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Phenotypes of Late-Onset Transthyretin Amyloid Neuropathy

A Diagnostic Challenge

Živković, Saša A. MD, PhD*; Mnatsakanova, Diana MD; Lacomis, David MD*,‡

Journal of Clinical Neuromuscular Disease: September 2019 - Volume 21 - Issue 1 - p 1–6
doi: 10.1097/CND.0000000000000252
Original Article

Hereditary transthyretin amyloidosis (hATTR) is a rare cause of severe neuropathy, typically with progressive sensorimotor and autonomic manifestations. The clinical course is marked by progressive worsening with typical survival of 7–11 years following the onset of symptoms. The phenotype may resemble other types of neuropathy, and dysautonomia may be absent at onset delaying the diagnosis. Two medications were recently approved for treatment of hATTR neuropathy in the United States and more may follow. Three major phenotypes of hATTR include neuropathic, cardiac, and mixed. Diagnostic clues include “red-flag” symptoms reflecting typical multisystem involvement, often presenting with cardiomyopathy, gastrointestinal dysmotility, or kidney insufficiency. We present a case series of 4 patients with late-onset hATTR neuropathy who were initially diagnosed with vasculitic neuropathy and chronic inflammatory demyelinating polyneuropathy to illustrate diagnostic challenges encountered with hATTR. Early diagnosis is even more urgent now given the availability of disease modifying treatments.

*Department of Neurology, UPMC, Pittsburgh, PA;

Department of Neurology and Rehabilitation, University of Illinois, Chicago, IL; and

Department of Pathology (Neuropathology), UPMC, Pittsburgh, PA.

Reprints: Sasa Zivkovic, MD PhD, Department of Neurology, UPMC, 3471 Fifth Avenue #810, Pittsburgh, PA 15213 (e-mail:

The authors report no conflicts of interest.

Hereditary transthyretin amyloidosis (hATTR) is a multisystemic disorder and rare cause of severe neuropathy, typically with progressive sensorimotor and autonomic manifestations.1 In addition to neuropathy, hATTR often involves the gastrointestinal system, salivary and thyroid glands, eyes, kidneys, and heart.2 There are more than 100 transthyretin (TTR) mutations causing hATTR with varying phenotypes, and Val30Met is the most common mutation with a neuropathy phenotype.1,3 Three major phenotypes of hATTR are characterized by predominant symptoms of amyloid neuropathy, cardiomyopathy, or both (mixed phenotype). The highest prevalence is in endemic areas in Portugal, Sweden, and Japan, and sporadic cases have been found on all 5 continents.4 Peripheral neuropathy associated with hATTR (hATTR-PN) may present with an early or late (after the age of 50) onset. Typical clinical features include progressive sensory loss and weakness with dysautonomia, but the symptoms of dysautonomia may be delayed with late onset hATTR.5 Many patients also have a history of carpal tunnel syndrome (often bilateral), but carpal tunnel syndrome is indistinct and found in 4%–6% of the general population.6,7 Because of phenotype variability, the diagnosis is often delayed by 4 years or longer in hATTR-PN.3,8

The clinical course of hATTR-PN is relentlessly progressive with a typical life expectancy of 7–11 years from the onset.9 The survival with the cardiac hATTR phenotype (hATTR-CM) is shorter at 2.5–4 years.10 Phenotypic features are significantly associated with the type of mutation and age of onset, but significant variability may exist even within the same family. Worldwide, there may be at least 10,000 patients with hATTR-PN,4 while hATTR-CM may be 4 times as frequent.1 In addition to hATTR, wild-type TTR amyloidosis (wtATTR) is associated with a normal TTR genotype and is typically associated with late-onset cardiomyopathy, while neuropathy is fairly rare.11,12

Until recently, available treatment options for hATTR included only liver or liver–heart transplantation and off-label use of the TTR stabilizer diflunisal, which slow progression.13,14 However, recent studies showed promising results with blocking of TTR expression, leading to FDA approval of siRNA-based patisiran and ASO-based inotersen.15,16 In addition, another TTR stabilizer tafamidis is already approved for clinical use in Europe, Japan, and Brazil,17 and it may become available in the United States in 2019.

To increase the awareness of this diagnostically challenging condition with treatment implications, we present a case series of 4 patients with late-onset hATTR who were evaluated at the University of Pittsburgh Medical Center and were previously diagnosed with other types of neuropathies.

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Our series includes 4 patients who were evaluated at the University of Pittsburgh Medical Center Neuromuscular clinic between 2012 and 2016 for progressive polyneuropathy and were later found to have hATTR as the cause. They presented with progressive sensorimotor PN without overt dysautonomia at the mean age of 69 years (range 65–76) (Table 1). Diagnosis was delayed by an average of 40.8 months from the onset of symptoms (range 29–49 months) (Table 2). The family history was positive for hATTR in 1 of 4 patients, but that patient was previously told that he does not have hATTR based on negative fat aspirate and normal cardiac magnetic resonance imaging (MRI) (case 2). Electrodiagnostic testing showed mixed axonal and demyelinating PN in 2 patients previously diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) and asymmetric axonal PN suggestive of mononeuritis multiplex in 2 others (Table 1). Nerve conduction studies met EFNS criteria for diagnosis of definitive CIDP in 1 patient (slowing in 3 motor nerves, F-wave latency prolonged by 150% in 1 nerve) and probable in another patient (low velocity in 1 motor nerve and temporal dispersion in 1 motor nerve).18 Two patients were initially diagnosed with CIDP and one with suspected vasculitic neuropathy/mononeuritis multiplex, but they did not respond to treatment with intravenous immunoglobulins,2 plasma exchange,1 corticosteroids,2 and steroid-sparing immunosuppressive agents.1 Another patient also had asymmetric axonal sensorimotor polyneuropathy, but he did not receive any immunomodulatory treatment (case 2). All 4 had a previous history of carpal tunnel syndrome and left ventricular hypertrophy on transthoracic echocardiograms (Table 2).





Clinical manifestations included those of a progressive sensorimotor PN with unsteadiness of gait, history of carpal tunnel syndrome, and cardiac left ventricular hypertrophy (n = 4 for each). Three patients reported significant neuropathic pain; 2 had weight loss, and one patient each had chronic diarrhea, orthostatic hypotension, atrial fibrillation and cardiac pacemaker placement. Three patients also had proteinuria that was not quantified (Table 2). Cerebrospinal fluid analysis showed normal white blood cell count and elevated protein in 2 patients who had lumbar punctures (range 117–169 mg/dL, normal 25–45 mg/dL) (Table 1). Nerve biopsy was nondiagnostic (technically limited) in one patient, with negative initial amyloid (Congo red) stains in the other 3 patients. Additional nerve sections were later suggestive of amyloid in 1 patient (Fig. 1A), and concurrent muscle biopsy did show amyloid deposition with transthyretin immunoreactivity in the muscle (Figs. 1B, C). The nerve biopsies with negative Congo red stains were reviewed again by 2 neuropathologists using polarized light and with fluorescence filters after the diagnosis of hATTR and were still considered negative. Teased fiber preparation showed evidence of axonal loss and segmental remyelination in case 4 (Fig. 1D). TTR amyloid cardiomyopathy was confirmed in 2 of 3 patients who had nuclear imaging and cardiac MRI. Salivary gland biopsy showed amyloid deposition in another patient (case 3). Genetic testing showed mutations in the transthyretin gene, including Val30Met (n = 2), Thr60Ala (n = 1), and Phe64Leu (n = 1). One patient died at the age of 80 years, 6 years after the onset of neuropathy (case 1).



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As our cases illustrate, late-onset hATTR-PN may mimic other acquired polyneuropathies including CIDP and vasculitic neuropathy and should be considered in the differential diagnosis of refractory progressive PN with other features of those conditions. In a French series, 20% of patients with sporadic hATTR were initially misdiagnosed with CIDP, akin to 2 patients in our series.3 Furthermore, another study showed that electrodiagnostic features of hATTR-PN may be difficult to distinguish from CIDP, and that nerve histopathology may show evidence of demyelination in addition to typical findings of axon loss.19 In addition, protein level in cerebrospinal fluid is similarly elevated in CIDP and hATTR-PN.

It has been recommended that hATTR-PN should be suspected in patients with progressive symmetric sensorimotor PNs accompanied with at least 1 “red-flag” feature or positive family history.2

These “red-flag” features include the following:

  1. Autonomic dysfunction;
  2. Cardiac hypertrophy;
  3. Gastrointestinal problems;
  4. Inexplicable weight loss;
  5. Carpal tunnel syndrome;
  6. Renal impairment;
  7. Ocular involvement.

In our series, hATTR-PN presented without signs of dysautonomia but was associated with at least 1 “red-flag” symptom or positive family history (range 1–4) (Table 2). Delayed onset of dysautonomia is relatively common with late-onset hATTR-PN and is contrasted with the high prevalence of neuropathic pain.19,20 In addition, the onset of overt cardiomyopathy may be delayed in patients with the predominant neuropathy phenotype.8 Nevertheless, all our patients already had left ventricular hypertrophy on transthoracic echocardiography at the time of neuromuscular evaluation, but we also have to consider the potential impact of ubiquitous hypertension that is the most common cause of acquired hypertrophic cardiomyopathy. However, imaging studies showed evidence of cardiac amyloid in 2 of 3 tested patients (Table 1). Cardiac amyloidosis typically manifests with left ventricular hypertrophy, arrhythmias (including atrial fibrillation), and heart failure with preserved ejection fraction.21 Early diagnosis of cardiac TTR amyloidosis is now facilitated by nuclear amyloid imaging scans, for example, technetium pyrophosphate (PYP) in the United States, and cardiac MRI that are very sensitive to the presence of amyloid in cardiac tissue.22 Nuclear imaging is relatively specific for TTR amyloidosis (to distinguish it from primary amyloidosis), but genetic testing is still needed to differentiate between wtATTR and hATTR.22 By contrast, cardiac MRI may not distinguish primary amyloidosis from TTR amyloidosis.

Even when hATTR-PN is clinically suspected, false-negative nerve biopsy or fat aspirate may delay the correct diagnosis.3 Sensitivity of nerve biopsy in hATTR-PN is limited by uneven distribution of amyloid deposits and has been estimated at 33%–74% in different series.3,23 There is not a single test, other than genetic testing, that is always abnormal in hATTR. This occurrence is well illustrated by the low yield of nerve biopsies in our series, although Congo red staining is performed routinely on all nerve and muscle biopsy specimens, and by false-negative cardiac MRI and PYP testing in individual patients, including one of our patients with a positive family history (Table 1). When hATTR-PN is suspected with refractory polyneuropathy, amyloid deposition may be demonstrated in other non-neural tissue as well (eg, salivary gland). Finally, concurrent monoclonal gammopathy may raise the possibility of primary amyloidosis requiring mass spectrophotometry to distinguish between the 2 types of amyloid deposits.24 In our series, the diagnosis of hATTR was delayed by almost 3.5 years, similarly as reported in other studies.3,8

In summary, our series demonstrates the complexity of issues and potential pitfalls in identifying hATTR patients with late-onset PN, especially since many patients may have a negative family history. There is a wide spectrum of clinical phenotypes of hATTR-related neuropathies, which may be mistaken for autoimmune neuropathies ranging from demyelinating and vasculitic axonal sensorimotor neuropathies to autonomic neuropathy,3,5,19,25 with the common trait of not responding to immunomodulatory treatments. Additional clues may include left ventricular hypertrophy, cardiac arrhythmias, proteinuria, and other symptoms commonly seen in patients with hATTR reflecting multisystemic involvement.2 Cardiac nuclear imaging and MRI can also support the diagnosis. Easier access and reduced cost of genetic testing may facilitate early diagnosis of hATTR which is even more paramount now given the availability of treatments, which should alter the clinical course and natural history of hATTR.

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hereditary transthyretin amyloidosis; neuropathy; late-onset

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