Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.
Hereditary transthyretin amyloidosis (hATTR) is a rare genetic disease deriving from mutations in the transthyretin (TTR) gene.1 This disease presents with clinical heterogeneity and is characterized by a progressive neuropathy of both the peripheral sensorimotor and autonomic systems, as well as by cardiomyopathy, nephropathy, and vitreous and central nervous system (CNS) complications.2
Correlation Between Genotype and Phenotype
Patients with hATTR can present with a neurological phenotype, a cardiac phenotype, or a mix of both.3,4 As the disease progresses, exclusive phenotypes tend to become mixed.4 The prognosis is typically poorer in patients with exclusive cardiac phenotypes, with a life expectancy of about 2 to 5 years after symptom onset in these patients.3
Phenotypes in hATTR derive from specific mutations, but they also depend on the age of onset. Mutations associated with cardiac phenotypes include Val122Ile, Ile68Leu, Thr60Ala, and Leu111Met, while Ser50Arg and Ala97Ser are genetic mutations linked to neurological phenotypes.3,4
In hATTR, other organs and tissues can be affected besides the nerves and the heart, but the association between the damage to these structures and each specific mutation is less clear. The Val30Met mutation, however, has been potentially associated with kidney damage and progressive renal failure.4
Age of Onset and Phenotype
The onset of hATTR has been classically divided according to studies conducted in regions where the Val30Met mutation has been found: Japan, Portugal, and Sweden.4 The disease may have an early onset, with patients manifesting the disease before 50 years of age, or a late onset, with patients being at least 50 years of age at the time of diagnosis.4 In Portugal and Japan, hATTR usually manifests between the third and fifth decades of life, while in other areas, the onset of the disease occurs later.2 In endemic areas, patients can share similar genotypes but present with distinct pathological and clinical features.3
The age at which patients develop hATTR appears to affect the phenotype and the clinical course of the disease.3 The disease does not have a penetrance of 100%, therefore, patients may carry pathogenic mutations and remain asymptomatic until later in life.2 There is, however, no association between age and specific mutations. For instance, patients presenting with a Val30Met mutation and a late onset of the disease and patients with a non-Val30Met mutation typically have a cardiac phenotype, a large-fiber neuropathy, or a mix of both phenotypes.3,4 In contrast, early-onset patients tend to present with a small-fiber neuropathy, upper-limb-onset neuropathy, pseudo-chronic inflammatory demyelinating polyneuropathy, and motor neuropathy.4
Clinical Description of Hereditary Transthyretin Amyloidosis
In hATTR, patients may describe having generalized symptoms such as weight loss or fatigue. These occur most frequently in patients with early-onset hATTR derived from Val30Met mutations. The Val30Met variant of TTR is responsible for ATTRv amyloidosis in the regions where it is endemic. Both the Val30Met and Thr119Met mutations has the potential to slow down the initial misfolding event related tetramer dissociation.4
Patients with a neurological phenotype experience sensory neuropathy that begins with paresthesia and hypoesthesia of the feet and progresses to motor neuropathy. This neuropathy has a slow progression, leading to muscle atrophy and weakness of the extremities over time.2 Other early features include carpal tunnel syndrome and autonomic dysfunction, such as orthostatic hypotension, constipation and/or diarrhea, nausea, and sexual impotence. Late clinical manifestations of the disease in these patients include cardiomyopathy, vitreous opacities, glaucoma, CNS symptoms, and kidney damage.2 With specific variants of the disease, including Ser77Tyr, Ile107Val, and Val122Leu, the first symptoms of hATTR can include gait instability or weakness of the limbs.4 Cachexia is typically observed toward the end of the disease, and patients usually die of cardiac failure, renal failure, or infection.2
In patients presenting with a cardiac phenotype, cardiomegaly, arrhythmias, angina, and congestive heart failure are expected. Sudden death can also occur. Cardiac amyloidosis is commonly associated with a late onset of the disease.2 Patients with a neurological phenotype may also develop cardiac amyloidosis that remains undiagnosed until later stages of the disease.4
The eyes and the CNS may be affected individually or in combination, including in combination with other organs.3,4 Ocular damage is frequent, and patients with Val30Met variants report dry eye syndrome, glaucoma, and vitreous disease.3 When the CNS is affected by leptomeningeal amyloid angiopathy, patients can develop epilepsy, brain hemorrhage, and dementia.4 These symptoms can be also found in patients with Val30Met mutations who are in the advanced stages of hATTR.3
1. Manganelli F, Fabrizi GM, Luigetti M, Mandich P, Mazzeo A, Pareyson D. Hereditary transthyretin amyloidosis overview. Neurol Sci. Published online November 14, 2020. doi:10.1007/s10072-020-04889-2
2. 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 26, 2022.
3. 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
4. Adams D, Koike H, Slama M, Coelho T. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol. 2019;15(7):387-404. doi:10.1038/s41582-019-0210-4
Reviewed by Debjyoti Talukdar, MD, on 7/31/2022.