Phenotypic Manifestations of Hereditary ATTR Amyloidosis

We aim to describe the phenotypic variables including preclinical, cardiological, neurological, and mixed manifestations in patients carrying the Val50Met variant. Our goal is to identify early disease onset criteria in initially asymptomatic patients, enhancing early detection and treatment strategies. Participants will undergo various clinical examinations and tests to gather comprehensive data.

• A complete physical examination of all body systems, including height and body weight (Other): These interventions will be carried out in a time-controlled population within a family cluster of VAL50MET
• Neurological examination includes motor strength testing; sensory testing with pinprick, light touch, temperature, and proprioception; deep tendon reflexes; and gait assessment. (Other): These interventions will be carried out in a time-controlled population within a family cluster of VAL50MET
• Electrocardiogram (12-lead ECG) (Diagnostic test): These interventions will be carried out in a time-controlled population within a family cluster of VAL50MET
• 24-Hour Holter Monitoring (Diagnostic test): These interventions will be carried out in a time-controlled population within a family cluster of VAL50MET
• Color Doppler echocardiography with "two-dimensional strain" (longitudinal strain) (Diagnostic test): These interventions will be carried out in a time-controlled population within a family cluster of VAL50MET
• The Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) (Other): These interventions will be carried out in a time-controlled population within a family cluster of VAL50MET
• questionnaire, the NIS-LL (Neuropathy Impairment Score in the Lower Limbs) (Other): These interventions will be carried out in a time-controlled population within a family cluster of VAL50MET
• COMPASS-31 (Composite Autonomic Symptom Score-31) (Other): These interventions will be carried out in a time-controlled population within a family cluster of VAL50MET
• Electromyogram (EMG) (Diagnostic test): These interventions will be carried out in a time-controlled population within a family cluster of VAL50MET
• [99mTc]Tc-DPD scintigraphy (Diagnostic test): These interventions will be carried out in a time-controlled population within a family cluster of VAL50MET
• Laboratory assessments (Diagnostic test): Laboratory assessments include blood and urine sample collection for serum chemistry, hematology, and urinalysis, with specific biomarker analyses (troponin T, NT-proBNP, Kappa, and Lambda light chains

Primary outcomes

• Describe the phenotypic variables (preclinical, cardiological, neurological and mixed) in patients carrying the TTR Val50Met variant in a non-endemic population. [2 years]: The predominantly cardiac phenotype includes patients with abnormal ECG due to rhythm disturbance, heart failure, or dyspnea, minimal neurologic or GI symptoms, and diagnostic findings such as interventricular septum hypertrophy (>12 mm), Holter monitoring, and \[99mTc\]Tc-DPD scintigraphy (Peugerini Score 1-3). The predominantly neurologic phenotype features patients with ongoing neurologic or GI symptoms definitively linked to ATTR amyloidosis, without abnormal ECG findings. Key assessments include autonomic neuropathy (orthostatic hypotension, sexual dysfunction), EMG, Norfolk QoL-DN (-4-246), COMPASS-31 (0-100), and NIS-LL (0-88). The mixed phenotype includes patients with abnormal ECG and neurologic or GI symptoms of any severity, failing to meet criteria for predominantly cardiac or neurologic phenotypes.

Secondary outcomes

• Explore minimum criteria considered for the onset of disease in patients carrying the Val50Met variant initially identified as asymptomatic. [2 years]: Minimum criteria for disease onset include: (1) one quantified symptom or sign definitively related to the disease, such as sensorimotor neuropathy, autonomic neuropathy, cardiac involvement, or renal/ocular involvement; (2) any symptom probably related with one abnormal test finding; or (3) absence of symptoms with two abnormal test findings.

Sex: All, ages: 20 Years to any

Inclusion Criteria:

* All subjects between 20 and 70 years of age, carriers of the Val50Met variant

Exclusion Criteria:

* Patients who refuse to participate.

• Saez MS, Aguirre MA, Perez de Arenaza D, Sorroche P, Nucifora E, Posadas Martinez ML. Epidemiology of variant transthyretin amyloidosis at a reference center in Argentina. Mol Genet Genomic Med. 2021 Nov;9(11):e1812. doi: 10.1002/mgg3.1812. Epub 2021 Oct 20. PMID 34668655
• Conceicao I, Damy T, Romero M, Galan L, Attarian S, Luigetti M, Sadeh M, Sarafov S, Tournev I, Ueda M. Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations. Amyloid. 2019 Mar;26(1):3-9. doi: 10.1080/13506129.2018.1556156. Epub 2019 Feb 22. PMID 30793974
• Maurer MS, Bokhari S, Damy T, Dorbala S, Drachman BM, Fontana M, Grogan M, Kristen AV, Lousada I, Nativi-Nicolau J, Cristina Quarta C, Rapezzi C, Ruberg FL, Witteles R, Merlini G. Expert Consensus Recommendations for the Suspicion and Diagnosis of Transthyretin Cardiac Amyloidosis. Circ Heart Fail. 2019 Sep;12(9):e006075. doi: 10.1161/CIRCHEARTFAILURE.119.006075. Epub 2019 Sep 4. PMID 31480867
• Gentile L, Coelho T, Dispenzieri A, Conceicao I, Waddington-Cruz M, Kristen A, Wixner J, Diemberger I, Gonzalez-Moreno J, Cariou E, Maurer MS, Plante-Bordeneuve V, Garcia-Pavia P, Tournev I, Gonzalez-Costello J, Duarte AG, Grogan M, Mazzeo A, Chapman D, Gupta P, Glass O, Amass L; THAOS investigators. A 15-year consolidated overview of data in over 6000 patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS). Orphanet J Rare Dis. 2023 Nov 10;18(1):350. doi: 10.1186/s13023-023-02962-5. PMID 37946256

• Mauricio MT Tomei, MD, Principal investigator, Hospital 9 de Julio de Las Breñas