Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 8955  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Resource Links
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Article in PDF (312 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this Article

 Article Access Statistics
    PDF Downloaded38    
    Comments [Add]    

Recommend this journal


Table of Contents    
Year : 2014  |  Volume : 62  |  Issue : 2  |  Page : 219-221

Missing link: Could the elusive Wartenberg's neuritis be a peripheral nerve variant of Fabry's disease?

Department of Neurology, Guglielmo da Saliceto Hospital, Piacenza, Italy

Date of Submission10-Oct-2013
Date of Decision02-Nov-2013
Date of Acceptance31-Mar-2014
Date of Web Publication14-May-2014

Correspondence Address:
Eugenia Rota
Department of Neurology, Guglielmo da Saliceto Hospital, Piacenza
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.132442

Rights and Permissions

How to cite this article:
Rota E, Morelli N, Terlizzi E, Iafelice I, Guidetti D. Missing link: Could the elusive Wartenberg's neuritis be a peripheral nerve variant of Fabry's disease?. Neurol India 2014;62:219-21

How to cite this URL:
Rota E, Morelli N, Terlizzi E, Iafelice I, Guidetti D. Missing link: Could the elusive Wartenberg's neuritis be a peripheral nerve variant of Fabry's disease?. Neurol India [serial online] 2014 [cited 2021 May 15];62:219-21. Available from:


Acute sensory multiplex neuropathies are uncommon. Wartenberg was the first to describe in 1958, a small series of patients with 'migrant sensory neuritis', consisting of "recurrent, intermittent, remittent neuritis", with pure sensory involvement both clinically and electrophysiologically. [1] Although evidence of perineuritis has been demonstrated by biopsy of affected cutaneous nerves in a few cases, suggesting an inflammatory -immune origin, the etiology and pathophysiology of Wartenberg's neuritis (WN) have so far remained elusive, [2] and WN is still a clinical diagnosis.

Fabry's disease (FD) is an X-linked multisystem disorder caused by impaired activity of the lysosomal enzyme alpha-galactosidase A (α-GAL). The neurological involvement of FD encompasses the entire nervous system, ranging from cerebrovascular disease to small fiber neuropathy (SFN). [3] A number of studies suggest that FD is underdiagnosed and that there is a wider clinical spectrum of the disease than previously thought, [4] including later-onset cardiac and renal variants with residual α-GAL activity. These variants are due to missense mutations and can be identified in subjects who lack the early manifestations of the classic phenotype. [5],[6]

So we are left asking: Is it really possible to hypothesize a 'peripheral nerve variant' of FD, with normal α-GAL activity? And is SFN the only phenotype of peripheral nerve involvement in FD? Herein, we report a small case series that, in our opinion, seemed to shine some light on the subject.

A 50-year-old Caucasian man was admitted for a minor stroke (left faciobrachial hemiparesis; National Institutes of Health Stroke Scale (NIHSS) <5). His medical history revealed two previous transient ischemic attacks and a diagnosis of WN with multiple episodes of remitting numbness, preceded by burning and shooting pain, in his upper and lower extremities. The first episode, at the age of 38 years, involved the medial aspect of his right hand; pain was used to be induced by movements of the right elbow. Afterwards, cutaneous areas pertaining to both sural nerves were sequentially affected by remitting numbness associated with pain. Electrodiagnostic studies revealed decreased amplitude of sensory nerve action potentials in the sural nerve bilaterally, and in the right ulnar nerve, although conduction velocities were normal. No motor involvement was detected. WN was diagnosed and left sural nerve biopsy performed. Light microscopy examination showed a slight homogeneous reduction in the density of large myelinated fibers in all fascicles. Except for thickening of some endoneurial blood vessels, the remaining epi-, peri- and endoneurium were unremarkable. Inflammatory and vasculitic infiltrates were not detected, and there were no amyloid deposits. Electron microscopy confirmed a widespread, slight loss of myelinated fibers. Punch skin biopsies were carried out from areas on the proximal thigh and distal leg, showing significantly decreased epidermal and sudomotor nerve fiber density, consistent with length-dependent SFN.

He was admitted for stroke evaluation and magnetic resonance imaging (MRI) revealed a small subcortical diffusion restriction on diffusion-weighted image (DWI) sequence in the right hemisphere, along with multiple signal hyperintensities in the periventricular white matter on T2-weighted sequences. Further diagnostic work-up neither revealed any abnormalities in the carotid duplex ultrasonography nor in transcranial color-coded sonography examination. The echocardiography and the laboratory work-up were unremarkable too.

A diagnosis of FD was considered in view of age of the patient, stroke, and sensory neuropathy, and biochemical and genetic testing was performed. The activity of leucocyte α-GAL was normal (6.7 nmol/h/ml; <1: FD; ≤3: Suspected α-GAL deficiency; >3: Normal α-GAL activity). Complete analysis of the α-GAL gene, including exon-intron boundaries, was then carried out and no mutations known to cause FD were detected, although a combined heterozygote intronic phenotype (−12 G>A; IVS4+68 A>G; IVS6−22 C>T; IVS4+866_867delAG), whose clinical significance is still unclear, was found. Single mutations have been reported in the literature as polymorphic loci, but the combination of the three has not yet been characterized.

Interestingly, we detected a combined heterozygote intronic phenotype (IVS2−76_80del5; IVS4−16 A>G; IVS6−22 C>T), sharing the same heterozygotic mutation (IVS6−22 C>T), in further two patients, a 62-year-old man and 60-year-old woman, admitted for acute minor stroke (in the posterior and anterior left circulation, respectively), who similarly presented a past history of episodes of remitting limb pain and paraesthesia, consistent with a diagnosis of WN. These two patients belonged to the same Caucasian ethnic group and had no family history of stroke and/or neuropathy, similar to the first patient. They did not show any clinical feature of the classic FD phenotype and were found to have normal leucocyte α-GAL activity. Both patients reported, at anamnesis, multiple episodes of migrant remitting numbness, associated with burning and shooting pain, involving upper and lower extremities, in their thirties. The diagnostic work-up ruled out any potential cause of neuropathy. Electrodiagnostic studies were unremarkable and the skin biopsy revealed a picture of SFN for both.

Some novel insights into the relationship between peripheral nerve involvement and FD have been recently provided by a pilot study of 29 patients with idiopathic SFN. [7] Typical pathogenetic mutations for FD were detected in one subject, whereas a complex intronic haplotype (IVS0−10 C>T; IVS4−16 A>G; IVS6−22 C>T) was found in four others, all of whom had normal α-GAL activity and no further manifestations of FD. [7] Our patients, who presented a clinical picture corresponding to WN, yet with histopathology pointing to SFN, exhibited normal α-GAL activity and an intronic haplotype, sharing the heterozygote mutation IVS6−22 C>T with the SFN patients recently reported in the pilot study and diagnosed as affected by probable FD. [7] We hypothesize that underlying WN, at least in some cases, may be a 'peripheral nerve variant' of FD that lacks the classical phenotype, owing to the presence of normal α-GAL activity. Indeed, WN would appear to be a heterogeneous clinical syndrome, with variable and aspecific histopathological findings corresponding to different pathophsyiological mechanisms.

However, although intriguing, the hypothesis of a putative late-onset 'peripheral nerve variant' of FD occasionally presenting clinical features consistent with WN requires further studies to confirm findings of FD with normal α-GAL activity in a proportion of patients with SFN of unknown etiology, the relationship to WN, and to clarify the significance of intronic haplotype and single heterozygote mutations. Indeed, a case-control study comparing allelic and genotypic frequencies of FD polymorphisms in patients and in healthy controls would be welcome in order to define the association of FD gene variations with SFN and WN phenotypes.

  References Top

1.Wartenberg R. Migrant sensory neuritis. In: Neuritis, sensory neuritis, neuralgia. A clinical study with review of the literature. New York: Oxford University Press; 1958. p. 233 -47.  Back to cited text no. 1
2.Windebank AJ, Blexrud MD, Dyck PJ, Daube JR, Karnes JL. The syndrome of acute sensory neuropathy: Clinical features and electrophysiologic and pathologic changes. Neurology 1990;40:584-91.  Back to cited text no. 2
3.Luciano CA, Russell JW, Banerjee TK, Quirk JM, Scott LJ, Dambrosia JM, et al. Physiological characterization of neuropathy in Fabry′s disease. Muscle Nerve 2002;26:622-9.  Back to cited text no. 3
4.Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, et al. High incidence of later-onset Fabry disease revealed by newborn screening. Am J Hum Genet 2006;79:31-40.  Back to cited text no. 4
5.von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann E, Hubner G, Olsen EG, et al. An atypical variant of Fabry′s disease with manifestations confined to the myocardium. N Engl J Med 1991;324:395-9.  Back to cited text no. 5
6.Nakao S, Kodama C, Takenaka T, Tanaka A, Yasumoto Y, Yoshida A, et al. Fabry disease: Detection of undiagnosed hemodialysis patients and identification of a "renal variant" phenotype. Kidney Int 2003;64:801-7.  Back to cited text no. 6
7.Tanislav C, Kaps M, Rolfs A, Böttcher T, Lackner K, Paschke E, et al. Frequency of Fabry disease in patients with small-fibre neuropathy of unknown aetiology: A pilot study. Eur J Neurol 2011;18:631-6.  Back to cited text no. 7


Print this article  Email this article
Online since 20th March '04
Published by Wolters Kluwer - Medknow