Edit concept Question Editor Create issue ticket

TTR Amyloidosis with Polyneuropathy

TTR-FAP

TTR amyloidosis is short for transthyretin amyloidosis, a disease that is characterized by slowly progressive peripheral sensorimotor and/or autonomic neuropathy. Other organs, such as the heart, meninges, kidneys, and eyes, may also be involved. In patients suffering from TTR amyloidosis with polyneuropathy, the accumulation of amyloid fibrils in nervous tissue initially provokes ascending sensory loss and dysautonomia. During later stages of the disease, motor deficits become evident. The disease is inherited in an autosomal dominant manner and may also be referred to as familial amyloid polyneuropathy (FAP).


Presentation

TTR amyloidosis is characterized by phenotypic heterogeneity. While neuropathic features are observed in the majority of patients, the involvement of other organs may occasionally dominate the clinical picture. As an example, patients suffering from TTR amyloidosis with cardiomyopathy or familial leptomeningeal amyloidosis typically present with congestive heart failure and neurological deficits due to cerebrovascular accidents, respectively [1]. Mixed phenotypes are common, though, and FAP patients should be checked for cardiac disease, cerebral angiopathy, renal dysfunction, and visual impairment.

Peripheral neuropathy is the cardinal feature of FAP and initially manifests in superficial sensory and autonomic impairments. Symptoms symmetrically affect both sides of the body and tend to progress from distal to more proximal regions [1] [2].

The textbook patient presents before the age of 50, claims loss of temperature and pain sensation in their feet or - less frequently - hands. Within years, these symptoms spread to the ankles, lower legs, knees, and thighs, or the respective regions of the arms. As-of-yet unaffected sensory modalities, such as tactile sensation, may eventually become disturbed.
While the progressive involvement of sensory modalities is characteristic of early-onset FAP, late-onset disease is more commonly related to peripheral neuropathy affecting all sensory modalities right from the beginning.
Motor deficits aren't usually evident during early stages of FAP but increasingly diminish life quality as the disease progresses. Similar to sensory dysfunctions, they develop in the distal extremities and spread proximally.
Autonomic dysfunction may manifest as cardiovascular instability and orthostatic hypotension, abnormal sweating, nausea, vomiting, diarrhea or constipation, dysuria or urinary retention, and sexual dysfunction. Involvement of the autonomous nervous system is most evident in early-onset FAP as described above; patients presenting beyond the age of 60 tend to show relatively mild autonomic symptoms.

Weakness
  • The patient had muscle weakness and sensory disturbances in her extremities caused by severe peripheral neuropathy. She also had vitreous opacity and orthostatic hypotension, and pyrophosphate scintigraphy showed a myocardial accumulation.[ncbi.nlm.nih.gov]
  • This study aims to explore the genetic features of a Han Chinese family with FAP, characterized by bloating, alternating diarrhea and constipation, and weakness in his feet.[ncbi.nlm.nih.gov]
  • In 5, muscular weakness and autonomic dysfunction were the initial symptoms followed by sensory disturbances. Amyloidotic cardiomyopathy was present in 3 of the subjects. Amyloid deposits showed an immunohistological relation to transthyretin (TTR).[ncbi.nlm.nih.gov]
  • The motor involvement occurs late in the disease, initially in the lower limbs, progressing to atrophy and weakness, predominantly observed in the feet and legs. Involvement of the upper limbs occurs later.[ceparm.com]
  • Characteristics [ 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]
Weight Loss
  • loss, carpal tunnel syndrome, renal impairment, or ocular involvement.[ncbi.nlm.nih.gov]
  • loss •Arrhythmia •Edema •Acroparaesthesia The currently available therapeutic approaches are either liver transplantation (as the liver mainly produces transthyretin this is a feasible approach) or as of more recently also a TTR-tetramer stabilizing[centogene.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]
Fatigue
  • Other side effects associated with therapy include injection site reactions, nausea, headache, fatigue, and fever. Tegsedi is available only through a restricted distribution program called the Tegsedi REMS program.[empr.com]
  • 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]
  • 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]
  • Patient 1 Patient 1 was a 58-year-old man from Navarre who attended the neurology department in December 2013 due to a 1-year history of fatigue and a “strange” sensation in the feet.[elsevier.es]
  • The most common adverse reactions observed in the clinical efficacy trial with Tegsedi were injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever. 1 In an effort to assist hATTR amyloidosis patients in gaining access to Tegsedi[pharmacytimes.com]
Walking with a Cane
  • The neurological symptoms remained largely stable, with distal weakness in the hands and feet and neuropathic pain; the patient was able to walk with a cane.[elsevier.es]
Difficulty Climbing Stairs
  • He attended the neurology department in March 2005 due to cramps and allodynia in the soles of the feet and difficulty climbing stairs, which had started 3 years earlier.[elsevier.es]
Severe Clinical Course
  • Although homozygotes have been reported to show late-onset and mild clinical manifestations, detailed analyses of the present and previously reported families suggest that homozygotes have a slightly more severe clinical course than heterozygotes.[ncbi.nlm.nih.gov]
Constipation
  • This study aims to explore the genetic features of a Han Chinese family with FAP, characterized by bloating, alternating diarrhea and constipation, and weakness in his feet.[ncbi.nlm.nih.gov]
  • Or you could have problems like diarrhea , constipation , feeling full as soon as you start eating, and trouble peeing. You might also feel very tired.[webmd.com]
Diarrhea
  • This study aims to explore the genetic features of a Han Chinese family with FAP, characterized by bloating, alternating diarrhea and constipation, and weakness in his feet.[ncbi.nlm.nih.gov]
  • The first patient, a 52-year-old lady carrying Thr49Ala mutation, had a disease duration of twelve years and had lost weight up to 35 kg because of daily diarrhea.[ncbi.nlm.nih.gov]
  • Or you could have problems like diarrhea , constipation , feeling full as soon as you start eating, and trouble peeing. You might also feel very tired.[webmd.com]
Nausea
  • Moreover, reduction of autonomic symptoms including postural hypotension, nausea and diarrhoea was recorded with ameliorated quality of life.[ncbi.nlm.nih.gov]
  • Other side effects associated with therapy include injection site reactions, nausea, headache, fatigue, and fever. Tegsedi is available only through a restricted distribution program called the Tegsedi REMS program.[empr.com]
  • […] peripheral nerves: •Dissociated anesthesia •Muscle paresis and atrophy •Dysaesthesia and paraesthesia •Reduced skin temperature •Coldness •Hoarseness Autonomic dysfunction: •Dysuria •Diarrhea •Constipation •Orthostatic dysregulation •Erectile dysfunction •Nausea[centogene.com]
  • If there is vomiting and diarrhea, careful administration of intravenous fluids and anti‑nausea drugs may be necessary.[ttrstudy.com]
  • Similar to sensory dysfunctions, they develop in the distal extremities and spread proximally.Autonomic dysfunction may manifest as cardiovascular instability and orthostatic hypotension, abnormal sweating, nausea, vomiting, diarrhea or constipation,[symptoma.com]
Orthostatic Hypotension
  • She also had vitreous opacity and orthostatic hypotension, and pyrophosphate scintigraphy showed a myocardial accumulation. Esophagogastroduodenoscopy revealed mucosal amyloid deposits, positive in anti-TTR antibody staining.[ncbi.nlm.nih.gov]
  • People with cardiac amyloidosis may arrythmia, cardiomegaly, or orthostatic hypotension. These abnormalities can lead to progressive heart failure and death.[ivami.com]
  • Autonomic neuropathy usually manifests with orthostatic hypotension, constipation alternating with diarrhea, vomiting, impotence or hypohidrosis.[genedx.com]
  • In addition, hATTR amyloidosis may cause CNS symptoms (eg, progressive dementia, headache, ataxia, and seizures), autonomic neuropathy (eg, orthostatic hypotension, urinary retention, and sexual dysfunction), and peripheral sensorimotor neuropathy (eg[mdedge.com]
  • Similar to sensory dysfunctions, they develop in the distal extremities and spread proximally.Autonomic dysfunction may manifest as cardiovascular instability and orthostatic hypotension, abnormal sweating, nausea, vomiting, diarrhea or constipation,[symptoma.com]
Xerostomia
  • 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]
Anisocoria
  • Symptoms such as anisocoria (unequal pupil diameter), constipation, diarrhea, bloating, impotence, lack of sphincter control, severe postural hypotension, among others, indicate the involvement of the autonomic nervous system by the disease.[ceparm.com]
Short Arm
  • Prevalence of TTR-FAP is estimated at 1/10 000 population globally 1 and 1/100 000 population in Europe. 7,8 TTR is a short gene, containing only 4 exons, located on the short arm of chromosome 18 (18q12.1). 5 Over 100 mutations have been described in[elsevier.es]
Paranoid Ideation
  • The independent predictors of higher BSI Depression, BSI Hostility, BSI Paranoid ideation and BSI Psychoticism were female gender and higher disease evolution time (years).[karger.com]
Urinary Incontinence
  • Factor significantly associated with higher post-transplantation death included severe sensorimotor neuropathy (Norris score below 55), permanent urinary incontinence, and postural hypotension with a fixed pulse rate.[bcm.edu]
  • Most patients with FAP have early and severe impairment of the autonomic nervous system, commonly manifested by dyshidrosis, sexual impotence, alternating diarrhoea and constipation, orthostatic hypotension, and urinary incontinence [ 17 - 19 ].[intechopen.com]
  • Symptomatic treatments include prophylactic pacemaker implantation to reduce major cardiac events; medications to treat cardiomyopathy, pain, diarrhea, orthostatic hypotension, urinary incontinence, hypothyroidism, and cardiac failure; erythropoietin[ojrd.biomedcentral.com]
Peripheral Neuropathy
  • Conclusions: Symptoms of peripheral neuropathy are common in patients with ATTRwt. Clinical presentation is sometimes masked by the history of spine disease and should be better evaluated.[n.neurology.org]
  • Sometimes, people with heart form of transthyretin amyloidosis have mild peripheral neuropathy. Transthyretin amyloidosis is due to mutations in the TTR gene, located on the long arm of chromosome 18 (18q12.1).[ivami.com]
  • Such a presentation makes it often difficult to distinguish ATTR amyloidosis-related peripheral neuropathy from other acquired peripheral neuropathies of adulthood.[jnnp.bmj.com]
  • The patient had muscle weakness and sensory disturbances in her extremities caused by severe peripheral neuropathy. She also had vitreous opacity and orthostatic hypotension, and pyrophosphate scintigraphy showed a myocardial accumulation.[ncbi.nlm.nih.gov]
  • We report a 58-year-old man presenting with progressive peripheral neuropathy, autonomic failure and chronic paroxysmal dry cough. His father, three elder brothers and an elder sister suffered from the similar symptoms.[ncbi.nlm.nih.gov]
Tingling
  • A 62-year-old Portuguese man, with no history of familial amyloid polyneuropathy (FAP), and a 2(1/2)-year history of tingling in the toes and sexual dysfunction was found neurophysiologically to have a sensory-motor axonal polyneuropathy.[ncbi.nlm.nih.gov]
  • Try a warm-water foot massager before bed to help with tingling and burning in your feet. What to Expect Although the disease continues to progress, some TTR-FAP symptoms can be controlled and treated.[webmd.com]
Dizziness
  • Do you get dizzy when standing up or stretching ? Have you had any eye or vision problems? Your doctor may want to do tests related to symptoms you have, too, especially for your nerves and heart. Blood and urine tests.[webmd.com]
Paresthesia
  • Here, we describe a 52-year-old man who had slight paresthesia for four years and whose final diagnosis of TTR-cardiac amyloidosis caused by sporadic FAP was delayed despite annual electrocardiography.[ncbi.nlm.nih.gov]
  • Characteristics [ 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]
  • Sensory neuropathy starts in the lower extremities with paresthesia, impaired pain and temperature sensation, followed by loss of motor function.[genedx.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]
  • Inaugural manifestations are paresthesiae, pain or trophic lesions of the feet, gastrointestinal disorders or weight loss. The most pronounced sensory loss involves pain and temperature sensation. Motor loss occurs later.[orpha.net]
Headache
  • Other side effects associated with therapy include injection site reactions, nausea, headache, fatigue, and fever. Tegsedi is available only through a restricted distribution program called the Tegsedi REMS program.[empr.com]
  • In addition, hATTR amyloidosis may cause CNS symptoms (eg, progressive dementia, headache, ataxia, and seizures), autonomic neuropathy (eg, orthostatic hypotension, urinary retention, and sexual dysfunction), and peripheral sensorimotor neuropathy (eg[mdedge.com]
  • The most common adverse reactions observed in the clinical efficacy trial with Tegsedi were injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever. 1 In an effort to assist hATTR amyloidosis patients in gaining access to Tegsedi[pharmacytimes.com]

Workup

FAP should be suspected if symmetric sensorimotor polyneuropathy is observed in combination with one or more of the following: family history of neuropathy, autonomic dysfunction, gastrointestinal complaints, bilateral carpal tunnel syndrome, cardiac disease (hypertrophy, conduction blocks, intractable arrhythmia, restrictive cardiomyopathy), renal function impairment (nephrotic syndrome or progressive renal failure), and vitreous opacities [3]. With regard to the family history, evidence of heritability can be gathered in about half of all cases [4] [5].

To confirm the suspected diagnosis, the deposition of amyloid in nervous tissue needs to be demonstrated. Biopsy specimens may be obtained from the subcutaneous adipous tissue of the abdominal wall, gastroduodenal mucosa, rectal mucosa, salivary glands or endomyocardium. If amyloid is detected in these tissues, the type of amyloid protein needs to be determined. This is usually done by means of immunohistochemistry [6].

Biopsies may also be performed on the sural nerve [1]. Histological analyses of these samples typically reveal the loss of both myelinated and unmyelinated fibers with or without adjacent amyloid deposition. The predominant loss of small fibers, which is often described as a general feature of FAP, is more commonly observed in early-onset cases. Both myelinated and unmyelinated fibers may be affected in these patients. Late-onset FAP, however, is frequently related to the depletion of large myelinated fibers [7].

In any case, it should be noted that a negative biopsy of an unaffected organ does not exclude FAP and that histological analyses should always be complemented by genetic studies to identify the underlying TTR mutation [6].

Treatment

As of today, FAP is considered a curable disease if diagnosed during early stages. Transthyretin is mainly produced in the liver, and orthotopic liver transplantation eliminates more than 95% of abnormal, amyloidogenic transthyretin from the circulation of affected individuals [8]. Liver transplantation is usually carried out in relatively young patients with early-onset FAP; it is not a viable option, though, in cases of co-existing cardiomyopathy or leptomeningeal amyloidosis [1]. What's more, FAP patients who underwent liver transplantation should be closely monitored for cardiac complications, since the procedure may trigger a paradoxical acceleration of cardiac amyloid deposition. This phenomenon is mainly observed in individuals carrying TTR variants other than p.V50M [8].

Even though liver transplantation remains the only curative therapy of FAP, intense research is carried out on new treatment strategies to improve the prognosis of patients who are not eligible for surgery. Today, research efforts focus on drugs that suppress the expression of the TTR gene, inhibit the translation of transthyretin, or stabilize the tetrameric transthyretin molecule [1] [4]. In this context, the safety and efficacy of compounds like tafamidis meglumine and diflunisal - both of which are classified as TTR tetramer stabilizers - have already been proven [9]. Patisiran, a double-stranded small interfering RNA, has recently received approval for FAP treatment [10], and promising results have also been achieved with antisense oligonucleotides like ISIS-TTRrx. Moreover, combination therapy with doxycycline and tauroursodeoxycholic acid has been shown to favor the removal of amyloid deposits in laboratory animals and is now tested in clinical trials. The anthracycline 4'-iodo-4'-deoxy-doxorubicin has been postulated to promote the dissolution of the amyloid matrix, although this effect has so far been observed in vitro only [1] [4].

In any case, patients should be provided symptomatic care according to their individual needs.

Prognosis

FAP follows a progressive course and is universally fatal. Median survival times, however, largely depend on the underlying phenotype: They may range between five and ten years in case of TTR variants p.V50M and p.T80A, but rare mutations in the TTR gene (e.g., p.L32P, p.F53L, p.G67E, and p.V91A) have been described to induce aggressive, rapidly progressing and disabling FAP [11].

In general, a timely diagnosis and adequate treatment significantly prolong the patient's survival. Neuropathy and organ impairment are not usually reversed following liver transplantation, so this procedure should be realized as early as possible [6].

Etiology

FAP is caused by mutations in the TTR gene. This gene is located on the long arm of chromosome 18 and encodes for transthyretin, a protein implied in the transport of thyroid hormones and retinol. Transthyretin forms homotetramers with two binding sites for thyroxine, and these tetramers associate with retinol-binding protein in support of intra- and extraocular retinol transport. Mutations in the TTR gene may result in the synthesis of less stable variant transthyretin. Tetramer dissociation, misfolding and misassembly may follow and lead to the formation of insoluble protofibrils, which accumulate in the extracellular space of nervous tissues and others. In sum, more than 140 variants of TTR have been described to date, and the vast majority of these variants has been classified as amyloidogenic.

Several studies have been carried out to elucidate genotype-phenotype correlations [4] [11]:

Isolated neuropathy is rare in FAP patients. This phenotype has been described for TTR variants p.I127F, p.L32P, p.F53L, p.G67R, and p.T69S, among others, all of which are of low incidence.
Concerning TTR variants inducing mixed-phenotype TTR amyloidosis, variants p.V50M and p.T80A have been identified as the most prevalent mutations. They are related to the replacement of valine by methionine at position 30 and threonine by alanine at position 60, respectively. This category also comprises p.S97Y, p.A117S, p.G67E, p.G67V, p.I127V, and many others.
The phenotypic heterogeneity of patients carrying identical mutations in the TTR gene suggests the influence of genetic modifiers [3]. They may be located either in the region next to TTR, or act through distant genes and gene-gene interaction. Additional research is necessary to shed more light on the underlying mechanisms.

Epidemiology

FAP has first been described in Portuguese kindreds but is now recognized as a global disease [3]. Both men and women may develop FAP, but the vast majority of patients is male. The patients' age at symptom onset largely depends on the underlying genotype. TTR variant p.V50M is related to symptom onset at a median age of 45 years, whereas those carrying TTR variant p.T80A usually present during their seventh decade of life. Homozygosity has rarely been reported for amyloidogenic variants of TTR but seems to be associated with a significantly earlier onset of symptoms [11].

In general, reported incidence and prevalence rates are increasing. This fact is generally attributed to improvements in the diagnosis of FAP and does most likely not reflect any change in disease demographics.

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 [4]. This means that it is an important mediator of vitamin A transport and utilization [2] [11]. 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 [2]. 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, nerves, eyes and the liver [7] [11].

Prevention

Families known to harbor amyloidogenic mutations of TTR may benefit from genetic counseling [5]. Carriers of the respective variants may be identified and be included in surveillance programs aiming at the early detection of amyloidosis. This way, diagnostic delays and misdiagnoses may be avoided, and curative treatment may be initiated during early stages of the disease.

Summary

Hereditary TTR amyloidosis has historically been split into two categories, a form predominantly affecting the nervous system and another one related to cardiomyopathy [4]. They are designated as FAP and TTR amyloidosis with cardiomyopathy, respectively. Some authors define a third type of FAP, which is related to cerebral amyloid angiopathy and amyloid deposition in the meninges. The latter is often referred to as familial leptomeningeal amyloidosis [1]. Notwithstanding the clinical relevance of these classification schemes, they don't do justice to the phenotypic spectrum of TTR amyloidosis, where the majority of patients presents with signs and symptoms of more than one subtype.

To provide a better understanding of the mechanisms leading to and consequences of amyloid neuropathy, this article focuses on what's known as FAP to the clinician. Readers interested in learning about additional features of TTR amyloidosis are referred to the respective entries on this platform, namely TTR amyloidosis with cardiomyopathy and leptomeningeal TTR amyloidosis.

Patient Information

Transthyretin is mainly produced in the liver and fulfills a variety of functions in the human body, e.g., assisting in the transport of thyroid hormones and vitamin A, which is essential for vision. Transthyretin may undergo conformational changes, either due to inherited mutations in the TTR gene or age-related modifications, and may form insoluble amyloid fibrils that accumulate in the extracellular compartment. This is a space-occupying process associated with the compression and obstruction of adjacent structures, whose function may be limited in the course of the disease. Transthyretin amyloid is preferentially deposited in the nervous system, heart, and eyes, and patients who present with peripheral neuropathy and concomitant symptoms due to transthyretin amyloidosis are diagnosed with TTR amyloidosis with polyneuropathy (FAP). It should be noted that multiple organ systems may be affected, and patients may develop other symptoms, such as carpal tunnel syndrome, cardiac or renal disease, or loss of visual acuity, before manifesting signs and symptoms of FAP.

FAP patients typically claim loss of temperature and pain sensation in their feet, and these sensory deficits tend to spread to more proximal parts of the legs. The disease follows a progressive course, and, eventually, other sensory modalities, such as tactile sensation, may become disturbed. Furthermore, patients may develop motor deficits and dysautonomia, whereby the latter may manifest in cardiovascular instability with hypotension, gastrointestinal complaints, urinary or sexual dysfunction.

Liver transplantation has long since been considered the only treatment option providing a chance for cure. But recently, several new drugs received approval for FAP therapy: They may help to maintain life quality, delay disease progression, and prolong survival times.

References

Article

  1. Sekijima Y. Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. J Neurol Neurosurg Psychiatry. 2015; 86(9):1036-1043.
  2. Finsterer J, Iglseder S, Wanschitz J, Topakian R, Loscher WN, Grisold W. Hereditary transthyretin-related amyloidosis. Acta Neurol Scand. 2019; 139(2):92-105.
  3. Plante-Bordeneuve V. Transthyretin familial amyloid polyneuropathy: an update. J Neurol. 2018; 265(4):976-983.
  4. Dubrey S, Ackermann E, Gillmore J. The transthyretin amyloidoses: advances in therapy. Postgrad Med J. 2015; 91(1078):439-448.
  5. Oliveira CR, Mendes A, Sousa L. From older to younger: intergenerational promotion of health behaviours in Portuguese families affected by familial amyloid polyneuropathy. Eur J Hum Genet. 2017; 25(6):687-693.
  6. Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, Prognosis, and Therapy of Transthyretin Amyloidosis. J Am Coll Cardiol. 2015; 66(21):2451-2466.
  7. Koike H, Ikeda S, Takahashi M, et al. Schwann cell and endothelial cell damage in transthyretin familial amyloid polyneuropathy. Neurology. 2016; 87(21):2220-2229.
  8. Stangou AJ, Hawkins PN. Liver transplantation in transthyretin-related familial amyloid polyneuropathy. Curr Opin Neurol. 2004; 17(5):615-620.
  9. Waddington Cruz M, Amass L, Keohane D, Schwartz J, Li H, Gundapaneni B. Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy. Amyloid. 2016; 23(3):178-183.
  10. Hoy SM. Patisiran: First Global Approval. Drugs. 2018; 78(15):1625-1631.
  11. Rowczenio D, Quarta CC, Fontana M, et al. Analysis of the TTR gene in the investigation of amyloidosis: A 25-year single UK center experience. Hum Mutat. 2019; 40(1):90-96.

Ask Question

5000 Characters left Format the text using: # Heading, **bold**, _italic_. HTML code is not allowed.
By publishing this question you agree to the TOS and Privacy policy.
• Use a precise title for your question.
• Ask a specific question and provide age, sex, symptoms, type and duration of treatment.
• Respect your own and other people's privacy, never post full names or contact information.
• Inappropriate questions will be deleted.
• In urgent cases contact a physician, visit a hospital or call an emergency service!
Last updated: 2019-07-11 20:01