Although mutations are present from birth, symptoms do not appear until adulthood, primarily because various degrees of penetrance are observed from one individual to another [15]. FAP patients frequently report peripheral neuropathy of sensory nerves, usually in the lower limbs and sensations such as pain and temperature are affected [5]. Wasting and weakness are also accompanying features, whereas autonomic system dysfunction is manifested by diarrhea, constipation, urinary incontinence, orthostatic hypotension and sexual impotence [5]. Apart from symptoms regarding the nervous system, both cardiac and renal dysfunction may be observed [5], particularly in patients with cardiomyopathy forms. Microalbuminuria, heavy proteinuria and progressive renal failure that leads to insufficiency is seen in patients with kidney deposits, but also anemia, since EPO production may be impaired [10] [11]. In some patients, a leptomeningeal form that include ataxia, spastic paralysis, seizures, dementia and visual disturbances as most important symptoms may be seen [1] [5]. Keratoconjuctivitis sicca, glaucoma, reduced vitreous opacity are most frequent ocular complaints [5].

• Pain

  […] sick (nausea) Stomach pain Feeling short of breath, cough, or other breathing problems Headache Chest discomfort or chest pain Rash Chills Dizziness Feeling tired (fatigue) Rapid heart rate Facial swelling If you have an infusion-related reaction, your [onpattro.com]

  […] weakness and pain Autonomic neuropathy – Light-headedness when standing (orthostatic hypotension), bladder problems, bowel problems, sexual dysfunction Gastrointestinal – Decreased appetite, diarrhea, nausea, stomach pain, weight loss Some ATTR variants [amyloidosis-austria.at]

  That neuropathy tends to be quite a bit of pain: sharp, stabbing pain, prickling and tingling, numbness. [neurologylive.com]

  Get emergency help immediately if you have any symptoms of a serious allergic reaction, including joint pain, chills, redness on palms of hands, muscle pain, chest pain, flushing, tremor or jerking movements, flu-like symptoms, high blood pressure, or [tegsedi.com]

  The first symptoms of TTR-FAP are paresthesia, pain or trophic foot injuries, gastrointestinal disorders and weight loss. In later stages, the most pronounced sensory loss involves pain and changes in the thermal sensation. [meetingcampus.com]

• Weakness

  Some people with this form of transthyretin amyloidosis develop carpal tunnel syndrome, which is characterized by numbness, tingling, and weakness in the hands and fingers. [medlineplus.gov]

  Wasting and weakness are also accompanying features, whereas autonomic system dysfunction is manifested by diarrhea, constipation, urinary incontinence, orthostatic hypotension and sexual impotence. [symptoma.com]

  I have to admit when I saw them, they did have very prominent weakness, and they often did not have prominent autonomic symptoms. [neurologylive.com]

  Neurological manifestations of hATTR include unrelated tingling, pain and numbness in the arms and / or legs, muscle weakness, muscle cramps and paralysis, bladder discomfort, constipation or diarrhea, and even impotence. [centogene.com]

  Weakness and paresthesias of one or both hands, suggesting carpal ligament involvement, is often the presenting symptom in patients with the variant TTR L58H. It can also be observed in patients with other variants. [emedicine.medscape.com]

• Weight Loss

  Autonomic neuropathy is manifest by gastrointestinal symptoms of diarrhea with weight loss and orthostatic hypotension. [bu.edu]

  On multivariate analysis, age at diagnosis (risk ratio, 15.65; p < 0.0001), Thr60Ala mutation (risk ratio, 1.52; p = 0.04), Val122Ile mutation (risk ratio, 2.83; p = 0.003), peripheral neuropathy (risk ratio, 1.69; p = 0.013) and weight loss (risk ratio [mayoclinic.pure.elsevier.com]

  loss Some ATTR variants are associated with specific symptoms. [amyloidosis-austria.at]

  The first symptoms of TTR-FAP are paresthesia, pain or trophic foot injuries, gastrointestinal disorders and weight loss. In later stages, the most pronounced sensory loss involves pain and changes in the thermal sensation. [meetingcampus.com]

• Fatigue

  […] symptoms.2 Ocular Manifestations1 Dark floaters Glaucoma Abnormal blood vessels in eye Pupillary abnormalities Cardiovascular Manifestations1-3 Irregular heartbeat Conduction blocks Congestive heart failure (including shortness of breath, generalized fatigue [hattrguide.com]

  […] temperature Carpal tunnel syndrome Decreased reflexes Weakness Difficulty walking Symptoms related to the digestive system: Diarrhea Severe constipation Nausea and vomiting Unintentional weight loss Symptoms related to the heart: Shortness of breath Fatigue [onpattro.com]

  Common symptoms include: Cardiomyopathy – Shortness of breath, palpitations and abnormal heart rhythm, ankle swelling (edema), fainting, fatigue, chest pain (angina) Peripheral neuropathy – Tingling and numbness in legs and feet, difficulty walking, limb [amyloidosis-austria.at]

  Signs of cardiac amyloidosis may include: Bilateral carpal tunnel syndrome Diarrhea or constipation Dizziness Fatigue Heart failure symptoms, such as shortness of breath and swelling in hands, arms, legs and feet Joint pain Kidney dysfunction Loss of [kansashealthsystem.com]

  Cardiac Amyloidosis Symptoms Symptoms of cardiac amyloidosis mimic those of heart failure, including: Thickened, less flexible heart tissue (restrictive cardiomyopathy, or “stiff heart syndrome”) Shortness of breath Fatigue Swelling in the legs Heart [hopkinsmedicine.org]

• Congestive Heart Failure

  As a result, it is important to look for a cluster of red-flag symptoms1,5 Progressive, symmetric Sensorimotor polyneuropathy1-3 + One or more of the following: Cardiovascular manifestations3 Peripheral edema Coronary artery disease Congestive heart failure [hattrguide.com]

  While the symptoms of ATTR often mimic those of heart disease, people with this condition can’t easily take medications that are intended for congestive heart failure. These include calcium channel blockers, beta-blockers, and ACE inhibitors. [healthline.com]

  Patient was recurrently admitted for congestive heart failure and he remained hypotensive which precluded further titration of heart failure medications. He developed progressive wasting over thenar muscle and small foot muscle. [clinmedjournals.org]

  Patients usually exhibit symptoms of congestive heart failure, including: Shortness of breath Labored breathing during exercise Peripheral swelling ( edema caused by a buildup of fluid in the lower limbs) Fainting ( syncope ) Generalized fatigue The mutation [pfizer.com]

  Major causes of disability include bowel dysfunction with severe diarrhea and weight loss, congestive heart failure with generalized weakness, and difficulties breathing from fluid retention. [medicine.iu.edu]

• Dyspnea

  These included exertional chest pain, dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, and bilateral lower extremity swelling. [oatext.com]

  He reported exertional dyspnea and worsening peripheral edema over the previous two months. [revportcardiol.org]

  R, a 70-year-old man, visited his physician for an evolving set of symptoms over several months that included dyspnea and palpitations. In retirement, Mr. [pennmedicine.org]

  Nosheen Reza Patient Summary A man in his early 70s, with a history of hypertension, a bicuspid aortic valve, chronic kidney disease and carpal tunnel syndrome presents with two weeks of worsening dyspnea on exertion. [cardionerds.com]

  For patients with heart involvement, the most common clinical feature is diastolic heart failure, which is manifested as progressive dyspnea. [scirp.org]

• Exertional Dyspnea

  He reported exertional dyspnea and worsening peripheral edema over the previous two months. [revportcardiol.org]

  These included exertional chest pain, dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, and bilateral lower extremity swelling. [oatext.com]

  Cardiac involvement can present with conduction system disease (sinus node or atrioventricular node dysfunction) or congestive heart failure including shortness of breath, peripheral edema, syncope, exertional dyspnea, generalized fatigue or with heart [amyloidosis.co.nz]

  The symptoms most often include fatigue and exertional dyspnea, as well as edema due to heart failure, in some cases. Signs may include a lateral shift of the cardiac point of maximal impulse, as well as adventitial heart sounds and murmurs. [intechopen.com]

  The typical presentation of ATTR-CM includes symptoms of heart failure (dyspnea on exertion, fatigue, orthostatic hypotension, syncope and edema) or arrhythmias due to involvement of the cardiac conduction system (1, 3, 22). [frontiersin.org]

• Labored Breathing

  Patients usually exhibit symptoms of congestive heart failure, including: Shortness of breath Labored breathing during exercise Peripheral swelling ( edema caused by a buildup of fluid in the lower limbs) Fainting ( syncope ) Generalized fatigue The mutation [pfizer.com]

• Constipation

  Autonomic Neuropathy1 Orthostatic hypotension Recurrent urinary tract infections (due to urinary retention) Sexual dysfunction Sweating abnormalities Alternating bouts of diarrhea and constipation Peripheral Sensorimotor Neuropathy1 Nerve damage beginning [hattrguide.com]

  Most commonly, it presents with motility symptoms (diarrhea, constipation, or diarrhea alternating with constipation), nausea, or vomiting.2 Isolated and predominant GI involvement is uncommon. [onlinelibrary.wiley.com]

  Neurological manifestations of hATTR include unrelated tingling, pain and numbness in the arms and / or legs, muscle weakness, muscle cramps and paralysis, bladder discomfort, constipation or diarrhea, and even impotence. [centogene.com]

  Impairments in bodily functions can include sexual impotence, diarrhea, constipation, problems with urination, and a sharp drop in blood pressure upon standing (orthostatic hypotension). Some people experience heart and kidney problems as well. [medlineplus.gov]

• Diarrhea

  Severe constipation Autonomic Neuropathy1 Orthostatic hypotension Recurrent urinary tract infections (due to urinary retention) Sexual dysfunction Sweating abnormalities Alternating bouts of diarrhea and constipation Peripheral Sensorimotor Neuropathy1 [hattrguide.com]

  Most commonly, it presents with motility symptoms (diarrhea, constipation, or diarrhea alternating with constipation), nausea, or vomiting.2 Isolated and predominant GI involvement is uncommon. [onlinelibrary.wiley.com]

  Autonomic neuropathy is manifest by gastrointestinal symptoms of diarrhea with weight loss and orthostatic hypotension. [bu.edu]

  Neurological manifestations of hATTR include unrelated tingling, pain and numbness in the arms and / or legs, muscle weakness, muscle cramps and paralysis, bladder discomfort, constipation or diarrhea, and even impotence. [centogene.com]

  Signs and symptoms hATTR amyloidosis is a multisystemic disease with a heterogeneous clinical presentation that includes sensory and motor, autonomic (e.g., diarrhea, sexual dysfunction, hypotension), and cardiac symptoms. [invitae.com]

• Nausea

  […] generalized fatigue, peripheral edema) Ventricular wall thickening with preserved ejection fraction and absence of left ventricular dilation Bilateral Carpal Tunnel Syndrome1,4 Spinal Stenosis4 Nephropathy1 Protein in urine Renal failure GI Manifestations1 Nausea [hattrguide.com]

  […] nerves in hands and feet, arms and legs: Tingling and/or numbness Burning pain Loss of sensitivity to temperature Carpal tunnel syndrome Decreased reflexes Weakness Difficulty walking Symptoms related to the digestive system: Diarrhea Severe constipation Nausea [onpattro.com]

  […] numbness in legs and feet, difficulty walking, limb weakness and pain Autonomic neuropathy – Light-headedness when standing (orthostatic hypotension), bladder problems, bowel problems, sexual dysfunction Gastrointestinal – Decreased appetite, diarrhea, nausea [amyloidosis-austria.at]

  The most common side effects of TEGSEDI include injection site reactions (such as redness or pain at the injection site), nausea, headache, tiredness, low platelet counts (thrombocytopenia), and fever. [tegsedi.com]

  […] palpitations and abnormal heart rhythms, most frequently atrial fibrillation, or atrial flutter ankle swelling (edema) fatigue dizziness and collapse (syncope or fainting), which may occur after exertion, or after eating angina (chest pain) weight loss nausea [abdalihospital.com]

• Vomiting

  […] fatigue, peripheral edema) Ventricular wall thickening with preserved ejection fraction and absence of left ventricular dilation Bilateral Carpal Tunnel Syndrome1,4 Spinal Stenosis4 Nephropathy1 Protein in urine Renal failure GI Manifestations1 Nausea and vomiting [hattrguide.com]

  Symptoms of inflammatory and immune system problems included unexpected change in walking, weakness and spasms in legs, back pain, weight loss, headache, vomiting, and problems with speech. Liver Effects. TEGSEDI may cause liver problems. [tegsedi.com]

  After 2 months, he felt fatigability, nausea, and vomited several times suddenly. He had normal blood pressure (BP), temperature, regular heartbeat, and rhythm. Physical examination revealed normal vital signs. [journals.lww.com]

  Symptoms may include: Loss of sensation, limb weakness and pain Alternating episodes of diarrhea, constipation, nausea, and vomiting Heart-related issues For a complete list of symptoms, see the hATTR amyloidosis Backgrounder below. [alnylam.com]

  Nausea, vomiting. Loss of appetite. Sexual dysfunction. Muscle weakness. Various eye problems. Sudden drop in blood pressure upon standing. Carpal tunnel syndrome. [gethealthystayhealthy.com]

• Early Satiety

  satiety Diarrhea Severe constipation Autonomic Neuropathy1 Orthostatic hypotension Recurrent urinary tract infections (due to urinary retention) Sexual dysfunction Sweating abnormalities Alternating bouts of diarrhea and constipation Peripheral Sensorimotor [hattrguide.com]

  According to the THAOS, unexplained weight loss is a major red flag for possible hATTR, followed by early satiety, diarrhea, and/or constipation. [clinicaloptions.com]

  […] alternation sensation [sensitivity to pain and temperature], numbness and tingling, muscle weakness, impaired balance, difficulty walking) Autonomic dysfunction (e.g., nausea and vomiting, changes in GI motility [diarrhea, constipation, gastroparesis, early [invitae.com]

• Heart Failure

  But ATTR cardiac amyloidosis is increasingly recognized as an important cause of heart failure, atrial arrhythmias and conduction system disease. [mayoclinic.org]

  It’s a predominantly diastolic heart failure or a heart failure with preserved ejection fraction, but if the disease progresses, people can have systolic heart failure. [neurologylive.com]

  Session Title: Heart Failure and Cardiomyopathies: Clinical 1 Abstract Category: 13. Heart Failure and Cardiomyopathies: Clinical Presentation Number: 1110-157 [jacc.org]

  Echocardiogram is often used as the initial investigation for heart failure. [clinmedjournals.org]

  Failure to recognize amyloidosis and tailor treatment may be responsible for variation in response to heart failure treatments, especially the heart failure with preserved ejection fraction phenotypes [2]. [hindawi.com]

• Orthostatic Hypotension

  hypotension Recurrent urinary tract infections (due to urinary retention) Sexual dysfunction Sweating abnormalities Alternating bouts of diarrhea and constipation Peripheral Sensorimotor Neuropathy1 Nerve damage beginning in the hands and feet that can [hattrguide.com]

  Autonomic neuropathy is manifest by gastrointestinal symptoms of diarrhea with weight loss and orthostatic hypotension. [bu.edu]

  hypotension), bladder problems, bowel problems, sexual dysfunction Gastrointestinal – Decreased appetite, diarrhea, nausea, stomach pain, weight loss Some ATTR variants are associated with specific symptoms. [amyloidosis-austria.at]

  Wasting and weakness are also accompanying features, whereas autonomic system dysfunction is manifested by diarrhea, constipation, urinary incontinence, orthostatic hypotension and sexual impotence. [symptoma.com]

• Palpitations

  Cardiac manifestations of hATTR include heart failure, shortness of breath, poor performance, palpitations and fluid retention The diagnosis of TTR-CM remains challenging. [centogene.com]

  Common symptoms include: Cardiomyopathy – Shortness of breath, palpitations and abnormal heart rhythm, ankle swelling (edema), fainting, fatigue, chest pain (angina) Peripheral neuropathy – Tingling and numbness in legs and feet, difficulty walking, limb [amyloidosis-austria.at]

  Cardiac Amyloidosis Symptoms Symptoms of cardiac amyloidosis mimic those of heart failure, including: Thickened, less flexible heart tissue (restrictive cardiomyopathy, or “stiff heart syndrome”) Shortness of breath Fatigue Swelling in the legs Heart palpitations [hopkinsmedicine.org]

  People with light chain amyloidosis in the heart may experience fatigue, shortness of breath, heart palpitations and chest pain. Wild-type ATTR amyloidosis is related to aging and most frequently causes heart damage that may lead to heart failure. [kansashealthsystem.com]

  They may include: shortness of breath, sometimes just after mild exertion palpitations and abnormal heart rhythms, most frequently atrial fibrillation, or atrial flutter ankle swelling (edema) fatigue dizziness and collapse (syncope or fainting), which [abdalihospital.com]

• Heart Block

  There’s a very high proportion of patients who have arrhythmias, in particular heart block. [neurologylive.com]

  Cardiac amyloidosis may affect the way electrical signals move through the heart (conduction system). This can lead to abnormal heartbeats (arrhythmias) and faulty heart signals (heart block). The condition can be inherited. [pennmedicine.org]

  Infiltration of the myocardium causes a restrictive cardiomyopathy, eventually leading to diastolic dysfunction and heart failure; heart block or arrhythmia may occur. Hypotension is common. [msdmanuals.com]

  […] failure Arrhythmias, including heart block, premature ventricular contractions, and various tachyarrhythmias Neurologic findings Typical findings include symmetric sensory impairment and weakness, sometimes accompanied by painless ulcers, similar to [emedicine.medscape.com]

• Hepatomegaly

  Hepatomegaly (enlarged liver). Systemic amyloidosis Lichen amyloidosis Also called papular amyloidosis Lichen amyloidosis is the most common form of primary localised cutaneous amyloidosis. [dermnetnz.org]

  Hepatic involvement is typically manifest as hepatomegaly, and biopsy typically documents the presence of amyloid [41]. [intechopen.com]

  Common physical findings in advanced disease include the following: Cachexia Peripheral edema Hepatomegaly Purpura Orthostatic hypotension Impaired sensation and/or strength in the upper and/or lower extremities Carpal tunnel syndrome Cardiac involvement [emedicine.medscape.com]

  Hepatomegaly results from infiltration of the liver or from hepatic congestion. Renal involvement causes profound proteinuria and nephrotic syndrome. [jamanetwork.com]

  Liver involvement typically presents as hepatomegaly and an increased ALP. Increased transaminase and bilirubin are late signs. Imaging shows homogenous enlargement of the liver. [karger.com]

• Blurred Vision

  vision, blindness, dry eyes, glaucoma, visual field abnormalities, retinal detachment) Biopsy positive for amyloid Genetic testing with Invitae The Alnylam Act ® program offers testing with one of the following three options: Ordering made easy Place [invitae.com]

  Over the past 9 months, he lost weight obviously, BMI 17.58 kg/m2 (height: 171 cm, weight: 51.4 kg), occasionally with blurred vision and conjunctival congestions. In addition, his mother had similar medical history. [journals.lww.com]

  vision, blindness, protein loss in the urine, kidney failure, goiter (thyroid swelling), etc. [ttrstudy.com]

  At age 46, she began to experience blurred vision first in her right eye and later in her left eye. At age 49, she was introduced to our department. [nature.com]

• Visual Impairment

  Visual impairment (2 patients [0.9%]) was the eye disorder most commonly newly reported after the initiation of tafamidis treatment. [clinicaltherapeutics.com]

  Ocular manifestations The TTR gene is also expressed in the retinal pigment epithelium of the eye, and approximately 20% of amyloidogenic TTR mutations are associated with vitreous opacities derived from amyloid, and may lead to visual impairment. [amyloidosis.co.nz]

  Hearing and visual impairment is common, particularly among low-income populations. A provider may think that a patient has limited health literacy when in reality he or she has bilateral wax impaction or a need for glasses. [ncbi.nlm.nih.gov]

• Eye Pain

  Ophthalmological involvement may present as follows: Dry eye, red eye, painful eye, conjunctivitis Floaters in eyes, decreased visual acuity A study by Phull et al showed a high prevalence of coexistent monoclonal gammopathy of undetermined significance [emedicine.medscape.com]

• Ulcer

  Her initial sigmoidoscopic evaluation in 2016 demonstrated loss of vascular pattern, granularity, friability, and superficial ulcerations in the rectosigmoid. A biopsy of rectosigmoid ulcers demonstrated features of chronic colitis with activity. [onlinelibrary.wiley.com]

  Previously known as secondary amyloidosis, this condition is the result of another chronic infectious or inflammatory disease such as rheumatoid arthritis, Crohn’s disease, or ulcerative colitis. [webmd.com]

  Lesions tend not to ulcerate, but some may crack or split, particularly those on the soles of the feet. [dermnetnz.org]

  […] dysfunction Chronic heart failure Arrhythmias, including heart block, premature ventricular contractions, and various tachyarrhythmias Neurologic findings Typical findings include symmetric sensory impairment and weakness, sometimes accompanied by painless ulcers [emedicine.medscape.com]

• Purpura

  Cutaneous findings may include purpura, which results from the vascular fragility produced by amyloid deposition in the subendothelium of the small blood vessels. Ando Y, Nakamura M, Araki S. [emedicine.medscape.com]

  Kyle also described purpura, particularly periorbital purpura, as a notable finding. AL amyloid is most commonly a systemic disorder. However, there are cases of AL amyloidosis localized to a single site. [intechopen.com]

  Light chain (AL) amyloidosis may present with highly specific signs such as macroglossia and periorbital purpura, but these signs are insensitive. [karger.com]

  Skin lesions The most common skin findings are purpura : petechiae (small red blood spots) and ecchymoses (small, flat blood spots that are a round or irregular shape and bluish/purplish). [dermnetnz.org]

  Areas of swelling, hemorrhages under the skin (purpura), hair loss (alopecia), inflammation of the tongue (glossitis) and a dry mouth (xerostomia) may also be present. [rarediseases.org]

• Anhidrosis

  Other system involvement Autonomic nervous system involvement includes anhidrosis, sexual impotence, disturbances of gastrointestinal motility (most commonly diarrhea alternating with constipation, but also constipation, diarrhea, nausea, and vomiting [ncbi.nlm.nih.gov]

• Muscle Weakness

  Neurological manifestations of hATTR include unrelated tingling, pain and numbness in the arms and / or legs, muscle weakness, muscle cramps and paralysis, bladder discomfort, constipation or diarrhea, and even impotence. [centogene.com]

  Components of muscle weakness (hip and knee flexion, hip and knee extension, ankle dorsiflexors, ankle plantar flexors, toe extensors, toe flexors) are scored on 0 to 4 scale (0=normal, 4=paralysis). [clinicaltrials.gov]

  Muscle weakness. Various eye problems. Sudden drop in blood pressure upon standing. Carpal tunnel syndrome. Symptoms of ATTR-PN generally occur in adulthood at widely varying ages, as early as in the 20s or as late as in the 70s or later. [gethealthystayhealthy.com]

  Signs and symptoms of hATTR amyloidosis can include: Sensory and/or motor neuropathy (e.g., neuropathic pain, alternation sensation [sensitivity to pain and temperature], numbness and tingling, muscle weakness, impaired balance, difficulty walking) Autonomic [invitae.com]

• Swelling of Hand

  Signs of cardiac amyloidosis may include: Bilateral carpal tunnel syndrome Diarrhea or constipation Dizziness Fatigue Heart failure symptoms, such as shortness of breath and swelling in hands, arms, legs and feet Joint pain Kidney dysfunction Loss of [kansashealthsystem.com]

  As a result, symptoms and signs are vague and can include fatigue, shortness of breath, weight loss, lack of appetite, numbness, tingling, carpal tunnel syndrome, weakness, hearing loss, enlarged tongue, bruising, and swelling of hands and feet. [medicinenet.com]

• Muscular Atrophy

  atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial. [researchmap.jp]

  atrophy, sensory loss, weight loss (75 pounds over 2 years), and a 2-year history of erectile dysfunction. [frontiersin.org]

• Leg Pain

  Dealing with painful neuropathy symptoms I find doing weekly muscle build-up and light exercise at the gym helps a lot. I find having a regular leg and feet massage eases my leg pains and stiffness. Keep your legs and feet always moisturised. [amyloidosis.org.uk]

• Numbness of the Feet

  Sensory-motor neuropathy1,3 Length-dependent neuropathic pain and numbness Altered sensation Weakness Difficulty walking Bilateral carpal tunnel syndrome Autonomic neuropathy1,3 Orthostatic hypotension Diarrhea, constipation, nausea and vomiting Unintentional [hattramyloidosis.com]

• Kidney Failure

  Kidney failure Most people with AL amyloidosis have a build-up of amyloid proteins in their kidneys, and are at risk of kidney failure. [thefamilypractice-stjohns.nhs.uk]

• Sexual Dysfunction

  dysfunction Sweating abnormalities Alternating bouts of diarrhea and constipation Peripheral Sensorimotor Neuropathy1 Nerve damage beginning in the hands and feet that can progress to the central part of the body Peripheral neuropathy generally initiates [hattrguide.com]

  (e.g., nausea and vomiting, changes in GI motility [diarrhea, constipation, gastroparesis, early satiety], orthostatic hypotension [fainting and dizziness upon standing], sexual dysfunction, bladder dysfunction) Heart disease (e.g., shortness of breath [invitae.com]

  dysfunction Gastrointestinal – Decreased appetite, diarrhea, nausea, stomach pain, weight loss Some ATTR variants are associated with specific symptoms. [amyloidosis-austria.at]

  Autonomic neuropathy: disturbances of bowel, bladder and blood pressure and sexual dysfunction. Heart failure - symptoms result from stiffening of the heart due to amyloid deposits (restrictive cardiomyopathy). [abdalihospital.com]

• Urinary Retention

  […] tract infections (due to urinary retention) Sexual dysfunction Sweating abnormalities Alternating bouts of diarrhea and constipation Peripheral Sensorimotor Neuropathy1 Nerve damage beginning in the hands and feet that can progress to the central part [hattrguide.com]

  Orthostatic hypotension 3% Urinary retention 1%¶¶ Urinary retention might be underdiagnosed as patients are usually not aware or cognisant of symptoms. [onlinelibrary.wiley.com]

  Common symptoms with ATTR amyloidosis with autonomic neuropathy may include postural hypotension, urinary retention, impotence, body temperature irregularities, and gastrointestinal problems. [raredr.com]

  The renal and urinary disorders most commonly (≥2 patients) reported during the study period were renal impairment, urinary retention, and dysuria. [clinicaltherapeutics.com]

• Renal Insufficiency

  Microalbuminuria, heavy proteinuria and progressive renal failure that leads to insufficiency is seen in patients with kidney deposits, but also anemia, since EPO production may be impaired. [symptoma.com]

  Another study from Sweden, which included 24 patients, showed that half had renal insufficiency and proteinuria (34). Nephropathy did not correlate with age, duration of disease, or severity of neuropathy. [cjasn.asnjournals.org]

  With respect to pre-existing renal insufficiency and a tendency towards cardiac decompensation, VD chemotherapy regimen was selected with reduced dexamethasone doses (Velcade 2.8 mg i.v. on days 1, 8 and 15; dexamethasone 20 mg tablet once a week). [openaccessjournals.com]

  […] and distal weakness; still seeking a diagnosis Returned for follow-up due to decline in ambulation over the past month; has started to use a cane when she leaves the house Under the care of a nephrologist for the last 12 months for management of mild renal [hattramyloidosis.com]

• Urinary Incontinence

  Wasting and weakness are also accompanying features, whereas autonomic system dysfunction is manifested by diarrhea, constipation, urinary incontinence, orthostatic hypotension and sexual impotence. [symptoma.com]

  The most common symptoms were orthostatic hypotension (OH,, which is a decrease in blood pressure after standing up), diarrhea, constipation, erectile dysfunction, urinary incontinence, and xerostomia (dry mouth). [fapnewstoday.com]

  People with TTR-FAP often also experience symptoms that affect multiple bodily systems at the same time, such as diarrhea, constipation, nausea, vomiting, unintended weight loss, feeling full quickly after eating, sexual dysfunction, urinary incontinence [gethealthystayhealthy.com]

  […] retention Effort urinary incontinence Permanent urinary incontinence Sexual dysfunction Mild Moderate Orthostatic hypotension Asymptomatic Dizziness with orthostatism Syncope with orthostatism Need for symptomatic treatment of hypotension or worsening [tandfonline.com]

  incontinence, orthostatic hypotension, sexual impotence, glaucoma) Lower-limb neuropathy (eg, in patients with the TTR V30M mutation) Upper-limb neuropathy (eg, TTR I84S, TTR L58H) [1] ATTR V30M variant: Lower extremity weakness, pain, and/or impaired [emedicine.medscape.com]

• Polyneuropathy

  Familial amyloid cardiomyopathy, FAC, Familial Amyloid Polyneuropathy Symptoms - Hereditary ATTR amyloidosis Causes - Hereditary ATTR amyloidosis hATTR amyloidosis is caused by a mutation in the transthyretin (TTR) gene that results in misfolded TTR [checkorphan.org]

  Transthyretin-related familial amyloidotic polyneuropathy. Arch Neurol. 2005 Jul. 62(7):1057-62. [Medline]. Ando Y, Suhr OB. Autonomic dysfunction in familial amyloidotic polyneuropathy (FAP). Amyloid. 1998 Dec. 5(4):288-300. [Medline]. [emedicine.medscape.com]

  Familial amyloid polyneuropathy Other names FAP Familial amyloid polyneuropathy has an autosomal dominant pattern of inheritance. [en.wikipedia.org]

  Isolated studies report that the onset of symptoms in familial amyloidotic polyneuropathy is quite wide, but almost 90% of patients develop symptoms before the age of 40. [symptoma.com]

  ( BUSINESS WIRE )-- Alnylam Pharmaceuticals (Nasdaq:ALNY), the leading RNAi therapeutics company, announced today that the results of the APOLLO Phase 3 study of patisiran in hereditary ATTR (hATTR) amyloidosis patients with polyneuropathy, as well [biospace.com]

• Tingling

  This can cause carpal tunnel syndrome, which causes your hand and arm to become numb and tingle. The spinal canal, which can cause narrowing of the spinal column (spinal stenosis). [my.clevelandclinic.org]

  Neurological manifestations of hATTR include unrelated tingling, pain and numbness in the arms and / or legs, muscle weakness, muscle cramps and paralysis, bladder discomfort, constipation or diarrhea, and even impotence. [centogene.com]

• Dizziness

  […] digestive system: Diarrhea Severe constipation Nausea and vomiting Unintentional weight loss Symptoms related to the heart: Shortness of breath Fatigue Leg swelling (edema) Palpitations and abnormal heart rhythms (atrial fibrillation) Other symptoms: Dizziness [onpattro.com]

  Disruption of the nervous system Dizziness or nearly fainting when standing up too quickly. This can happen if the condition affects the nerves that control blood pressure and a sudden drop in blood pressure occurs when standing up. [cedars-sinai.edu]

  Possible Complications Complications may include: Atrial fibrillation or ventricular arrhythmias Congestive heart failure Fluid buildup in the abdomen (ascites) Increased sensitivity to digoxin Low blood pressure and dizziness from excessive urination [pennmedicine.org]

  They may include: shortness of breath, sometimes just after mild exertion palpitations and abnormal heart rhythms, most frequently atrial fibrillation, or atrial flutter ankle swelling (edema) fatigue dizziness and collapse (syncope or fainting), which [abdalihospital.com]

• Paresthesia

  The first symptoms of TTR-FAP are paresthesia, pain or trophic foot injuries, gastrointestinal disorders and weight loss. In later stages, the most pronounced sensory loss involves pain and changes in the thermal sensation. [meetingcampus.com]

  Presentation [ edit ] Usually manifesting itself between 20 and 40 years of age, it is characterized by pain, paresthesia, muscular weakness and autonomic dysfunction. In its terminal state, the kidneys and the heart are affected. [en.wikipedia.org]

  2 years prior with alternating diarrhea and constipation, which have become more severe over the past month Recent onset of paresthesia in the hands Recent onset of early satiety and weight loss Neurologic exam reveals: Muscle weakness in the hands and [hattramyloidosis.com]

  (ATTRm) has a genetic component (>130 TTR mutations have been described), is known to affect African American, Swedish and Portuguese communities, among others, and is associated with peripheral and autonomic neuropathies and carpal tunnel syndrome (paresthesias [pennmedicine.org]

  Patients described many symptoms of hATTR amyloidosis, particularly those associated with peripheral neuropathy such as pain, numbness, weakness, and paresthesia. [jpro.springeropen.com]

• Ataxia

  A buildup of protein in this tissue can cause stroke and bleeding in the brain, an accumulation of fluid in the brain (hydrocephalus), difficulty coordinating movements (ataxia), muscle stiffness and weakness (spastic paralysis), seizures, and loss of [medlineplus.gov]

  In some patients, a leptomeningeal form that include ataxia, spastic paralysis, seizures, dementia and visual disturbances as most important symptoms may be seen. [symptoma.com]

  Furuya H et al. (1987) Molecular analysis of a variant type of familial amyloidotic polyneuropathy showing cerebellar ataxia and pyramidal tract signs. [^] 23. [moldiag.com]

Cardiac ultrasonography should be performed in patients with heart-related symptoms and an unexplained increase in thickness of the left ventricular wall [6]. In fact, a growing number of studies have emphasized the need of cardiologists to include amyloidosis into the differential diagnosis in such patients [12]. To make a definite diagnosis, tissue biopsy using Congo red staining, demonstrating amyloid deposits is a necessary procedure [8], which can be confirmed by immunohistochemistry. If the target tissue is sensitive for biopsy, abdominal fat may serve as a valid source for confirmation of deposits [13]. Determination of the specific subtype of amyloid deposit is of great importance, as is the underlying genetic mutation, primarily for determining the therapeutic strategy [10].

• Microalbuminuria

  After microalbuminuria, overt nephropathy developed in half of the patients, usually 2 years later. Renal failure generally occurred 5 years after microalbuminuria, and even sooner in women. [cjasn.asnjournals.org]

  Microalbuminuria can precede the onset of neuropathy [43] and therefore may be a useful parameter to assess in the early stages of disease. [tandfonline.com]

  Microalbuminuria, heavy proteinuria and progressive renal failure that leads to insufficiency is seen in patients with kidney deposits, but also anemia, since EPO production may be impaired. [symptoma.com]

  Familial ATTR amyloidosis: microalbuminuria as a predictor of symptomatic disease and clinical nephropathy. Nephrol Dial Transplant 2003;18:532–8. Cited Here [15]. Lachmann HJ, Booth DR, Booth SE, et al. [journals.lww.com]

• Normocytic Anemia

  Diagnostic exams revealed type 2 respiratory failure with acidosis (pH 7.24; PaO2 58 mmHg, PaCO2 55 mmHg, HCO3 23.6 mmol/l, and lactates 2.66 mmol/l); normocytic anemia (hemoglobin 12.1 g/dl), with no increase in inflammatory markers; NT-pro-BNP 43300 [revportcardiol.org]

  Laboratory results for different types of amyloidosis are generally nonspecific, including the following: Complete blood count: Normochromic normocytic anemia Chemistry panel: Electrolyte abnormalities (due to heart failure or malabsorption) Renal function [emedicine.medscape.com]

• Right Bundle Branch Block

  An electrocardiogram showed atrial fibrillation with right bundle branch block. Echocardiography showed concentric LV hypertrophy. An endomyocardial biopsy showed severe ATTR amyloid deposits. [jstage.jst.go.jp]

  • An ECG revealed low voltage QRS, first-degree atrioventricular block (despite a very thick left ventricle) and conduction system abnormality with PR interval prolongation (290 ms) with right bundle branch block (RBBB) (Figure 8A). [frontiersin.org]

  His electrocardiogram showed a right bundle branch block and left anterior fascicular block. Shortly thereafter, the patient suffered a PEA arrest and despite prolonged standard advanced cardiovascular life support for 45 minutes, the patient died. [oatext.com]

• Ventricular Hypertrophy

  Figure 2 (1) Apical four-chamber view depicting the left ventricular hypertrophy and calculated left ventricular ejection fraction (LVEF) using the biplane Simpson method. (2) Subcostal view depicting the right ventricular hypertrophy. (3) Global longitudinal [academic-oup-com.eres.qnl.qa]

  This study revealed concentric left ventricular hypertrophy (measuring up to 2.3 cm in the inferoseptum) as well as right ventricular hypertrophy, biatrial enlargement, and a diffuse pattern of patchy mid-myocardial delayed enhancement within the left [academic.oup.com]

  It showed cardiomegaly with left ventricular hypertrophy present. There was a diffuse transmural enhancement in the septal, inferior, and lateral left ventricular walls along with enhancement of the lateral wall of the right ventricle. [cureus.com]

  An echocardiogram revealed severe asymmetric left ventricular hypertrophy, biatrial dilatation, pericardial effusion, and preserved left ventricular ejection fraction of 50% with severe diastolic dysfunction. [jmedicalcasereports.biomedcentral.com]

  The presence of prominent right-sided HF symptoms, low voltage on ECG, biatrial enlargement, ventricular hypertrophy, conduction disease, and pericardial effusion should prompt a high suspicion for cardiac amyloid. [cardionerds.com]

• Left Ventricular Hypertrophy

  Figure 2 (1) Apical four-chamber view depicting the left ventricular hypertrophy and calculated left ventricular ejection fraction (LVEF) using the biplane Simpson method. (2) Subcostal view depicting the right ventricular hypertrophy. (3) Global longitudinal [academic-oup-com.eres.qnl.qa]

  This study revealed concentric left ventricular hypertrophy (measuring up to 2.3 cm in the inferoseptum) as well as right ventricular hypertrophy, biatrial enlargement, and a diffuse pattern of patchy mid-myocardial delayed enhancement within the left [academic.oup.com]

  It showed cardiomegaly with left ventricular hypertrophy present. There was a diffuse transmural enhancement in the septal, inferior, and lateral left ventricular walls along with enhancement of the lateral wall of the right ventricle. [cureus.com]

  An echocardiogram revealed severe asymmetric left ventricular hypertrophy, biatrial dilatation, pericardial effusion, and preserved left ventricular ejection fraction of 50% with severe diastolic dysfunction. [jmedicalcasereports.biomedcentral.com]

  Ronald Witteles, MD: The typical phenotype will be of a thick heart, so it will often get called left ventricular hypertrophy [LVH]. It’s not hypertrophy truly, it’s an amyloid infiltration, but it will get called that on imaging. [neurologylive.com]

Liver transplantation may be indicated in the setting of familial amyloidotic polyneuropathy, but because of limited availability and significant morbidity, this procedure must be cautiously performed [1]. More importantly, this procedure may ameliorate liver and nervous system-related symptoms, but ocular or cardiac complaints will still persist because extra-hepatic production of TTR will persist [7]. In the recent years, the approval of novel therapies, such as tafamidis, a stabilizer of TTR tetramer and drugs that interfere with RNA signalling, is promising [1]. Tafamidis binds to the unoccupied thyroxine-binding sites on the TTR tetramer and is able to stabilize the dissociation rate of TTR, thus it reduces amyloid deposition [4]. Additionally, two nanoparticle agents, ALN-TTR01 and ALN-TTR02 have been developed and are able to neutralize mutated TTR by disrupting gene expression and function of the mRNA, causing reduced TTR production [1]. Although a superior effect compared to transplantation is observed [1], liver transplant recipients in whom an early diagnosis was made showed prolonged survival rates [16].

The prognosis is poor, as fatal outcomes are expected within 10 years from the onset of the disease [4]. One of the most important factors in providing a chance for therapy is an early diagnosis, which is not the case for many patients due to a lack of clinical suspicion [12]. Despite liver transplantation that inexorably removes the primary source of TTR production, its deposition in numerous organs after the procedure has been documented, thus confirming the presence of an extra-hepatic source of TTR synthesis [17].

The cause of amyloidogenic TTR amyloidosis stems from mutations of genes that code of TTR and so far, more than 100 mutations have been discovered [2]. Two modes have been described so far - autosomal dominant type, divided into familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy, in which two TTR mutations, V30M (substitution of valine for methionine at position 30) [9], and V122I are responsible for the disease, respectively [4].

Familial amyloidotic polyneuropathy was initially discovered in areas of Portugal and Sweden, with established prevalence rates of 1 per 1,000 individuals, implying a strong familial component [10]. Brazil and Japan are other countries that have reported clusters of patients [14]. Crude general prevalence rates, however, are estimated at 1 per 100,000 [10]. Isolated studies report that the onset of symptoms in familial amyloidotic polyneuropathy is quite wide, but almost 90% of patients develop symptoms before the age of 40 [3]. Not all individual carrying TTR mutations develop the same disease severity, i.e. a variable degree of penetrance is observed, indicating that some other factors (genetic, epigenetic or environmental) are responsible for its occurrence [10].

Under physiological conditions, TTR is produced in the liver, the choroid plexus and several other sites, after which it is distributed throughout the circulation and the CSF. It's presumed primary role is to bind thyroxine and transport it to the CNS, but it also binds retinol in the endoplasmic reticulum of hepatocytes and transports it throughout the circulation without loss of retinol-binding protein molecules through kidney filtration [10]. This means that it is an important mediator of vitamin A transport and utilization [2] [5]. Since TTR passes through the blood-brain barrier in minimal concentrations, it was subsequently determined that another source of its production must exist in the CNS, with the most prominent candidate so far being the choroid plexus [5]. In the setting of genetic mutations, destabilization of the TTR tetrameric structure and subsequent degradation to dimers and monomers is thought to be the main pathophysiological mechanism, resulting in accumulation of fibrils in numerous tissues, including the heart, kidneys, eyes and the liver [2] [4]. In kidneys, it was discovered that the deposits directly inhibit the production of erythropoietin in the distal nephron, a phenomenon that presumably explains the appearance of anemia in these patients [11]. The basis of TTR binding and deposition in these tissues remains to be discovered, but presumably involves binding to glycosaminoglycans (GAGs) that are present on the cell membrane. Unstable monomers are confirmed neurotoxic substances, but their exact mechanism of damage is not understood [4] [5].

Genetic counselling of families in whom TTR mutations have been identified may be considered as a valid preventive strategy [7], but despite the fact that mutations responsible for this disease have been discovered, it is not possible to prevent their development, as the cause remains unknown.

Hereditary ATTR amyloidosis, also referred to as amlyoidogenic transthyretin amyloidosis, familial transthyretin (TTR) amyloidosis or transthyretin-related amyloidosis, is a condition resulting from transthyretin (TTR) amyloid accumulation in the liver, gastrointestinal (GI) tract, heart, kidneys and the eyes [1]. Namely, various mutations of TTR, which is coded on chromosome 18, lead to protein misfolding and abundant accumulation of amyloid fibrils in tissues. More than 100 TTR mutations have been discovered [2]. The vast majority of mutations are transferred by autosomal dominant patterns of inheritance and two forms have been recognized - Familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy [1]. The two most common mutations identified, V30M and V122I are responsible for the development of these two forms, respectively [4]. TTR is a thyroid-binding protein found in both plasma and cerebrospinal fluid (CSF) and it is primarily synthesized in the liver, but several extra-hepatic sites of production are identified, most likely the choroid plexus [2]. In circulation, TTR carries thyroxine (T4) and retinol and it is assumed that one of the roles are delivery of thyroxine to the central nervous system [2]. The clinical presentation may depend on the subtype. FAP is distinguished by diminished pain and temperature sensations in the lower limbs as a result of sensory polyneuropathy, together with autonomic dysfunction (inadequate sphincter control, impotence and orthostatic hypotension) and wasting [5]. Familial amyloidotic cardiomyopathy manifests as weakness, fatigue and disturbed heart conduction system, whereas proteinuria and renal insufficiency, but also anemia may be seen in all forms of the disease due to protein accumulation in the kidneys [10]. Ocular symptoms, such as glaucoma and keratoconjunctivitis are also observed [5]. An initial diagnosis can be made by obtaining a detailed patient history that might reveal familial occurrence of symptoms, but a proper physical examination and imaging studies including echocardiography or electrophysiologic studies are used for further investigation [8]. To confirm amyloidogenic transthyretin amyloidosis, a biopsy of the affected tissue with visualization of amyloid deposits is necessary. Treatment options are currently aimed at liver transplantation and management of renal disease, but novel drugs that attempt to stabilize TTR and prevent its further accumulation have been developed in recent years [4]. Despite current therapeutic options, the diagnosis carries a fatal prognosis within 10 years due to severe nervous system involvement, as well as cardiac, renal and liver failure [7]. However, appropriate therapy in early diagnosed patients carries a much better prognosis, which is why high clinical suspicion is necessary in patients suffering from undisclosed polyneuropathy or renal/cardiac disease.

Hereditary ATTR amyloidosis is a rare disease caused by genetic mutations that cause accumulation of transthyretin (TTR), a protein that serves as a transport molecule for thyroid hormone and constituents of vitamin A. TTR is synthesized primarily in the liver, but other sites of its production have been identified as well, including the choroid plexus (the site of cerebrospinal fluid production in the brain). In the presence of mutations on chromosome 18 that are transferred by an autosomal dominant pattern of inheritance (meaning that if one parent has the disease, there is a 50% chance his/her child will have it), TTR does not fold properly and thus accumulates in various tissues. The two familial forms of this disease are known as familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy. Depending on the underlying subtype, different symptoms may dominate the clinical presentation. In the setting of FAP, progressive damage of peripheral nerves responsible for pain and temperature sensation is most prominent, followed by weakness and dysfunction of the autonomic nervous system (ANS) - inadequate bowel movement, urinary incontinence and sexual impotence are the most common signs. On the other hand, familial amyloidotic cardiomyopathy may be diagnosed in patients with unexplained heart rhythm disorders. In addition, renal disease that manifesting as increased protein loss, anemia and rapidly progressive end-stage kidney failure is not uncommon for all types, while visual disturbances are also a frequent finding. The diagnosis is not made easily, as clinical finding are not that specific, but a thorough physical examination and a properly obtained patient history may reveal vital clues for further workup. Cardiac ultrasound and studies that evaluate nerve signalling should be performed. To confirm amyloidogenic transthyretin amyloidosis, a biopsy of the tissue in which TTR amyloid accumulates is necessary. Until recently, liver transplantation and management of kidney disease were the only therapeutic strategies, but novel drugs that attempt to reduce the level of TTR degradation and accumulation have been developed. Tafamidis is a drug that is able to bind to TTR and prevent its destabilization, whereas nanoparticle drugs that alter gene expression have also been synthesized. Despite available treatment strategies, the prognosis is rather poor, as the progressive nature of this disease leads to fatal outcomes within 10 years after the diagnosis. Unfortunately, many patients are undiagnosed for years due to a lack of clinical suspicion and having in mind the fact that early recognition carries a much better prognosis, physicians need to be aware of this condition in patients with unexplained nervous, cardiac and renal symptoms.

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