Journal of the Peripheral Nervous System 19:180–182 (2014)
CASE REPORT
Multifocal motor neuropathy with high titers of anti-MAG antibodies Claire Bridel1 , Judit Horvath1 , Mary Kurian2 , André Truffert1 , Andreas Steck3 , and Patrice H. Lalive1,4 1
Department of Clinical Neurosciences, Division of Neurology; 2 Department of Pediatrics, Geneva University Hospital, Geneva, Switzerland; 3 Department of Neurology, Basel University Hospital, Basel, Switzerland; and 4 Department of Genetics and Laboratory Medicine, Laboratory Medicine Service, Geneva University Hospital, Geneva, Switzerland
Abstract Multifocal motor neuropathy (MMN) and anti-myelin-associated glycoprotein (anti-MAG)-associated neuropathy are clinically and electrophysiologically distinct entities. We describe a patient with characteristic features of both neuropathies, raising the possibility of an overlap syndrome. A 49-year-old patient reported a history of slowly progressive predominantly distal tetraparesis, with mild sensory deficits. Nerve conduction studies demonstrated persistent motor conduction blocks outside compression sites, typical of MMN. Laboratory findings revealed persistently high titers of anti-MAG immunoglobulin M𝜆 (IgM𝜆) paraprotein in the context of a monoclonal gammapathy of unknown significance. Skin biopsy of distal lower limb revealed IgM positive terminal nerve perineurium deposits. This case suggests that the distinction between subtypes of chronic inflammatory neuropathies may not be as clear as initially thought, and that the pattern of pathogenicity of anti-MAG antibodies may vary. Key words: anti-MAG neuropathy, immune-mediated peripheral neuropathy, multifocal motor neuropathies
been described as a chronic, length-dependent, symmetrical, sensory–motor demyelinating neuropathy, also referred to as distal acquired demyelinating symmetric (DADS) neuropathy. Monoclonal anti-MAG IgM paraprotein is detected in the context of an underlying MGUS (monoclonal gammapathy of undetermined significance), myeloma, Waldenström disease, or lymphoma. Several lines of evidence suggest a causal relationship between anti-MAG antibodies and neuropathy (Dalakas, 2010). Here, we describe a case illustrating a rare situation with simultaneous features of MMN and anti-MAG neuropathies.
Introduction Multifocal motor neuropathy (MMN) is a rare immune-mediated chronic motor neuropathy clinically characterized by asymmetrical muscle weakness in peripheral nerve territories. Persistent motor conduction blocks outside compression sites are the electrophysiological hallmark. Anti-GM1 immunoglobulin M (IgM) antibodies have been described in association with MMN, but their role in pathogenesis is not established (Cats et al., 2010). Anti-myelin-associated glycoprotein (anti-MAG)-associated neuropathy has
Case Report A 49-year-old female presented with a history of slowly progressive predominantly distal tetraparesis, without pain or sensory deficit. The first symptom she reported was progressive left foot drop 10 years prior.
Address correspondence to: Dr. Claire Bridel, MD, PhD, Department of Clinical Neurosciences, Division of Neurology, Geneva University Hospital and Faculty of Medicine, Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland. Tel: +(41)22-372-83-18; Fax: +(41)22-372-83-32; E-mail: [email protected]. © 2014 Peripheral Nerve Society
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Bridel et al.
Journal of the Peripheral Nervous System 19:180–182 (2014)
Physical examination revealed asymmetrical bilateral calf amyotrophy and moderate foot drop predominating on the left side, as well as bilateral thenar and right interosseous amyotrophy with moderate weakness. Myotatic reflexes were present except ankle jerk reflexes. Sensibility was reduced on the lateral aspect of right foot. Gait assessment revealed left steppage and her walk perimeter was reduced. Nerve conduction studies demonstrated proximal motor conduction blocks on right ulnar nerve, right tibial nerve, left median nerve, and both fibular nerves. Distal compound muscle action potential amplitudes were slightly reduced, but sensory nerve action potential amplitudes and conduction velocities were normal in lower limbs. Lumbar magnetic resonance image (MRI) was unremarkable. Cerebrospinal fluid analysis and immunoelectrophoresis were normal, and genetic investigation ruled out PMP22 deletion. Mild clinical improvement followed a 5-day intravenous immunoglobulin infusion (intravenous immunoglobulins, 0.4 g/kg/day). Nerve conduction studies performed 2 months after treatment showed a slight improvement of the proximal right ulnar motor conduction block. The patient refused further treatment and follow-up. Eight years later, aged 57, the patient sought medical advice again. By then, her gait was unstable and required assistance. Severe bilateral foot drop and marked paresis of the right hand were observed. Sensibility was reduced on lateral aspect of right foot and leg and medial aspect of right hand. Immunological workup showed elevated anti-MAG (22′ 265 BTU; N < 1′ 000 BTU) and anti-SGPG (6.11; N < 1.0) antibodies, as well as mildly elevated anti-GM1 IgM antibodies (1,510; N < 800). Immunofixation revealed a minor IgM𝜆 paraprotein. Further investigations including bone-marrow aspirate ruled out myeloma, lymphoma, or Waldenström macroglobulinemia and MGUS was diagnosed. Nerve conduction studies showed persistence of all previously detected conduction blocks, with aggravation of distal motor axonal degeneration. No signs of motor or sensory segmental conduction slowing or temporal dispersion were documented. Skin biopsy of distal lower limb revealed IgM positive terminal nerve deposits similar to those seen in anti-MAG-associated polyneuropathy (Lombardi et al., 2005) (Fig. 1). Response to repetitive intravenous immunoglobulin infusions was poor, and cyclophosphamide or rituximab was considered, but the patient refused immunosuppression, and regular immunoglobulin infusions were pursued. A year later, laboratory analysis showed increased levels of the IgM𝜆 paraprotein, without signs of malignant progression of MGUS. anti-GM1 antibody
Figure 1. Confocal imaging of cutaneous nerve. Neurofilament (red), myelin (green), immunoglobulin M (IgM) deposits (blue), heavy IgM deposits on the perineurium (blue), and slight deposits on a myelinated fiber (arrows).
titers were persistently high (27′ 605 BTU; N < 1,000), but anti-ganglioside antibodies, including anti-GM1, were negative. In the following years, anti-MAG levels further increased up to 49′ 582 BTU. Conduction blocks persisted despite treatment, and motor axonal degeneration progressed toward subtotal axonotomesis in both fibular nerves. Marked axonal loss in left median and right ulnar nerves was observed, with no evidence of distal conduction slowing of the surviving motor axons. Recently, an isolated sensory loss in the left ulnar nerve was observed, while all other sensory nerve parameters remained normal. The patient is now aged 62 and severely disabled.
Discussion Chronic inflammatory neuropathies are a heterogeneous group of peripheral nerve disorders for which there is evidence of immune-mediated pathogenic mechanisms. The disease spectrum is wide and includes chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), DADS neuropathy, multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy (or Lewis-Sumner syndrome), and MMN (Latov et al., 2006). Each type of chronic inflammatory neuropathy is defined by its clinical presentation, electrophysiological pattern, and biological findings. Beyond the seminal descriptions of MMN (Parry and Clarke, 1988), 181
Bridel et al.
Journal of the Peripheral Nervous System 19:180–182 (2014)
References
anti-MAG (Hafler et al., 1986) and MADSAM (Lewis et al., 1982s) neuropathies, overlap cases of these disorders have been described, suggesting the distinction between subtypes of chronic inflammatory neuropathies may not be as clear as initially thought. Sensory nerve conduction velocities and action potential amplitudes must be normal to meet diagnostic criteria of MMN, although mild clinical deficits are tolerated (Joint Task Force of the EFNS and the PNS, 2010). Prominent sensory abnormalities do appear in some patients diagnosed with MMN, usually in the same nerve territories as weakness and conduction blocks (Joint Task Force of the EFNS and the PNS, 2010). A disease continuum including MMN and MADSAM neuropathy rather than two distinct pathologies has been suggested by some authors (Mezaki et al., 1999). We describe a patient with clinically and electrophysiologically typical MMN, who also features some aspects of anti-MAG neuropathy, including mild sensory deficits and, foremost, high anti-MAG IgM𝜆 titers. Skin biopsy revealed IgM𝜆 positive nerve terminal deposits (Fig. 1). However, the IgM𝜆 deposits were located on the perineurium rather than on myelin sheaths, as described in classical anti-MAG neuropathies (Lombardi et al., 2005). This atypical pattern of antibody deposition could explain the unusual clinical and electrophysiological presentation in our patient. Indeed, high titers of anti-MAG antibodies have been described in a case of small fiber neuropathy without major large fiber neuropathy (Luigetti et al., 2010), and in a case of predominantly motor demyelinating neuropathy (Kawagashira et al., 2010), suggesting the pattern of pathogenicity of anti-MAG may vary. While a correlation between nerve IgM deposition and IgM blood levels has been reported (Stalder et al., 2009), the role of additional factors such as complement remains to be demonstrated. Recognizing possible overlap cases of chronic inflammatory neuropathies is not trivial, because it may have important therapeutic consequences. However, until the immuno-pathological mechanisms underlying these neuropathies are better understood, this may prove difficult.
Cats EA, Jacobs BC, Yuki N, Tio-Gillen AP, Piepers S, Franssen H, van Asseldonk JT, van den Berg LH, van der Pol WL (2010). Multifocal motor neuropathy: association of anti-GM1 IgM antibodies with clinical features. Neurology 75:1961–1967. Dalakas MC (2010). Pathogenesis and treatment of anti-MAG neuropathy. Curr Treat Options Neurol 12:71–83. Hafler DA, Johnson D, Kelly JJ, Panitch H, Kyle R, Weiner HL (1986). Monoclonal gammopathy and neuropathy: myelin-associated glycoprotein reactivity and clinical characteristics. Neurology 36:75–78. Joint Task Force of the EFNS and the PNS (2010). European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of multifocal motor neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society--first revision. J Peripher Nerv Syst 15:295–301. Kawagashira Y, Kondo N, Atsuta N, Iijima M, Koike H, Katsuno M, Tanaka F, Kusunoki S, Sobue G (2010). IgM MGUS anti-MAG neuropathy with predominant muscle weakness and extensive muscle atrophy. Muscle Nerve 42:433–435. Latov N, Gorson KC, Brannagan TH III, Freeman RL, Apostolski S, Berger AR, Bradley WG, Briani C, Bril V, Busis NA, Cros DP, Dalakas MC, Donofrio PD, Dyck PJ, England JD, Fisher MA, Herrmann DN, Menkes DL, Sahenk Z, Sander HW, Triggs WJ, Vallat JM (2006). Diagnosis and treatment of chronic immune-mediated neuropathies. J Clin Neuromuscul Dis 7:141–157. Lewis RA, Sumner AJ, Brown MJ, Asbury AK (1982). Multifocal demyelinating neuropathy with persistent conduction block. Neurology 32:958–964. Lombardi R, Erne B, Lauria G, Pareyson D, Borgna M, Morbin M, Arnold A, Czaplinski A, Fuhr P, Schaeren-Wiemers N, Steck AJ (2005). IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy. Ann Neurol 57:180–187. Luigetti M, Madia F, Conte A, Tonali P, Sabatelli M (2010). Neuropathy with predominant small fiber involvement associated with abnormal anti-MAG titer. Intern Med 49:2627–2629. Mezaki T, Kaji R, Kimura J (1999). Multifocal motor neuropathy and Lewis Sumner syndrome: a clinical spectrum. Muscle Nerve 22:1739–1740. Parry GJ, Clarke S (1988). Multifocal acquired demyelinating neuropathy masquerading as motor neuron disease. Muscle Nerve 11:103–107. Stalder AK, Erne B, Reimann R, Renaud S, Fuhr P, Thomann S, Arnold A, Probst A, Schaeren-Wiemers N, Steck AJ (2009). Immunoglobulin M deposition in cutaneous nerves of anti-myelin-associated glycoprotein polyneuropathy patients correlates with axonal degeneration. J Neuropathol Exp Neurol 68:148–158.
Acknowledgement We thank BÜHLMANN laboratories AG, Schönenbruch, Switzerland for performing the SGPG antibody assay.
182
CASE REPORT
Multifocal motor neuropathy with high titers of anti-MAG antibodies Claire Bridel1 , Judit Horvath1 , Mary Kurian2 , André Truffert1 , Andreas Steck3 , and Patrice H. Lalive1,4 1
Department of Clinical Neurosciences, Division of Neurology; 2 Department of Pediatrics, Geneva University Hospital, Geneva, Switzerland; 3 Department of Neurology, Basel University Hospital, Basel, Switzerland; and 4 Department of Genetics and Laboratory Medicine, Laboratory Medicine Service, Geneva University Hospital, Geneva, Switzerland
Abstract Multifocal motor neuropathy (MMN) and anti-myelin-associated glycoprotein (anti-MAG)-associated neuropathy are clinically and electrophysiologically distinct entities. We describe a patient with characteristic features of both neuropathies, raising the possibility of an overlap syndrome. A 49-year-old patient reported a history of slowly progressive predominantly distal tetraparesis, with mild sensory deficits. Nerve conduction studies demonstrated persistent motor conduction blocks outside compression sites, typical of MMN. Laboratory findings revealed persistently high titers of anti-MAG immunoglobulin M𝜆 (IgM𝜆) paraprotein in the context of a monoclonal gammapathy of unknown significance. Skin biopsy of distal lower limb revealed IgM positive terminal nerve perineurium deposits. This case suggests that the distinction between subtypes of chronic inflammatory neuropathies may not be as clear as initially thought, and that the pattern of pathogenicity of anti-MAG antibodies may vary. Key words: anti-MAG neuropathy, immune-mediated peripheral neuropathy, multifocal motor neuropathies
been described as a chronic, length-dependent, symmetrical, sensory–motor demyelinating neuropathy, also referred to as distal acquired demyelinating symmetric (DADS) neuropathy. Monoclonal anti-MAG IgM paraprotein is detected in the context of an underlying MGUS (monoclonal gammapathy of undetermined significance), myeloma, Waldenström disease, or lymphoma. Several lines of evidence suggest a causal relationship between anti-MAG antibodies and neuropathy (Dalakas, 2010). Here, we describe a case illustrating a rare situation with simultaneous features of MMN and anti-MAG neuropathies.
Introduction Multifocal motor neuropathy (MMN) is a rare immune-mediated chronic motor neuropathy clinically characterized by asymmetrical muscle weakness in peripheral nerve territories. Persistent motor conduction blocks outside compression sites are the electrophysiological hallmark. Anti-GM1 immunoglobulin M (IgM) antibodies have been described in association with MMN, but their role in pathogenesis is not established (Cats et al., 2010). Anti-myelin-associated glycoprotein (anti-MAG)-associated neuropathy has
Case Report A 49-year-old female presented with a history of slowly progressive predominantly distal tetraparesis, without pain or sensory deficit. The first symptom she reported was progressive left foot drop 10 years prior.
Address correspondence to: Dr. Claire Bridel, MD, PhD, Department of Clinical Neurosciences, Division of Neurology, Geneva University Hospital and Faculty of Medicine, Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland. Tel: +(41)22-372-83-18; Fax: +(41)22-372-83-32; E-mail: [email protected]. © 2014 Peripheral Nerve Society
180
Bridel et al.
Journal of the Peripheral Nervous System 19:180–182 (2014)
Physical examination revealed asymmetrical bilateral calf amyotrophy and moderate foot drop predominating on the left side, as well as bilateral thenar and right interosseous amyotrophy with moderate weakness. Myotatic reflexes were present except ankle jerk reflexes. Sensibility was reduced on the lateral aspect of right foot. Gait assessment revealed left steppage and her walk perimeter was reduced. Nerve conduction studies demonstrated proximal motor conduction blocks on right ulnar nerve, right tibial nerve, left median nerve, and both fibular nerves. Distal compound muscle action potential amplitudes were slightly reduced, but sensory nerve action potential amplitudes and conduction velocities were normal in lower limbs. Lumbar magnetic resonance image (MRI) was unremarkable. Cerebrospinal fluid analysis and immunoelectrophoresis were normal, and genetic investigation ruled out PMP22 deletion. Mild clinical improvement followed a 5-day intravenous immunoglobulin infusion (intravenous immunoglobulins, 0.4 g/kg/day). Nerve conduction studies performed 2 months after treatment showed a slight improvement of the proximal right ulnar motor conduction block. The patient refused further treatment and follow-up. Eight years later, aged 57, the patient sought medical advice again. By then, her gait was unstable and required assistance. Severe bilateral foot drop and marked paresis of the right hand were observed. Sensibility was reduced on lateral aspect of right foot and leg and medial aspect of right hand. Immunological workup showed elevated anti-MAG (22′ 265 BTU; N < 1′ 000 BTU) and anti-SGPG (6.11; N < 1.0) antibodies, as well as mildly elevated anti-GM1 IgM antibodies (1,510; N < 800). Immunofixation revealed a minor IgM𝜆 paraprotein. Further investigations including bone-marrow aspirate ruled out myeloma, lymphoma, or Waldenström macroglobulinemia and MGUS was diagnosed. Nerve conduction studies showed persistence of all previously detected conduction blocks, with aggravation of distal motor axonal degeneration. No signs of motor or sensory segmental conduction slowing or temporal dispersion were documented. Skin biopsy of distal lower limb revealed IgM positive terminal nerve deposits similar to those seen in anti-MAG-associated polyneuropathy (Lombardi et al., 2005) (Fig. 1). Response to repetitive intravenous immunoglobulin infusions was poor, and cyclophosphamide or rituximab was considered, but the patient refused immunosuppression, and regular immunoglobulin infusions were pursued. A year later, laboratory analysis showed increased levels of the IgM𝜆 paraprotein, without signs of malignant progression of MGUS. anti-GM1 antibody
Figure 1. Confocal imaging of cutaneous nerve. Neurofilament (red), myelin (green), immunoglobulin M (IgM) deposits (blue), heavy IgM deposits on the perineurium (blue), and slight deposits on a myelinated fiber (arrows).
titers were persistently high (27′ 605 BTU; N < 1,000), but anti-ganglioside antibodies, including anti-GM1, were negative. In the following years, anti-MAG levels further increased up to 49′ 582 BTU. Conduction blocks persisted despite treatment, and motor axonal degeneration progressed toward subtotal axonotomesis in both fibular nerves. Marked axonal loss in left median and right ulnar nerves was observed, with no evidence of distal conduction slowing of the surviving motor axons. Recently, an isolated sensory loss in the left ulnar nerve was observed, while all other sensory nerve parameters remained normal. The patient is now aged 62 and severely disabled.
Discussion Chronic inflammatory neuropathies are a heterogeneous group of peripheral nerve disorders for which there is evidence of immune-mediated pathogenic mechanisms. The disease spectrum is wide and includes chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), DADS neuropathy, multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy (or Lewis-Sumner syndrome), and MMN (Latov et al., 2006). Each type of chronic inflammatory neuropathy is defined by its clinical presentation, electrophysiological pattern, and biological findings. Beyond the seminal descriptions of MMN (Parry and Clarke, 1988), 181
Bridel et al.
Journal of the Peripheral Nervous System 19:180–182 (2014)
References
anti-MAG (Hafler et al., 1986) and MADSAM (Lewis et al., 1982s) neuropathies, overlap cases of these disorders have been described, suggesting the distinction between subtypes of chronic inflammatory neuropathies may not be as clear as initially thought. Sensory nerve conduction velocities and action potential amplitudes must be normal to meet diagnostic criteria of MMN, although mild clinical deficits are tolerated (Joint Task Force of the EFNS and the PNS, 2010). Prominent sensory abnormalities do appear in some patients diagnosed with MMN, usually in the same nerve territories as weakness and conduction blocks (Joint Task Force of the EFNS and the PNS, 2010). A disease continuum including MMN and MADSAM neuropathy rather than two distinct pathologies has been suggested by some authors (Mezaki et al., 1999). We describe a patient with clinically and electrophysiologically typical MMN, who also features some aspects of anti-MAG neuropathy, including mild sensory deficits and, foremost, high anti-MAG IgM𝜆 titers. Skin biopsy revealed IgM𝜆 positive nerve terminal deposits (Fig. 1). However, the IgM𝜆 deposits were located on the perineurium rather than on myelin sheaths, as described in classical anti-MAG neuropathies (Lombardi et al., 2005). This atypical pattern of antibody deposition could explain the unusual clinical and electrophysiological presentation in our patient. Indeed, high titers of anti-MAG antibodies have been described in a case of small fiber neuropathy without major large fiber neuropathy (Luigetti et al., 2010), and in a case of predominantly motor demyelinating neuropathy (Kawagashira et al., 2010), suggesting the pattern of pathogenicity of anti-MAG may vary. While a correlation between nerve IgM deposition and IgM blood levels has been reported (Stalder et al., 2009), the role of additional factors such as complement remains to be demonstrated. Recognizing possible overlap cases of chronic inflammatory neuropathies is not trivial, because it may have important therapeutic consequences. However, until the immuno-pathological mechanisms underlying these neuropathies are better understood, this may prove difficult.
Cats EA, Jacobs BC, Yuki N, Tio-Gillen AP, Piepers S, Franssen H, van Asseldonk JT, van den Berg LH, van der Pol WL (2010). Multifocal motor neuropathy: association of anti-GM1 IgM antibodies with clinical features. Neurology 75:1961–1967. Dalakas MC (2010). Pathogenesis and treatment of anti-MAG neuropathy. Curr Treat Options Neurol 12:71–83. Hafler DA, Johnson D, Kelly JJ, Panitch H, Kyle R, Weiner HL (1986). Monoclonal gammopathy and neuropathy: myelin-associated glycoprotein reactivity and clinical characteristics. Neurology 36:75–78. Joint Task Force of the EFNS and the PNS (2010). European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of multifocal motor neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society--first revision. J Peripher Nerv Syst 15:295–301. Kawagashira Y, Kondo N, Atsuta N, Iijima M, Koike H, Katsuno M, Tanaka F, Kusunoki S, Sobue G (2010). IgM MGUS anti-MAG neuropathy with predominant muscle weakness and extensive muscle atrophy. Muscle Nerve 42:433–435. Latov N, Gorson KC, Brannagan TH III, Freeman RL, Apostolski S, Berger AR, Bradley WG, Briani C, Bril V, Busis NA, Cros DP, Dalakas MC, Donofrio PD, Dyck PJ, England JD, Fisher MA, Herrmann DN, Menkes DL, Sahenk Z, Sander HW, Triggs WJ, Vallat JM (2006). Diagnosis and treatment of chronic immune-mediated neuropathies. J Clin Neuromuscul Dis 7:141–157. Lewis RA, Sumner AJ, Brown MJ, Asbury AK (1982). Multifocal demyelinating neuropathy with persistent conduction block. Neurology 32:958–964. Lombardi R, Erne B, Lauria G, Pareyson D, Borgna M, Morbin M, Arnold A, Czaplinski A, Fuhr P, Schaeren-Wiemers N, Steck AJ (2005). IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy. Ann Neurol 57:180–187. Luigetti M, Madia F, Conte A, Tonali P, Sabatelli M (2010). Neuropathy with predominant small fiber involvement associated with abnormal anti-MAG titer. Intern Med 49:2627–2629. Mezaki T, Kaji R, Kimura J (1999). Multifocal motor neuropathy and Lewis Sumner syndrome: a clinical spectrum. Muscle Nerve 22:1739–1740. Parry GJ, Clarke S (1988). Multifocal acquired demyelinating neuropathy masquerading as motor neuron disease. Muscle Nerve 11:103–107. Stalder AK, Erne B, Reimann R, Renaud S, Fuhr P, Thomann S, Arnold A, Probst A, Schaeren-Wiemers N, Steck AJ (2009). Immunoglobulin M deposition in cutaneous nerves of anti-myelin-associated glycoprotein polyneuropathy patients correlates with axonal degeneration. J Neuropathol Exp Neurol 68:148–158.
Acknowledgement We thank BÜHLMANN laboratories AG, Schönenbruch, Switzerland for performing the SGPG antibody assay.
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