No Fabry Disease in Patients Presenting with Isolated Small Fiber Neuropathy

Greef, Bianca T A de; Hoeijmakers, Janneke G. J.; Wolters, E.Ch.; Smeets, H.; Wijngaard, Arthur van den; Merkies, Ingemar S. J.; Faber, Catharina G.; Gerrits, Monique M.

doi:10.1371/journal.pone.0148316

Cited by 33 publications

(34 citation statements)

References 35 publications

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“…In this multicenter study of 155 Nordic patients with idiopathic SFN and mixed neuropathy, no definite FD and hATTR amyloidosis cases were identified. This result is concordant with earlier screening studies for FD and hATTR amyloidosis in patients with idiopathic SFN …”

Section: Discussionsupporting

confidence: 92%

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Screening for Fabry disease and Hereditary ATTR amyloidosis in idiopathic small‐fiber and mixed neuropathy

et al. 2018

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Introduction: In this study we assessed the value of genetic screening for Fabry disease (FD) and hereditary ATTR amyloidosis in patients with idiopathic small-fiber neuropathy (SFN) or mixed neuropathy in a clinical setting. Methods: This was a Nordic multicenter study with 9 participating centers. Patients with idiopathic SFN or mixed neuropathy were included. Genetic sequencing of the TTR and GLA genes was performed. Results: There were 172 patients enrolled in the study. Genetic screening was performed in 155 patients. No pathogenic mutations in the TTR gene were found. A single patient had a possible pathogenic variant, R118C, in the GLA gene, but clinical investigation showed no firm signs of FD. Discussion: Screening for hereditary ATTR amyloidosis and FD in patients with idiopathic SFN or mixed neuropathy without any additional disease-specific symptoms or clinical characteristics in a Nordic population appears to be of little value in a clinical setting.

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Section: Discussionsupporting

confidence: 92%

“…Two treatable, possibly underdiagnosed hereditary diseases, known to cause painful polyneuropathy with involvement of small fibers, are Fabry disease (FD) and hereditary ATTR (hATTR) amyloidosis . The results of previous screening studies of the 2 conditions have been inconsistent …”

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confidence: 99%

Screening for Fabry disease and Hereditary ATTR amyloidosis in idiopathic small‐fiber and mixed neuropathy

et al. 2018

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“…Another smaller study confirmed the presence of immunological abnormalities (eg, antinuclear antibodies, extractable nuclear antigens, and celiac autoantibodies), whereas diabetes, prediabetes, and hypertriglyceridemia were not associated with SFN . A large study demonstrated that the prevalence of Fabry disease is irrelevant in adult SFN patients, a finding that allows excluding this genetic screening in patients with confirmed diagnosis of SFN . Early degeneration of small nerve fibers can occur in the pre‐symptomatic stage of patients carrying transthyretin mutations, whereas patients with a symptomatic stage of familial amyloid neuropathy more likely present with a mixed neuropathy …”

Section: Epidemiologymentioning

confidence: 99%

“…158 A large study demonstrated that the prevalence of Fabry disease is irrelevant in adult SFN patients, a finding that allows excluding this genetic screening in patients with confirmed diagnosis of SFN. 159 Early degeneration of small nerve fibers can occur in the pre-symptomatic stage of patients carrying transthyretin mutations, 160 whereas patients with a symptomatic stage of familial amyloid neuropathy more likely present with a mixed neuropathy. 161 Even in patients with a known possible etiology, additional underlying causes can be found in 27% of patients.…”

Section: Underlying Conditions and Pathophysiologymentioning

confidence: 99%

Small‐fiber neuropathy: Expanding the clinical pain universe

Sopacua

Hoeijmakers

Merkies

et al. 2019

J Peripheral Nervous Sys

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Small‐fiber neuropathy (SFN) is a disorder of thinly myelinated Aδ and unmyelinated C fibers. SFN is clinically dominated by neuropathic pain and autonomic complaints, leading to a significant reduction in quality of life. According to international criteria, the diagnosis is established by the assessment of intraepidermal nerve fiber density and/or quantitative sensory testing. SFN is mainly associated with autoimmune diseases, sodium channel gene variants, diabetes mellitus, and vitamin B12 deficiencies, although in more than one half of patients no etiology can be identified. Recently, gain‐of‐function variants in the genes encoding for the Nav1.7, Nav1.8 and Nav1.9 sodium channel subunits have been discovered in SFN patients, enlarging the spectrum of underlying conditions. Sodium channel gene variants associated with SFN can lead to a diversity of phenotypes, including different pain distributions and presence or absence of autonomic symptoms. This suggests that SFN is part of a clinical continuum. New assessments might contribute to a better understanding of the cellular and molecular substrates of SFN and might provide improved diagnostic methods and trial designs in the future. Identification of the underlying mechanisms may inform the development of drugs that more effectively address neuropathic pain and autonomic symptoms of SFN.

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“…However, among 457 patients with cryptogenic or diabetic neuropathy, sequence changes in these genes were no more common than among control populations . Other studies exploring the diagnostic yield of GLA sequencing for Fabry disease among patients with small‐fiber neuropathy have demonstrated an extremely low diagnostic yield . Even the clinical trial data from the confirmatory hTTR amyloidosis studies supports the rarity of this disorder.…”

mentioning

confidence: 99%