The Temporal Profiles of Changes in Nerve Excitability Indices in Familial Amyloid Polyneuropathy

Lai, Hsing-Jung; Chiang, Ya Wen; Yang, Chih‐Chao; Hsieh, Sung‐Tsang; Chao, Chi‐Chao; Lee, Ming-Jen; Kuo, Chung‐Chin

doi:10.1371/journal.pone.0141935

Cited by 14 publications

(9 citation statements)

References 53 publications

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“…In the present study, the IENF density was already reduced in carriers with the highest abnormal rate compared with other examinations. Despite previous studies showing changes in various tests on carriers of mutant TTR , the significance was not well elucidated (ie, whether these changes could reflect the progression and predict fully developed FAP). The current study indicates that structural degeneration in skin nerve terminals might occur 10 to 20 years before the onset of fully developed polyneuropathy.…”

Section: Discussionmentioning

confidence: 90%

“…Nerve fibers of different categories and functions in mutant TTR carriers can be examined with various tests, such as magnetic resonance neurography, nerve excitability tests, neurophysiological studies, and skin biopsies . Except for skin biopsies and autonomic functional tests, all of these mainly evaluate deficits in large‐diameter nerves, which usually follow impairments of small‐diameter nerves over the natural course of FAP .…”

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confidence: 99%

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Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy

Chao

Hsueh

Kan

et al. 2019

Annals of Neurology

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Objective: Small-fiber sensory and autonomic symptoms are early presentations of familial amyloid polyneuropathy (FAP) with transthyretin (TTR) mutations. This study aimed to explore the potential of skin nerve pathologies as early and disease-progression biomarkers and their relationship with skin amyloid deposits. Methods: Skin biopsies were performed in patients and carriers to measure intraepidermal nerve fiber (IENF) density, sweat gland innervation index of structural protein gene product 9.5 (SGII[PGP9.5]) and peptidergic vasoactive intestinal peptide (SGII[VIP]), and cutaneous amyloid index. These skin pathologies were analyzed with clinical disability assessed by FAP stage score (stage 0-4) and compared to neurophysiological and psychophysical tests. Results: There were 70 TTR-mutant subjects (22 carriers and 48 patients), and 66 cases were TTR-A97S. Skin nerve pathologies were distinct according to stage. In carriers, both skin denervation and peptidergic sudomotor denervation were evident: (1) IENF density was gradually reduced from stage 0 through 4, and (2) SGII(VIP) was markedly reduced from stage 1 to 2. In contrast, SGII(PGP9.5) was similar between carriers and controls, but it declined in patients from stage 2. Skin amyloids were absent in carriers and became detectable from stage 1. Cutaneous amyloid index was correlated with SGII(PGP9.5) and stage in a multivariate mixed-effect model. When all tests were compared, only IENF density, SGII(PGP9.5), and cutaneous amyloid index were correlated with stage, and IENF density had the highest abnormal rate in carriers. Interpretation: Biomarkers of sensory and sudomotor innervation exhibited a stage-dependent progression pattern, with sensory nerve degeneration as the early skin nerve pathology.

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Section: Discussionmentioning

confidence: 90%

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confidence: 99%

Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy

Chao

Hsueh

Kan

et al. 2019

Annals of Neurology

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“…The patients were from four pedigrees carrying two different mutations. Two families (13 patients) with c.349G >T (p.Ala117Ser), a variant that mainly originated from Taiwan [27–30] and mainland China [31], were distinguished by a late‐onset age and moderate or slow progression [32]. The remaining patients had a c.148G >A (p.Val50Met) mutation.…”

Section: Resultsmentioning

confidence: 99%

Corneal sub‐basal whorl‐like nerve plexus: a landmark for early and follow‐up evaluation in transthyretin familial amyloid polyneuropathy

Zhang¹,

Liu

Wang

et al. 2020

Euro J of Neurology

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Background and purposeSmall‐fiber nerves are the first to be involved in transthyretin familial amyloid polyneuropathy (TTR‐FAP) patients. In vivo corneal confocal microscopy (CCM) is a noninvasive technique to detect small‐fiber polyneuropathy (SFN) by quantifying corneal nerve morphology. The characteristic whorl‐like pattern of the corneal nerve provides a static landmark for observation. We aimed to evaluate whether CCM images of the whorl‐like plexus can sensitively evaluate and monitor disease progression in FAP patients.MethodsFifteen FAP patients and 15 controls underwent neurological evaluation and CCM observation. Corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) detected by conventional method and inferior whorl length (IWL), inferior whorl fiber density (IWFD), and inferior whorl branch density (IWBD) were compared in controls and patients. The Langerhans cell (LC) density in each image was calculated.ResultsAll CCM parameters were significantly reduced with disease progression. Preclinical patients had significantly lower IWL (P = 0.008) than age‐matched controls. IWL (P = 0.006), CNFL (P = 0.005), CNBD (P = 0.008), and CNFD (P = 0.014) were significantly lower in early‐phase patients. LC density was significantly increased around the central whorl in early‐phase patients and was relatively lower in progressive patients. Both IWL and CNFL correlated with the severity of neuropathy, and IWL was more significantly reduced. The area under the receiver operating characteristic (ROC) curve for FAP with CNFL and IWL was 88.0% (95% CI, 70.9%–96.9%) and 89.3% (95% CI, 72.6%–97.6%), respectively, exceeding other parameters.ConclusionsIWL is a more sensitive surrogate to detect preclinical SFN in FAP and can best discriminate patients from controls. The clustering of immature LCs at the inferior whorl area might reflect the inflammatory response of small‐fiber nerves at the early stage.

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“…This study documents sensory nerve pathology and its consequent physiological and behavioural abnormalities as the major manifestations in human TTR‐A97S knock‐in mice (Table ). The phenotype of the knock‐in mice is reminiscent of what has been observed in the early stage of FAP , including (1) small fibre neuropathy with reduced intraepidermal nerve fibres of the pad skin and decreased mechanical thresholds, as well as (2) large fibre sensory neuropathy with reduced myelinated nerve fibre density in sural nerves accompanied by reduced sural sensory nerve action potential amplitudes.…”

Section: Discussionmentioning

confidence: 89%

“…The major discrepancy between this model and clinical FAP patients is the lack of motor deficits. Reduced compound muscle action potential amplitude is an indicator of motor nerve degeneration and dysfunctions in the late stage of full‐blown neuropathy in FAP . In the natural course of FAP, sensory neuropathy is an early event in stage I.…”

Section: Discussionmentioning

confidence: 99%