Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Hereditary transthyretin amyloidosis (hATTR) is a genetic condition characterized by the deposition of amyloid fibers in different tissues and organs following the misfolding of transthyretin protein.1 This abnormal amyloid deposition often leads to clinical manifestations in the peripheral and autonomic nervous system and the heart.2 Other organ systems, such as the musculoskeletal and gastrointestinal, can also be affected.3 As a result of affecting multiple organs, the hATTR care team encompasses a wide range of healthcare professionals.
The diagnosis of hATTR is challenging and usually delayed, as patients experience many symptoms that can mimic other diseases, while there is also a low awareness of the disease among clinicians.2,3 Reports show that misdiagnosis can reach up to 74% in patients with hATTR and that about 18% of patients have received multiple diagnoses.3 A previous survey involving patients with ATTR revealed that an accurate diagnosis was reached within 6 months in only 35% of patients with the mutant form of the disease and in 46% of patients with wild-type ATTR.4 About 10% of patients were correctly diagnosed by the first specialist consulted, and many patients consulted more than 5 clinicians to receive an accurate diagnosis.5,6 The time needed to reach an ATTR diagnosis has been reported to be 3 years or more.3
Very recently, experts have suggested that the course of hATTR should be accompanied by a multidisciplinary team of specialists with knowledge in monitoring the symptoms and manifestations of the disease. Experts recommend that patients are assessed by a care team comprising a neurologist, a cardiologist, an ophthalmologist, and a genetic counselor. Other specialists may be involved in the evaluation of these patients, such as gastroenterologists, nutritionists, physical therapists, nephrologists, and urologists.1
Patients with hATTR can experience neuropathy that starts in the feet and presents as numbness. These patients are commonly referred to a neurologist.7 A neurologist will be focused on determining neuropathic symptoms and evaluating the progression of the disease. These tasks can be accomplished using different tools and multiple scales, including nerve conduction studies, electromyography, the polyneuropathy disability score, the neuropathy symptom score, and the neurologic disability score.8
Cardiologists are specialists that assess and treat diseases of the cardiovascular system.9 Patients with hATTR commonly experience cardiomyopathy and congestive heart failure, and these specialists can assess cardiac function and structural changes using tools such as electrocardiography, echocardiography, and the 6-minute walk test. They can also help patients manage the disease based on current recommendations.8,10
About 10% of patients with hATTR have vitreous deposits of amyloid, which can be visible on direct ophthalmoscopy.7 Patients can present with a mass or patch at the bulbar or tarsal conjunctiva or an orbital mass that causes ocular displacement with proptosis.11 An ophthalmologist therefore plays an important role in the diagnosis, treatment, and monitoring of the ocular manifestations of hATTR in these patients.
Due to the autosomal dominant character of hATTR, genetic counseling can have an important role in allowing patients to understand how the disease affects them and their families.12 Genetic counseling has been recommended for presymptomatic genetic testing as well as for following up with carriers of genetic mutations, many of whom do not show symptoms until late adulthood.13 Genetic testing can contribute to an early diagnosis of the disease, which is important for ensuring the highest efficacy of currently available medications.12
If a genetic variant is identified in a family, all first-degree relatives should be advised to undergo genetic testing. A genetic counselor will work with the family in this process, prioritizing patient education and explaining the potential results and risks involved.12
Monitoring renal function is important for evaluating kidney impairment. Gastrointestinal symptoms are frequent among patients with hATTR, and these can have a negative impact on a patient’s nutritional state. Follow-up with a nutritionist can be important for controlling the disease’s progression through the measurement of body mass index.8
The progression of neuropathy can involve sensory and motor nerve fibers, resulting in weakness that requires patients to use walking aids and wheelchairs.7 Even though specific guidelines for physical therapy assessment and rehabilitation of patients with amyloidosis are yet to be defined, rehabilitation may help patients by improving quality of life and mobility and by reducing the risk of functional decline.14,15
Talking to the Healthcare Team
There are a few steps that patients can take to prepare for a conversation with their healthcare team. These include gathering information on family history and preparing a list of symptoms, which may help clinicians refer patients to the right specialist.16
Preparing a list of questions may also help guide consultations with the care team. These can focus on which specialists will have a role in the healthcare team, which tests need to be performed, which team will be the point of contact, and which medications are available to address different symptoms.17
1. Adams D, Algalarrondo V, Polydefkis M, Sarswat N, Slama MS, Nativi-Nicolau J. Expert opinion on monitoring symptomatic hereditary transthyretin-mediated amyloidosis and assessment of disease progression. Orphanet J Rare Dis. 2021;16(1):411. doi:10.1186/s13023-021-01960-9
2. Gertz M, Adams D, Ando Y, et al. Avoiding misdiagnosis: expert consensus recommendations for the suspicion and diagnosis of transthyretin amyloidosis for the general practitioner. BMC Fam Pract. 2020;21(1):198. doi:10.1186/s12875-020-01252-4
3. Vera-Llonch M, Reddy SR, Chang E, Tarbox MH, Pollock M. The patient journey toward a diagnosis of hereditary transthyretin (ATTRv) amyloidosis. Orphanet J Rare Dis. 2021;16(1):25. doi:10.1186/s13023-020-01623-1
4. Lousada I, Comenzo RL, Landau H, Guthrie S, Merlini G. Patient experience with hereditary and senile systemic amyloidoses: a survey from the Amyloidosis Research Consortium. Orphanet J Rare Dis. 2015;10(Suppl 1):P22. doi:10.1186/1750-1172-10-S1-P22
5. Lousada I, Comenzo RL, Landau H, Guthrie S, Merlini G. Patient experience with hereditary and wild-type transthyretin amyloidosis: a survey from the Amyloidosis Research Consortium. Poster presented at: First European Congress on Hereditary ATTR Amyloidosis; November 2-3, 2015; Paris, France.
6. Lane T, Fontana M, Martinez-Naharro A, et al. Natural history, quality of life, and outcome in cardiac transthyretin amyloidosis. Circulation. 2019;140(1):16-26. doi:10.1161/CIRCULATIONAHA.118.038169
7. Kapoor M, Rossor AM, Jaunmuktane Z, Lunn MPT, Reilly MM. Diagnosis of amyloid neuropathy. Pract Neurol. 2019;19(3):250-258. doi:10.1136/practneurol-2018-002098
8. Conceição I, Coelho T, Rapezzi C, et al. Assessment of patients with hereditary transthyretin amyloidosis – understanding the impact of management and disease progression. Amyloid. 2019;26(3):103-111. doi:10.1080/13506129.2019.1627312
9. Cardiologist. National Health Service (NHS). Accessed July 25, 2022.
10. Maurer MS, Bokhari S, Damy T, et al. Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis. Circ Heart Fail. 2019;12(9):e006075. doi:10.1161/CIRCHEARTFAILURE.119.006075
11. Dammacco R, Merlini G, Lisch W, et al. Amyloidosis and ocular involvement: an overview. Semin Ophthalmol. 2020;35(1):7-26. doi:10.1080/08820538.2019.1687738
12. Genetic testing and counseling for hATTR amyloidosis. American Heart Association. Accessed July 25, 2022.
13. Obici L, Kuks JB, Buades J, et al; European Network for TTR-FAP (ATTReuNET). Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis. Curr Opin Neurol. 2016;29(Suppl 1):S27-S35. doi:10.1097/WCO.0000000000000290
14. Redder E, Zhao Q, Bumma N, et al. Functional impairments of amyloidosis patients: physical therapy assessment. Hemato. 2022;3(3):414-421. doi:10.3390/hemato3030028
15. Exercise + physical therapy for neuropathy. The Foundation for Peripheral Neuropathy. Accessed July 25, 2022.
16. Start the hATTR amyloidosis conversation with your doctor. Alnylam Pharmaceuticals, Inc. Accessed July 25, 2022.
17. Treatment overview: hereditary transthyretin amyloidosis. Amyloidosis Research Consortium (ARC). Accessed July 25, 2022.
Reviewed by Kyle Habet, MD, on 7/27/2022.