What Is Hereditary ATTR Amyloidosis (hATTR)?

Hereditary transthyretin amyloidosis (hATTR) is a rare, progressive, and fatal disease1,2

hATTR amyloidosis had been previously referred to as transthyretin familial amyloid polyneuropathy (TTR-FAP) or familial amyloid cardiomyopathy (TTR-FAC), deriving its name from the most predominant clinical presentation.3,4

Whereas the nonhereditary, wild-type ATTR amyloidosis primarily affects the heart, hATTR amyloidosis affects multiple organs and body systems, such as the heart, nervous system, gastrointestinal tract, and kidney.3,5,6

Hereditary ATTR amyloidosis causes

hATTR amyloidosis is a systemic disorder characterized by the extracellular deposition of misfolded transthyretin (TTR) protein. Normally, TTR is a tetramer made up of 4 single-chain monomers. TTR gene mutations are thought to destabilize the protein and cause tetramer dissociation into monomers, which aggregate into amyloid fibrils. These amyloid fibrils then accumulate in multiple organs throughout the body.3,4,7,8

hATTR AMYLOIDOSIS AND TTR PROTEIN MISFOLDING

Transthyretin Tetramer

Transthyretin Tetramer

Correctly Folded Protein

Correctly Folded Protein

Misfolded Protein

Misfolded Protein

Amyloid

Amyloid

hATTR & Protein Misfolding

Transthyretin Tetramer

Transthyretin Tetramer

Correctly Folded Protein

Correctly Folded Protein

Misfolded Protein

Misfolded Protein

Amyloid

Amyloid

 

hATTR amyloidosis progression

hATTR amyloidosis is a physically debilitating disease that can contribute significantly to morbidity and a decline in quality of life, negatively affecting activities of daily living. The rate at which hATTR amyloidosis progresses is unpredictable, but left untreated, death can occur within a few years of initial clinical presentation.4

hATTR amyloidosis diagnosis

Unfortunately, recognizing hATTR amyloidosis is complicated, because symptoms are nonspecific and can resemble other, more common conditions. This often results in patients having to see 5 or more physicians across multiple specialties before receiving an accurate diagnosis of hATTR amyloidosis. Further, because of misdiagnosis, many patients undergo treatment for unrelated conditions or diseases.4 Learn more about how to diagnosis hereditary ATTR amyloidosis.

Genetics and the hereditary nature of hATTR amyloidosis

hATTR amyloidosis is an autosomal dominant disease with variable penetrance. Amyloid deposition or symptomatic disease typically occurs in adults ranging from 30 to 70 years of age, depending on mutation. In fact, more than 120 amyloidogenic TTR mutations have been identified. In the United States, the most common mutations are V122I, T60A, and V30M.4

Although some mutations are more predominantly associated with polyneuropathy or cardiomyopathy, many patients with hATTR amyloidosis have mixed clinical phenotypes, including neurologic, cardiac, GI, and other signs and symptoms. Even those mutations on the far end of the spectrum, such as V30M and V122I, often have both cardiac and neuropathic manifestations; however, symptomatology is not always predictable, and it can differ even among affected family members.4

Genotype-phenotype relationship in hATTR

Genotype Phenotype Relationship in hATTR

Adapted with permission from Eur Heart J. 2013;34(7):520-528 and Am J Pathol. 1996;148(2):351-354.9,10

In Life-Threatening hATTR Amyloidosis, Hope Starts With Diagnosis.2

References: 1. Adams D, Amitay O, Coelho T. Patients with hereditary ATTR amyloidosis experience an increasing burden of illness as the disease progresses. Orphanet J Rare Dis. 2015;10(suppl 1):P58. 2. Conceição I, González-Duarte A, Obici L, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5-9. 3. Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31. 4. Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 2017;23(suppl 7):S107-S112. 5. Coelho T, Maurer MS, Suhr OB. THAOS—The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29(1):63-76. 6. Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D, Suhr OB. Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625-638. 7. Coelho T, Ericzon B-G, Falk R, et al. A guide to transthyretin amyloidosis. Amyloidosis Foundation. http://www.amyloidosis.org/wp-content/uploads/2017/05/2017-ATTR-guide.pdf. Accessed February 14, 2018. 8. Johnson SM, Connelly S, Fearns C, Powers ET, Kelly JW. The transthyretin amyloidosis: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory agency approved drug. J Mol Biol. 2012;421(2-3):185-203. 9. 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):520-528.10. Benson MD. Leptomeningeal amyloid and variant transthyretins. Am J Pathol. 1996;148(2):351-354.