Hereditary amyloid polyneuropathy …

Rebecca E Traub MD

Peripheral Neuropathies

Updated 01.26.2024
Released 12.13.2018
Expires For CME 01.26.2027

Hereditary amyloid polyneuropathy

Author: Rebecca E Traub MD

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Editor: Louis H Weimer MD

Hereditary amyloid polyneuropathy

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Introduction

Overview

Hereditary amyloidosis is a disease caused by mutations in the transthyretin gene that leads to systemic deposition of amyloid protein. Although patients have multisystem involvement of amyloidosis, cardiomyopathy and peripheral neuropathy with autonomic neuropathy are typically the most prominent disease manifestations and the primary drivers of disability and mortality. Small interfering RNA, or antisense oligonucleotide therapies approved by the United States Food and Drug Administration, reduce the production of transthyretin protein and slow the progression of hereditary amyloid polyneuropathy and, in some cases, improve measures of neuropathy severity and associated disability. Although hereditary transthyretin amyloidosis is a rare disease, it is an exciting model for developing new treatments for genetic disease in neurology and in medicine broadly.

Key points

	• Hereditary amyloid polyneuropathy primarily refers to patients with mutations in the transthyretin gene, although mutations in other genes may present with amyloidosis and neuropathy.
	• The symptoms of transthyretin-associated familial amyloid polyneuropathy are those of a sensory or sensorimotor polyneuropathy, with progressive sensory loss and weakness, often with prominent autonomic neuropathy. Neuropathy is often accompanied by amyloid cardiomyopathy.
	• hATTR polyneuropathy is diagnosed and confirmed with genetic testing for TTR gene mutations. Amyloidosis may be detected on tissue biopsy in the workup of idiopathic neuropathy or cardiomyopathy, which may lead to suspicion of a genetic diagnosis.
	• Small interfering RNA and antisense oligonucleotide therapies that reduce or “silence” TTR gene expression are effective treatments to slow the progression of hATTR polyneuropathy.

Historical note and terminology

Rudolf Virchow first described amyloid deposits in 1858, noting their starch-like appearance and reaction to iodine and sulfuric acid. Congo red staining of amyloid was first described in 1922, and the typical apple-green birefringence was noted in 1927 in patients with Alzheimer disease (48).

Transthyretin protein is named in reference to its two primary transport functions: binding thyroxine and retinol-binding protein (45). The TTR gene was sequenced in 1974 by Kanda and colleagues; at that time the transthyretin protein was referred to as plasma thyroxine-binding prealbumin (32). In 1991, Benson described 10 TTR gene mutations associated with familial amyloid polyneuropathy (14). The number of TTR gene mutations associated with disease has grown. More than 140 mutations in the TTR gene have been described (http://amyloidosismutations.com/mut-attr.php).

Clinical manifestations

Presentation and course

TTR gene mutations result in multisystem amyloid protein deposition, but the cardiac system and the peripheral nervous system are most prominently affected. Some mutations in the TTR gene are more associated with cardiac involvement and others with more prominent peripheral neuropathy. The V122I mutation is noted to have primarily cardiac manifestations whereas the V30M is the most common form of familial amyloid polyneuropathy, particularly amongst Portuguese, Swedish, and Japanese populations (13; 11). Polyneuropathy may be more common with V122I mutations than previously reported (43).

Often the first neurologic symptom associated with transthyretin-associated familial amyloid polyneuropathy is carpal tunnel syndrome, related to amyloid deposition in the carpal tunnel causing a compressive median mononeuropathy. Carpal tunnel syndrome may precede other amyloid symptoms by years or even decades.

The generalized polyneuropathy of TTR-FAP typically begins with primarily small fiber involvement with paresthesias, loss of small fiber sensory modalities (temperature and pain), and neuropathic pain. Skin biopsy in presymptomatic TTR mutation carriers may show reduced epidermal nerve fiber density (28; 35; 20), and patients with early symptoms of peripheral neuropathy may have normal nerve conduction studies but low epidermal nerve fiber density on skin biopsy consistent with small fiber neuropathy (55). Skin biopsy may also be used to detect amyloid deposition and correlates with disease severity in TTR-FAP (28; 20). As the peripheral neuropathy of TTR-FAP progresses, there is increasing loss of large fiber nerve function, with more loss of sensation, weakness, and gait imbalance. Symptoms that initially begin in the feet and lower legs will eventually progress to affect the hands and arms.

Autonomic neuropathy is often prominent in patients with TTR-FAP. Symptoms and signs may include orthostatic hypotension, resting tachycardia, urinary retention, gastroparesis, erectile dysfunction, and abnormal sweating. In contrast to other types of autonomic neuropathy in which constipation predominates, patients with hereditary amyloidosis typically have prominent diarrhea, likely related to direct amyloid deposition in the bowel wall.

Depending on the genetic subtype of TTR-FAP, some patients will have an associated amyloid cardiomyopathy. Although the cardiac manifestations of amyloidosis are outside the scope of this article, the typical findings of are of a hypertrophic or infiltrative cardiomyopathy. When evaluating a patient with an otherwise “idiopathic” peripheral neuropathy, autonomic neuropathy, and hypertrophic cardiomyopathy, a diagnosis of transthyretin amyloidosis should be considered.

Other organ systems that can often be affected by amyloidosis in TTR-FAP include ocular deposition, other musculoskeletal structures, gastrointestinal dysfunction with diarrhea, and renal involvement.

Prognosis and complications

Untreated, transthyretin-associated familial amyloid polyneuropathy leads to progressive worsening of peripheral neuropathy, with increasing sensory loss, weakness, and gait imbalance as well as more severe autonomic dysfunction with orthostatic hypotension. Combined with the associated cardiac amyloidosis, patients are at increased risk for cardiac arrhythmia. Historically, this has been a fatal disease in many patients, primarily driven by the cardiac and autonomic morbidity, although significant phenotypic variability occurs within and between families (19; 03). One series of patients with V30M mutations described life expectancy average of 7.3 years from time of disease diagnosis (34).

Disease-modifying treatment, including gene silencing therapies and amyloid stabilizers, can now significantly slow down the course of the disease and in some cases may lead to clinical improvement. The expected prognosis for this disease is now significantly improved since the approval of these medications, and this is no longer considered a fatal disease.

With the approval of disease-modifying therapies, there has been increased attention and access to genetic testing for TTR gene mutations. Many family members of patients with amyloidosis are now aware that they are asymptomatic carriers of TTR mutations and are monitored for development of symptoms suggestive of clinical amyloidosis. Variable penetrance makes it difficult to predict which patients will develop disease and at what age. In a natural history study of asymptomatic TTR gene mutation carriers, 36% developed symptoms of amyloidosis at a median of 2.2 years after enrollment (21). The average age of onset of amyloidosis symptoms was 40 to 48 years, depending on mutation, although the Val122Ile (p.Val142Ile) mutation, which is most common in the United States, was not well represented.

Clinical vignette

A 58-year-old man presented with years of sensory loss in the lower legs and feet that had slowly worsened; at the time of presentation, he reported weakness and trouble walking as well as increased sensory loss and weakness in the hands with prominent neuropathic pain over the past year. He had orthostatic dizziness with multiple syncopal events, difficulty with urinary retention, chronic diarrhea, and nausea and abdominal pain after eating. He had no other significant medical history. He underwent carpal tunnel release surgery bilaterally 10 years earlier.

Family history was notable for peripheral neuropathy in his father, who died in middle age from cardiac complications, and a younger brother had milder sensory symptoms in his feet. Physical examination was notable for orthostatic hypotension on vital sign testing; there was distal sensory loss to light touch, pinprick, and vibration in the lower legs and hands; there was mild weakness of ankle dorsiflexion and interosseous muscles bilaterally; deep tendon reflexes were reduced in the arms and absent at the patellae and ankles. Electrodiagnostic testing demonstrated a severe axonal sensorimotor polyneuropathy. In evaluation for his chronic diarrhea, he underwent colonoscopy, and colonic biopsy showed amyloid deposits with Congo red staining. Echocardiography showed a hypertrophic cardiomyopathy. Testing for multiple myeloma and light-chain amyloid was negative. Genetic testing demonstrated the V30M mutation in the TTR gene, confirming the diagnosis of familial amyloid polyneuropathy.

He was initiated on TTR silencing therapy for hereditary transthyretin amyloidosis with stabilization of his symptoms. He required treatment with gabapentin for pain, midodrine and pyridostigmine for orthostatic hypotension, and close cardiology management for his cardiomyopathy. He was counseled regarding risk to family members and offered the option for genetic testing for others in the family.

Biological basis

Etiology and pathogenesis

Amyloidosis generally refers to a group of diseases that share the common pathological feature of amyloid deposition on tissue pathology. Amyloid may be formed from a number of different proteins that assemble into a beta-sheet conformation causing the common pathological findings noted on tissue biopsy (47). The type of amyloidosis is categorized by associated disease or cause, including immunoglobulin light-chain amyloidosis, reactive systemic amyloidosis in chronic disease, wild type transthyretin (“senile”) amyloidosis (ATTR), and hereditary transthyretin amyloidosis (hATTR). Although this article focuses on hereditary amyloidosis and its neurologic manifestations, it should be noted that when patients present with systemic amyloidosis with neurologic involvement, it is often not known initially which subtype of amyloid is present, and evaluation requires workup with a multidisciplinary team of specialists.

Familial amyloidosis is most often caused by mutations in the TTR gene, encoding transthyretin protein, but other genetic mutations may also cause hereditary amyloidosis, including mutations in fibrinogen alpha-chain, lect2, apolipoproteinA1, lysozyme, and gelsolin. Transthyretin-associated familial amyloid polyneuropathy is the type most strongly associated with peripheral neuropathy, but neuropathy can occur in some of these other subtypes of hereditary amyloidosis. Mutations in the TTR gene result in expression of abnormal transthyretin protein that then forms the beta-sheet conformation of amyloid, depositing in tissues and causing multisystem manifestations of disease. The majority of transthyretin protein is produced in the liver, but other tissues also produce transthyretin protein, including choroid plexus and retinal pigment epithelium.

Diagnostic workup

Hereditary amyloid polyneuropathy, particularly in the early stages, may mimic other, more common causes of peripheral neuropathy and may not be considered a cause for neuropathy until there is more advanced multiorgan involvement or the finding of amyloid deposits is discovered on tissue biopsy.

When encountering a patient with “idiopathic” peripheral neuropathy with prominent autonomic neuropathy and hypertrophic cardiomyopathy, hATTR must be strongly considered. Testing for hereditary transthyretin amyloidosis should also be considered in any patient with peripheral neuropathy with prominent autonomic neuropathy, peripheral neuropathy with a family history of similar, or sensorimotor neuropathy that is more severe than typically seen in other “idiopathic” cases. Expert consensus recommendations to improve diagnosis of transthyretin amyloidosis with polyneuropathy suggest that the diagnosis be considered in any patient with neuropathy plus at least one “red flag” symptom suggestive of multisystem involvement. This would include any patient with an idiopathic progressive sensorimotor polyneuropathy together with a suggestive family history, bilateral carpal tunnel syndrome, autonomic dysfunction, gait change, unexplained weight loss, cardiac hypertrophy or heart rhythm disorder, vitreous opacities, or renal abnormalities (01). Some guidelines suggest that TTR gene testing may be indicated in any patient with an idiopathic peripheral neuropathy, even without red flag symptoms (07).

When encountering a patient in whom a diagnosis of hATTR polyneuropathy is considered, initial testing typically includes routine studies obtained in the general evaluation of peripheral neuropathy, including electrodiagnostic testing (nerve conduction studies and electromyography). Nerve conduction studies in hATTR polyneuropathy most often demonstrate a length-dependent, axonal sensorimotor polyneuropathy or sensory polyneuropathy, but electrodiagnostic patterns can be variable (50). When electrodiagnostic testing is normal, skin biopsy for epidermal nerve fiber density to evaluate for small fiber neuropathy is usually indicated. In the initial evaluation, lab testing for common reversible and treatable causes of neuropathy is performed. When the clinical picture is suggestive of hATTR polyneuropathy, the next step is typically genetic testing to assess for mutations in the TTR gene.

In some cases of severe idiopathic polyneuropathy, nerve biopsy is obtained in an effort to find treatable causes of the disease, and pathology can demonstrate Congo red staining of deposits leading to the amyloidosis diagnosis and, thus, suspicion for hereditary cause. Nerve biopsy for amyloid has been reported to have a sensitivity of 80% in patients with hATTR polyneuropathy (19; 03; 34).

Other tissues may also be biopsied in evaluating a patient with a systemic syndrome in whom there is a concern of amyloidosis, including but not limited to endomyocardium, bowel, kidney, fat pad (51; 11), or labial salivary gland (27). The finding of amyloid deposits then leads to evaluation to determine the type of amyloidosis--whether hereditary or acquired. Mass spectrometry can be performed on amyloid detected on tissue biopsy to determine the type, TTR, or light-chain amyloidosis and, thus, guide further testing and management (33).

Nuclear medicine imaging can also be used to identify cardiac transthyretin deposition. Bone-seeking radionucleotide tracers ⁹⁹m-technetium-3,3-diphosphono-1,2-propanodicarboxylic acid (⁹⁹mTc-DPD) and ⁹⁹mTc-pyrophosphate (⁹⁹mTc-PYP) can be used when cardiac transthyretin amyloidosis (including hereditary and wild type transthyretin) is suspected and may be used by cardiologists or amyloid specialists when evaluating patients with a cardiomyopathy suspected to be related to amyloidosis (44; 30; 18). Additional cardiac testing in patients suspected or confirmed to have transthyretin amyloidosis include echocardiogram, 12-lead electrocardiogram, serum B-type natriuretic peptide (BNP), and in some cases, cardiac magnetic resonance imaging (MRI). Collaboration with cardiologists familiar with the management of amyloidosis is key to the interdisciplinary management of these patients.

Management

Treatment of transthyretin-associated familial amyloid polyneuropathy is currently primarily with medications that reduce expression or “silence” the TTR gene to prevent further progression of amyloidosis. Prior to the approval of these gene-silencing therapies, treatment included amyloid stabilizing medications to prevent misfolding of the protein and liver transplantation.

There are now four approved gene-silencing treatments for patients with hATTR polyneuropathy: patisiran, inotersen, vutrisiran, and eplontersen. A fourth drug, eplontersen, is currently in clinical trials. Patisiran is an RNA-interfering drug that targets the 3’ untranslated region of transthyretin mRNA in the liver and inhibits the synthesis of both mutant and wild-type transthyretin protein. The APOLLO study, published in 2018, was a phase 3 randomized placebo-controlled trial in which intravenous patisiran or placebo was given every 3 weeks over 18 months. The patisiran treatment group had improved outcome when compared to placebo in a number of measurements of neuropathy severity and quality of life. Over half of the patients treated with patisiran in this trial had improvement in their neuropathy impairment score over the course of the study. The most common side effects were related to infusion reactions (02). Open label extension studies of the phase II and APOLLO trials of patisiran demonstrated continued improvement in neuropathy impairment scores with extended use. Exploratory analyses showed improved nerve fiber density and reduced amyloid burden in skin biopsies (04).

Inotersen is an antisense oligonucleotide that targets the transthyretin RNA transcript, reducing production of transthyretin protein. The NEURO-TTR study, also published in 2018, was a phase 3 randomized placebo-controlled trial in which patients were treated with either inotersen or placebo subcutaneously three times in the first week followed by once weekly over 64 weeks. Results from this study showed that patients receiving inotersen when compared to placebo had better outcome in neuropathy severity scores and quality of life. Thirty-six percent of patients receiving inotersen had improvements in neuropathy impairment score over the course of the study. Glomerulonephritis and thrombocytopenia were noted as adverse events in the inotersen treatment group, and strict platelet and renal monitoring are now implemented in patients receiving this medication (12). Open label extension studies of inotersen showed continued benefit in those continuing on the medication, and those patients who switched from placebo to inotersen had improvement in scores of neuropathy severity and quality of life (17).

Vutrisiran is an RNAi therapy that utilizes a similar mechanism as patisiran to reduce TTR production. A lipid nanoparticle formulation directs the drug to the liver, which is the primary site of transthyretin protein production. It is administered subcutaneously once every 3 months. In the 2022 HELIOS-A study, vutrisiran was demonstrated to be noninferior to patisiran in reducing TTR production and met primary clinical endpoints when compared to the historical controls from the APOLLO study (06).

Eplontersen is an antisense oligonucleotide therapy, similar to inotersen, that also targets hepatic transthyretin synthesis. It is administered subcutaneously once monthly. The 2023 NEURO-TTRansform study was an open-label, single-group phase 3 trial that showed the eplontersen treatment group with significantly lower serum transthyretin levels, less neuropathy impairment, and better quality of life compared to historical placebo (25).

Both vutrisiran and eplontersen are additionally in ongoing clinical trials for the treatments of transthyretin amyloid cardiomyopathy, both hereditary and wild type.

Multiple therapies for hATTR polyneuropathy are approved by the United States Food and Drug Administration. Selection of which RNA-interfering therapy to prescribe for any given patient may be driven by accessibility of infusion facilities, medical comorbidity, and laboratory monitoring requirements.

Other TTR gene silencing therapies in development include those using a CRISPR-Cas9 system for gene editing. A 2021 study reported safety and pharmacodynamic effects of a single dose of CRISPR-Cas9 based gene editing therapy, with 87% reduction in TTR protein concentration at the highest tested dose (29). Longer-term follow up studies of safety and efficacy of this therapy are planned.

Prior to the approval of siRNA and antisense oligonucleotide therapies, the primary treatment strategies for the management of hereditary transthyretin amyloidosis were amyloid stabilization and liver transplantation.

Transthyretin stabilizers are medications that aim to stabilize the transthyretin protein and prevent misfolding and tissue deposition. Tafamidis is a benzoxazole derivative lacking nonsteroidal antiinflammatory drug activity that binds to transthyretin and prevents the dissociation of tetramers into monomers, thus, stabilizing the protein and preventing transthyretin-amyloid deposition. A large double-blind, placebo-controlled, phase 3 trial of tafamidis in transthyretin amyloid cardiomyopathy (both hereditary and wild-type) showed reductions in mortality and cardiovascular hospitalization as well as reduced decline in functional capacity and quality of life (37). Tafamidis has been studied in hATTR polyneuropathy in a number of trials. In a phase II/III placebo-controlled study, a greater percentage of patients with hATTR polyneuropathy receiving tafamidis were responders when compared to placebo with regards to preventing worsening on neuropathy severity measures (23; 24). Another randomized study demonstrated delay in neuropathy progression in patients treated with tafamidis (52). Long-term safety and efficacy of tafamidis in TTR-FAP has also been reported (10; 22). Tafamidis has been available for a number of years in Europe and is approved by the Food and Drug Administration for use in the United States for the indication of transthyretin amyloid cardiomyopathy.

Diflunisal, a prostaglandin inhibitor, also has been demonstrated to be a transthyretin stabilizer. Studies have shown diflunisal to be effective and generally well tolerated in treating hATTR polyneuropathy (16; 46) but is not FDA approved for this indication. Other transthyretin stabilizers sometimes used in clinical practice include doxycycline and tauroursodeoxycholic acid (38).

It is not known whether the combination of an amyloid stabilizing medication together with a TTR suppressing therapy is superior to use of the gene silencing therapies alone.

As the majority of transthyretin protein is produced in the liver, liver transplantation has been used to reduce mutant transthyretin protein production in the treatment of hATTR polyneuropathy. Two large studies have demonstrated that patients treated with liver transplant had significantly improved survival compared to an untreated group (53; 54). Liver transplantation may also be combined with heart transplant in patients with severe cardiomyopathy associated with their amyloidosis (09; 53). A cohort study of patients who have received liver transplantation for familial transthyretin amyloidosis has been reported and used to create an online calculator to predict 5-year survival after transplant (08). There are obvious barriers to using liver transplantation on a large scale. With the development of genetic therapies, it will likely become a less utilized therapeutic intervention.

In addition to amyloid stabilization and reduction of transthyretin production through either RNA interference therapy or liver transplantation, patients with hATTR polyneuropathy require symptomatic management of peripheral neuropathy and autonomic dysfunction. Pain is common and can be treated with medications typically used for management of neuropathic pain, including gabapentin, pregabalin, duloxetine, tricyclic antidepressants, and others. For patients with significant weakness, ankle foot orthotics and other bracing measures can help with mobility. Assistive devices and physical therapy are critical for fall prevention.

Autonomic dysfunction in patients with amyloidosis can be challenging to manage, but a number of medications can be used to treat autonomic symptoms. Treatments for orthostatic hypotension include elimination of medications that reduce intravascular volume or lower blood pressure, liberal salt and fluid intake, use of compression stockings, and pharmacologic treatment. Medications that can be prescribed for orthostatic hypotension include midodrine, fludrocortisone, and droxidopa (42). Caution must be taken with these agents in patients with significant cardiomyopathy. Pyridostigmine can also be used to treat orthostatic hypotension and has less risk of causing supine hypertension. Treatment of urinary dysfunction can include pelvic floor exercises, duloxetine, intermittent catheterization, antimuscarinic agents, pyridostigmine, and botulinum injections (15). Treatment of gastrointestinal dysmotility due to amyloidosis can include dietary changes and nutritional supplementation, erythromycin, metoclopramide, and other promotility agents. For diarrhea related to amyloidosis, cholestyramine, loperamide, and octreotide can be used (40).

Patients with hereditary transthyretin amyloidosis have an increased risk for entrapment neuropathies, particularly carpal tunnel syndrome at the wrist. In some cases, referral for carpal tunnel release surgery is indicated to alleviate progressive sensory loss and weakness in the hands. Patients are also at increased risk for spinal stenosis. In cases of severe spinal stenosis, surgical management in collaboration with neurosurgery or orthopedic surgery may be necessary.

Multidisciplinary care is critical for the management of patients with hATTR polyneuropathy and has been recommended by a European consensus statement on the diagnosis and management of the disease (05). The physician team typically includes at least a neurologist, cardiologist, and ophthalmologist. In evaluation of patients with amyloidosis of uncertain cause, oncologists and nephrologists are often involved. Geneticists and genetic counselors are key to guiding testing in patients and asymptomatic family members (39). Many allied health providers are critical for multidisciplinary care, including physical and occupational therapists, nutritionists, social workers, and many others.

Other supportive measures are discussed in the article titled “Peripheral neuropathies: supportive measures and rehabilitation.”

Outcomes

As discussed, treatment of hATTR polyneuropathy with TTR gene silencing therapies results in slowed progression, and in some cases improvement in scores of neuropathy severity. Treatment earlier in the course of the neuropathy before severe axonal loss and weakness has developed results in better outcomes.

References

01: Adams D, Ando Y, Beirão JM, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol 2021a;268(6):2109-22. PMID 31907599
02: Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):11-21.** PMID 29972753
03: Adams D, Lozeron P, Theaudin M, et al. Regional difference and similarity of familial amyloidosis with polyneuropathy in France. Amyloid 2012;19(S1):61-4. PMID 22620968
04: Adams D, Polydefkis M, González-Duarte A, et al. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. Lancet Neurol 2021b;20(1):49-59. PMID 33212063
05: Adams D, Suhr OB, Hund E, et al. First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol 2016;29 Suppl 1:S14-26. PMID 26734952
06: Adams D, Tournev IL, Taylor MS, et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid 2022;1-9. PMID 35875890
07: Alcantara M, Mezei MM, Baker SK, et al. Canadian guidelines for hereditary transthyretin amyloidosis polyneuropathy management. Can J Neurol Sci 2022;49(1):7-18. PMID 33631091
08: Algalarrondo V, Antonini T, Théaudin M, et al. Prediction of long-term survival after liver transplantation for familial transthyretin amyloidosis. J Am Coll Cardiol 2015;66(19):2154-6. PMID 26541929
09: Barreiros AP, Post F, Hoppe-Lotichius M, et al. Liver transplantation and combined liver-heart transplantation in patients with familial amyloid polyneuropathy: a single-center experience. Liver Transpl 2010;16:314-23. PMID 20209591
10: Barroso FA, Judge DP, Ebede B. Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years. Amyloid 2017;24(3):194-204. PMID 28758793
11: Benson MD, Dasgupta NR, Rao R. Diagnosis and screening of patients with hereditary transthyretin amyloidosis (hATTR): current strategies and guidelines. Ther Clin Risk Manag 2020;16:749-58. PMID 32884276
12: Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):22-31.** PMID 29972757
13: Benson MD. Amyloidosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. Vol. IV. 8th ed. New York: McGraw-Hill, 2001:5345-78.
14: Benson MD. Inherited amyloidosis. J Med Genet 1991;28(2):73-8. PMID 1848299
15: Bentellis I, Amarenco G, Gamé X, et al. Diagnosis and treatment of urinary and sexual dysfunction in hereditary TTR amyloidosis. Clin Auton Res 2019;29(Suppl 1):65-74. PMID 31452024
16: Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 2013;310(24):2658-67. PMID 24368466
17: Brannagan TH, Coelho T, Wang AK, et al. Long-term efficacy and safety of inotersen for hereditary transthyretin amyloidosis: NEURO-TTR open-label extension 3-year update. J Neurol 2022;269(12):6416-27. PMID 35908242
18: Brownrigg J, Lorenzini M, Lumley M, Elliott P. Diagnostic performance of imaging investigations in detecting and differentiating cardiac amyloidosis: a systematic review and meta-analysis. ESC Heart Fail 2019;6(5):1041-51. PMID 31487121
19: Cappellari M, Cavallaro T, Ferrarini M, et al. Variable presentations of TTR related familial amyloid polyneuropathy in seventeen patients. J Peripher Nerv Syst 2011;16:119-29. PMID 21692911
20: Chao CC, Hsueh HW, Kan HW et al. Skin nerve pathology: biomarkers of premanifest and manifest amyloid neuropathy. Ann Neurol 2019;85(4):560-73. PMID 30737830
21: Coelho T, Conceição I, Waddington-Cruz M, et al. A natural history analysis of asymptomatic TTR gene carriers as they develop symptomatic transthyretin amyloidosis in the Transthyretin Amyloidosis Outcomes Survey (THAOS). Amyloid 2022;29(4):228-36. PMID 35730447
22: Coelho T, Inês M, Conceição I, Soares M, de Carvalho M, Costa J. Natural history and survival in stage 1 Val30Met transthyretin familial amyloid polyneuropathy. Neurology 2018;91(21):1999-2009. PMID 30333157
23: Coelho T, Maia L, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 2012;79(8):785-92. PMID 22843282
24: Coelho T, Merlini G, Bulawa CE, et al. Mechanism of action and clinical application of tafamidis in hereditary transthyretin amyloidosis. Neurol Ther 2016;5(1):1-25. PMID 26894299
25: Coelho T, Marques W Jr, Dasgupta NR, et al. Eplontersen for hereditary transthyretin amyloidosis with polyneuropathy. JAMA 2023;330(15):1448-58. PMID 37768671
26: Cortese A, Vegezzi E, Lozza A et al. Diagnostic challenges in hereditary transthyretin amyloidosis with polyneuropathy: avoiding misdiagnosis of a treatable hereditary neuropathy. J Neurol Neurosurg Psychiatry 2017;88(5):457-8. PMID 28188196
27: Do Amaral B, Coelho T, Sousa A, Guimarães A. Usefulness of labial salivary gland biopsy in familial amyloid polyneuropathy Portuguese type. Amyloid 2009;16:232-8. PMID 19922336
28: Ebenezer GJ, Liu Y, Judge DP, et al. Cutaneous nerve biomarkers in transthyretin familial amyloid polyneuropathy. Ann Neurol 2017;82(1):44-56. PMID 28598015
29: Gillmore JD, Gane E, Taubel J, et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med 2021;385(6):493-502.** PMID 34215024
30: Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 2016;133(24):2404-12. PMID 27143678
31: Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 1997;336:466-73. PMID 9017939
32: Kanda Y, Goodman DS, Canfield RE, Morgan FJ. The amino acid sequence of human plasma prealbumin. J Biol Chem 1974;249(21):6796-805. PMID 4607556
33: Klein CJ, Vrana JA, Theis JD, et al. Mass spectrometric-based proteomic analysis of amyloid neuropathy type in nerve tissue. Arch Neurol 2011;68:195-9. PMID 20937937
34: Koike H, Tanaka F, Hashimoto R, et al. Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from nonendemic areas. J Neurol Neurosurg Psychiatry 2012;83:152-8. PMID 22228785
35: Masuda T, Ueda M, Suenaga G, et al. Early skin denervation in hereditary and iatrogenic transthyretin amyloid neuropathy. Neurology 2017;88(23):2192-7. PMID 28490654
36: Mathis S, Magy L, Diallo L, Boukhris S, Vallat JM. Amyloid neuropathy mimicking chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 2012;45:26-31. PMID 22190302
37: Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379(11):1007-16.** PMID 30145929
38: Obici L, Cortese A, Lozza A, et al. Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study. Amyloid 2012;19 Suppl 1:34-6. PMID 22551192
39: Obici L, Kuks JB, Buades J, et al. Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis. Curr Opin Neurol 2016;29 Suppl 1:S27-35.** PMID 26734953
40: Obici L, Suhr OB. Diagnosis and treatment of gastrointestinal dysfunction in hereditary TTR amyloidosis. Clin Auton Res 2019;29(Suppl 1):55-63. PMID 31452022
41: Ohashi N, Kodaira M, Morita H, Sekijima Y. Electrophysiological demyelinating features in hereditary ATTR amyloidosis. Amyloid 2019;26(1):15-23. PMID 30688105
42: Palma JA, Gonzalez-Duarte A, Kaufmann H. Orthostatic hypotension in hereditary transthyretin amyloidosis: epidemiology, diagnosis and management. Clin Auton Res 2019;29(Suppl 1):33-44. PMID 31452021
43: Parker MM, Damrauer SM, Tcheandjieu C, et al. Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry. Sci Rep 2021;11(1):11645. PMID 34079032
44: Perugini E, Guidalotti PL, Salvi F, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol 2005;46(6):659-70. PMID 16168294
45: Saraiva, MJ. Transthyretin mutations in hyperthyroxinemia and amyloid diseases. Hum Mutat 2001;17:493-503. PMID 11385707
46: Sekijima Y, Tojo K, Morita H, Koyama J, Ikeda S. Safety and efficacy of long-term diflunisal administration in hereditary transthyretin (ATTR) amyloidosis. Amyloid 2015;22(2):79-83. PMID 26017328
47: Sipe JD, Benson MD, Buxbaum JN, et al. Nomenclature 2014: amyloid fibril proteins and clinical classification of the amyloidosis. Amyloid 2014;21:221-4. PMID 25263598
48: Sipe JD, Cohen AS. Review: history of the amyloid fibril. J Struct Biol 2000;130:88-98. PMID 10940217
49: Sousa A, Coelho T, Barros J, Sequeiros J. Genetic epidemiology of familial amyloidotic polyneuropathy (FAP)-type I in Póvoa do Varzim and Vila do Conde (north of Portugal). Am J Med Genet 1995;60:512-21. PMID 8825887
50: Tozza S, Palumbo G, Severi D, et al. Heterogenous electrophysiological features in early stage of hereditary transthyretin amyloidosis neuropathy. Neurol Sci 2023. [Epub ahead of print] PMID 37870643
51: van Gameren II, Hazenberg BP, Bijzet J, van Rijswijk MH. Diagnostic accuracy of subcutaneous abdominal fat tissue aspiration for detecting systemic amyloidosis and its utility in clinical practice. Arthritis Rheum 2006;54:2015-21. PMID 16732553
52: 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):178-83. PMID 27494299
53: Wilczek HE, Larsson M, Ericzon BG; FAPWTR. Long-term data from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR). Amyloid 2011;18(Suppl 1):188-90. PMID 21838484
54: Yamashita T, Ando Y, Okamoto S, et al. Long-term survival after liver transplantation in patients with familial amyloid polyneuropathy. Neurology 2012; 78:637–643. PMID 22345221
55: Yang NC, Lee MJ, Chao CC, et al. Clinical presentations and skin denervation in amyloid neuropathy due to transthyretin Ala97Ser. Neurology 2010;75:532-8. PMID 20697105

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Rebecca E Traub MD

Dr. Traub of the University of North Carolina received research support from Alnylam Pharmaceuticals, Ionis Pharmaceuticals, Pharnext, and Argenx as principal investigator.
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Editor

Louis H Weimer MD

Dr. Weimer of Columbia University has no relevant financial relationships to disclose.
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Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: Female = Male

Male patients with hATTR polyneuropathy have been reported to have more severe clinical phenotype
Heredity: Heredity is a primary factor

Autosomal dominant with variable penetrance
Population groups selectively affected: V30M mutations occur with higher frequency in Portuguese, Swedish and Japanese populations

V122I mutations occur with higher frequency in African American populations

ICD & OMIM codes

ICD-9: Amyloidosis: 277.3
ICD10: Neuropathic heredofamilial amyloidosis: E85.1
OMIM: Amyloidosis, hereditary, transthyretin-related: # 105210

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Hereditary amyloid polyneuropathy

Associated Disorders

Hereditary TTR amyloid cardiomyopathy
Carpal tunnel syndrome
Spinal stenosis

Differential Diagnosis

light-chain amyloidosis
light-chain associated amyloid polyneuropathy
hereditary neuropathy
hereditary sensorimotor polyneuropathy
Charcot Marie Tooth disease
- diabetes
- toxic exposures
- immune-mediated causes
- celiac disease
- vitamin toxicity or deficiency
- chronic inflammatory demyelinating polyneuropathy
- idiopathic peripheral neuropathy

Also Relevant

Amyloid myopathy
Cerebral amyloid angiopathy
Chronic autonomic neuropathies
Neuropathies associated with monoclonal gammopathies
Primary systemic amyloidosis: neurologic complications
- Sensory ganglionopathy
- Small fiber neuropathies

Clinical Categories

Peripheral Neuropathies

Hereditary amyloid polyneuropathy …

Hereditary amyloid polyneuropathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

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Also in This Category

Neuropathies associated with cytomegalovirus infection

Clinical evaluation of peripheral neuropathies

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Amyotrophic lateral sclerosis

Amiodarone neuropathy

Autoimmune autonomic neuropathy

Hereditary amyloid polyneuropathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Neuropathies associated with cytomegalovirus infection

Clinical evaluation of peripheral neuropathies

Hypothyroidism

Monoclonal gammopathy of neurologic significance

Chronic inflammatory demyelinating polyradiculoneuropathy

Amyotrophic lateral sclerosis

Amiodarone neuropathy

Autoimmune autonomic neuropathy

This is an article preview.
Start a Free Account
to access the full version.