records as mild (sensory symptoms and/or mild distal weakness without impairment of walking), moderate (weakness and/or ataxia interfering with walking) or severe (walking with aid or wheelchair-bound). == Table 2. (without neuropathy) and in MGUS-N, progression to smoldering MM, MM or Waldenstrom’s macroglobulinemia (WM) occurred in 17% of the pts. The Immunoglobulin subtype was predominantly IgG in MGUS-NN and IgM in MGUS-N and 5.5% plasma cells in the bone-marrow predicted progression to MM and AL-amyloidosis in MGUS-NN and to WM in MGUS-N (p<0.05). == Conclusion == Due to the substantial prevalence of neuropathies, MGUS pts. should be monitored Besifloxacin HCl carefully and referred to a specialized center if neurological symptoms occur. Keywords:monoclonal gammopathy of undetermined significance, MGUS, MGUS associated neuropathy, multiple myeloma == INTRODUCTION == Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant disorder with a 0.5-1.5% per year risk of progression to multiple myeloma (MM) or other related hematological malignancies [1,2]. According to the International Myeloma Working Group (IMWG), MGUS is characterized by a monoclonal (M)-protein in the serum of <30 g/l, a clonal plasma cell count in the bone marrow of <10%, and the absence of Besifloxacin HCl clinical symptoms [3]. Risk factors for a progression include an M-protein >15 g/l, an abnormal ratio of free kappa () and lambda () light chains, and the non-IgG isotype [4]. MGUS associated neuropathies (MGUS-N) are heterogeneous with respect to the clinical presentation and the underlying pathophysiology and can be caused by deposition of immunoglobulins or amyloid as well as through the interaction with specific antigens on peripheral nerves. Although the prevalence of neuropathy among MGUS patients (pts.) varies considerably in the literature and the identification often depends on patient selection and diagnostic procedures, it is estimated at about 17% [57]. Vice versa, 5-10% of pts. investigated for neuropathy have a monoclonal gammopathy [8]. There are three major forms of neuropathy in paraproteinemic disorders: axonal sensory-motor neuropathy, chronic inflammatory demyelinating polyneuropathy (CIDP), and distal acquired demyelinating symmetric (DADS) polyneuropathy. Axonal neuropathy usually presents with sensory symptoms (paresthesia, dysesthesia, anesthesia, neuropathic pain) of distal Besifloxacin HCl lower limbs and slowly evolving motor weakness in a length-dependent fashion. It may be associated with IgG/A/M MGUS, but the causal link between the serum paraprotein and axonal nerve damage remains elusive in many cases, although severe pain and autonomic dysfunction may raise the suspicion of amyloidosis [6]. In the demyelinating entities CIDP and DADS a causal relationship with monoclonal gammopathy is considered likely [6,9]. CIDP is a relapsing or progressive immune mediated neuropathy with proximal and distal weakness and sensory deficits of upper and lower limbs and 22-30% of CIDP pts. are described to have MGUS, commonly IgG or IgA subtypes [1012]. DADS neuropathy is characterized by predominant distal sensory impairment, ataxia and often tremor, but little or no weakness and has a close association with IgM kappa monoclonal gammopathy that is present in about two-thirds of pts. [13]. In 50-67% of these pts. the IgM monoclonal protein binds to myelin-associated-protein (MAG) [13,14] causing a characteristic widening of myelin lamellae in nerve biopsies [15]. Despite potent agents in the treatment of pts. with MGUS associated neuropathies, e.g. immunomodulatory agents, plasmapheresis or monoclonal antibodies, some pts. may still present with a high morbidity [9]. The aim of this retrospective single center analysis was to describe the prevalence of neurological manifestations in MGUS pts. and to compare clinical C19orf40 features and risk factors for disease progression in MGUS pts. with and without neuropathy. == RESULTS == == Patient characteristics == 223 pts. fulfilled the criteria for MGUS according to the International Myeloma Working Group (IMWG) criteria, thereof 187 pts. had a MGUS without (MGUS-NN; 84%) and 36 showed a MGUS associated with neuropathy (MGUS-N; 16%). Table1summarizes demographic data and laboratory features of MGUS-NN and MGUS-N pts. == Table 1. Demographic data and laboratory features at diagnosis; comparison of the two cohorts MGUS-NN and MGUS-N. == MGUS-NN, monoclonal gammopathy of undetermined significance without neuropathy; MGUS-N, monoclonal gammopathy of undetermined significance associated neuropathy; N, number of patients; Ig, Immunoglobulin; UNV, upper normal value; LDH, lactate dehydrogenase. * p-value <0.05. Median age at diagnosis was 68 years (range 26-97 years) in the MGUS-NN group and 64 years (range 42-82 years) in the MGUS-N group, respectively. Sex ratio was similar in MGUS-NN pts. (female n=92, 49%; male n=95, 51%), while in the MGUS-N group significantly more pts. were male (female n=7, 19%; male n=29, 81%; p<0.05). In the MGUS-NN cohort more IgG isotype was present than in MGUS-N pts. (n=137, 74% vs. n=17, 47%; p<0.05), whereas more MGUS-N pts. had an IgM isotype.