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Hereditary ATTR Amyloidosis

Hereditary ATTR amyloidosis is a progressively fatal genetic disease caused by an accumulation of transthyretin in the liver and several other organs. The diagnosis is made by biopsy and supportive imaging studies. Liver transplantation is currently the mainstay of therapy. Novel treatment strategies are being developed, but the disease carries a poor prognosis despite all efforts.

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Presentation

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
  • You probably know someone with a heart condition, GI problems, or nerve pain.[gethealthystayhealthy.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]
  • FAP patients frequently report peripheral neuropathy of sensory nerves, usually in the lower limbs and sensations such as pain and temperature are affected.[symptoma.com]
  • Tell your doctor or nurse right away if you experience any of the following signs of an infusion-related reaction during treatment: • Reddening of the face or body (flushing), skin warm • Body aches or pain, including pain in the back, neck, or joints[alnylam.com]
  • Treatment of visceral amyloid and symptomatic treatments are also major to improve the quality of life : digestive and sexual disorders and pain. Recently, a therapeutic education program has been developed.[allcongress.com]
Weakness
  • Secondary objectives are to evaluate the effect of patisiran on Norfolk-Diabetic Neuropathy quality of life questionnaire score, nutritional status (as evaluated by modified body mass index), motor function (as measured by NIS-weakness and timed 10-m[ncbi.nlm.nih.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]
  • 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]
  • Amyloid staining properties vary and Congo red affinity and birefringence may be very weak, particularly in amyloid consisting of TTR fragments which is common (1). Therefore is amyloid sometimes difficult to recognize also in biopsies.[link.springer.com]
Weight Loss
  • 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, 1.81[mayoclinic.pure.elsevier.com]
  • Autonomic neuropathy is manifest by gastrointestinal symptoms of diarrhea with weight loss and orthostatic hypotension.[bu.edu]
  • 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]
  • Tafamidis (20 mg once daily) slowed the progression of FAP over a 36-month period and importantly reversed the weight loss and muscle wasting associated with disease progression.[en.wikipedia.org]
  • 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]
Fatigue
  • 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]
  • ., heart failure, enlarged heart, irregular heart beat) and may include: fatigue, swelling, shortness of breath, low blood pressure, and a general feeling of illness. Some people, however, do not experience symptoms until later into their disease.[gethealthystayhealthy.com]
  • […] aches or pain, including pain in the back, neck, or joints • Feeling 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[alnylam.com]
  • 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.[symptoma.com]
  • If there is light-headedness, fatigue on minor exertion or fainting due to blood pressure drops, doctors may advise careful position changing from lying to sitting, sitting to standing and standing to walking.[ttrstudy.com]
Anemia
  • 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]
  • P74 ) Endocrine, nutritional and metabolic diseases E70-E88 2019 ICD-10-CM Range E70-E88 Metabolic disorders Type 1 Excludes androgen insensitivity syndrome ( E34.5- ) congenital adrenal hyperplasia ( E25.0 ) Ehlers-Danlos syndrome ( Q79.6 ) hemolytic anemias[icd10data.com]
  • Kidney and anemia in familial amyloidosis type I. Kidney Int. 2004; 66 :2004–2009. doi: 10.1111/j.1523-1755.2004.00971.x. [ PubMed ] [ CrossRef ] Ando E, Ando Y, Okamura R, Uchino M, Ando M, Negi A.[ncbi.nlm.nih.gov]
  • Kidney and anemia in familial amyloidosis type I. Kidney Int. 2004; 66 :2004–9. [ PubMed : 15496172 ] Benson MD. Amyloidosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Diseases. 8 ed. Vol 4.[ncbi.nlm.nih.gov]
Dyspnea
  • Cardiovascular involvement Patients with cardiac deposition often present with symptoms suggesting chronic heart failure (ie, dyspnea on exertion, peripheral edema, elevated jugular venous pressure, hepatojuglular reflux) and/or arrhythmias (ie, palpitations[emedicine.medscape.com]
Constipation
  • Affiliated tissues include heart , spinal cord and kidney , and related phenotypes are constipation and dysautonomia Disease Ontology : 12 An amyloidosis that is characterized by a loss of sensation in the extremities, cardiomyopathy, nephropathy, vitreous[malacards.org]
  • Other manifestations are impotence, incontinence, voiding problems, diarrhoea or constipation, bowel motility disturbances, changed sweating, dry mouth, and dry eyes. Bowel complaints may sometimes result in severe loss of weight.[amyloid.nl]
  • 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]
  • 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]
  • ., 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, edema[invitae.com]
Diarrhea
  • Autonomic neuropathy is manifest by gastrointestinal symptoms of diarrhea with weight loss and orthostatic hypotension.[bu.edu]
  • ., diarrhea, sexual dysfunction, hypotension), and cardiac symptoms.[invitae.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]
  • In later stages of the disease severe diarrhea with malabsorption, cachexia, incapacitating neuropathy, severe cardiac disturbances, and marked orthostatic hypotension dominate the clinical picture.[malacards.org]
Nausea
  • 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]
  • […] or nurse right away if you experience any of the following signs of an infusion-related reaction during treatment: • Reddening of the face or body (flushing), skin warm • Body aches or pain, including pain in the back, neck, or joints • Feeling sick (nausea[alnylam.com]
  • ., 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, edema[invitae.com]
  • […] feet and hands weakness and pain in the arms and legs loss of sensation Autonomic neuropathy: postural hypotension (blood pressure drops on standing leading to dizziness or fainting) disturbed bowel function – alternating diarrhea and constipation, nausea[ttrstudy.com]
  • Intravenous fluids and anti‑nausea drugs may be necessary, but it is important to avoid fluid overload if there is heart disease.[amyloidosis.org.uk]
Vomiting
  • 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]
  • ., 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, edema[invitae.com]
  • Nausea and vomiting also occur. 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]
  • […] and hands weakness and pain in the arms and legs loss of sensation Autonomic neuropathy: postural hypotension (blood pressure drops on standing leading to dizziness or fainting) disturbed bowel function – alternating diarrhea and constipation, nausea, vomiting[ttrstudy.com]
  • Care should be taken to avoid dehydration if there is vomiting and diarrhoea. Intravenous fluids and anti‑nausea drugs may be necessary, but it is important to avoid fluid overload if there is heart disease.[amyloidosis.org.uk]
Early Satiety
  • ., 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, edema[invitae.com]
  • Other organ involvement Gastrointestinal symptoms, as a manifestation of autonomic neuropathy, are recognized from an early stage of TTR-FAP and include nausea, early satiety, recurrent vomiting, watery diarrhea, severe constipation, and/or alternating[ncbi.nlm.nih.gov]
Heart Failure
  • TTR-CM results when amyloid build up in the myocardium, or heart muscles, and results in heart failure. It comes in two forms: familial amyloid cardiomyopathy (TTR-FAC) and age-related, or senile, amyloidosis.[pfizer.com]
  • Patients present during adulthood (usually after 30 years of age) with restrictive cardiomyopathy (with varying degrees of chronic heart failure and possible brady/tachyarrhythmias).[orpha.net]
  • ., heart failure, enlarged heart, irregular heart beat) and may include: fatigue, swelling, shortness of breath, low blood pressure, and a general feeling of illness. Some people, however, do not experience symptoms until later into their disease.[gethealthystayhealthy.com]
  • Patients with TTR Thr-60-Ala and several other mutations have myocardial thickening similar to that caused by AL amyloidosis, although heart failure is less common and the prognosis is better.[bu.edu]
  • In ATTR amyloidosis this may include: Heart disease treatment ATTR amyloid deposits in the heart cause the heart to stiffen which can lead to symptoms of heart failure. Patients can benefit from supportive treatment measures for heart failure.[amyloidosis.org.uk]
Orthostatic Hypotension
  • Autonomic neuropathy is manifest by gastrointestinal symptoms of diarrhea with weight loss and orthostatic hypotension.[bu.edu]
  • 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]
  • As a consequence blood pressure can drop sharply from supine to prone position (orthostatic hypotension), resulting in complaints of dizziness.[amyloid.nl]
  • In later stages of the disease severe diarrhea with malabsorption, cachexia, incapacitating neuropathy, severe cardiac disturbances, and marked orthostatic hypotension dominate the clinical picture.[malacards.org]
  • ., 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, edema[invitae.com]
Palpitations
  • ., shortness of breath, edema, palpitations, arrhythmias, conduction abnormalities, heart failure, abnormal cardiac imaging [echo, MRI, or technetium]) Bilateral carpal tunnel syndrome Spinal stenosis or spinal radiculopathy Ocular changes (e.g., blurred[invitae.com]
  • Weak toenails Symptoms indicating the head and neck are affected include: Lighheadedness upon standing Purple color on the eyelids and/or around they eyes Enlarged tongue Symptoms indicating the heart and lungs are affected include: Shortness of breath Palpitations[my.clevelandclinic.org]
  • They may include: shortness of breath, sometimes just after mild exertion palpitations and abnormal heart rhythms, most frequently atrial fibrillation or atrial flutter leg swelling (oedema) weight loss nausea fatigue dizziness and collapse (syncope or[amyloidosis.org.uk]
  • For each patient, the symptoms will depend on which organs are affected by the protein deposits: Heart Nausea Weight loss Insomnia Progressive fatigue Dizziness Shortness of breath Leg swelling Palpitations and abnormal heart rhythms (atrial fibrillation[patientworthy.com]
  • Cardiovascular involvement Patients with cardiac deposition often present with symptoms suggesting chronic heart failure (ie, dyspnea on exertion, peripheral edema, elevated jugular venous pressure, hepatojuglular reflux) and/or arrhythmias (ie, palpitations[emedicine.medscape.com]
Heart Block
  • block, premature ventricular contractions, and various tachyarrhythmias Neurologic findings Typical findings include symmetric sensory impairment and weakness, sometimes accompanied by painless ulcers, similar to the picture in diabetic neuropathy.[emedicine.medscape.com]
Hepatomegaly
  • 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 (enlarged liver). Systemic amyloidosis Lichen amyloidosus Also called papular amyloidosis Lichen amyloidosus is the most common form of primary localised cutaneous amyloidosis.[dermnetnz.org]
Muscle Weakness
  • ., neuropathic pain, 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[invitae.com]
Muscular Atrophy
  • atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial.[researchmap.jp]
Leg Pain
  • I find having a regular leg and feet massage eases my leg pains and stiffness. Keep your legs and feet always moisturised. Carry out daily hand exercise to keep them working.[amyloidosis.org.uk]
Ulcer
  • […] 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]
  • Lesions tend not to ulcerate but some may crack or split, particularly those on the soles of the feet.[dermnetnz.org]
  • This is important in order to prevent painless ulcers at pressure points and to protect areas of the foot that lack sensation.[amyloidosis.org.uk]
  • Loss of pain sensation with preservation of strength leads to painless trauma and the development of plantar ulcers and foot osteoarthropathy (Charcot’s joints) [ 33 ].[ncbi.nlm.nih.gov]
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]
  • Skin lesions The most common skin findings are purpura : petechiae (small red blood spots) and ecchymoses (small, flat blood spots that are round or irregular shape and bluish/purplish in colour).[dermnetnz.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]
Blurred Vision
  • ., blurred vision, blindness, dry eyes, glaucoma, visual field abnormalities, retinal detachment) Biopsy positive for amyloid Genetic testing with Invitae The Alnylam Act TM program offers testing with one of the following three options: Ordering made[invitae.com]
  • vision, blindness, protein loss in the urine, kidney failure, goiter (thyroid swelling), etc.[ttrstudy.com]
Visual Impairment
  • Some patients also develop vitreous amyloid deposition that leads to visual impairment (oculoleptomeningeal amyloidosis).[malacards.org]
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]
Red Eye
  • 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]
Polyneuropathy
  • 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]
  • Eligible patients are 18-85 years old with hATTR amyloidosis, investigator-estimated survival of 2 years, Neuropathy Impairment Score (NIS) of 5-130, and polyneuropathy disability score IIIb.[ncbi.nlm.nih.gov]
  • Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA . 2013 Dec 25. 310(24):2658-67. [Medline] . Anderson P. NSAID halts progression in familial amyloid polyneuropathy. December 30, 2013.[emedicine.medscape.com]
  • Pathology of early- vs late-onset TTR Met30 familial amyloid polyneuropathy.[ncbi.nlm.nih.gov]
  • Neuropathy can manifest itself as peripheral polyneuropathy or autonomic neuropathy. In peripheral polyneuropathy sensory changes can be felt in the soles of the feet and in the toes with a slow progression upwards in the lower limbs.[amyloid.nl]
Tingling
  • When people get it in their nerves for example, they all get numbness and tingling which is very common nerve conditions like diabetes, and alcoholism, and drugs can cause nerve disease that causes numbness and tingling.[healthprofessionalradio.com.au]
  • Often diminished feeling sensation, tingling, decreased perception of hot and cold, shooting pain, and loss of muscle strength.[amyloid.nl]
  • It can cause loss of sensation, tingling, numbness or pain in the hands and feet (also known as peripheral neuropathy).[gethealthystayhealthy.com]
  • ., neuropathic pain, 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[invitae.com]
  • Carpal tunnel syndrome (pain and tingling in the wrists and hands) often appears several years before heart disease. It may be caused by TTR amyloid deposits in the wrists.[ttrstudy.com]
Dizziness
  • As a consequence blood pressure can drop sharply from supine to prone position (orthostatic hypotension), resulting in complaints of dizziness.[amyloid.nl]
  • 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, headaches, dizziness[gethealthystayhealthy.com]
  • […] flushing), skin warm • Body aches or pain, including pain in the back, neck, or joints • Feeling sick (nausea) • Stomach pain • Feeling short of breath, cough, or other breathing problems • Headache • Chest discomfort or chest pain • Rash • Chills • Dizziness[alnylam.com]
  • ., 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, edema[invitae.com]
  • Heart failure: shortness of breath, sometimes just after mild exertion, sometimes when lying flat palpitations due to abnormal heart rhythms, most frequently atrial fibrillation or atrial flutter ankle swelling (edema) fatigue, nausea, weight loss dizziness[ttrstudy.com]
Ataxia
  • […] oculoleptomeningeal, and cardiac. (105210) MalaCards based summary : Amyloidosis, Hereditary, Transthyretin-Related, also known as transthyretin amyloidosis , is related to polyneuropathy and amyloid neuropathy , and has symptoms including neuralgia , ataxia[malacards.org]
  • 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]
  • […] spastic paraparesis. [3] Patients with leptomeningeal and cerebrovascular deposits can have seizures, subarachnoid hemorrhages, and dementia. [3] Patients with isolated leptomeningeal TTR disease, a rare presentation, can have hearing loss and cerebellar ataxia[emedicine.medscape.com]
  • Typical clinical central nervous system manifestations include cerebral infarction and hemorrhage, hydrocephalus, ataxia, spastic paralysis, convulsion, and dementia.[ncbi.nlm.nih.gov]
Seizure
  • Clinical features include seizures, stroke-like episodes, dementia, psychomotor deterioration, variable amyloid deposition in the vitreous humor.[malacards.org]
  • 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]
  • […] a wide range of abnormalities observed upon mental status and neurologic examination. [3] Objective findings may include nystagmus and pyramidal signs, with spastic paraparesis. [3] Patients with leptomeningeal and cerebrovascular deposits can have seizures[emedicine.medscape.com]
Kidney Failure
  • 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.[symptoma.com]
  • Kidney failure Most people with AL amyloidosis have a build-up of amyloid proteins (amyloid deposits) in their kidneys, and are at risk of kidney failure.[nhs.uk]
  • failure, goiter (thyroid swelling), etc.[ttrstudy.com]
  • The kidneys' ability to remove waste products from your body is lowered, which may eventually lead to kidney failure. Heart. Amyloid reduces your heart's ability to fill with blood between heartbeats.[mayoclinic.org]
Sexual Dysfunction
  • ., diarrhea, sexual dysfunction, hypotension), and cardiac symptoms.[invitae.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]
  • Symptoms Symptoms of hereditary ATTR amyloidosis may include: peripheral neuropathy: limb weakness and pain, loss of sensation autonomic neuropathy: disturbances of bowel, bladder and blood pressure and sexual dysfunction heart failure – symptoms result[amyloidosis.org.uk]
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]
  • 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]
  • incontinence Distigmine Anemia Erythropoietin, iron Hypothyroidism Levothyroxine Ocular amyloidosis Vitrectomy, trabeculectomy Liver transplant Orthotopic liver transplant is the only disease-modifying treatment available to patients with TTR-FAP.[ncbi.nlm.nih.gov]
Urinary Retention
  • Common symptoms with ATTR amyloidosis with autonomic neuropathy may include postural hypotension, urinary retention, impotence, body temperature irregularities, and gastrointestinal problems.[raredr.com]
  • retention impotence reduced sweating Heart disease (restrictive cardiomyopathy): amyloid deposits in the heart cause stiffening and thickening of the heart muscle, so the heart cannot pump the blood around the body as efficiently as usual.[ttrstudy.com]
Renal Insufficiency
  • Patients with transthyretin amyloidosis typically present with polyneuropathy, carpal tunnel syndrome, autonomic insufficiency, cardiomyopathy, and gastrointestinal features, occasionally accompanied by vitreous opacities and renal insufficiency.[malacards.org]
  • 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.[symptoma.com]

Workup

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
  • 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]
  • A lesser degree of renal dysfunction in our patients may be related to an early diagnosis through repeated measurements of microalbuminuria and serum creatinine.[scielo.mec.pt]

Treatment

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].

Prognosis

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].

Etiology

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].

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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].

Prevention

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.

Summary

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.

Patient Information

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.

References

Article

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Last updated: 2019-01-08 10:14