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 ::  Abstract
 :: Introduction
 :: Case Report
 :: Discussion
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  Table of Contents     
Year : 2012  |  Volume : 58  |  Issue : 1  |  Page : 57-59

Anti-myelin-associated glycoprotein polyneuropathy coexistent with CREST syndrome

Department of Neurology, Athens National University, "Aeginition" Hospital, Athens, Greece

Date of Submission30-Aug-2011
Date of Decision29-Sep-2011
Date of Acceptance02-Nov-2011
Date of Web Publication25-Feb-2012

Correspondence Address:
E Andreadou
Department of Neurology, Athens National University, "Aeginition" Hospital, Athens
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0022-3859.93254

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 :: Abstract 

Clinical involvement of the peripheral nervous system in the calcinosis cutis, raynaud's phenomenon, esophageal dismotility, sclerodactyly and telangiectasia (CREST) variant of systemic sclerosis occurs infrequently and is characterized by axonal degeneration due to necrotizing vasculitis. We report a female patient with a known history of CREST syndrome, which developed a slowly progressive, distal symmetric demyelinating sensorimotor polyneuropathy (PN), with tremor and ataxia as prominent features, compatible with anti-myelin associated glycoprotein (MAG) PN. The diagnosis of PN was established by the presence of monoclonal immunoglobulin M anti-MAG antibodies (Thin-Layer Chromatography, Western Blot and enzyme-linked immunoabsorbent assay). Given the evidence that in CREST activation of T-helper cells is observed and that anti-MAG antibodies, despite the fact that they are T-cell-independent, may be influenced by an increase in T-helper function, the coexistence of these two rare autoimmune disorders in the same patient may not be incidental but related to the underlying immunological mechanisms involved.

Keywords: CREST syndrome, demyelinating polyneuropathy, IgM paraprotein, myelin-associated glycoprotein

How to cite this article:
Andreadou E, Zouvelou V, Karandreas N, Kilidireas C. Anti-myelin-associated glycoprotein polyneuropathy coexistent with CREST syndrome. J Postgrad Med 2012;58:57-9

How to cite this URL:
Andreadou E, Zouvelou V, Karandreas N, Kilidireas C. Anti-myelin-associated glycoprotein polyneuropathy coexistent with CREST syndrome. J Postgrad Med [serial online] 2012 [cited 2023 Sep 24];58:57-9. Available from:

 :: Introduction Top

In the calcinosis cutis, Raynaud's phenomenon, esophageal dismotility, sclerodactyly and telangiectasia (CREST) variant of systemic sclerosis polyneuropathy occurs infrequently and is characterized by axonal degeneration due to necrotizing vasculitis. [1],[2]

Immunoglobulin M (IgM) paraproteinemic polyneuropathy with myelin-associated glycoprotein (MAG) autoantibodies is a chronic symmetric demyelinating sensorimotor polyneuropathy with tremor and ataxia as prominent features affecting patients in the sixth and seventh decade of life. [3]

Searching the literature we found no cases of anti-MAG polyneuropathy in association with CREST syndrome. We report a patient with a known history of CREST syndrome, who presented with signs and symptoms of anti-MAG polyneuropathy and discuss the possible association of the two conditions.

 :: Case Report Top

A 74-year-old female was referred to us because of gait imbalance, dysesthesias and weakness of distal upper and lower extremities and action and position tremor, slowly evolving during the preceding seven years. Past medical history was unremarkable except from Raynaud's phenomenon of 27 years' duration. Initially the patient felt numbness of the lower limbs and was referred to a rheumatologist who found on physical examination edematous thickened skin (sclerodactyly) and telangiectasia. Serologic studies revealed the presence of antinuclear (1:160) and anticentromere antibodies (1:640) and a diagnosis of CREST syndrome was made. Increased amount of IgM (230 mg/dl) was detected at that time.

During the following months, dysesthesias of the upper extremities were added and the patient was referred to a neurologist. Electromyography showed markedly reduced sensory and motor conduction velocities, prolonged distal latencies and low motor and sensory amplitudes [Table 1] and a demyelinating sensorimotor polyneuropathy was diagnosed. As there was no family history of polyneuropathy, the patient was initially treated with oral steroids (40 mg prednisolone/day) without any improvement which were progressively withdrawn after one month. The following years she experienced a slowly progressive evolution of gait imbalance. Subsequent attempts with oral steroids were disappointing as they resulted in deterioration. Deterioration had been accelerated the two years preceding presentation with frequent falls.
Table 1: Motor and sensory conduction studies of the patient

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At presentation, physical examination revealed sclerodactyly, telangiectasia, muscle weakness in distal upper and lower extremities (Medical Research Council Grade 3 to 4/5, atrophy in the anterior tibial, gastrocnemius, first dorsal interossei and thenar muscles bilaterally, areflexia, "glove and stocking" hypesthesia and severe impairment of deep sensation. Gait was galloping and ataxic and action and position tremor were evident. Hand X-ray revealed hardening and destructive changes at the far phalangeal joints and subcutaneous radiodense deposits. Fingernail capillaroscopy revealed enlargement of capillaries and telangectasias. Blood cell count, serum calcium and phosphorus levels, renal function, thyroid hormones and transthoracic echocardiography were normal. On immunological investigation antinuclear (ANA) and anti-centromere antibodies were present, whereas tests for anti-DNA, serum antibodies to Extractable Nuclear Antigen (ENA), anti-Scl70 antibodies, rheumatoid factor and cryoglobulinemia were negative. Assay of immunuglobulins and immunofixation revealed monoclonal IgM-κ paraprotein (541 mg/dl). A complete skeletal survey did not reveal any lytic or sclerotic bone lesions. Examination of bone marrow smears showed a 6% proliferative rate of plasma cells. Bence-Jones protein was not detected in the urine. Computed tomography (CT) of the abdomen excluded the presence of malignancy. CT of the thorax showed mild scar tissue at the lower lobes and calcified granuloma at the lingula. Electrophysiological investigation showed deterioration of the severe predominantly demyelinating polyneuropathy, with significantly prolonged distal latencies. Motor and sensory amplitudes were also greatly reduced [Table 1]. Concentric needle electromyography showed fibrillation and positive potentials at rest and polyphasic high-amplitude motor units during contraction with markedly reduced recruitment pattern in distal lower extremities (anterior tibial and gastrocnemius muscles). Cerebrospinal fluid protein was elevated (77 mg/dl).

Thin-layer chromatography overlay with glycolipid extracts of bovine equine as antigen (a gift of Dr. Latov), carried out as previously described, [4] revealed anti-SGPG (sulfoglucuronyl paragloboside) and anti-SGLPG (sulfoglucuronyl lactosaminyl paragloboside) monoclonal IgM-k antibodies. Subsequently enzyme-linked immunoabsorbent assay (ELISA), performed as previously described, [5] showed that anti-GM1, anti-asialo GM1, anti-GD1a, anti-GD1b and anti-sulfatide elements were within the normal limits (fluctuated 0/0 to 200/400). [4] Western Blot analysis with pure MAG using immunoblot anti-MAG kit (IMMCO diagnostics, Buffalo NY, USA) revealed patient's immunoreactivity against MAG [Figure 1]. Increased titers to MAG (32,491 Bülhmann units, normal <1000) and also SGPG (2.98 ratio, normal <1.92 ratio Bülhmann units) were detected using ELISA commercial kits (Bülhmann Laboratories, Schönenbuch, Switzerland).
Figure 1: Immunodetection of anti‑MAG antibodies with Western Blot analysis. Lane I (17K): Patient with sensory neuropathy and no monoclonal gammopathy (negative control). Lane II (13K): Patient's serum. Lanes III (18K) and IV (15K): Patients with anti‑MAG paraproteinemic neuropathy (positive controls)

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By the severity of symptoms treatment with intravenous pulsed cyclophosphamide every month was initiated. Approximately six months after commencement of treatment cyclophospamide remains well tolerated and slight improvement of gait has been observed. Long-term tolerance and effectiveness of the treatment remains to be evaluated.

 :: Discussion Top

The clinical course in our patient, who had been diagnosed as suffering from CREST syndrome, was complicated by the evolution of a slowly progressive polyneuropathy. Diagnosis of CREST was based on the presence of Raynaud's phenomenon, calcinosis, sclerodactyly, telangiectasia and anticentromere antibodies and therefore could not be challenged. [6] Activity of CREST syndrome was mild: Calcific deposits were asymptomatic and visceral involvement was minor. Unexpectedly, despite the coexistence of CREST syndrome, the polyneuropathy of our patient was demyelinating, not axonal as would be expected. [2] Moreover, a monoclonal gammopaphy of undetermined significance of the IgM subtype was found. Since workup for an underlying plasma cell dyscrasia was negative and there was no family history of polyneuropathy, chronic acquired demyelinating neuropathies associated with IgM paraproteins were considered in the differential diagnosis. [7] Of those, the polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome was excluded as there was no monoclonal plasma cell proliferative disorder and there was absence of proximal weakness. Chronic ataxic neuropathy, ophthalmoplegia, M-protein, agglutination disialosyl antibodies (CANOMAD) was also unlikely because there was significant, predominantly distal motor disability, no cranial nerve involvement and absence of anti-disialosyl antibodies. [8] Given that the patient had the typical clinical presentation of anti-MAG polyneuropathy (PN), i.e. a slowly progressive, distal symmetric sensorimotor PN that initially presented with paresthesias, and that approximately 50% of cases with IgM paraproteinemic neuropathy have anti-MAG autoantibodies, the diagnosis of anti-MAG neuropathy was postulated [3] and confirmed by the presence of high titers to MAG (ELISA) and a positive band in Western Blot analysis.

To the best of our knowledge, association of anti-MAG polyneuropathy with CREST syndrome has not been previously described. Considering the extremely rare occurrence of monoclonal gammopathies in CREST we cannot exclude the possibility that our patient had two different autoimmune diseases. However, there are common immunological mechanisms involved in the pathogenesis of both disorders. A variety of cellular and humoral autoimmune phenomena have been observed in CREST syndrome, such as polyclonal activation of B-cells leading to hypergammaglobulinemia and activation of helper T-cells. [9] On the other hand, anti-MAG antibodies, despite being T-cell independent, belonging to the natural immune repertoire, they may be produced by a reduction in suppressor inducer cells or even by an increase in T-helper function. [10] Taking into consideration the observed activation of helper T-cells in CREST syndrome as well as the increase of total IgM protein in our patient, during the years following the diagnosis of CREST syndrome (from 230 to 541#8197;mg/dl), an association of the two autoimmune disorders could be hypothesized. Should this relation be established, the evolution of anti-MAG demyelinating neuropathy linked to the IgM monoclonal gammopathy rather than an axonal neuropathy related to the CREST syndrome, could be explained.

conclusion, our case suggests that in coexisting immunological disorders the clinical manifestations may be related to all the underlying immunological mechanisms involved.

 :: References Top

1.Oddis C, Eisenbeis C, Reidbord H, Steen V, Medseger T. Vasculitis in systemic sclerosis: Association with Sjögrens syndrome and the CREST syndrome variant. J Rheumatol 1987;14:942-8.  Back to cited text no. 1
2.Dyck PJ, Hunder GG, Dyck PJ. A case control and nerve biopsy study of CREST multiple mononeuropathy. Neurology 1997;49:1641-5.  Back to cited text no. 2
3.Steck AJ, Stalder AK, Renaud S. Anti-myelin-associated glycoprotein neuropathy. Curr Opin Neurol 2006;19:458-63.  Back to cited text no. 3
4.Kusunoki S, Kohriyama T, Pachner AR, Latov N, Yu RK. Neuropathy and IgM paraproteinemia: Differential binding of IgM M-proteins to peripheral nerve glycolipids. Neurology 1987;37:1795-7.  Back to cited text no. 4
5.Sadiq SA, Thomas FP, Kilidireas K, Protopsaltis S, Hays AP, Lee KW, et al. The spectrum of neurologic disease associated with anti-GMl antibodies. Neurology 1990;40:1067-72.  Back to cited text no. 5
6.Maricq HR, Valter I. A working classification of scleroderma spectrum disorders: A proposal and the results of testing on a sample of patients. Clin Exp Rheumatol 2004;22 (3 Suppl 33): S5-13.  Back to cited text no. 6
7.Lewis RA. Chronic inflammatory demyelinating polyneuropathy. Neurol Clin 2007;25:71-87.  Back to cited text no. 7
8.Willison HJ, O'Leary CP, Veitch J, Blumhardt LD, Busby M, Donaghy M, et al. The clinical and laboratory features of chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies. Brain 2001;124:1968-77.  Back to cited text no. 8
9.White B. Immunopathogenesis of systemic sclerosis. Rheum Dis Clin North Am 1996;22:695-708.  Back to cited text no. 9
10.Latov N, Goodfrey M, Thomas Y, Nobile-Orazio E, Spatz L, Abraham J, Pennan G, et al. Neuropathy and anti-myelin-associated glycoprotein IgM M proteins: T cell regulation of M protein secretion in vitro. Ann Neurol 1985;18:182-8.  Back to cited text no. 10


  [Figure 1]

  [Table 1]

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