Hereditary ATTR (hATTR ) Amyloidosis: .What is amyloidosis? • The amyloidoses are a heterogeneous group of disorders characterized by deposition of insoluble misfolded protein

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  • Hereditary ATTR (hATTR) Amyloidosis: CardiomyopathyAn OverviewIdentifying the link can lead to a crucial diagnosis

  • Hereditary ATTR (hATTR) Amyloidosis: CardiomyopathyInformation about mechanism of disease, signs and symptoms, diagnosis, and treatment

  • What is amyloidosis?

    The amyloidoses are a heterogeneous group of disorders characterized by deposition of insoluble misfolded protein aggregates, known as amyloid fibrils, in tissues1,2

    36 unique amyloid fibril proteins have been identified in humans2

    Amyloidosis can be acquired or hereditary, and systemic or localized3

    References:1. Shin S, et al. Mt Sinai J Med. 2012:79(6):733-748. 2. Sipe JD, et al. J Protein Fold Disord. 2016:23(4):209-213. 3. Rowczenio OM, et al. Human Mutat. 2014;35(9):E2403-E2412. As of

    8/22/17

  • The most common types of systemic amyloidosis1

    Four types are seen most frequently1,2:

    Type Precursor Protein Organs/Systems Targeted

    AL lmmunoglobulin light chain All organs except central nervous system

    AA (Apo) serum amyloid A All organs except central nervous system

    A2M2-microglobulin, wild type2-microglobulin, variant

    Musculoskeletal systemAutonomic nervous system

    ATTRTransthyretin, wild typeTransthyretin, variants

    Heart mainly in men, tenosynoviumNerves, heart, and GI tract

    References:1. Hazenberg BPC. Rheum Dis Clin N Am. 2013;39:323-345. 2. Damy T, et al. J Cardiovasc Transl Res. 2015;8(2):117-127. 3. Sipe JD, et al. J Protein Fold Disord. 2016:23(4):209-213.

    Nomenclature: The amyloidoses are named based on the disease-causing protein, with an A designating amyloid fibril. For example, when the type is ATTR the A

    designates amyloid fibril, and the TTR designates the transthyretin protein.3

    As of 8/22/17

  • Types of ATTR amyloidosis

    wtATTR hATTR

    DescriptionWild-type ATTR (wtATTR) amyloidosis, formerly known as senile systemic amyloidosis (SSA), is a nonhereditary, progressive disease of undefined etiology.1-3

    Hereditary ATTR (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease.8-10

    EtiologyMisfolded transthyretin (TTR) proteins accumulate as amyloid fibrils in multiple organs, including the heart.4,5

    Caused by a mutation in the TTR gene that results in misfolded TTR proteins accumulating as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal tract.1,8,11

    Symptoms Can cause cardiomyopathy and neuropathy, resulting in heart failure and mortality.4,6,7

    A multisystemic disease with a heterogeneous clinical presentation that includes sensory and motor, autonomic (e.g., diarrhea, erectile dysfunction, hypotension), and cardiac symptoms.8,12,13 Can lead to significant morbidity, disability, and mortality.4,8-10

    Time to Mortality

    Within 2 to 6 years (median overall survival of 3.6 years).4,6 Within 2 to 15 years.

    4,8

    References:1. Hawkins PN, et al. Ann Med. 2015;47(8):625-638. 2. Dubrey S, et al. Postgrad Med J. 2015;91(1078):439-448. 3. Kourelis TV, et al. Expert Rev Cardiovasc Ther. 2015;13(8):945-961. 4. Castao A, et al. Heart Fail Rev. 2015;20(2):163-178. 5. Westermark P, et al. Amyloid. 2003;10(suppl 1):48-54. 6. Pinney JH, et al. J Am Heart Assoc. 2013;2:e000098 doi:10.1161/JAHA.113.000098. 7. Coelho T, et al. Curr Med Res Opin. 2013;29(1):63-76. 8. Hanna M. Curr Heart Fail Rep. 2014;11(1):50-57. 9. Mohty D, et al. Arch Cardiovasc Dis. 2013;106(10):528-540. 10. Adams D, et al. Neurology. 2015:85(8):675-682. 11. Damy T, et al. J Cardiovasc Transl Res. 2015;8(2):117-127. 12. Conceio I, et al. J Peripher Nerv Syst. 2016;21(1):5-9. 13. Shin SC, et al. Mt Sinai J Med. 2012;79(6):733-748. As of

    8/22/17

  • Formation of amyloid fibrils in hATTR amyloidosis1,2

    Liver TTR TTR Misfolded Amyloid Fibrils

    Amyloid Deposits

    TTR is primarily synthesized in the liver

    Normally, TTR is a tetramer composed

    of four identical monomers

    In hATTR amyloidosis, the tetramer becomes destabilized, resulting in protein misfolding and aggregation into

    amyloid fibrils

    Amyloid fibrils are deposited at multiple

    sites in the body, including the nerves,

    heart, and the GI tract, causing damage that

    leads to clinical symptoms

    References:1. Sekijima Y. J Neurol Neurosurg Psychiatry. 2015;86(9):1036-1043. 2. Hawkins PN, et al. Ann Med. 2015;47(8):625-638. As of 8/22/17

  • hATTR amyloidosisa hereditary condition

    hATTR amyloidosis is an autosomal dominant disease; thus, a person only needs to inherit one copy of the mutated TTR gene from one parent to develop the condition1,2

    Penetrance is variable, and some individuals may remain asymptomatic despite having a TTR mutation1-3

    References: 1. Hanna M. Curr Heart Fail Rep. 2014;11(1):50-57. 2. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. 3. Hawkins PN, et al. Ann Med. 2015;47(8):625-638. As of

    8/22/17

  • TTR gene mutations

    More than 120 different TTR gene mutations have been discovered1-3

    The most common mutation is Val30Met. Individuals with this mutation often initially present with polyneuropathy

    Prevalence is higher in Portugal, Sweden, Japan, Brazil, and Spain

    The Val122Ile mutation is common in individuals who initially present with cardiomyopathy; found in 3 to 4% of the African American population

    Symptoms can present differently, even among people in the same family and in the same mutation3

    References: 1. Sekijima Y. J Neurol Neurosurg Psychiatry. 2015;86(9):1036-1043. 2. Rowczenio DM, et al. Hum Mutat. 2014;35(9):E2403-E2412. 3. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. As of

    8/22/17

  • hATTR amyloidosis affects an estimated 50,000 patients worldwide1

    In the disease continuum of hATTR amyloidosis:

    Disease symptoms fall along a spectrum

    References:1. Hawkins PN, et al. Ann Med. 2015;47(8):625-638. 2. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. 3. Rapezzi C, et al. Eur Heart J. 2013;34(7):520-528. 4. Adams D, et al. In: The XVth International Symposium on Amyloidosis. Uppsala, Sweden: ISA International Society of Amyloidosis; July 3-7, 2016. PA 82.

    Polyneuropathy Cardiomyopathy

    A substantial proportion of patients with hATTR amyloidosis presents with a mixed phenotype3,4

    Some patients present primarily with polyneuropathy symptoms, historically known as familial amyloidotic polyneuropathy (FAP)1,2

    Other patients present primarily with cardiomyopathy symptoms, historically known as familial amyloidotic cardiomyopathy (FAC)1,2

    As of 8/22/17

  • hATTR amyloidosis: a life-threatening,multisystem disease1-4

    Because amyloid fibrils are deposited in tissues throughout the body, including the nerves, heart, and GI tract, patients with hATTRamyloidosis can present across a spectrum that includes sensory and motor, autonomic, and cardiac symptoms1-6

    In addition to the varied symptom presentation, age of onset varies among patientswith a median age of 39 years, with some presenting as early as their 20s7,8

    References:1. Conceio I, et al. J Peripher Nerv Syst. 2016;21(1):5-9. 2. Mohty D, et al. Arch Cardiovasc Dis. 2013;106(10):528-540. 3. Shin SC, et al. Mt Sinai J Med. 2012;79(6):733-748. 4. Hanna M. Curr Heart Fail Rep. 2014;11(1):50-57. 5. Damy T, et al. J Cardiovasc Transl Res. 2015;8(2):117-127. 6. Hawkins PN, et al. Ann Med. 2015;47(8):625-638. 7. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. 8. Coelho T, et al. Curr Med Res Opin. 2013;29(1):63-76. As of

    8/22/17

  • Constellation of possible signs and symptoms of hATTR amyloidosis1

    Progressive dementia Headache Ataxia Seizures Spastic paresis Stroke-like episodes

    Proteinuria Renal failure

    Orthostatic hypotension Recurrent urinary tract

    infections (due to urinary retention)

    Sexual dysfunction Sweating abnormalities

    Vitreous opacification Glaucoma Abnormal conjunctival vessels Papillary abnormalities

    Conduction block Cardiomyopathy Arrhythmia

    Nausea & vomiting Early satiety Diarrhea Severe constipation Alternating episodes of diarrhea & constipation Unintentional weight loss

    Neuropathic pain Altered sensation (i.e., change in

    sensitivity to pain and temperature) Numbness and tingling Muscle weakness Impaired balance Difficulty walking

    Reference:1. Conceio I, et al. J Peripher Nerv Syst. 2016;21(1):5-9. As of

    8/22/17

  • Symptom presentation can vary among patients1

    In a multicenter study that included 186 individuals with hATTR amyloidosis, 58% (109/186) of hATTRamyloidosis patients presented with a mixed phenotype characterized by cardiac and neurologic involvement2

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    Sensory and motor Autonomic Cardiac

    References: 1. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. 2. Rapezzi C, et al. Eur Heart J. 2013;34(7):520-528. https://doi.org/10.1093/eurheartj/ehs123.

    Baseline clinical characteristics of 186 individuals with hereditary ATTR amyloidosis in a multicenter study2 Echocardiographic abnormalities included increased LV wall thickness, granular sparkling of ventricular myocardium, increased thickness of

    atrioventricular valves or interatrial septum, or pericardial effusion2 Electrocardiographic abnormalities included advanced A-V block or intraventricular conduction disturbances2

    As of 8/22/17

  • Symptoms of hATTR amyloidosis can progress quickly, leading to life-threatening dysfunction1-3

    As the disease progresses, symptoms increase in severity, leading to significant disability, decreased quality of life, and untimely