Skin biopsy and quantitative sensory assessment in an Italian cohort of ATTRv patients with polyneuropathy and asymptomatic carriers: possible evidence of early non-length dependent denervation

Leonardi, Luca; Galosi, Eleonora; Vanoli, Fiammetta; Fasolino, Alessandra; Pietro, Giuseppe Di; Luigetti, Marco; Sabatelli, Mario; Fionda, Laura; Garibaldi, Matteo; Alfieri, Girolamo; Lauletta, Antonio; Morino, Stefania; Salvetti, Marco; Truini, Andrea; Antonini, Giovanni

doi:10.1007/s10072-021-05434-5

Cited by 12 publications

(19 citation statements)

References 26 publications

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“…However, although NCS represents the gold standard for diagnosis of large fiber involvement, it can be completely unremarkable in an asymptomatic subject. Therefore, in the last years, to improve the capability in demonstrating PNS involvement in late onset phenotype, several tests exploring the smallest nerve fiber function were proposed to monitor carriers (e.g., skin biopsy, cutaneous silent period, QST) [ 13 , 14 , 16 , 17 ]. Among these tests, thermal QST allows for contemporary study and to discriminate the function of C and Aδ nerve fibers through the warm and cold stimulation, respectively.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Sensory Testing in Late-Onset ATTRv Presymptomatic Subjects: A Single Center Experience

et al. 2022

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Backgrounds Hereditary transthyretin amyloidosis (ATTRv) presymptomatic subjects undergo multidisciplinary evaluation to detect, as early as possible, a subclinical involvement of multisystem disease. Quantitative sensory testing (QST) that investigates and discriminates the function of C, Aδ and Aβ fibers is included as an instrumental test to monitor nerve fiber function. The purpose of this study was to evaluate the role of QST in the context of the multidisciplinary evaluation in late onset carriers. Methods Four-teen presymptomatic (namely carriers) were enrolled. Subjects underwent thermal [cold and warm detection threshold (CDT, WDT), cold and heat pain (CP and HP)] and tactile QST in four body sites: foot dorsum, distal lateral leg, distal thigh, hand dorsum. Results Overall, presymptomatic subject showed a significant difference in all thermal QST findings compared to the control group. All subjects had at least one altered thermal QST finding; the sites more frequently altered were foot and leg, whilst the thermal modalities which were more frequently abnormal were CDT, WDT and CP. Conclusions Our study highlights the importance of performing thermal QST in subjects carrying TTR mutation, given the high frequency of abnormal findings. Notably, performing both innocuous and painful stimulation in foot and/or leg increases the chance of detecting nerve fiber dysfunction. Moreover, the investigation of the hand may provide useful information in monitoring disease progression before the Predicted Age of Disease Onset (PADO).

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Section: Discussionmentioning

confidence: 99%

Quantitative Sensory Testing in Late-Onset ATTRv Presymptomatic Subjects: A Single Center Experience

et al. 2022

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“…A predominant NLD phenotype is seen in the expanding subgroup of SFN related to gain‐of‐function mutations in the genes encoding for the voltage‐gated sodium channels, 42,123‐125 reflecting the main expression of mutated sodium channels in DRG small sensory neurons 206,207 . Familial transthyretin amyloidosis typically presents with early or subclinical distal SFN 227 rapidly progressing to mixed neuropathy, 228 ; however, NLD‐SFN phenotype has been described, 99 and early NLD denervation has been demonstrated in asymptomatic carriers 182 . A neuropathological model of small fiber ganglionopathy has been documented in a patient with Fabry disease 229 The sensory disturbances in men with Fabry disease have been consistently described as distal and length dependent, 230,231 whereas NLD pattern has been reported in heterozygous females 183 .…”

Section: Associated Conditionsmentioning

confidence: 99%

“…206,207 Familial transthyretin amyloidosis typically presents with early or subclinical distal SFN 227 rapidly progressing to mixed neuropathy, 228 ; however, NLD-SFN phenotype has been described, 99 and early NLD denervation has been demonstrated in asymptomatic carriers. 182 A neuropathological model of small fiber ganglionopathy has been documented in a patient with Fabry disease 229 The sensory disturbances in men with Fabry disease have been consistently described as distal and length dependent, 230,231 whereas NLD pattern has been reported in heterozygous females. 183 Hereditary sensory and autonomic neuropathies (HSAN) involve primarily, but not exclusively, small fibers, with the main features being insensitivity to pain and autonomic disturbances.…”

Section: Associated Conditionsmentioning

confidence: 99%

Non‐length‐dependent small fiber neuropathy: Not a matter of stockings and gloves

et al. 2021

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The clinical spectrum of small fiber neuropathy (SFN) encompasses manifestations related to the involvement of thinly myelinated A‐delta and unmyelinated C fibers, including not only the classical distal phenotype, but also a non–length‐dependent (NLD) presentation that can be patchy, asymmetrical, upper limb‐predominant, or diffuse. This narrative review is focused on NLD‐SFN. The diagnosis of NLD‐SFN can be problematic, due to its varied and often atypical presentation, and diagnostic criteria developed for distal SFN are not suitable for NLD‐SFN. The topographic pattern of NLD‐SFN is likely related to ganglionopathy restricted to the small neurons of dorsal root ganglia. It is often associated with systemic diseases, but about half the time is idiopathic. In comparison with distal SFN, immune‐mediated diseases are more common than dysmetabolic conditions. Treatment is usually based on the management of neuropathic pain. Disease‐modifying therapy, including immunotherapy, may be effective in patients with identified causes. Future research on NLD‐SFN is expected to further clarify the interconnected aspects of phenotypic characterization, diagnostic criteria, and pathophysiology.

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“…We suggested to also evaluate in ATTRv sural/DSN amplitude ratio that, if increased, can confirm length-dependent nerve damage: distal nerve fibers may be firstly involved not only in early-onset ATTRv but also in late-onset, as recently suggested by studies about intra-epidermal nerve fibers density [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Nerve Conduction Studies of Dorsal Sural Nerve: Normative Data and Its Potential Application in ATTRv Pre-Symptomatic Subjects

et al. 2022

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The objective of the study is to provide age-related normative values for dorsal sural nerve (DSN) and to analyse its application during follow-up of hereditary transthyretin amyloidosis (ATTRv) pre-symptomatic subjects. We consecutively recruited ATTRv pre-symptomatic carriers in which clinical examination, cardiological evaluation, and nerve conduction studies of the sural nerve and DSN were performed. To provide normative data of DSN, neurophysiologic parameters from healthy controls referred to our service were entered into linear regression analyses to check the relative influence of age and height. A correction grid was then derived. We collected 231 healthy subjects: the mean DSN sensory nerve action potential (SNAP) amplitude was 9.99 ± 5.48 μV; the mean conduction velocity was 49.01 ± 5.31 m/s. Significant correlations were found between age and height with DSN SNAP amplitude. Fifteen ATTRv pre-symptomatic carriers were examined. Sural nerve NCS were normal in 12/15 and revealed low/borderline values in three subjects. Considering our correction grid, we found an abnormal DNS amplitude in 9/15 subjects and low/borderline values in 2/15. In ATTRv, early detection of peripheral nerve damage is crucial to start a disease-modifying treatment. DSN may be easily and reliably included in the routine neurophysiological follow-up of ATTRv pre-symptomatic subjects.

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Skin biopsy and quantitative sensory assessment in an Italian cohort of ATTRv patients with polyneuropathy and asymptomatic carriers: possible evidence of early non-length dependent denervation

Cited by 12 publications

References 26 publications

Quantitative Sensory Testing in Late-Onset ATTRv Presymptomatic Subjects: A Single Center Experience

Quantitative Sensory Testing in Late-Onset ATTRv Presymptomatic Subjects: A Single Center Experience

Non‐length‐dependent small fiber neuropathy: Not a matter of stockings and gloves

Nerve Conduction Studies of Dorsal Sural Nerve: Normative Data and Its Potential Application in ATTRv Pre-Symptomatic Subjects

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