years is four times more frequent in Black than in White people, and 23% of DNA samples from Black patients with cardiac amyloidosis at autopsy carried the variant [2, 40]. Variant prevalence in North America has been estimated at 3.4% [3]. Clinical penetrance in high-frequency African countries is unknown, owing to the absence of clinical studies [87]. For Portugal and Brazil, with large populations of African ancestry (including communities of Cape Verdean, Guinean and Angolan origin in Portugal), there are no published estimates of p.Val142Ile frequency or its contribution to heart failure — a relevant gap, since cardiomyopathy trials included only 4.7–7% Black patients [13, 15].

9.4. Ireland and the p.Thr80Ala variant

The p.Thr80Ala variant (Thr60Ala) results from an early founder effect in County Donegal, Ireland, and is the most frequent genotype in the Irish population; it is also found in North America among descendants of Irish people from Donegal [3, 7]. The phenotype is mixed and multiorgan, with onset in the seventh decade (section 3.5) [7].

9.5. Sex differences

In Portuguese p.Val50Met families, women develop disease later than men, and maternal transmission is associated with greater anticipation [6, 9]. In cardiac forms, male predominance is marked: cardiomyopathy trials included approximately 90% men (90.6–93%) [13, 15, 66, 73], limiting extrapolation of the results to women.

9.6. Regional gaps

No population prevalence data for ATTRv were identified for most countries in Latin America (except series from Brazilian centres), Africa (except p.Val142Ile allele frequencies), the Middle East and much of Asia. The frequency of 1:100,000 for ATTRv p.Val50Met in North Americans of European ancestry is an old single-variant estimate and should not be interpreted as global prevalence [2].

9.7. Referral networks and patient associations

In the European Union, ATTRv polyneuropathy falls within the European Reference Network for neuromuscular diseases (ERN EURO-NMD) and cardiomyopathy within the network for rare, low-prevalence and complex cardiac diseases (ERN GUARD-Heart), which link national referral centres [88]. In Portugal, the Associação Portuguesa de Paramiloidose supports patients and families from the historical northern foci; in Brazil, the Associação Brasileira de Paramiloidose (ABPAR) provides information on diagnosis, treatment, in vitro fertilisation and referral centres; the Amyloidosis Alliance brings together patient organisations from several countries [89]. These structures do not produce epidemiological data but are relevant to counselling, referral and access to trials.

9.8. France: a non-endemic area and the organisation of care

France is considered a non-endemic area, with several dozen different TTR variants; p.Val50Met is the most frequent, early-onset patients are mainly of Portuguese origin, and late-onset forms, often without a family history, account for about 75% of cases (sections 2.2 and 3.2) [10]. Diagnosis and follow-up are coordinated by the reference and competence centres of the neuromuscular diseases health network (FILNEMUS), with the national reference centre for rare peripheral neuropathies at Bicêtre Hospital (Assistance Publique–Hôpitaux de Paris), in priority liaison with cardiology and ophthalmology; complex cases are discussed at a national multidisciplinary team meeting, open to clinicians upon registration [10]. The PNDS serves as the reference for the care protocol that the attending physician draws up with the health insurance medical adviser when exemption from co-payment is requested for a condition not on the list (ALD hors liste) [10].

There are two therapeutic education programmes: édAmyl, from the Bicêtre reference centre, for carriers and patients (individual educational diagnosis, two group workshops on the disease and treatments and optional workshops on self-rehabilitation, maintaining independence and socio-occupational life and managing anxiety, with a final evaluation), and ORIGAMY, from the Association Française contre l'Amylose (AFCA), for all types of amyloidosis, with three workshops (understanding amyloidosis, treatments, organisation of follow-up) [10]. The AFCA represents patients with all forms of amyloidosis, distributes materials (self-rehabilitation booklet, caregivers' booklet) and an annual newsletter and provides a social worker, a psychologist and discussion groups between patients [10]. The attending physician prevents and detects complications (depression, malnutrition, skin wounds), coordinates home care (renutrition, rehabilitation, nursing), takes part in psychological support and in informing relatives about presymptomatic testing, contacts the reference centre in the event of an acute problem and refers asymptomatic carriers to a specialised centre close to home [10].

On the cardiac side, the reference is the reference centre for cardiac amyloidoses at Henri Mondor Hospital (Créteil), part of the CARDIOGEN network, with regional competence centres (including Martinique and Guadeloupe, where p.(Val142Ile) is frequent) and liaison with the reference centre for familial peripheral neuropathies at Bichat Hospital (FILNEMUS network) and with the Réseau Amylose network [34]. In an AFCA survey, 74% of patients described themselves as worried, 57% as discouraged and 49% considered that the disease disrupted family relationships; the protocol includes a coordinating nurse, a care pathway coordinator, a psychologist (recommended in presymptomatic diagnosis), a dietitian and a social worker, and the AmyloPEP therapeutic education programme (Henri Mondor, accredited by the regional health agency, active since 2017), in addition to ORIGAMY [34]. There is no specific long-term condition (ALD) for cardiac amyloidoses: the attending physician requests exemption through the list of conditions or, more rarely, as a condition not on the list (ALD 31) or as disabling multiple pathology (ALD 32), which require chronicity, severity and a costly basket of care (at least three of five elements, one of them necessarily drug treatment or a regular device); in asymptomatic carriers, the physician watches for signs of onset (unexplained weight loss, gastrointestinal symptoms, carpal tunnel, lumbar spinal stenosis) and informs relatives about voluntary genetic counselling [34].

10. Illustrative Clinical Case

10.1. Presentation (published case)

A 66-year-old man, born in Santa Maria da Feira and living in Vila Nova de Gaia, apparently healthy, was seen in March 2010 for blurred vision and floaters in the right eye of 2 months' duration [36]. Corrected visual acuity was 20/30 in the right eye and 20/20 in the left; the anterior segment was normal, without abnormal conjunctival vessels, pupillary changes or deposits at the pupillary margin or on the lens capsule, and intraocular pressure was normal. There were whitish-yellow vitreous opacities in the right eye that prevented examination of the fundus [36]. The original open-access article (PMC3985800) includes a retinal photograph of the left eye (Fig. 1), an image of left-eye vitrectomy (Fig. 2) and the family pedigree (Fig. 3), which are not reproduced here: https://pmc.ncbi.nlm.nih.gov/articles/PMC3985800/ [36].

Complete clinical assessment revealed only asymptomatic first-degree atrioventricular block, without neurological or cardiac signs of disease. Full TTR sequencing identified the Val30Met variant [p.(Val50Met)]; salivary gland biopsy showed no amyloid [36]. In November 2010, with visual acuity of 20/100, he underwent pars plana vitrectomy; histopathological examination of the vitreous with Congo red showed yellow-green birefringence consistent with amyloid, and acuity recovered to 20/20 [36].

In the summer of 2011 he had several episodes of dizziness and syncope; Holter monitoring documented Mobitz II second-degree atrioventricular block, and a pacemaker was implanted, with resolution of symptoms. In September 2012, acuity fell to 20/100 bilaterally, owing to a cataract in the right eye and vitreous opacities in the left; he underwent phacoemulsification with an intraocular lens and, one month later, left-eye vitrectomy, recovering 20/20 bilaterally in February 2013 [36]. At the time of publication he remained without neurological symptoms or signs. There was no evidence of disease in any relative: his parents died at an advanced age without manifestations, and nine siblings and half-siblings, three children and seven grandchildren had no suggestive symptoms [36].

10.2. Discussion

The case illustrates several teaching points. First, p.Val50Met ATTRv in Portugal is not limited to the classical early-onset form in Póvoa de Varzim: late-onset forms exist outside the endemic municipalities and without a family history, in which the initial manifestation may be extraneurological [8, 36, 50]. Numerous vitreous opacities are virtually pathognomonic when present, and vitrectomy permits both treatment and histological diagnosis [36]. Second, a negative salivary gland biopsy does not exclude the diagnosis, and amyloid was diagnosed in tissue from the affected organ, in accordance with the recommendation to repeat biopsies when suspicion persists [25]. Third, progression from first-degree atrioventricular block to Mobitz II in approximately one year confirms the indication for electrocardiographic and Holter surveillance and early pacing in the presence of conduction defects [2, 52]. Finally, the absence of disease in a large family reflects the reduced penetrance of late-onset forms and raises specific genetic counselling issues: the children (and potentially grandchildren) have a 50% risk of being carriers, but penetrance and age at onset in this family may differ from those in Póvoa de Varzim families [2, 48].

In 2026, a patient with this profile would be managed differently from what was possible in 2010–2013. Identification of the variant and amyloid in the vitreous, with conduction block, would constitute symptomatic disease; a complete cardiac assessment (echocardiography with strain, MRI with ECV, NT-proBNP, troponin and 99mTc-DPD/PYP scintigraphy), neurological studies with nerve conduction, autonomic tests and intraepidermal fibre density, and testing for a monoclonal protein would be required [2, 25, 27]. If cardiomyopathy were present, vutrisiran (effective in neuropathy and cardiomyopathy), tafamidis or acoramidis would be options; with neuropathy without cardiomyopathy, a second-generation silencer or tafamidis 20 mg [2, 15, 26]. Ocular disease, resulting from retinal TTR, would not be prevented by these drugs and would require ongoing ophthalmological surveillance, including for glaucoma [2]. The children should be invited to a genetics consultation, with predictive testing offered and, if positive, annual surveillance.

11. Prognosis and Long-Term Follow-Up

In the natural history, sensory-motor and autonomic neuropathy progresses over 10 to 20 years, with cachexia in the final stages; patients usually die of heart failure, renal failure or infection [2]. In Portuguese early-onset forms, the total duration of the three Coutinho stages is of the order of 10 to 13 years, and late-onset forms and other variants progress more rapidly (5 to 9 years) [25, 51]; the Brazilian consensus reports death in about 10 years without treatment [29]. In ATTR cardiomyopathy, median survival depends on the NT-proBNP and eGFR stage (69.2, 46.7 and 24.1 months in stages I, II and III) [56], and cardiac involvement is the main determinant of prognosis in all forms of amyloidosis [3]. The French PNDS reports, in untreated disease, a mean survival of 7 to 12 years after symptom onset, need for walking assistance at 5 years and becoming bedridden at 10 years of disease; in early-onset forms, life expectancy is about 12 years, and in late-onset forms progression is faster (walking stick at about 3 years and death at about 7) [10]. Vital prognosis depends mainly on the heart and functional prognosis on neurological involvement. Worse vital prognosis is associated with the p.Ile127Val (Ile107Val) variant and late-onset p.Val50Met, early gastrointestinal disturbances with low mBMI, heart failure with hospitalisation, elevated BNP/NT-proBNP and troponin, cardiac uptake on bone scintigraphy, transmural late enhancement on magnetic resonance and cardiovascular dysautonomia (orthostatic hypotension, abnormal atropine test or MIBG scintigraphy); the same two variants are associated with earlier gait disturbance, and deposits on the pupillary margin or a scalloped pupil predict glaucoma [10].

The determinants of prognosis after liver transplantation — mBMI, age and disease duration at transplantation, early onset and the p.Val50Met variant — reinforce the principle that treatment should be instituted early [42, 75]. With current drugs, neuropathy progression can be halted or attenuated (mNIS+7 changes close to zero with patisiran, vutrisiran and eplontersen, against worsening of 15–28 points with placebo), and in cardiomyopathy all-cause mortality fell by approximately 30% with tafamidis and 35% with vutrisiran (at 42-month follow-up) [43, 66, 70–72]. A consequence of prolonged survival is the emergence of manifestations dependent on locally produced TTR — leptomeningeal (TFNE, dementia, haemorrhage) and ocular (vitreous opacities, glaucoma) — which do not respond to current therapies [2, 36].

Follow-up of treated patients is multidisciplinary (neurology, cardiology, genetics, ophthalmology, nephrology, gastroenterology, nutrition, physical and rehabilitation medicine, psychology) and uses the examinations of carrier surveillance (section 7.7), with assessment every 6 to 12 months according to severity and response [2, 25]. Specific monitoring should include: neurological response (NIS, PND, nerve conduction, COMPASS-31), mBMI, cardiac biomarkers (NT-proBNP, troponin), ECG and Holter monitoring (to detect blocks and indications for a pacemaker), echocardiography, renal function and proteinuria, ophthalmological examination with intraocular pressure, signs of central nervous system involvement and, in patients receiving silencers, vitamin A and ocular symptoms; in patients receiving inotersen, platelets and renal function [2, 26, 62]. Progression on a drug justifies discussion at a reference centre of a change of class or of combination treatment (for example, a silencer with a stabiliser), although evidence of additive benefit is limited: in HELIOS-B, the effect of vutrisiran was consistent in patients on baseline tafamidis, and in CARDIO-TTRansform eplontersen did not reduce events [71, 73]. Patients should be warned of the risk of burns from local heat sources, and surgery and anaesthesia should take dysautonomia and conduction defects into account [2, 52]. In the French scheme (annex 12 of the PNDS), the symptomatic patient repeats every 6 months weight, questionnaires, clinical examination with scales, cardiac biomarkers and renal function, and annually electrophysiology, echocardiography with Holter and ophthalmology; on anti-amyloid treatment, blood tests are performed every 3 months and a neurology appointment every 6 months; the carrier repeats the baseline panel at the schedule defined in section 7.7 [10].

12. Summary and Final Considerations

Hereditary transthyretin amyloidosis is an autosomal dominant toxic gain-of-function disease, caused by more than 130 missense variants of TTR that destabilise the tetramer and lead to deposition of amyloid fibrils in peripheral and autonomic nerves, the heart, eye, kidney and leptomeninges. Described by Corino de Andrade in 1952 from families in Póvoa de Varzim and molecularly characterised by Portuguese researchers (p.Val50Met, Val30Met, 1984), it constitutes a spectrum ranging from early-onset, high-penetrance polyneuropathy with anticipation following maternal transmission in Portuguese foci, to late-onset, reduced-penetrance cardiomyopathy associated with p.Val142Ile in people of African ancestry and the mixed p.Thr80Ala phenotype in Ireland.

Diagnosis combines clinical suspicion — guided by red flags and the endemic or non-endemic setting — demonstration of amyloid (Congo red biopsy and typing or, in cardiomyopathy, grade 2–3 bone scintigraphy in the absence of a monoclonal protein) and TTR sequencing, which is essential to distinguish ATTRv from ATTRwt and for family studies. Coutinho staging and the PND scale guide neurological treatment, and NT-proBNP and eGFR staging stratifies cardiac prognosis.

Treatment has evolved from liver transplantation to stabilisers (tafamidis, acoramidis) and silencers (patisiran, vutrisiran, inotersen, eplontersen); vutrisiran is the only drug with simultaneous indications for polyneuropathy and cardiomyopathy following HELIOS-B, whereas eplontersen did not demonstrate cardiovascular benefit in CARDIO-TTRansform. In the European Union, diflunisal (Attrogy®) for stage 1–2 polyneuropathy and a generic tafamidis restricted to hereditary cardiomyopathy were added in 2025–2026. Gene editing with nexiguran ziclumeran resumed phase 3 trials in 2026 following a hold for hepatic toxicity; nucresiran, a six-monthly silencer, is in phase 3; amyloid-depleting antibodies are in phase 3 following a phase 2 trial of coramitug with a reduction in NT-proBNP but no effect on walking; and the ACT-EARLY trial is testing, for the first time, prevention with acoramidis in asymptomatic carriers — a setting in which, until results become available, any treatment is off-label. For the geneticist, the central tasks are early diagnosis, interpretation of the variant in the light of population-specific penetrance and the sex of the transmitting parent, predictive testing with structured carrier surveillance so as to initiate treatment at conversion to disease, and discussion of reproductive options, including PGT-M, with live-birth rates of about 48% per cycle in the Portuguese experience. The 2022 French national protocol, which predates most recent authorisations, diverges from the other sources mainly on the place and age limit of liver transplantation and on the rejection of routine biopsies in carriers. Leptomeningeal and ocular disease, which current drugs do not address, the scarcity of population data outside the classical foci, and the cost of and access to therapies remain challenges.

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