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Transthyretin amyloidosis (ATTR) is a rare disease caused by the extracellular accumulation of misfolded transthyretin (TTR) amyloid fibrils. ATTR can be either hereditary (ATTRv) or acquired (wtATTR). ATTRv is caused by a mutation in the transthyretin gene (TTR) with an autosomal dominant pattern of inheritance. In ATTRv amyloidosis, some patients primarily exhibit symptoms of polyneuropathy others mainly or exclusively present with symptoms of cardiomyopathy. However, many patients present with a multisystemic involvement that includes sensory, motor, autonomic, and cardiac symptoms. Early diagnosis and detection of disease progression are emerging as a crucial need for ATTR amyloidosis in order to significantly impact survival, patients’ functions and quality of life. Currently, parameters to be monitored in ATTR patients in the real life might refer to some publicly available recommendations regarding the monitoring and assessment of disease progression in the real-world setting of patients with ATTRv. Nonetheless, a standardized disease monitoring protocol has not been established in Italy, posing a significant unmet need for a prompt and equal access to care. Therefore, in the Emilia-Romagna Region the “ATTR Working Group” has sought to tailor the recommendations to the Regional “real clinical setting” in order to optimize and standardize a monitoring protocol aimed at identifying disease progression. Patients’ and carriers’ access to uniform monitoring routes across the entire Region ensures optimal disease management and economic sustainability.
Transthyretin amyloidosis (ATTR) is a rare disease caused by the extracellular accumulation of misfolded transthyretin (TTR) amyloid fibrils. This accumulation can affect multiple sites, including the nerves, heart and gastrointestinal tract. ATTR can be either hereditary (ATTRv) or acquired (wtATTR). ATTRv is caused by a mutation in the transthyretin gene (
A recent national survey revealed a 50% increase in diagnosed ATTRv cases in Italy over a 4-year period, with a shift towards p.Ile88Leu and p.Phe84Leu variants, and a rising prevalence of mixed phenotypes, underlining the importance of broad-based genotype–phenotype monitoring protocols (
In ATTRv amyloidosis, some patients primarily exhibit symptoms of polyneuropathy, traditionally referred to as familial amyloidotic polyneuropathy (FAP) or ATTR polyneuropathy (ATTR-PN); others mainly or exclusively present with symptoms of cardiomyopathy, traditionally known as familial amyloidotic cardiomyopathy (FAC) or more recently as ATTR cardiac amyloidosis (ATTR-CA). However, many patients present with a multisystemic involvement that includes sensory, motor, autonomic, and cardiac symptoms. Notably, incomplete penetrance has been observed, meaning that not all individuals carrying a pathogenic TTR mutation will develop clinical manifestations of the disease. This variability complicates both diagnosis and genetic counseling. However, once symptoms of ATTRv amyloidosis emerge, the disease often progresses rapidly, leading to severe disability and reduced life expectancy, thus, monitoring of carriers is mandatory (
Importantly, the genotype–phenotype association can widely vary depending on the
In order to provide an optimal and appropriate health care service to ATTR patients, a structured referral network was established in 2022, involving both tertiary and peripheral ATTR-CA cardiology and neurology centers. This network, referred to as the ‘ATTR Working Group,’ brings together cardiologists and neurologists from across the Emilia-Romagna Region (
To ensure that all patients in the Emilia-Romagna Region have equal access to the best possible diagnostic and therapeutic opportunities through standardized approaches to the management of ATTR patients;
To address Regional epidemiology-related needs of patients affected by specific
To facilitate and support scientific data dissemination.
Early diagnosis and detection of disease progression are emerging as a crucial need for ATTR amyloidosis in order to significantly impact survival, patients’ functions and quality of life (
Therefore, in the Emilia-Romagna Region the “ATTR Working Group” has sought to tailor the above mentioned recommendations to the Regional “real clinical setting” in order to optimize and standardize a monitoring protocol aimed at identifying disease progression. Patients’ and carriers’ access to uniform monitoring routes across the entire Region ensures optimal disease management and economic sustainability.
Moreover, ATTRv patients and
In this article we aim to describe the ATTRv monitoring protocol that has been employed in the Emilia-Romagna Region since January 2023.
To agree on a Regional monitoring protocol specifically tailored to the clinical needs of ATTRv patients and carriers, a specific survey of the previously identified centers (Working Group) managing ATTRv patients (
The Working Group identified the three most frequently observed clinical scenarios in routine medical practice and agreed on the following definitions:
According to current scientific literature, monitoring of asymptomatic carriers should begin approximately 10 years before the predicted age of disease onset (PADO) (
Specifically, asymptomatic carriers should undergo baseline clinical and neurophysiological evaluations, followed by annual assessments starting 15 years before the predicted onset of the disease in their family cluster. This recommendation is based in part on findings from a recent study by Cisneros-Barroso et al., which demonstrated that the onset of ATTRv occurs, on average, 16 years earlier in offspring compared to their parents (
The follow-up program includes clinical and instrumental multidisciplinary assessments to be conducted annually, biennially, or every three years (
Assessments type and timing of carrier monitoring.
| Every year | Every 2 years | Every 3 years |
|---|---|---|
| Electrocardiogram | 24-h Holter ECG monitoring | Whole-body scintigraphy with a bone-avid tracer (in Emilia Romagna: DPD/HDP/HMDP), or cardiac MRI with gadolinium contrast. |
| Echocardiogram | Neurological evaluation | |
| Local laboratory blood tests including NT-proBNP and troponin |
Gastroenterology consultancy | |
| Ophthalmology consultancy | ||
| Nephrology consultancy |
From a neurological standpoint, the Working Group proposes a unified protocol of clinical and instrumental evaluations for both carriers and symptomatic patients, applied with different timing based on the patient category (
Neurological follow-up across the three clinical scenarios of ATTRv.
| Patient category | Clinical evaluation | Neurophysiological studies |
|---|---|---|
| Asymptomatic Carrier | Baseline and every 2 years during the 15 years before PADO | Baseline and every 2 years during the 15 years before PADO |
| Cardiological phenotype | Every 6 months | Every 6 months |
| Neurological/mixed phenotype | Every 6 months | Annually |
PADO, predicted age of disease onset.
Specifically, the working group recommends clinical evaluations every 6 months for all ATTR patients. Neurophysiological assessments should be performed annually in patients with a neurological or mixed phenotype, and every 6 months in patients with a predominantly cardiac phenotype.
This differentiated approach reflects the distinct prognostic trajectories of patients with cardiac amyloidosis (CA) and the variability in therapeutic options available for neurological versus cardiological involvement (
The neurological monitoring protocol includes: (1) clinical assessment, and (2) neurophysiological studies.
1.
Experts agree on performing a comprehensive series of clinical evaluations, which include a neurological physical examination and the use of validated self-administered scales and questionnaires, specifically:
Complete neurological physical examination
Measurement of weight and height for Body Mass Index (BMI, kg/m2) calculation
Measurement of blood pressure (mmHg) and heart rate (bpm) in the supine position and after 3 min of standing (orthostasis)
Application of scales selected for their relevance and feasibility in clinical practice:
2.
The Working Group proposes the same neurophysiological assessment protocol for all three patient groups, with timing variations based on the clinical scenario (as outlined in
Neurophysiological tests will be performed according to a standardized methodology:
With surface electrodes;
Using the antidromic technique for sensory nerve conduction studies and ortodromic for motor nerves;
Measuring amplitude of compoud motor action potential (CMAP) and sensory nerve action potential (SNAP) from the negative to the positive peak
Unilaterally on the clinically most affected side, or randomly (right or left) in asymptomatic carriers for the Tibial, Peroneal, Radial, nerves; Bilaterally for the Median, Sural, Dorsal Sural nerves (the and Ulnar nerve is also examined bilaterally in presence of bilateral signs of distal slowing of the sensory and/or motor conduction of the Median nerve);
Applying normative reference values derived from available scientific evidence (
Reference values for each parameter measured in the individual neurophysiological tests, along with detailed information on stimulation and recording techniques, are provided in
Neurophysiological tests in the follow-up of patients with ATTR.
| Tests and normative value | Assembly |
|---|---|
DML, distal motor latency; MCV, motor conduction velocity; CMAP, compound motor action potential; SCV, sensory conduction velocity; SNAP, sensory nerve action potential; SRAR, sural/radial amplitude ratio; S/DNS, SNAP ratio between sural and dorsal sural branch; SSR, sympathetic skin response; APB, abductor pollicis brevis; ADM, abductor digiti minimi; AH, abductor hallucis; EDB, extensor digitorum brevis.
The most suitable neurophysiological scores applicable to real practice, derived from individual measurements, should be calculated as follows:
For patients diagnosed with TTR-related cardiac amyloidosis, experts recommend cardiological evaluations every six months (i.e., cardiology visit, ECG, echocardiogram, and laboratory tests including NT-proBNP and local Troponin T-hs o I-hs), and annually (24-h Holter ECG).
In addition, it is recommended that the following assessments be performed every 6 months:
Kansas City Cardiomyopathy Questionnaire
EuroQoL-5D
6-Minute Walk Test
Patients presenting with exclusively neurological involvement undergo the same evaluation protocol on a yearly basis.
The Working Group also agrees on the need for the following at the onset of specific symptoms and every 2 years afterwards:
Nephrology consultation
Gastroenterology consultation
Ophthalmology consultation
Implementation of a regionally shared protocol for the monitoring of ATTR amyloidosis represents a relevant advancement in standardizing care and addressing both diagnostic delays and heterogeneous disease management across healthcare settings. Compared with international recommendations (
From a neurological standpoint, including of both clinical scales and neurophysiological studies within a structured timeline for asymptomatic carriers and symptomatic patients reflects an effort to balance sensitivity in early detection with feasibility in daily clinical practice. While the selected scales (NIS, FAP/PND, R-ODS, CADT, Norfolk QOL-DN) are consistent with international standards, the regional protocol emphasizes routine and scheduled use of such tools, which are often underutilized in real-world settings due to logistical constraints. Moreover, standardizing of nerve conduction techniques and adopting of composite scores (e.g., SNS, MNS, SRAR, Sural/DNS) aim to improve comparability across centers and over time, an essential step toward objective disease monitoring. These methodological refinements go beyond current recommendations by proposing specific parameters and thresholds, which may serve as a benchmark for other regional systems.
In the cardiology domain, the protocol remains aligned with ESC and AHA guidelines regarding frequency and type of assessments, including echocardiography, NT-proBNP, troponin levels, and quality of life measures such as KCCQ and EQ-5D. However, the regional approach underlines the importance of integrating functional tests (6MWT) and periodic imaging (in asymptomatic carriers whole-body scintigraphy or cardiac MRI) as part of routine monitoring, even without overt clinical progression. This reflects a proactive rather than reactive strategy, supported by evidence that early identification of subclinical changes can impact prognosis and therapeutic timing. Furthermore, while most centers adopt current cardiology staging systems, the protocol guides interdisciplinary consultations (e.g., nephrology, gastroenterology, ophthalmology), anticipating multisystemic involvement.
A key strength of this initiative lies in the formalization of a shared referral chain between tertiary and peripheral centers, allowing patients and asymptomatic carriers to access the same clinical tools regardless of geographic location. This organizational framework fosters equity of care, improves early detection, and enhances the regional capacity to manage a rare and complex condition. Continuous patient-level data collection through the REDCap-based registry provides the infrastructure for prospective outcome analyses. This will allow the identification of variability in care delivery, gaps in adherence to the protocol, and opportunities for improvement, consistent with the principles of implementation science (
Some limitations must be acknowledged: although the survey captured variability across centers, some differences in resources and expertise may persist, potentially affecting the uniform application of monitoring tools. Secondly, while the protocol has been designed for generalizability, its applicability to other regions or healthcare systems may require adjustments.
Nonetheless, the Emilia-Romagna ATTR monitoring protocol demonstrates that it is possible to implement a structured, multidisciplinary, and scalable disease management model even within a heterogeneous regional context. Its success will depend not only on its initial design but also on continuous quality control, training of professionals, and alignment with evolving clinical evidence and therapeutic advances.
While our regional protocol emphasizes standardized clinical, neurophysiological, and cardiological assessments, other innovative approaches are under investigation and may soon influence carrier monitoring strategies. Among these, cutaneous amyloid detection using minimally invasive skin punch biopsies has demonstrated promising diagnostic yield, even in pre-symptomatic stages, by identifying early amyloid deposition in peripheral small fibers (
Another area of growing interest is the use of circulating biomarkers of axonal damage, particularly neurofilament light chain (NfL). Elevated plasma NfL levels have been associated with early axonal injury and correlate with disease severity in a variety of neurodegenerative and neuroinflammatory disorders (
Although neither cutaneous amyloid detection nor NfL assays are currently widely available in our region, their incorporation into future standardized protocols could further enhance early detection and risk stratification. By combining these emerging biomarkers with established clinical and instrumental tools, a multimodal monitoring approach may become feasible, ultimately improving personalized timing for therapeutic intervention.
The multidisciplinary and multicentric ATTR Working Group project represents a response to the diagnostic and therapeutic unmet needs in managing patients and asymptomatic carriers with ATTRv. Since 2022, it has involved all hospital facilities across the Emilia-Romagna region, enabling the identification and validation of a sustainable and standardized diagnostic and care pathway. The program is tailored to the specific needs of ATTRv patients, with particular emphasis on both clinical management (care and follow-up) and the practical and psychological dimensions, including quality of life (QoL).
The ATTRv monitoring protocol is continuously evolving, whereby analysis of patients’ data collected into a web-based registry, will enhance the clinical setting of ATTRv, promote the uptake of research findings into routine healthcare and inform Healthcare providers on patient care pathway efficiency and treatment outcomes.
PG: Writing – original draft, Writing – review & editing. IA: Methodology, Validation, Writing – review & editing. AA: Data curation, Methodology, Writing – review & editing. TB: Investigation, Project administration, Supervision, Writing – review & editing. ABa: Conceptualization, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing. FeB: Data curation, Resources, Validation, Writing – review & editing. MB: Methodology, Software, Validation, Writing – review & editing. EB: Formal analysis, Funding acquisition, Supervision, Writing – review & editing. FrB: Methodology, Validation, Visualization, Writing – review & editing. ABo: Data curation, Validation, Visualization, Writing – review & editing. CB: Data curation, Formal analysis, Visualization, Writing – review & editing. GB: Formal analysis, Investigation, Methodology, Visualization, Writing – review & editing. IC: Investigation, Methodology, Validation, Visualization, Writing – review & editing. SC: Investigation, Supervision, Validation, Visualization, Writing – review & editing. LC: Formal analysis, Supervision, Validation, Writing – review & editing. MC: Supervision, Validation, Visualization, Writing – review & editing. FD: Resources, Supervision, Validation, Writing – review & editing. RD'A: Validation, Visualization, Writing – review & editing. RG: Formal analysis, Supervision, Visualization, Writing – review & editing. FS: Data curation, Resources, Validation, Writing – review & editing. EG: Conceptualization, Supervision, Validation, Visualization, Writing – review & editing. GL: Supervision, Validation, Visualization, Writing – review & editing. CL: Conceptualization, Supervision, Validation, Visualization, Writing – review & editing. FM: Supervision, Validation, Visualization, Writing – review & editing. MM: Supervision, Validation, Visualization, Writing – review & editing. GM: Supervision, Validation, Visualization, Writing – review & editing. EM: Supervision, Validation, Visualization, Writing – review & editing. AM: Supervision, Validation, Visualization, Writing – review & editing. DM: Supervision, Validation, Visualization, Writing – review & editing. EnP: Project administration, Supervision, Validation, Visualization, Writing – review & editing. AP: Data curation, Supervision, Visualization, Writing – review & editing. EmP: Supervision, Validation, Visualization, Writing – review & editing. MR: Supervision, Validation, Visualization, Writing – review & editing. RR: Methodology, Supervision, Validation, Visualization, Writing – review & editing. DS: Supervision, Validation, Visualization, Writing – review & editing. KS: Supervision, Validation, Visualization, Writing – review & editing. MSe: Formal analysis, Supervision, Validation, Visualization, Writing – review & editing. MSg: Supervision, Validation, Visualization, Writing – review & editing. ES: Methodology, Supervision, Validation, Visualization, Writing – review & editing. AS: Supervision, Validation, Visualization, Writing – review & editing. CT: Supervision, Validation, Visualization, Writing – review & editing. CV: Supervision, Validation, Visualization, Writing – review & editing. GV: Methodology, Validation, Visualization, Writing – review & editing. MV: Supervision, Validation, Visualization, Writing – review & editing. SL: Writing – original draft, Writing – review & editing.
The author(s) declare that financial support was received for the research and/or publication of this article. The work reported in this publication was funded by the Italian Ministry of Health, RC-2025-2794599.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The reviewer LL declared a past co-authorship with the author IC to the handling editor.
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