Hereditary Transthyretin Amyloidosis (hATTR)

Hereditary transthyretin-related amyloidosis (hATTR) is a rare, multisystem, progressive, debilitating disease that, if left untreated, can be fatal. The disease shows an autosomal dominant pattern of inheritance.¹ In hATTR, the transport protein transthyretin (TTR), which is made by the liver, forms amyloid fibrils that are deposited extracellularly. The most prevalent type of familial amyloidosis is hATTR, which can be caused by 100 amyloidogenic TTR gene mutations. The clinical spectrum of the disease ranges considerably from predominantly cardiac manifestations to an involvement that is purely neurological.²

This multisystemic condition has a wide range of clinical manifestations, making it frequently misdiagnosed or vulnerable to delayed diagnosis. Improper or late diagnosis due to the varied nature of its presentation can significantly lower these patients’ quality of life. Hereditary transthyretin-related amyloidosis can cause serious disability and death. Patients should start receiving appropriate therapy as soon as possible when a precise diagnosis of hATTR has been made.³ Phenotypes of hATTR have been divided into cardiac, neurological, and mixed. These phenotypes are influenced by mutations and the age at symptom onset. For instance, some mutations, like Val122Ile and Leu111Met, are linked to a cardiac phenotype, while others, like Ser50Arg89 and Ala97Ser74, are linked to a neurological phenotype.⁴

Differential Diagnosis of Neurological Phenotype

Early diagnosis and treatment of hATTR with polyneuropathy are crucial because there are treatments that can reduce the progression of neuropathy. TTR protein misfolds to produce amyloid, which then accumulates in the endoneurium, causing this progressive, severe, and systemic form of hATTR disease.⁵ Misdiagnosis may occur based on the early clinical signs and nerve conduction investigations.⁴ 

One of the most common misdiagnoses is chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), which shares many characteristics with late-onset hATTR, such as sensorimotor impairment with areflexia, common albuminocytological dissociation in the cerebrospinal fluid, and, in 12.5% to 15% of cases, nerve conduction studies that meet the criteria for CIDP set forth by the European Federation of Neurological Sciences/Peripheral Nerve Society (EFNS/PNS).⁴ Patients with hATTR may be misdiagnosed with CIDP, especially those in the advanced disease stage; however, a thorough review of electrophysiological evidence shows that slow nerve conduction velocity is related to axonal loss and a large decrease in compound muscle action potential amplitudes. A lack of responsiveness to treatment (such as immunoglobulins) favors a diagnosis of hATTR.⁵ 

It is important to identify amyloid deposits in peripheral nerve biopsies to differentiate hATTR from other diseases. In the late stages of the disease, examination of sural nerve biopsies usually shows amyloid deposits, marked loss of axons, and abnormal myelin findings. Additionally, skin biopsies reveal a loss of nerve fibers in the early stages of the disease but little to no amyloid deposition compared to advanced disease stages.⁵ 

Paraproteinemic neuropathies including amyloid light-chain (AL) amyloidosis and POEMS syndrome, which share features like axonal and demyelinating disease nature as well as multisystem involvement (eg, heart in AL amyloidosis), represent another misdiagnosis. A hematological assessment is required to rule out plasmacellular dyscrasia because a paraproteinemia of unknown significance can coincide with hATTR.^1,5

Other frequent misdiagnoses include Charcot-Marie-Tooth neuropathy, idiopathic axonal polyneuropathy, lumbar spinal stenosis, paraproteinemic neuropathy, vasculitis peripheral neuropathy, toxic peripheral neuropathy, alcoholic neuropathy, CIDP, and diabetic neuropathies. Early investigation of concomitant clinical characteristics, particularly cardiac involvement, can aid in the identification of amyloidosis in individuals with peripheral neuropathy of unknown cause. The presence of amyloid in a biopsy sample and/or the finding of an amyloidogenic mutation on TTR gene sequencing can help confirm the diagnosis.⁶ 

Differential Diagnosis of Cardiac Phenotype 

Hereditary transthyretin-related amyloidosis with mainly cardiac involvement (also called familial amyloidotic cardiomyopathy) is underdiagnosed. It can resemble other causative factors of left ventricular hypertrophy, like hypertensive heart disease, hypertrophic cardiomyopathy, and the nonmutant form of hATTR (senile systemic amyloidosis).² The aim of undergoing various cardiac tests in hATTR is to identify severe conduction diseases that can cause infiltrative cardiomyopathies and sudden death. Echocardiogram may offer many useful hints for a differential diagnosis. Evaluation of LV systolic function in amyloidotic cardiomyopathy patients may show lower LV ejection fraction and greater LV end-diastolic dimension.⁴ 

References

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. Rapezzi C, Quarta CC, Obici L, et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J. 2013;34(7):520-528. doi:10.1093/eurheartj/ehs123
3. Gertz MA, Mauermann ML, Grogan M, Coelho T. Advances in the treatment of hereditary transthyretin amyloidosis: a review. Brain Behav. 2019;9(9):e01371. doi:10.1002/brb3.1371
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
5. 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
6. 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

Reviewed by Debjyoti Talukdar, MD, on 7/19/2022.

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Harshi Dhingra, MD

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.