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).
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
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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