Erum Naqvi obtained her Ph.D. in Molecular Medicine from Hannover Medical School (Germany) after completing her Masters in Biomedical Science and Bachelors in Microbiology from University of Delhi (India). She has several years of experience as a science writer.
Hereditary transthyretin-mediated amyloidosis (hATTR) is a rare, inherited, progressive, degenerative, physically debilitating, and fatal disease caused by mutations in the transthyretin (TTR) gene that lead to misfolding of the transthyretin protein. This results in the deposition of insoluble, misassembled amyloid fibrils in various organs and tissues of the body that disrupt normal tissue structure and function.1
The disease course may progress with symptoms of somatic and autonomic neuropathy, cardiac dysfunction and restrictive cardiomyopathy, significant disability, and eventually mortality if left untreated.2
More than 130 gene mutations have been reported to be related to hATTR. The most common TTR mutations in the world are Val30Met, Val122Ile, and Glu89Gln, with Val30Met being predominant in Portugal, Spain, France, Japan, Sweden, and some nonendemic areas of Africa.3
There is considerable variability in the penetrance, symptoms, and course of the disease across TTR variants, even within families. Thus, the age of disease onset and rate of disease progression can differ among the patient population. However, once symptoms appear, the disease advances rapidly without treatment. Due to the variable nature of disease penetrance, clinical manifestations, and the course of disease across TTR variants, timely and appropriate diagnosis can be difficult. This may even result in an incorrect or delayed diagnosis, which can severely impact the quality of life of these patients, and they may go on to develop severe end-organ impairment.2
In patients with predominant polyneuropathy, the disease progresses from sensory loss in the feet to sensory loss in the proximal lower limbs, lower limb weakness that later extends to the hands, and increasingly severe autonomic dysfunction. Deterioration is more rapid in patients with late-onset disease than in those with early-onset disease. Locomotion is significantly affected in a progressive manner, with patients requiring assistance with walking within 3 to 5 years of onset and becoming wheelchair-bound within 5 to 10 years, depending on the age of onset and TTR variant. Multisystem impairment is associated with poor prognosis, with the median overall survival time after diagnosis reported to be 4.7 years.2,4
Once an accurate diagnosis is established, newly diagnosed patients should undergo appropriate therapy as soon as possible. There is no known cure for hATTR, but early diagnosis and treatment may slow the progression of the disease. With advances in diagnostic imaging and the emergence of novel TTR-targeted therapies, the prognosis of hATTR is improving.
Prognostic Staging Systems
Several prognostic staging systems have been devised in patients with hATTR with cardiomyopathy.
According to a study conducted at the UK National Amyloidosis Centre, 3 prognostic stages were defined based on renal dysfunction (estimated glomerular filtration rate [eGFR] threshold <45 mL/min) and elevations in N-terminal pro-B-type natriuretic peptide level (NT-proBNP; >3000 ng/L). Stage I included patients with no elevation in NT-proBNP level and an eGFR above or equal to the threshold, stage II included patients with either an elevated NT-proBNP level or a low eGFR alone, and stage III included patients with an elevation in NT-proBNP level and an eGFR below the threshold. The outcomes were significantly worse in patients with higher stages of disease, with the median survival time decreasing from 69.2 months in stage I patients to 24.1 months in stage III patients.5
A group from Columbia University studied the additive prognostic value of diuretic dose and New York Heart Association (NYHA) functional class to pre-existing risk staging systems. A point system was used for the daily diuretic dosing and was categorized into furosemide equivalents, with 0 points for 0 mg/kg, 1 point for >0 to 0.5 mg/kg, 2 points for >0.5 to 1 mg/kg, and 3 points for >1 mg/kg. The NYHA functional class was similarly assigned to a point system with 1 point per class, ranging from 1 to 4 points. The addition of these variables significantly improved the accuracy of the pre-existing risk staging systems, increasing the area under the curve for the UK risk model from 0.711 to 0.813 for all-cause mortality.6
In patients with hATTR with polyneuropathy, plasma neurofilament light chain may be a useful prognostic biomarker, demonstrating a 4-fold increase compared to healthy controls and correlating with disease severity. It may also discriminate between asymptomatic Val30Met mutation carriers and those with hATTR polyneuropathy in the early disease stages.7
- Sekijima Y. Hereditary transthyretin amyloidosis. In: Adam MP, Mirzaa GM, Pagon RA, et al, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 2001. Updated June 17, 2021. Accessed July 28, 2022.
- 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
- Obi CA, Mostertz WC, Griffin JM, Judge DP. ATTR epidemiology, genetics, and prognostic factors. Methodist Debakey Cardiovasc J. 2022;18(2):17-26. doi:10.14797/mdcvj.1066
- Swiecicki PL, Zhen DB, Mauermann ML, et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123-131. doi:10.3109/13506129.2015.1019610
- Gillmore JD, Damy T, Fontana M, et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018;39(30):2799-2806. doi:10.1093/eurheartj/ehx589
- Cheng RK, Levy WC, Vasbinder A, et al. Diuretic dose and NYHA functional class are independent predictors of mortality in patients with transthyretin cardiac amyloidosis. JACC CardioOncol. 2020;2(3):414-424. doi:10.1016/j.jaccao.2020.06.007
- Ticau S, Sridharan GV, Tsour S, et al. Neurofilament light chain as a biomarker of hereditary transthyretin-mediated amyloidosis. Neurology. 2021;96(3):e412-e422. doi:10.1212/WNL.0000000000011090
Reviewed by Hasan Avcu, MD, on 7/28/2022.