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 systemic and progressive disease that derives from mutations in the transthyretin (TTR) gene that lead to the formation and deposit of amyloid fibers in organs and tissues. Amyloid fibers most often accumulate in the peripheral nerves (hATTR with polyneuropathy) and heart (hATTR with cardiomyopathy), although other organs and tissues, including the eyes and kidneys, may be affected.1,2
The first insights on hereditary amyloidosis date back to 1929, when De Bruyn and Stern described a 52-year-old patient who complained of pain and numbness in his extremities for the previous 3 years in addition to severe diarrhea and loss of energy. This patient had 2 brothers and 1 sister who had died following similar signs and symptoms. An autopsy revealed the presence of a non-nucleated substance in the peripheral nerves, which the authors believed to represent hypertrophy of the sheaths of Schwann. They suggested that these findings possibly corresponded to an early stage of a known disease or to a different process. These observations were indeed linked to hereditary amyloidosis.3
In 1952, Mário Corino de Andrade described the first form of hereditary amyloidosis, named familial amyloidotic polyneuropathy (FAP), also known as Andrade’s disease.4 Back in 1939, Andrade had observed a 37-year-old woman from the northern area of Portugal, Póvoa de Varzim, near Porto, who presented with a condition known in the area as “foot disease.”4,5 Up until 1952, 74 different patients with peripheral nervous system symptoms had been observed. Patients presented with a loss of sensitivity to temperature or pain. Andrade also observed that multiple other families within the same area were affected. These families were mainly those of fishermen who complained about a lack of foot sensitivity when touching the ropes of their fishing boats.4,5 The condition presented in the second or third decade of life and manifested as paresthesia or analgesia with muscle weakness and impaired reflexes. Other symptoms included abdominal distension and gastrointestinal and sexual issues, while death occurred mainly from cachexia and infection.4,5 Andrade believed this was a rare hereditary disease, and by collaborating with different colleagues from genetics and pathology, he confirmed the genetic nature of the disease and observed amyloid deposits in the peripheral nervous system.4
In 1968 and 1976, similar cases of the disease were reported in Swedish patients.6,7 These patients, however, showed a later onset of the disease, around 55 years of age, and more frequently presented with peptic ulcers.5 Cases of familial amyloid polyneuropathy starting between 25 and 35 years of age were thereafter reported in 1981 in Japan, in the Kumamoto and Nagano prefectures.8 In addition to Portugal, Sweden, and Japan, the disease has now been identified in many other countries, including the United States and some countries of South America.9
Costa et al reported in 1978 that the familial amyloid polyneuropathy cases related to Portuguese, Swedish, and Japanese families derived from amyloid fibrils of transthyretin (TTR) protein, also known as prealbumin.10 The primary structure of TTR had already been determined in 1974.11 In 1985, Saraiva et al concluded that this form of the disease derived from a methionine substitution for a valine at position 30 on the TTR gene,12 while the structure of the TTR protein was later revealed.13 Ducla-Soares et al determined that autonomic dysfunction was typically the first sign in most patients with this mutation, preceding other known neurologic changes.14 It is still unclear how gene transmission occurred between the 3 countries, although the high prevalence of the disease in the coastal region near Porto, Portugal may link the transmission to possible Viking visits between Sweden and Western Europe in the 8th century.5
Other manifestations of hereditary amyloidosis related to known TTR mutations have been described. Carpal tunnel syndrome was reported in a family of Swiss origin in 1956, with mild cardiac involvement, related to the SER84 mutation. Other examples include Danish and American families with cardiac amyloid deposits.5
1. Ando Y, Adams D, Benson MD, et al. Guidelines and new directions in the therapy and monitoring of ATTRv amyloidosis. Amyloid. Published online June 2, 2022. doi:10.1080/13506129.2022.2052838
2. Luigetti M, Romano A, Di Paolantonio A, Bisogni G, Sabatelli M. Diagnosis and treatment of hereditary transthyretin amyloidosis (hATTR) polyneuropathy: current perspectives on improving patient care. Ther Clin Risk Manag. 2020;16:109-123. doi:10.2147/TCRM.S219979
3. De Bruyn RS, Stern RO. A case of the progressive hypertrophic polyneuritis of Dejerine and Sottas, with pathological examination. Brain. 1929;52(1):84-107. doi:10.1093/brain/52.1.84
4. Andrade C. A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain. 1952;75(3):408-427. doi:10.1093/brain/75.3.408
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9. Benson MD. Transthyretin amyloidosis: a little history of hereditary amyloidosis. Amyloid. 2017;24(sup1):76-77. doi:10.1080/13506129.2017.1281116
10. Costa PP, Figueira AS, Bravo FR. Amyloid fibril protein related to prealbumin in familial amyloidotic polyneuropathy. Proc Natl Acad Sci U S A. 1978;75(9):4499-4503. doi:10.1073/pnas.75.9.4499
11. Kanda Y, Goodman DS, Canfield RE, Morgan FJ. The amino acid sequence of human plasma prealbumin. J Biol Chem. 1974;249(21):6796-6805. doi:10.1016/S0021-9258(19)42128-5
12. Saraiva MJ, Costa PP, Goodman DS. Biochemical marker in familial amyloidotic polyneuropathy, Portuguese type. Family studies on the transthyretin (prealbumin)-methionine-30 variant. J Clin Invest. 1985;76(6):2171-2177. doi:10.1172/JCI112224
13. Monaco HL, Rizzi M, Coda A. Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science. 1995;268(5213):1039-1041. doi:10.1126/science.7754382
14. Ducla-Soares J, Alves MM, Carvalho M, Póvoa P, Conceição I, Sales Luis ML. Correlation between clinical, electromyographic and dysautonomic evolution of familial amyloidotic polyneuropathy of the Portuguese type. Acta Neurol Scand. 1994;90(4):266-269. doi:10.1111/j.1600-0404.1994.tb02719.x