September 2026 Research Update

Across these papers, the main message was that finding inherited transthyretin amyloidosis (ATTRv) earlier often depends on putting the right people into the right testing pathway before symptoms are clearly labeled as ATTRv. Studies described practical ways to do this, including electronic health record-based alerts, structured questions for carriers, and heart and nerve tests that can show changes even when a person feels mostly well. At the same time, several reports highlighted how easy it can be to miss or misinterpret ATTRv because symptoms overlap with other conditions, or because social and communication barriers delay genetic testing and referrals.

One health system described using a phenotype risk score to flag African American adults age 60 and older with heart failure who may be more likely to carry the TTR V142I (also written Val142Ile) gene change, then prompting clinicians and offering an asynchronous, message-only genetics e-visit to speed up genetic testing. [1] This was presented as an implementation approach intended to shorten the time to a genetic diagnosis in a higher-risk group. [1]

In a retrospective European study of 217 people who carried an ATTRv gene change (128 without symptoms and 89 newly symptomatic), 17 of 23 questions on an asymptomatic carrier neurologic assessment were linked to being newly symptomatic. [2] The strongest signals were nerve pain in the arms or legs, reduced ability to sense hot or cold, and unexplained weight loss, suggesting a structured question set may help focus attention on early nerve-related changes (but it was not designed as a stand-alone diagnosis and still needs prospective testing). [2]

Two studies emphasized that heart involvement can sometimes be detected before clear polyneuropathy (nerve damage causing numbness, pain, or weakness) is diagnosed in carriers. In premanifest carriers of the p.A117S variant, none had polyneuropathy, but some had carpal tunnel syndrome and a subset showed higher uptake on a heart scan and measurable changes on heart magnetic resonance imaging compared with controls; these heart-related measures also tracked with nerve degeneration measures. [3] In a Swedish cohort of 152 people with ATTRv (mostly Val30Met), heart scan results lined up more closely with the overall clinical picture than did fibril typing from an abdominal fat biopsy, and the authors noted that a normal heart scan did not rule out ATTRv. [4]

Smaller studies and case reports illustrated how ATTRv can look like other conditions, and why confirming the cause matters. A small ultrasound study in 20 people with transthyretin amyloidosis (inherited or non-inherited) found that many wrists with carpal tunnel syndrome had a normal median nerve size, but some had atypical tissue changes around the nerve that could reflect amyloid involvement, although this was not confirmed by tissue testing. [5] Case reports described delayed recognition when symptoms were atypical (for example, mainly motor weakness with little sensory loss) and how some new symptoms in a gene carrier may be due to a different, treatable condition rather than ATTRv progression. [6] [7]

Several papers focused on real-world barriers that can delay diagnosis even when testing exists. In interviews with 11 Black patients seen at a specialty amyloidosis clinic, people described misdiagnosis, mistrust of healthcare providers, misunderstanding of personal risk, and gaps in family communication as factors that contributed to underdiagnosis, while timely referral and genetic testing with counseling were viewed as helpful. [8] Separately, a Chilean neurologist consensus document described recommendations to increase suspicion for inherited ATTR with polyneuropathy and supported early genetic testing when there is family history or multisystem involvement. [9]

Finally, one case report showed why clinicians may need more than one type of test when evaluating amyloidosis. A man with heart failure had hereditary transthyretin amyloidosis cardiomyopathy along with monoclonal gammopathy of undetermined significance (MGUS), and the diagnosis used blood testing plus a heart scan, heart biopsy, and genetic testing. [10]

For patients and families, this group of studies mainly adds background on how earlier diagnosis might be improved at the health-system level and during follow-up of gene carriers, rather than changing care right now. The evidence ranges from moderate observational studies to small imaging studies, qualitative interviews, and single-patient case reports, so it cannot tell how well any one approach will work everywhere. What remains uncertain is how these tools (risk scores, symptom question sets, and imaging markers) perform over time in broader, more diverse groups, and how best to reduce non-medical barriers like mistrust and limited family communication that can delay genetic testing and referral.

Taken together, these papers show that heart involvement in transthyretin (ATTR) amyloidosis can look very different from person to person, and that risk is better understood when several heart measurements and personal factors are considered at the same time. Large cohort data suggest that reduced heart pumping function is not rare, and combining multiple heart performance measures separates people into clearer risk groups. Other real-world studies suggest that outcomes can differ by sex and by other medical problems such as severe kidney disease, but some results are based on hospital coding or shorter follow-up and remain uncertain. [11] [12] [13]

In a large French referral-center cohort of cardiac amyloidosis (including hereditary ATTR, wild-type ATTR, and AL), 39% of people had mildly or clearly reduced left-ventricular ejection fraction (a measure of pumping strength). Survival differed across these groups, and a combined approach using ejection fraction, a heart strain measure, and cardiac index sorted patients into four groups with clearly different 4-year death risks; these results were also supported in an external validation set. [11]

A US national study of 23,119 hospital admissions coded as cardiac amyloidosis reported higher in-hospital death risk in people who also had end-stage kidney disease and in those with multiple myeloma, and risk increased with older age. The same analysis found that hereditary transthyretin amyloidosis and familial Mediterranean fever were strongly linked with having a cardiac amyloidosis code, but the authors noted that ICD-10 coding can limit accuracy. [12]

In a smaller, prospective study from Crete that compared hereditary versus wild-type ATTR cardiomyopathy after genetic testing (39 people), hereditary cases were younger and had better heart muscle function and better walking distance at baseline, but higher arterial stiffness. Over 6 months after starting tafamidis, quality of life favored hereditary ATTR, while wild-type ATTR showed a trend toward reduced heart wall thickness that was not seen in hereditary ATTR. [14]

In pooled real-world tafamidis-treated cohorts (1,924 people), women were a small minority and were more likely than men to have hereditary ATTR cardiomyopathy and African descent, and they more often had more advanced symptoms at baseline. Over an average of 1.5 years, men had a higher adjusted risk of death from any cause than women. [13]

One case report described a 57-year-old man with hereditary ATTR (Glu109Gln) whose first major sign was sustained ventricular tachycardia (a dangerous fast heart rhythm). After receiving an implantable defibrillator and transthyretin-stabilizer therapy, he had no recurrent ventricular tachycardia or device shocks over 2.5 years, with improved heart blood markers and stable daily function; as a single-person report, this may not apply to others. [15]

For patients and caregivers, this set of studies mainly helps explain why two people with ATTRv (hereditary ATTR) heart involvement may have different symptom patterns and different risks over time. Some results are immediately relevant as background for how clinicians estimate outlook (using more than one heart measure) and how other health issues, like severe kidney disease, can affect hospital outcomes, but several studies include mixed amyloidosis types or rely on hospital coding. Differences by sex, genetic type, and arrhythmia presentations are real-world signals that need more follow-up to understand what is driving them and how broadly they apply to ATTRv specifically. [11] [12] [14] [13] [15]

Across this months papers, a consistent pattern was that treatments designed to lower transthyretin (TTR) production (gene-silencing medicines) were linked with stabilization or slower worsening of nerve symptoms in hereditary transthyretin amyloidosis with polyneuropathy, with signals that earlier treatment may help more than treating later-stage disease. The evidence also highlighted limits in comparing individual drugs, because many comparisons are indirect rather than head-to-head. [16] [17] [18] [19] [20]

In an exploratory post hoc analysis from the NEURO-TTRansform study, eplontersen was linked with sustained stabilization or improvement in neuropathy measures, daily function, and quality of life across mild, moderate, and more severe baseline nerve involvement through about 85 weeks, alongside large and sustained drops in blood TTR levels. The analysis also suggested that people treated earlier in their disease course tended to show greater benefit than those with more advanced neuropathy, although the comparisons were not randomized and used historical placebo data. [16]

A systematic review that summarized eplontersen data reported that trials showed strong lowering of serum TTR and improvements in neurological function and quality of life, while also noting common treatment-emergent side effects that were usually mild and remaining gaps in long-term safety and use in broader patient groups. The review also described important safety topics tracked in trials (for example low platelet counts and kidney inflammation), with no kidney inflammation observed in the eplontersen group in NEURO-TTRansform as summarized by the authors. [17]

Two retrospective studies focused on how people did on different treatments over time. One multicenter study of 32 people with the Val30Met (p.V50M) variant reported that nerve worsening, measured by the Neuropathy Impairment Score, was slower after switching from the TTR stabilizer tafamidis to patisiran following progression on tafamidis. [18]

In a separate non-endemic cohort of 53 patients treated with either tafamidis or patisiran, better response to each therapy was linked to milder nerve disease at baseline, and for tafamidis, a shorter delay to diagnosis and better sweat-gland nerve function in the feet. The authors emphasized baseline nerve severity as a key factor tied to response, but this was not a randomized comparison. [19]

Evidence on heart involvement was limited but included two small reports. In five Ala97Ser patients from the NEURO-TTRansform cohort, serial heart scans showed reduced tracer uptake over time during eplontersen treatment, which may suggest reduced heart amyloid signal on imaging in that small group. [21]

A single-patient case report described an 83-year-old woman with Val142Ile hereditary transthyretin amyloid cardiomyopathy who had progression on tafamidis and then started vutrisiran, with reported clinical stabilization and improvement in a heart-failure blood marker (NT-proBNP). Because this is one persons experience, it may not predict what will happen for others. [22]

Finally, a commentary cautioned against interpreting network meta-analyses as proving a clear ranking of individual gene-silencing drugs, arguing that indirect comparisons and differences among trials can create a misleading hierarchy when there are few head-to-head studies. It supported the idea that gene silencers may outperform stabilizers overall, while emphasizing that which specific silencer is best remains unproven. [20]

For patients and caregivers, these papers mainly add context for treatment conversations: several studies support that gene-silencing approaches can stabilize or slow nerve decline, and small reports suggest changes in heart imaging or heart-related blood markers may occur in some situations. At the same time, deciding between specific medicines is still complicated because many comparisons are not head-to-head and because study populations and disease stage differ; longer follow-up and more direct comparisons are still needed, especially for long-term safety and for people with different variants or more advanced disease. [16] [17] [18] [19] [21] [22] [20]

Taken together, these papers highlight that nerve involvement can be missed or under-described in hereditary transthyretin (ATTR) amyloidosis, especially when heart disease is the main focus, and that objective testing can uncover neuropathy even when symptoms are not obvious. They also suggest that the strength of documented evidence for neuropathy can influence whether certain disease-modifying therapies are used. In contrast, one exploratory blood marker (plasma sTREM2) did not separate ATTR-related neuropathy or asymptomatic carriers from controls, so its role in monitoring ATTR neuropathy remains uncertain. [23] [24] [25]

In a prospective single-center study of 60 adults with hereditary ATTR cardiomyopathy, half were found to have polyneuropathy on specialist neurologic assessment (exam plus nerve conduction studies, although nerve conduction results were missing for 8 of these 30 people), and another 10% had abnormal nerve conduction studies despite no clear neuropathy on exam. This means some people labeled as having primarily heart involvement may also have mixed heart-and-nerve disease that only becomes clear with formal nerve testing. [23]

In a separate retrospective chart review of 54 people with hereditary ATTR (mostly the V142I variant), most had some notes supporting polyneuropathy, but only a subset had additional testing such as EMG/nerve conduction studies. Use of gene-silencing therapies tracked more with how strong the neuropathy documentation was than with the diagnosis label alone, and neurology consultation and EMG were much more common when neuropathy status was considered confirmed or suspected rather than unclear. [24]

A cross-sectional study measuring plasma sTREM2 in several neurologic conditions included small groups with ATTR polyneuropathy and asymptomatic ATTR gene carriers, and found no difference in sTREM2 levels compared with controls after accounting for age. This suggests that plasma sTREM2, as measured here, is not a useful stand-alone blood marker to identify ATTR neuropathy or carrier status, and the authors noted it may reflect broader immune activity in the body rather than nerve-specific damage. [25]

For patients and caregivers, these studies mainly matter now as context for why neuropathy may be recognized differently across clinics and why objective nerve testing and clear records can change how the overall disease pattern (heart-only vs mixed involvement) is described. They do not show that any single test is best for everyone, and they do not prove that changing documentation or testing changes long-term outcomes. The blood marker study is background research at this stage for ATTR, because it did not separate ATTR neuropathy or carriers from controls and needs more validation in larger ATTR groups. [23] [24] [25]

This months papers together suggest that brain-related symptoms in hereditary transthyretin amyloidosis (ATTRv) can look quite different depending on the genetic change and how long someone has had the disease. One larger cohort highlighted short-lasting, stroke-like episodes and other neurological symptoms in people with long-standing V30M ATTRv, while a separate MRI study did not find clear evidence of widespread small-vessel brain damage compared with controls. A case report reminded readers that some rare ATTRv variants can involve the lining around the brain and the eyes, with striking changes on imaging and vision symptoms. [26] [27] [28]

In a prospective cohort of 151 adults with the V30M ATTRv variant, transient focal neurological episodes (brief stroke-like episodes) were reported by 44 people (29.1%), along with headaches (23.8%) and seizures (6.6%), while strokes were uncommon (1.3%). People with longer disease duration (more than 15 years) were more likely to have had these brief episodes, suggesting they may become more relevant later in the disease course. A blood marker of nerve cell injury (plasma neurofilament light chain) decreased between 6 and 12 months overall, but it did not show a distinct pattern linked specifically to these brief episodes. [26]

In an Italian case-control MRI study of 32 ATTRv patients and carriers compared with age- and sex-matched healthy controls, researchers did not find group differences in brain microbleeds or in the amount of white matter changes often used as signs of small-vessel disease. The number of microbleeds also did not track with disease stage, years since symptoms started, or age within the ATTRv group. These results suggest that certain types of small-vessel brain changes may be limited or not easily detected in this sample. [27]

A case report described one Chinese family with the rare TTR p.Y89H variant, where the proband had headaches and progressive vision loss along with imaging changes involving the leptomeninges (the lining around the brain). Left-eye vitrectomy (surgery to remove cloudy material in the gel of the eye) improved her vision, but follow-up imaging continued to show diffuse leptomeningeal abnormalities. A literature review in the same paper summarized 12 previously reported p.Y89H cases and highlighted that leptomeningeal and eye involvement were common, while some family members could carry the variant without symptoms. [28]

For patients and caregivers, these studies add context that nervous system and eye involvement in ATTRv is not one single pattern: some groups (such as people with long-standing V30M disease) may experience short-lasting, stroke-like episodes and headaches, while MRI markers of small-vessel disease may not always differ from people without ATTRv. The case report mainly matters as background that certain rare genetic variants (such as Y89H) can involve the brain lining and the eyes, which may show up on brain scans and affect vision, but evidence from one family cannot predict what will happen for others. Overall, what remains uncertain is how to best use blood markers and MRI patterns to anticipate who will develop symptoms over time, especially across different ATTRv variants. [26] [27] [28]

Across these reports, rare changes in the transthyretin gene were linked to inherited (variant) ATTR amyloidosis with a wide range of patterns, even within the same family. Heart involvement often looked like thickened heart muscle on scans, and many people also had nerve and autonomic symptoms such as numbness or lightheadedness on standing. Because most papers were case reports or a small case series, they describe what happened in specific people and cannot predict outcomes for everyone with the same gene change. [29] [30] [31] [32] [33] [34] [35]

In a mainland Chinese family with the rare TTR p.Ser43Asn variant, the main patient had strong uptake on a heart amyloid scan and negative blood tests for a different type of amyloidosis, and genetic testing confirmed the variant; relatives who carried the same variant showed variable features. The report highlighted that a non-biopsy pathway was used and that the range of symptoms in carriers can differ within one family. [29]

A case series from the Brazilian Amazon described 10 people with the p.Asp58Ala variant, most commonly with combined heart and nerve involvement, while some relatives identified through screening had no symptoms at the time reported. Deaths occurred among several index cases during follow-up, and only a few people were reported to be receiving specific disease-modifying therapy, reflecting real-world limitations in care access and follow-up data. [30]

Several single-patient reports showed how ATTR can be mistaken for other heart conditions until multiple tests point to amyloid. One woman previously labeled as having nonobstructive hypertrophic cardiomyopathy was later found to have ATTR cardiomyopathy due to the rare p.Lys35Asn variant, with nerve testing also showing moderate to severe neuropathy. [31]

Other rare variants were reported with combined heart and nerve involvement and differing courses. One man with a Val142del deletion improved in symptoms and had a large drop in a heart-stress blood marker after tafamidis plus standard heart failure care, and family testing identified two relatives carrying the same deletion who did not have symptoms at that time. [33]

Access to disease-modifying therapy and coexisting medical problems also shaped what was reported. A Peruvian man with the rare p.Ala65Val variant had early-onset mixed heart and nerve disease and was reported to have no access to disease-modifying therapy locally, with worsening markers over time. In a separate report, a Nigerian man with homozygous p.V142I and complex congenital heart disease deteriorated to cardiogenic shock and died, underscoring how complicated heart anatomy and delayed recognition can make diagnosis and management harder. [34] [32]

One report from Kuzbass described a man with the TTR Gly73Glu mutation who had severe autonomic symptoms and heart involvement resembling hypertrophic cardiomyopathy, with changes in heart structure and function described over two years on tafamidis. The paper adds to the list of rare variants linked to both autonomic and cardiac features, but it does not establish what typically happens for this mutation in larger groups. [35]

For patients and caregivers, these papers mainly add background knowledge: rare inherited ATTR variants can cause different combinations of heart symptoms, nerve symptoms, and autonomic problems, and people in the same family can be affected differently. They also show that genetic testing and family screening sometimes identify relatives before symptoms appear, but the reports do not provide reliable predictions about when or whether symptoms will develop. Many details remain uncertain because most evidence here comes from single cases or small series, and access to specialized testing and disease-modifying therapy differed by country and health system. [29] [30] [31] [32] [33] [34] [35]