ATTR-CM | Suspect & Detect | Hereditary ATTR-CM

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Hereditary ATTR-CM (hATTR-CM)

About hATTR-CM
Patient population
Importance of early detection
Understanding genetic risk

hATTR-CM is a type of amyloidosis caused by a mutation in the TTR gene¹

Looking for infomation about wild-type ATTR-CM? Read more

hATTR-CM is inherited in an autosomal dominant pattern, meaning only 1 affected relative is required to pass on the mutation.²The most common mutations responsible for a cardiac phenotype are in patients of African American (V122I), Irish (T60A), Italian (I68L), and Danish (L111M) descent.³

Not all patients who carry a TTR mutation will go on to have clinical signs and symptoms of this disease⁴

About 75% of patients with hATTR-CM exhibited cardiomyopathic features of the disease.³

Carpal tunnel syndrome is also common and can often be the initial symptom in more than 30% of hATTR-CM patients, with cardiomyopathy symptoms following as the disease progresses.⁵

Penetrance data has shown great heterogeneity of the disease, depending on the phenotype, genotype, and environmental factors.⁶

An overview of hATTR-CM patient population

Who is at risk?

Men and women⁷
Age at symptom onset depends on the mutation, but may occur as early as 30 to 40 years (V30M, L111M), or 50 to 60 years (V122I, V30M, T60A), and 55 years (I68L)^8-10

Common characteristics of hATTR-CM

Heart failure¹¹
Peripheral dysfunction (eg, peripheral sensorimotor dysfunction, peripheral neuropathy)¹¹
History of bilateral carpal tunnel syndrome^11,12
Autonomic dysfunction (eg, autonomic neuropathy, gastrointestinal symptoms, unexplained weight loss, orthostatic hypotension, erectile dysfunction)^11,13

Early detection is critical

Advanced hATTR-CM in untreated patients is associated with rapid progression, serious cardiac complications, and increased mortality, regardless of phenotype.^7,11,14

Prognosis

Once diagnosed, untreated patients have a median survival of ~2 to 3 years¹¹

Early recognition of cardiac involvement in hereditary amyloidosis is critical¹⁵

Increased serum levels of NT-proBNP can reveal cardiac involvement

NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Understanding genetic risk for hATTR-CM

Diagnosis of hATTR-CM in an index patient should prompt genetic counselling and testing of relatives.¹⁰

A targeted approach may enable diagnosis of disease at the first detectable sign or symptom¹⁰:

Early identification of ATTR-CM is important to enable timely treatment
Genetic testing is used to detect the presence of a mutation in the TTR gene and therefore confirm a diagnosis of hATTR-CM
Genetic counselling and testing can be especially beneficial in at-risk relatives of an index patient

Timing of genetic testing in at-risk relatives should take into account¹⁰:

The particular mutation
The penetrance of the mutation
The age of onset and severity of disease in the index patient

Suspect ATTR-CM >

References:

Benson MD, Buxbaum JN, Eisenberg DS, et al. Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee. Amyloid. 2018;25(4):215-219. doi:10.1080/13506129.2018.1549825

Sekijima Y. Hereditary Transthyretin Amyloidosis. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. Seattle, WA: University of Washington; 1993-2022.

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

Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31. doi:10.1186/1750-1172-8-31

Kapoor M, Rossor AM, Laura M, Reilly MM. Clinical presentation, diagnosis, and treatment of TTR amyloidosis. J Neuromuscul Dis. 2019;6(2):189-199. doi:10.3233/JND-180371

Lahuerta Pueyo C, Aibar Arregui MÁ, Gracia Gutierrez A, Bueno Juana E, Menao Guillén S. Estimating the prevalence of allelic variants in the transthyretin gene by analysing large-scale sequencing data. Eur J Hum Genet. 2019;27(5):783-791. doi:10.1038/s41431-019-0337-1

Maurer MS, Hanna M, Grogan M, et al. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol. 2016;68(2):161-172. doi:10.1016/j.jacc.2016.03.596

Rapezzi C, Quarta CC, Riva L, et al. Transthyretin-related amyloidoses and the heart: a clinical overview. Nat Rev Cardiol. 2010;7(7):398-408. doi:10.1038/nrcardio.2010.67

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

Conceição I, Damy T, Romero M, et al. Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations. Amyloid. 2019;26(1):3-9. doi:10.1080/13506129.2018.1556156

Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135(14):1357-1377. doi:10.1161/CIRCULATIONAHA.116.024438

Witteles RM, Bokhari S, Damy T, et al. Screening for transthyretin amyloid cardiomyopathy in everyday practice. JACC Heart Fail. 2019;7(8):709-716. doi:10.1016/j.jchf.2019.04.010

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. doi:10.1185/03007995.2012.754348

Conceição I, Coelho T, Rapezzi C, et al. Assessment of patients with hereditary transthyretin amyloidosis–understanding the impact of management and disease progression. Amyloid. 2019;26(3):103-111. doi:10.1080/13506129.2019.1627312

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

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