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]

  […] symptoms (eg, progressive dementia, headache, ataxia, and seizures), autonomic neuropathy (eg, orthostatic hypotension, urinary retention, and sexual dysfunction), and peripheral sensorimotor neuropathy (eg, neuropathic pain, altered sensitivity, muscle weakness [mdedge.com]

  The study is measuring a number of clinical endpoints every 6 months, including mNIS 7, which is an evaluation of muscle weakness, sensory and autonomic function, and nerve conductance, where neuropathy progression leads to an increased score over time [raredr.com]

• 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]

  loss at diagnosis [HR: 2.85 (95% CI: 1.08–7.54) for weight loss vs. no weight loss; P 0.03] were associated with reduced survival in univariable analyses. [academic.oup.com]

  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]

• 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]

• 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]

  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

  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]

  Moreover, reduction of autonomic symptoms including postural hypotension, nausea and diarrhoea was recorded with ameliorated quality of life. [ncbi.nlm.nih.gov]

  […] 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]

  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]

• Xerostomia

  At last follow-up, autonomic involvement (orthostatic hypotension, diarrhea/stypsis, erectile dysfunction, urinary incontinence, xerostomia) paralleled sensory and motor dysfunction in 12/20 cases; 4 patiens had only sensory disturbances, 1 sensory-motor [content.iospress.com]

  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]

• 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]

  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 latter was: distal paraesthesias in 6, muscle weakness in 3, walking difficulty, orthostatic hypotension and constipation in 2 each. [content.iospress.com]

  Autonomic neuropathy usually manifests with orthostatic hypotension, constipation alternating with diarrhea, vomiting, impotence or hypohidrosis. [genedx.com]

• Muscular Atrophy

  Back to Top Spinal and bulbar muscular atrophy Spinal and bulbar muscular atrophy (SBMA), also known as spinobulbar muscular atrophy, bulbospinal atrophy, X-linked bulbospinal neuropathy (XBSN), X-linked spinal muscular atrophy type 1 (SMAX1), and Kennedy's [bitanlab.neurology.ucla.edu]

• 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]

  At last follow-up, autonomic involvement (orthostatic hypotension, diarrhea/stypsis, erectile dysfunction, urinary incontinence, xerostomia) paralleled sensory and motor dysfunction in 12/20 cases; 4 patiens had only sensory disturbances, 1 sensory-motor [content.iospress.com]

  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

  Such a presentation makes it often difficult to distinguish ATTR amyloidosis-related peripheral neuropathy from other acquired peripheral neuropathies of adulthood. [jnnp.bmj.com]

  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]

  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]

  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]

• 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]

  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]

  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]

  He experienced subsequent transient episodes of aphasia and extremity paresthesias superimposed on a persistent mild gait and cognitive deficits from his initial event. [ingentaconnect.com]

  Sensory neuropathy starts in the lower extremities with paresthesia, impaired pain and temperature sensation, followed by loss of motor function. [genedx.com]

• Headache

  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]

  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]

  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]

  Individuals with leptomeningeal amyloidosis show CNS signs and symptoms including: dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage. [pharmaceuticalintelligence.com]

  Transthyretin amyloidosis (serine 44) with headache, hearing loss, and peripheral neuropathy. Neurology. 51:1462-1464. Ala45Asp Jacobson R, Gertz MA, Kane I, and Buxbaum JN. (1993). [bumc.bu.edu]

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].

• Cardiomegaly on Chest X-ray

  Detection of subclinical cardiac involvement (e.g. cardiomegaly on chest X-ray, and thickening of the interventricular septum and granular sparkling on echocardiography [ 31 ]) may help diagnose late-onset ATTR-FAP Val30Met in patients without a family [ojrd.biomedcentral.com]

• Poor R Wave Progression

  Only 7/44 patients with cardiac amyloidosis on echocardiography and evaluable (i.e. non-paced) electrocardiograms had small QRS complexes, whereas the pseudo-infarction pattern of poor R-wave progression in the chest leads was present in 25/44 (57%) patients [academic.oup.com]

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.

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].

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.

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.

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].

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.

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.

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.

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.