Hereditary Transthyretin Amyloidosis (hATTR)

Hereditary transthyretin amyloidosis (hATTR) is a rare and autosomal dominant disease characterized by the accumulation of amyloid protein in several organs due to changes in the transthyretin (TTR) gene.^1,2 Amyloid protein can typically build up in the nerves, heart, eyes, and gastrointestinal tract, leading to multiple signs and symptoms. Peripheral neuropathy (neuropathic pain, numbness in the hands and feet, and walking difficulties, among others), areflexia, apallesthesia, balance disorder, and cardiomyopathy are frequently identified.²

Hereditary transthyretin amyloidosis is a debilitating and fatal disease for which there is a lack of management guidelines.² Few reports are available on the monitoring of presymptomatic individuals and symptomatic patients.^3-5 Recent recommendations have been made available for the diagnosis, monitoring, and treatment of the disease, tailored for specific healthcare systems, such as those in Canada⁶ and Switzerland.⁷ Other publications intend to help specialists such as neurologists, cardiologists, and general practitioners to properly identify signs and symptoms of the disease.^8,9

Improving Diagnosis of hATTR With Polyneuropathy or Cardiac Amyloidosis

An international working group comprising amyloidosis specialists, the Amyloidosis Research Consortium (ARC), has collaborated with companies conducting research on amyloidosis, such as GSK and Ionis, to prepare a set of recommendations for the suspicion and diagnosis of all forms of ATTR.¹⁰ These recommendations were approved in consensus and have been set to provide the basis for early diagnosis of the disease so that targeted pharmacological treatment can be implemented.¹¹

For hATTR with predominant neuropathy, the expert group recommends consultation with a multidisciplinary team, which should include neurologists, cardiologists, and ophthalmologists. Improving the diagnosis of the disease with polyneuropathy may include the use of DNA testing to identify genetic mutations, amyloid typing, and biopsy of salivary glands, skin, and/or nerve tissue. Family members of patients are recommended to consult with a genetic counselor, and patients should follow up with their care team every 6 to 12 months according to the severity of symptoms and their response to medication.¹⁰

Recommendations focused on the best practices for the suspicion and diagnosis of ATTR associated with cardiomyopathy have also been published. Genetic testing is recommended to differentiate the hereditary form of the disease from the wild-type form. Diagnostic tests include echocardiography and cardiac magnetic resonance imaging (MRI), testing for monoclonal protein, scintigraphy, biopsy, and TTR genotyping. An early diagnosis of the condition in patients presenting with heart failure can be achieved through the evaluation of myocardial uptake on bone scintigraphy. Myocardial scintigraphy has advantages in terms of cardiac ATTR amyloid deposits. It is highly sensitive and specific to ATTR-CM. It is effective in identifying increases in atrial, ventricular, or septal wall thickness.¹¹

hATTR Monitoring and Evaluation of Disease Progression

Recently, a panel of neurologists and cardiologists from the United States and France have reached a consensus on recommendations for monitoring hATTR and its progression. This consensus has been achieved through a questionnaire on their clinical opinion following a round table meeting and 4 rounds of feedback.² 

The recommendations deriving from this consensus are set to identify symptoms and tests that allow clinicians to monitor patients with hATTR, determine disease progression following the tests performed, and establish the frequency of monitoring, aiming for early identification of disease progression. The published recommendations establish that patient assessment should be performed by a multidisciplinary team, including a neurologist, a cardiologist, a genetic counselor, and an ophthalmologist, ideally in a specialized center. Other medical professionals such as physical therapists may also be part of the specialized team.² 

Target organs must be assessed at baseline and during follow-ups, and signs and symptoms of autonomic neuropathy and cardiac dysfunction should be evaluated. Signs of autonomic neuropathy may be assessed through skin conductance, while cardiac dysautonomia can be identified by evaluating orthostatic hypotension, heart rate variability, or the Valsalva maneuver. For the study of cardiomyopathy, patients should undergo electrocardiography, measurement of cardiac biomarkers, and functional tests such as the 6-minute walk test. Cardiac imaging such as echocardiography and cardiac MRI can be used for disease monitoring. Experts recommend, however, that these tests are performed by the same operator with expertise in amyloid cardiomyopathy using the same machines and software. Tests to evaluate disease manifestations in the eyes include testing for vitreous opacities and glaucoma, while assessing creatinine clearance, albuminuria, and proteinuria is recommended to evaluate kidney function.²

Progression of the disease may be identified by the worsening of symptoms, the development of a new symptom, the worsening of a single symptom that leads to a significant functional impairment, or a combination of different signs and symptoms that indicate progression of the disease. Symptoms associated with general health, such as weight loss, and quality of life should also be considered when evaluating disease progression.² 

Follow-ups should be individualized to each patient. Patients that have at least 1 class of symptoms, such as neuropathy or cardiac symptoms, should be followed up at least once per year. Patients presenting with cardiac symptoms are recommended to follow up every 6 months. Pharmacological therapy with disease-modifying therapies should be started immediately in symptomatic patients.²

References

1. Familial transthyretin amyloidosis. Genetic and Rare Diseases Information Center (GARD). Updated November 8, 2021. Accessed July 5, 2022.

2. 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

3. 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

4. Conceição I, Damy T, Romero M, et al. Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations. Amyloid. 2019;26(1):3-9. doi:10.1080/13506129.2018.1556156

5. 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

6. Alcantara M, Mezei MM, Baker SK, et al. Canadian guidelines for hereditary transthyretin amyloidosis polyneuropathy management. Can J Neurol Sci. 2022;49(1):7-18. doi:10.1017/cjn.2021.34

7. Condoluci A, Théaudin M, Schwotzer R, et al. Management of transthyretin amyloidosis. Swiss Med Wkly. 2021;151:w30053. doi:10.4414/smw.2021.w30053

8. Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31. doi:10.1186/1750-1172-8-31

9. 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

10. Adams D, Ando Y, Beirão JM, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268(6):2109-2122. doi:10.1007/s00415-019-09688-0

11. 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

Reviewed by Debjyoti Talukdar, MD, on 7/31/2022.

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Diana Diez Gaspar, PharmD, PhD

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.