Objective To assess the clinical course of multifocal motor neuropathy (MMN) in a large cohort of patients and to identify predictive factors of a progressive disease course. Methods Between May 2015 and February 2016, we collected clinical data from 100 patients with MMN, of whom 60 had participated in a nationwide cross-sectional cohort study in 2007. We documented clinical characteristics using standardized questionnaires and performed a standardized neurologic examination. We used multiple linear regression analysis to identify factors that correlated with worse outcome. Results We found that age at diagnosis (45.2 vs 48.6 years, p < 0.02) was significantly increased between 2007 and 2015-2016, whereas diagnostic delay decreased by 15 months. Seven out of 10 outcome measures deteriorated over time (all p < 0.01). Patients who had a lower Medical Research Council (MRC) sumscore and absence of 1 or more reflexes at the baseline visit showed a greater functional loss at follow-up (p = 0.007 and p = 0.016). Conclusions Our study shows that MMN is a progressive disease. Although 87% of patients received maintenance treatment, muscle strength, reflexes, vibration sense, and the Self-Evaluation Scale score significantly deteriorated over time. Lower MRC sumscore and absence of reflexes predicted a more progressive disease course. Classification of evidence This study provides Class II evidence that lower MRC sumscore and the absence of reflexes predict a more progressive disease course in patients with MMN.

INTRODUCTION:Polyneuropathy with immunoglobulin M monoclonal gammopathy (IgM-PNP) is associated with the presence of IgM antibodies against nerve constituents such as myelin associated glycoprotein (MAG) and gangliosides.METHODS:To test whether B-cell-stimulating cytokines are increased in IgM-PNP, we measured serum concentrations of 11 cytokines in 81 patients with IgM-PNP and 113 controls.RESULTS:Median interleukin (IL)-6 concentrations were higher in patients with IgM-PNP, and median IL-10 concentrations were higher in the subgroup with anti-MAG IgM antibodies. These serum concentrations were not increased in 110 patients with multifocal motor neuropathy.DISCUSSION:Median IL-6 and IL-10 serum concentrations differ between patients with anti-MAG neuropathy and other patients with IgM-PNP compared with healthy and neuropathy controls. These differences may indicate differences in immune-mediated disease mechanisms. Muscle Nerve 59:694-698, 2019.

Objective We investigated the pathogenicity of immunoglobulin M (IgM) anti‐GM1 antibodies in serum from patients with multifocal motor neuropathy (MMN) using human induced pluripotent stem cell (iPSC)‐derived motor neurons (MNs). Methods iPSCs were generated from fibroblasts and differentiated into MNs. We studied the binding of IgM to MNs, their complement‐activating properties, and effects on structural integrity using fluorescence and electron microscopy. Live cell imaging was used to study effects of antibody binding on MNs in the presence and absence of complement. Results IgM antibody binding to MNs was detected using sera from MMN patients with and without detectable anti‐GM1 IgM antibody titers in enzyme‐linked immunosorbent assay, but not with sera from (disease) controls. Competition and depletion experiments showed that antibodies specifically bound to GM1 on iPSC‐derived MNs. Binding of these antibodies disrupted calcium homeostasis by both complement‐dependent and complement‐independent pathways. MNs showed marked axonal damage after complement activation, and reduced antibody pathogenicity following treatment with immunoglobulin preparations. Interpretation Our data provide evidence for the pathogenicity of anti‐GM1 IgM antibodies in MMN patients and link their presence to the clinical characteristics of axonal damage and immunoglobulin responsiveness. This iPSC‐derived disease model will facilitate diagnosis, studies on autoantibody pathogenicity, drug development, and screening in immune‐mediated neuropathies. Ann Neurol 2016;80:71–88

Multifocal motor neuropathy (MMN) and progressive muscular atrophy (PMA) are associated with IgM monoclonal gammopathy or the presence IgM anti-GM1-antibodies. To further investigate the pathophysiology of MMN and PMA we determined concentrations of 16 mainly B-cell associated inflammatory markers in serum from 25 patients with MMN, 55 patients with PMA, 25 patients with amyotrophic lateral sclerosis (ALS) and 50 healthy controls. Median serum concentrations of the 16 tested cytokines and chemokines were not significantly increased in patients with MMN or patients with PMA, irrespective of the presence of IgM monoclonal gammopathy or high IgM anti-GM1 antibodies. These results argue against a systemic B-cell mediated immune response underlying the pathogenesis of MMN and PMA.

Monoclonal gammopathy in patients with amyotrophic lateral sclerosis (ALS) and related disorders has been reported in small studies but the validity of the reported associations remains uncertain. Presence of monoclonal gammopathy may indicate specific pathogenic pathways and may facilitate the development of novel treatment strategies. The objective of this large case-control study was to determine the prevalence of monoclonal gammopathy in motor neuron diseases (MND) and multifocal motor neuropathy (MMN). Monoclonal gammopathy was determined by immunoelectrophoresis and immunofixation in serum from 445 patients with ALS, 158 patients with progressive muscular atrophy (PMA), 60 patients with primary lateral sclerosis (PLS), 88 patients with MMN and in 430 matched healthy controls. Anti-ganglioside antibody titers were determined in sera from patients with MMN and PMA, and in ALS and PLS patients with monoclonal gammopathy. Logistic regression analysis was used to investigate associations of monoclonal gammopathy with motor neuron diseases and clinical characteristics. Neither ALS nor PLS was associated with monoclonal gammopathy. IgM monoclonal gammopathy was more frequent in patients with PMA (8 %) (OR = 4.2; p = 0.001) and MMN (7 %) (OR = 5.8; p = 0.002) than in controls (2 %). High titers of anti-GM1 IgM antibodies were present in 43 % of MMN patients and 7 % of PMA patients. Patients with PMA and IgM monoclonal gammopathy or anti-GM1 antibodies had a higher age at onset, more often weakness of upper legs and more severe outcome than patients with MMN. PMA and MMN, but not ALS and PLS, are significantly associated with IgM monoclonal gammopathy and anti-GM1 antibodies. These results may indicate that a subset of patients presenting with PMA share pathogenic mechanisms with MMN.

Polyneuropathy associated with IgM monoclonal gammopathy (IgM-PNP) is a slowly progressive, sensorimotor neuropathy. It is assumed that complement activation contributes to IgM-PNP pathogenesis. We investigated whether innate differences in complement activity of the classical and mannose binding lectin (MBL) pathways are associated with IgM-PNP or its severity. We measured complement activity using ELISA and determined MBL serumc oncentrations and MBL gene polymorphisms in 83 patients and 83 healthy controls. We did not observe differences between IgM-PNP patients and healthy controls nor associations with different disease severities. Differences in innate complement activity are not likely to explain susceptibility to or severity of IgM-PNP.

OBJECTIVE:To investigate whether high innate activity of the classical and lectin pathways of complement is associated with multifocal motor neuropathy (MMN) and whether levels of innate complement activity or the potential of anti-GM1 antibodies to activate the complement system correlate with disease severity.METHODS:We performed a case-control study including 79 patients with MMN and 79 matched healthy controls. Muscle weakness was documented with Medical Research Council scale sum score and axonal loss with nerve conduction studies. Activity of the classical and lectin pathways of complement was assessed by ELISA. We also determined serum mannose-binding lectin (MBL) concentrations and polymorphisms in the MBL gene (MBL2) and quantified complement-activating properties of anti-GM1 IgM antibodies by ELISA.RESULTS:Activity of the classical and lectin pathways, MBL2 genotypes, and serum MBL concentrations did not differ between patients and controls. Complement activation by anti-GM1 IgM antibodies was exclusively mediated through the classical pathway and correlated with antibody titers (p < 0.001). Logistic regression analysis showed that both high innate activity of the classical pathway of complement and high complement-activating capacity of anti-GM1 IgM antibodies were significantly associated with more severe muscle weakness and axonal loss.CONCLUSION:High innate activity of the classical pathway of complement and efficient complement-activating properties of anti-GM1 IgM antibodies are determinants of disease severity in patients with MMN. These findings underline the importance of anti-GM1 antibody-mediated complement activation in the pathogenesis and clinical course of MMN.

BACKGROUND:Multifocal motor neuropathy (MMN) is associated with IgM antibodies to GM1 ganglioside. The importance of the lipid milieu that might facilitate or inhibit antibody binding to GM1 in immunoassays is well recognised. Existing studies, using a range of different approaches, generally concur that anti-GM1 IgM antibody detection rates are improved by the addition of galactocerebroside (GalC) to the GM1 assay.OBJECTIVE:The current study sought to formally evaluate the clinical utility of the GM1:GalC complex assay in the diagnosis of MMN.METHODS:Anti-GM1 and -GM1:GalC antibodies were examined using ELISA and glycoarray (dot blot) in a fully blinded study design, consisting of 100 MMN patients, 100 ALS cases and 100 healthy controls.RESULTS:The detection of anti-GM1 Abs using glycoarray was 67% sensitive and 85% specific. The addition of GalC to GM1, (1:1 weight to weight ratio), increased the sensitivity to 81% , whilst dropping specificity to 80% . Increasing the GalC content to a 1:5 ratio (or higher) further decreased specificity, and in doing so limited the usefulness of the GM1:GalC assay to the level of GM1 alone. The addition of GalC to the ELISA method also significantly increased sensitivity compared with GM1 alone, albeit with a significant decrease in specificity.CONCLUSIONS:This study indicates that the GM1:GalC assay is an advantageous assay adaptation for detecting anti-GM1 antibodies in MMN, using either glycoarray or ELISA, and warrants introduction into clinical diagnostic practice.

BACKGROUND:Multifocal motor neuropathy (MMN) is often responsive to treatment with intravenous immunoglobulin (IVIg), but the optimal dose and intervals of IVIg maintenance treatment have not been established. Increase in IgG concentration (ΔIgG) after IVIg infusion has recently been identified as determinant of outcome in Guillain-Barré syndrome. ΔIgG may therefore represent a potentially useful biomarker to optimise IVIg dosing in patients with MMN.OBJECTIVE:The aims of this study were to determine variability of IVIg pharmacokinetics in patients with MMN in relation to treatment response, and to establish whether interindividual differences in IVIg pharmacokinetics were associated with genetic polymorphisms of the endothelial IgG receptor (FcRn) which determines IgG half-life.METHODS:Twenty-three patients with MMN receiving their first IVIg treatment at a cumulative dose of 2.0 g/kg in 5 days were included. A good treatment response was defined as an increase in muscle strength of at least one Medical Research Council point in minimally two muscle groups. IgG concentrations in serum were determined at baseline, at day 1 and day 5 of the IVIg course, and 3 weeks after treatment. FcRn copy number variation and differences in repeat length of the variable number of tandem repeats in the FcRn gene were determined by quantitative PCR and Sanger sequencing.RESULTS:Seventeen patients (74%) had a good response to treatment. Total IgG and ΔIgG levels showed large variation between patients. Mean ΔIgG was higher in IVIg responders than in non-responders, with the largest difference on day 1 (11.1 g/L vs 4.5 g/L, p=0.06), but our study lacked power to show statistically significant differences. Genetic variation in the FcRn gene was not associated with ΔIgG levels or response to treatment.CONCLUSIONS:IVIg pharmacokinetics varies in patients with MMN and may be associated with clinical response.

OBJECTIVE: The aim of this study is to determine variability of intravenous immunoglobulins (IVIg) pharmacokinetics in patients with multifocal motor neuropathy (MMN), to study the association of variability with genetic heterogeneity of FcRn and to study associations with treatment response.

Objective: To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS).Methods: Included were 78 patients with fALS, 1,422 with sALS, 246 with PMA, and 110 with PLS, and 768 control subjects. Repeat expansions were determined by a repeat primed PCR. Familial aggregation of dementia and Parkinson disease (PD) was examined among patients with ALS who carried the repeat expansion.Results: The expanded repeat was found in 33 (37%) of all patients with fALS, in 87 (6.1%) patients with sALS, in 4 (1.6%) patients with PMA, and in 1 (0.9%) patient with PLS. None of the controls carried the mutation. Patients with ALS with the repeat expansion had an earlier age at onset (median 59.3 vs 61.9 years, hazard ratio 1.55, p = 5 x 10(-5)) and shorter survival (median 2.5 vs 2.7 years, hazard ratio 1.46, p = 8 x 10(-4)). Dementia, but not PD, occurred nearly twice as often in relatives of patients with the expansion compared to all patients with ALS or controls (p = 9 x 10(-4)).Conclusions: The hexanucleotide repeat expansion in C9ORF72 is a major cause of fALS and apparently sporadic ALS in the Netherlands. Patients who carry the repeat expansion have an earlier onset, shorter survival, and familial aggregation of dementia. These results challenge the classic definition of fALS and may justify genetic testing in patients with sALS. Neurology (R) 2012;79:878-882

From June 24–27, 2012, the Inflammatory Neuropathy Consortium (INC) held its off-year meeting in Rotterdam, Holland. The local organizing committee of the Peripheral Nerve Society (PNS)/INC meeting led by PA van Doorn and BC Jacobs did an excellent job. The meeting started with a successful teaching course. The Scientific Program included 9 plenary lectures, 12 platform presentations including the results of 3 randomized controlled trials, and 103 posters for over 280 attendees. New and successful were the two debate sessions and the selected 3 min/3 slides pre-poster oral introductions as a variant on the wellknown 10-min oral presentations. A several-hour-long INC Symposium presented the current work of the INC and gave all present the opportunity to bring up new projects for the group. Currently, the INC is supporting the IGOS study in GBS, the I-SID study of a second dose of IVIg in GBS, the successful PeriNoms collaboration, the MMN database, and two about to start clinical trials in CIDP. Scientific highlights of the meeting included a new CIDP model with a putative T-cell target, new developments in neurophysiology and electrical excitability studies, and validation and development of outcome measures and diagnostic criteria. Several studies in children were also presented. We must thank the generous sponsors of the meeting for their support and especially the support that allows junior investigators to attend. Platinum sponsors were Baxter, CSL Behring, Grifols, Kedrion, and Rabobank. Gold sponsors were GBS/CIDP Foundation International and Octapharma AG. Bronze sponsors were Astellas Pharma BV and TerumoBCT Europe. Additional sponsors were Bühlmann Laboratories AG, Bitfactory BV, Erasmus MC, Eurocept BV, and Rotterdam Marketing. As is the tradition at PNS and INC meetings, awards were given for the best presentations: the Arthur K. Asbury Award went to Gavin Meehan; the Peter James Dyck Award went to Maureen Su; and the P.K. Thomas Award went to Marija Sajic. New this year, the GBS-CIDP Foundation International in addition to their usual generous support provided three new travel awards honoring Arthur K. Asbury to Jonathan Baets, Lars Markvardsen, and Nevena Tzekova. Rabobank, a Platinum-level sponsor, gave 15 travel awards to promote young people, the theme of their generous corporate giving program worldwide.

Multifocal motor neuropathy (MMN) is a rare, probably immune-mediated chronic disorder characterized by asymmetric distal limb weakness and conduction block. The exact pathogenesis of MMN is still unclear, but IgM anti-GM1 antibodies, which can be detected in sera from approximately half of all MMN patients, are thought to play an important role. Treatment with intravenous immunoglobulin (IVIG) is effective in the vast majority of patients, but, despite IVIG maintenance treatment, many patients experience a slowly progressive decline in muscle strength. In this review we will summarize the results from studies on pathogenesis. We will discuss current treatment strategies of MMN and how insight into MMN pathogenesis may translate into novel therapies in the future.

Progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) are devastating motor neuron diseases (MNDs), which result in muscle weakness and/or spasticity. We compared mutation frequencies in genes known to be associated with MNDs between patients with apparently sporadic PMA and ALS. A total of 261 patients with adult-onset sporadic PMA, patients with sporadic ALS, and control subjects of Dutch descent were obtained at national referral centers for neuromuscular diseases in The Netherlands. Sanger sequencing was used to screen these subjects for mutations in the coding regions of superoxide dismutase-1 (SOD1), angiogenin (ANG), fused in sarcoma/translated in liposarcoma (FUS/TLS), TAR DNA-binding protein 43 (TARDBP), and multivesicular body protein 2B (CHMP2B). In our cohort of PMA patients we identified two SOD1 mutations (p.D90A, p.I113T), one ANG mutation (p.K17I), one FUS/TLS mutation (p.R521H), one TARDBP mutation (p.N352S), and one novel CHMP2B mutation (p.R69Q). The mutation frequency of these genes was similar in sporadic PMA (2.7%) and ALS (2.0%) patients, and therefore, our findings demonstrate a genetic overlap between apparently sporadic PMA and ALS.

Recently, repeat expansions in several genes have been shown to cause or be associated with amyotrophic lateral sclerosis (ALS). It has been demonstrated that an intronic hexanucleotide repeat expansion in C9ORF72 is a major cause of both familial (approximately 40%) and sporadic (approximately 5%) ALS, as well as frontotemporal dementia (FTD). In addition, a CAG-repeat expansion in exon 1 of ATXN2, otherwise known to cause spinocerebellar ataxia type 2, has been identified as a major risk factor for sporadic ALS. Intermediate repeat expansions in the fragile X mental retardation 1 (FMR1) gene (55-200 repeats) are known to cause fragile X-associated premature ovarian insufficiency [(FX)POI; female carriers] or fragile X-associated tremor/ataxia syndrome (FXTAS; male carriers) by CGG-mediated RNA toxicity. The present investigation involves screening FMR1 repeat length in 742 sporadic ALS patients and 792 matched controls. Our conclusion is that FMR1 repeat expansions are not associated with ALS.

Multifocal motor neuropathy (MMN) is a rare inflammatory neuropathy characterized by slowly progressive, asymmetric distal limb weakness without sensory loss. The clinical presentation of MMN may mimic amyotrophic lateral sclerosis, other variants of motor neuron disease, or chronic inflammatory demyelinating polyneuropathy with asymmetric onset. Differentiation is important, as these diseases differ in prognosis and treatment. The electrophysiological finding of conduction block in the absence of abnormalities in sensory nerves is the hallmark of MMN, but can be difficult to detect. Intravenous immunoglobulin is efficacious in most patients, but long-term maintenance therapy does not prevent slowly progressive axonal degeneration. Moreover, cyclophosphamide, although effective, has substantial adverse effects, and the efficacy of other immunosuppressive drugs, including rituximab, is not established. The underlying pathological mechanisms of MMN are unclear, but IgM autoantibodies against the ganglioside GM1 may cause changes in nodal and perinodal structures that compromise nerve conduction. Further elucidation of the disease mechanisms may ultimately lead to improved treatment strategies. In this Review, we discuss the diagnostic criteria for MMN, and provide an update on the current understanding of MMN pathogenesis. We also describe available treatments and promising new therapeutic strategies.