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 (hATTR) amyloidosis is a rare systemic disorder associated with mutations in the transthyretin (TTR) gene, in which abnormal proteins (amyloid) accumulate in various organs and tissues, impairing function. As the disease progresses, the symptoms become more severe. If hATTR is not treated, serious complications may result. Early detection and intervention are essential to arresting or delaying disease progression.1,2
The symptoms of hATTR amyloidosis differ depending on the genetic variant, the organs affected, and the amount of damage caused by the amyloid deposits. Symptoms may appear at any time during adulthood. In addition to the peripheral nerves and heart, the gastrointestinal tract, kidney, and eyes may be affected. Thus, hATTR amyloidosis is a multisystem disease that varies widely in its clinical presentation and course, is life-threatening, and typically results in death within 10 years.3,4
Peripheral Nervous System Complications
Continuous pain and paresthesias, abnormal gait and walking difficulties, irreversible disabilities, and problems with fine motor skills are the complications of peripheral nerve involvement. Sensitivity to pain is increased, and sensitivity of heat is decreased. Muscle stiffness and weakness can develop as the condition worsens. Walking and other activities that depend on fine motor skills can be challenging when coordination is compromised.1,2 Bilateral carpal tunnel syndrome is particularly noted in individuals with a family history of hATTR amyloidosis.5
Autonomic Nervous System Complications
Autonomic dysfunction is usually present, especially in patients with an early onset of disease. The complications of autonomic neuropathy can include syncope, orthostatic hypotension, recurrent urinary tract infection, bladder dysfunction, erectile dysfunction, sexual dysfunction, and sweating abnormalities. Constipation, diarrhea, alternating constipation and diarrhea, early satiety, nausea, and vomiting are gastrointestinal symptoms that can be manifestations of autonomic dysfunction.2,4,5
While hATTR amyloidosis remains latent for a long time, the following cardiac conditions may develop: progressive biventricular wall thickening, diastolic dysfunction due to loss of compliance, irregular heartbeat (including atrial fibrillation), conduction disorders (arrhythmias, bundle branch blocks), symptoms of congestive heart failure with preserved ejection fraction (including dyspnea, generalized fatigue, and peripheral edema), cardiomyopathy, and mild regurgitation. Arrhythmias and/or conduction blocks are frequent in early-onset disease associated with the Val30Met mutation or other mutations (eg, Glu89Gln).4,5
Chronic diarrhea, severe constipation, alternating diarrhea and constipation, and unintentional weight loss are caused by the presence of amyloid deposits in the gastrointestinal system.5
Leptomeningeal amyloid angiopathy has been linked to central nervous system (CNS) dysfunction in hATTR amyloidosis, sometimes in conjunction with ocular impairment (oculoleptomeningeal amyloidosis). Leptomeningeal and meningovascular amyloidosis are uncommon types of amyloidosis associated with rare TTR mutations, such as Ala25Thr or Tyr69His, but advanced stages of hATTR-Val30Met amyloidosis may also cause CNS dysfunction, leading to stroke, hydrocephalus, cerebellar ataxia, spastic paresis, seizures, dementia, subarachnoid hemorrhage, and loss of hearing.4
Ophthalmologic complications occur as a result of the almost ubiquitous accumulation of mutant TTR protein in ocular tissues. The manifestations are variable and include vitreous opacities, chronic open-angle glaucoma, abnormal conjunctival vessels, sicca keratoconjunctivitis, loss of corneal sensitivity and neurotrophic corneal ulcers, lens anterior capsule opacities, retinal vascular changes, pupillary light-near dissociation, irregular pupil, and optic neuropathy. Several complications are associated with each of these that can impair a patient’s quality of life and result in irreparable blindness if diagnosis and treatment are delayed.6
Renal involvement usually causes complications such as nephrotic syndrome and/or progressive renal failure, seen in approximately one third of Portuguese patients with the Val30Met mutation, but in only 6% of patients with sporadic hATTR amyloidosis.2,5
General health complications include cachexia, fatigue, and reduced quality of life.4 Other possible severe complications are lumbar spinal stenosis and spontaneous rupture of the distal biceps tendon.5
- Hereditary transthyretin amyloidosis. Amyloidosis Research Consortium (ARC). Published 2021. Accessed July 27, 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;16:411. doi:10.1186/s13023-021-01960-9
- Hereditary ATTR amyloidosis. Amyloidosis Research Consortium (ARC). Published 2022. Accessed July 27, 2022.
- 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
- Gertz MA, Mauermann ML, Grogan M, Coelho T. Advances in the treatment of hereditary transthyretin amyloidosis: a review. Brain Behav. 2019;9(9):e01371. Published online August 1, 2019. doi:10.1002/brb3.1371
- Minnella AM, Rissotto R, Antoniazzi E, et al. Ocular involvement in hereditary amyloidosis. Genes (Basel). 2021;12(7):955. doi: 10.3390/genes12070955
Reviewed by Hasan Avcu. MD, on 7/27/2022.