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Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼ 45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.

Neuromuscular transmission failure in myasthenia gravis (MG) is most commonly elicited by autoantibodies (ab) to the acetylcholine receptor or the muscle-specific kinase, constituting AChR-MG and MuSK-MG. It is controversial whether these MG subtypes arise through different T helper (Th) 1, Th2 or Th17 polarized immune reactions and how these reactions are blunted by immunosuppression. To address these questions, plasma levels of cytokines related to various Th subtypes were determined in patients with AChR-MG, MuSK-MG and healthy controls (CON). Peripheral blood mononuclear cells (PBMC) were activated in vitro by anti-CD3, and cytokines were quantified in supernatants. In purified blood CD4+ T cells, RNA of various cytokines, Th subtype specific transcription factors and the co-stimulatory molecule, CD40L, were quantified by qRT-PCR. Plasma levels of Th1, Th2 and Th17 related cytokines were overall not significantly different between MG subtypes and CON. By contrast, in vitro stimulated PBMC from MuSK-MG but not AChR-MG patients showed significantly increased secretion of the Th1, Th17 and T follicular helper cell related cytokines, IFN-γ, IL-17A and IL-21. Stimulated expression of IL-4, IL-6, IL-10 and IL-13 was not significantly different. At the RNA level, expression of CD40L by CD4+ T cells was reduced in both AChR-MG and MuSK-MG patients while expression of Th subset related cytokines and transcription factors were normal. Immunosuppression treatment had two effects: First, it reduced levels of IL12p40 in the plasma of AChR-MG and MuSK-MG patients, leaving other cytokine levels unchanged; second, it reduced spontaneous secretion of IFN-γ and increased secretion of IL-6 and IL-10 by cultured PBMC from AChR-MG, but not MuSK-MG patients. We conclude that Th1 and Th17 immune reactions play a role in MuSK-MG. Immunosuppression attenuates the Th1 response in AChR-MG and MuSK-MG, but otherwise modulates immune responses in AChR-MG and MuSK-MG patients differentially.

Regulatory T cells were investigated in early-onset (EO) and late-onset (LO) myasthenia gravis patients with anti-acetylcholine receptor antibody (AChR-MG). Alterations in PD-1 and PD-L1 on CD4(+)CD25(++) (Treg) and responder T cells (Tresp, CD4(+)CD25(-)) were observed in LOMG patients. GITR was decreased on CD4(+)CD25(++) of all patients. Decrease of FOXP3 was associated with lower phosphorylation of STAT5.1,25-dihydroxyvitamin D3 (VitD3) increased suppression in co-culture with a stronger effect in patients by acting possibly both on cell groups. Changes in surface molecules and intracellular pathways contribute to the defects of Treg in non-thymomatous AChR-MG and VitD3 can have modulatory effects., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The frequency of amyotrophic lateral sclerosis (ALS) mutations has been extensively investigated in several populations; however, a systematic analysis in Turkish cases has not been reported so far. In this study, we screened 477 ALS patients for mutations, including 116 familial ALS patients from 82 families and 361 sporadic ALS (sALS) cases. Patients were genotyped for C9orf72 (18.3%), SOD1 (12.2%), FUS (5%), TARDBP (3.7%), and UBQLN2 (2.4%) gene mutations, which together account for approximately 40% of familial ALS in Turkey. No SOD1 mutations were detected in sALS patients; however, C9orf72 (3.1%) and UBQLN2 (0.6%) explained 3.7% of sALS in the population. Exome sequencing revealed mutations in OPTN, SPG11, DJ1, PLEKHG5, SYNE1, TRPM7, and SQSTM1 genes, many of them novel. The spectrum of mutations reflect both the distinct genetic background and the heterogeneous nature of the Turkish ALS population., (Copyright © 2015 Elsevier Inc. All rights reserved.)

N-glycanase 1 (NGLY1) is a conserved enzyme that is responsible for the deglycosylation of misfolded N-glycosylated proteins in the cytoplasm prior to their proteasome-mediated degradation. Disruption of this degradation process has been associated with various neurologic diseases including amyotrophic lateral sclerosis and Parkinson's disease. Here, we describe two siblings with neuromotor impairment, apparent intellectual disability, corneal opacities, and neuropathy who were found to possess a novel homozygous frame-shift mutation due to a 4 base pair deletion in NGLY1 (c.1533_1536delTCAA, p.Asn511LysfsX51). We hypothesize that this mutation likely limits the capability of neuronal cells to respond to stress due to accumulation of misfolded proteins, thereby impairing their survival and resulting in progressive loss of neurological function., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Autosomal recessive forms of Charcot-Marie-Tooth disease (ARCMT) are rare but severe disorders of the peripheral nervous system. Their molecular basis is poorly understood due to the extensive genetic and clinical heterogeneity, posing considerable challenges for patients, physicians, and researchers. We report on the genetic findings from a systematic study of a large collection of 174 independent ARCMT families. Initial sequencing of the three most common ARCMT genes (ganglioside-induced differentiation protein 1—GDAP1, SH3 domain and tetratricopeptide repeats-containing protein 2—SH3TC2, histidine-triad nucleotide binding protein 1—HINT1) identified pathogenic mutations in 41 patients. Subsequently, 87 selected nuclear families underwent single nucleotide polymorphism (SNP) genotyping and homozygosity mapping, followed by targeted screening of known ARCMT genes. This strategy provided molecular diagnosis to 22% of the families. Altogether, our unbiased genetic approach identified pathogenic mutations in ten ARCMT genes in a total of 41.3% patients. Apart from a newly described founder mutation in GDAP1, the majority of variants constitute private molecular defects. Since the gene testing was independent of the clinical phenotype of the patients, we identified mutations in patients with unusual or additional clinical features, extending the phenotypic spectrum of the SH3TC2 gene. Our study provides an overview of the ARCMT genetic landscape and proposes guidelines for tackling the genetic heterogeneity of this group of hereditary neuropathies.

Invertebrate model systems are powerful tools for studying human disease owing to their genetic tractability and ease of screening. We conducted a mosaic genetic screen of lethal mutations on the Drosophila X chromosome to identify genes required for the development, function, and maintenance of the nervous system. We identified 165 genes, most of whose function has not been studied in vivo. In parallel, we investigated rare variant alleles in 1,929 human exomes from families with unsolved Mendelian disease. Genes that are essential in flies and have multiple human homologs were found to be likely to be associated with human diseases. Merging the human data sets with the fly genes allowed us to identify disease-associated mutations in six families and to provide insights into microcephaly associated with brain dysgenesis. This bidirectional synergism between fly genetics and human genomics facilitates the functional annotation of evolutionarily conserved genes involved in human health., (Copyright © 2014 Elsevier Inc. All rights reserved.)

A functional single nucleotide polymorphism (SNP) of the PTPN22 gene encoding a protein tyrosine phosphatase has been associated with autoimmune disorders including myasthenia gravis (MG). As the PTPN22 R620W polymorphism has a wide variation of allele frequencies among different populations, this polymorphism was investigated in MG in Turkey. An emphasis is put on MG subgroups according to autoantibody (Abs) production and presence of thymoma. DNA samples from 416 patients with clinically diagnosed generalized MG (231 with Abs to acetylcholine receptor, AChR-MG), 53 with Abs to muscle-specific kinase (MuSK-MG), 55 patients with no detectable Abs (SN-MG), 77 patients with thymoma (TAMG) and 293 healthy controls (HC) were genotyped for the SNP (PTPN22 R620W, C1858T, rs2476601). The PTPN22 T allele was increased in AChR-MG patients (odds ratio [OR]: 2.5, 95%CI: 1.2-5.1). The association was stronger in late disease-onset AChR (LOMG, OR: 3.1, 95%CI: 1.2-8.2). MuSK-MG, SN-MG and TAMG groups did not carry the variant allele more frequently than the HC. In contrast to findings in other autoimmune diseases, the distribution of the PTPN22 polymorphism in this population provides a susceptibility marker for AChR-MG. The strongest association is detected in patients with LOMG.

Purpose: Copy-number variations as a mutational mechanism contribute significantly to human disease. Approximately one-half of the patients with Charcot-Marie-Tooth (CMT) disease have a 1.4 Mb duplication copy-number variation as the cause of their neuropathy. However, non-CMT1A neuropathy patients rarely have causative copy-number variations, and to date, autosomal-recessive disease has not been associated with copy-number variation as a mutational mechanism., Methods: We performed Agilent 8 × 60 K array comparative genomic hybridization on DNA from 12 recessive Turkish families with CMT disease. Additional molecular studies were conducted to detect breakpoint junctions and to evaluate gene expression levels in a family in which we detected an intragenic duplication copy-number variation., Results: We detected an ~6.25 kb homozygous intragenic duplication in NDRG1, a gene known to be causative for recessive HMSNL/CMT4D, in three individuals from a Turkish family with CMT neuropathy. Further studies showed that this intragenic copy-number variation resulted in a homozygous duplication of exons 6-8 that caused decreased mRNA expression of NDRG1., Conclusion: Exon-focused high-resolution array comparative genomic hybridization enables the detection of copy-number variation carrier states in recessive genes, particularly small copy-number variations encompassing or disrupting single genes. In families for whom a molecular diagnosis has not been elucidated by conventional clinical assays, an assessment for copy-number variations in known CMT genes might be considered.

Anti-MuSK positive myasthenia gravis (MuSK-MG) is rare prepuberty. We report a female patient with MuSK-MG starting at 3.5years with ptosis as the sole symptom for 2years. A brief period of generalization was followed by complete stable remission for 6years. Prolonged ocular symptoms and long remissions are not features of MuSK-MG, but are often seen in prepubertal onset MG. The patient then presented at age 12 with moderately severe symptoms which were almost confined to oculobulbar muscles and were unresponsive to pyridostigmine. She was dependent on corticosteroids and thymectomy did not seem to be effective. She was later noted to have tongue atrophy after a period without treatment. Our patient thus presented with features seen in many prepubertal patients, but the later course was quite typical of MuSK-MG., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Susceptibility to myasthenia gravis (MG) has been demonstrated with several HLA in different disease subgroups. HLA-DR14, -DR16 and -DQ5 were reported as predisposing factors in muscle-specific kinase antibody positive MG (MuSK-MG). These markers were evaluated in MG subgroups from Turkey. Among 164 generalized MG patients, 116 had antibodies against anti-acetylcholine receptor (AChR-MG) and 48 had MuSK-MG. Only HLA-DRB1 and DQB1 allele groups reported to be associated with MuSK-MG were compared with 250 healthy controls (HC). Highly significant associations of both DRB1(∗)16 and DRB1(∗)14 were found with MuSK-MG compared to HC (p = 1.9 × 10(-5), OR: 4.95 and p = 0.0028, OR: 3.1). On the contrary, HLA-DRB1(∗)03 was less frequent in MuSK-MG (p = 0.006, OR: 0.09). DQB1(∗)05 was also associated with MuSK-MG (p = 2.5 × 10(-6) OR: 4.8). This study provides a replication of the highly significant associations of both HLA-DRB1(∗)16,-DRB1(∗)14 and -DQB1(∗)05 with MuSK-MG. Moreover, HLA-DRB1(∗)03 appears to have a distinguishing role for this disease subgroup compared to early-onset and AChR-MG., (Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of our study was to show neuromuscular transmission abnormality in the masseter muscle of generalised myasthenia gravis (MG) patients and to compare motor end-plate failure of the masseter with the extensor digitorum communis (EDC) and periocular muscles., Methods: Motor end-plate function was evaluated during voluntary contraction of the masseter muscle of 20 generalised MG patients aged between 16 and 63 years, as well as 20 age-matched healthy volunteers. The mean jitter value was calculated for each group and compared. The upper limit of normal jitter was also calculated and the number of jitters exceeding this cut-off value was counted for each group for comparison. In MG patients, jitter analysis was also performed in periocular and EDC muscles along with the masseter and the number of single fibre-like potentials with abnormal jitter was counted for each muscle. All tests were performed during the same session with a concentric needle electrode (CNE)., Results: For the masseter muscle, the mean jitter of all potential pairs was significantly higher in the patient group (24.7 ± 9.6 μs in healthy volunteers, 71.9 ± 41 μs in patients). The calculated mean jitter for the 18th highest value in healthy volunteers was 33.8 ± 5.9 μs (upper 95% confidence limit was 45.6 μs). The number of abnormal jitters (≥ 46 μs) was significantly higher in the patient group (276 out of 402 jitters) compared to healthy volunteers (10 out of 400 jitters). In the patient group, the number of single fibre-like potentials with abnormal jitter was found to be similar for the masseter, periocular and EDC muscles., Conclusion: The masseter muscle has diagnostic importance in generalised MG. The ratio of high jitters to all of the calculated jitters in a particular muscle was similar for masseter, periocular and EDC muscles., Significance: Jitter analysis of the masseter muscle during voluntary contraction is easy to perform and it was found as informative as other muscles in patients with generalised MG., (Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

The genome-wide presence of copy number variations (CNVs), which was shown to affect the expression and function of genes, has been recently suggested to confer risk for various human disorders, including Amyotrophic Lateral Sclerosis (ALS). We have performed a genome-wide CNV analysis using PennCNV tool and 733K GWAS data of 117 Turkish ALS patients and 109 matched healthy controls. Case-control association analyses have implicated the presence of both common (>5%) and rare (<5%) CNVs in the Turkish population. In the framework of this study, we identified several common and rare loci that may have an impact on ALS pathogenesis. None of the CNVs associated has been implicated in ALS before, but some have been reported in different types of cancers and autism. The most significant associations were shown for 41 kb and 15 kb intergenic heterozygous deletions (Chr11: 50,545,009-50,586,426 and Chr19: 20,860,930-20,875,787) both contributing to increased risk for ALS. CNVs in coding regions of the MAP4K3, HLA-B, EPHA3 and DPYD genes were detected however, after validation by Log R Ratio (LRR) values and TaqMan CNV genotyping, only EPHA3 deletion remained as a potential protective factor for ALS (p = 0.0065024). Based on the knowledge that EPHA4 has been previously shown to rescue SOD1 transgenic mice from ALS phenotype and prolongs survival, EPHA3 may be a promising candidate for therepuetic interventions.

Behçet's disease (BD) is a multisystemic, recurrent and inflammatory disorder. Neurological involvement is rare and affects mainly the central nervous system (CNS) in the form of brainstem meningoencephalitis or dural sinus thrombosis. Peripheral neuropathy is usually not observed during the course of BD but some reports have shown electrophysiologic evidence of subclinical neuropathy, mononeuritis multiplex and cranial neuropathy in BD patients. The co-occurrence of Guillain-Barré syndrome (GBS), an acute inflammatory demyelinating neuropathy, with other autoimmune or systemic diseases is rare. We present a case of BD with clinical and electrophysiological diagnosis of GBS. The findings of the patient were discussed with reference to literature.

Recessively transmitted predominantly motor neuropathies are rare and show a severe phenotype. They are frequently observed in populations with a high rate of consanguineous marriages. At least 15 genes and six loci have been found to be associated with autosomal recessive CMT (AR-CMT) and X-linked CMT (AR-CMTX) and also distal hereditary motor neuronopathy (AR-dHMN). These disorders are genetically heterogeneous but the clinical phenotype is relatively homogeneous. Distal muscle weakness and atrophy predominating in the lower extremities, diminished or absent deep tendon reflexes, distal sensory loss, and pes cavus are the main clinical features of this disorder with occasional cranial nerve involvement. Although genetic diagnosis of some of subtypes of AR-CMT are now available, rapid advances in the molecular genetics and cell biology show a great complexity. Animal models for the most common subtypes of human AR-CMT disease provide clues for understanding the pathogenesis of CMT and also help to reveal possible treatment strategies of inherited neuropathies. This chapter highlights the clinical features and the recent genetic and biological findings in these disorders based on the current classification., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Inherited peripheral neuropathies are frequent neuromuscular disorders known for their clinical and genetic heterogeneity. In 33 families, we identified 8 mutations in HINT1 (encoding histidine triad nucleotide-binding protein 1) by combining linkage analyses with next-generation sequencing and subsequent cohort screening of affected individuals. Our study provides evidence that loss of functional HINT1 protein results in a distinct phenotype of autosomal recessive axonal neuropathy with neuromyotonia.

Neurological involvement may be seen in 5-30% of the patients with Behcet's disease (BD). Occasionally, parenchymal neurological involvement in BD can present as a spinal cord syndrome. However, motor neuron disease-like presentation is extremely uncommon. Here we are reporting five patients (all male; median age, 38) fulfilling both International Study Group criteria for BD and El Escorial criteria for amyotrophic lateral sclerosis (ALS). These patients were identified by a questionnaire sent to the members of the Neuro-Behcet Study Group of the International Study Group for BD. Three out of five patients had only motor presentations. In two patients, sensory and urinary manifestations were present as well. Spinal cord MRIs were normal in all, and brain MRIs were normal in four patients; one patient had nonspecific white matter changes. Two patients passed away 1-3 years after diagnosis of ALS, and two patients were lost to follow-up 3 and 11 years after admission; one patient is still alive 3 years after onset. The patients that are presented here might represent a rare form of neurological involvement in BD as well as sole coincidence. Larger prospective series are needed to further answer this issue.

Expansions of the polyglutamine (polyQ) domain (≥ 34) in Ataxin-2 (ATXN2) are the primary cause of spinocerebellar ataxia type 2 (SCA2). Recent studies reported that intermediate-length (27-33) expansions increase the risk of Amyotrophic Lateral Sclerosis (ALS) in 1-4% of cases in diverse populations. This study investigates the Turkish population with respect to ALS risk, genotyping 158 sporadic, 78 familial patients and 420 neurologically healthy controls. We re-assessed the effect of ATXN2 expansions and extended the analysis for the first time to cover the ATXN2 locus with 18 Single Nucleotide Polymorphisms (SNPs) and their haplotypes. In accordance with other studies, our results confirmed that 31-32 polyQ repeats in the ATXN2 gene are associated with risk of developing ALS in 1.7% of the Turkish ALS cohort (p=0.0172). Additionally, a significant association of a 136 kb haplotype block across the ATXN2 and SH2B3 genes was found in 19.4% of a subset of our ALS cohort and in 10.1% of the controls (p=0.0057, OR: 2.23). ATXN2 and SH2B3 encode proteins that both interact with growth receptor tyrosine kinases. Our novel observations suggest that genotyping of SNPs at this locus may be useful for the study of ALS risk in a high percentage of individuals and that ATXN2 and SH2B3 variants may interact in modulating the disease pathway.

In a muscle biopsy based study, only 9 out of 5450 biopsy samples, received from all parts of greater Istanbul area, had typical clinical and most suggestive light microscopic sporadic-inclusion body myositis (s-IBM) findings. Two other patients with and ten further patients without characteristic light microscopic findings had referring diagnosis of s-IBM. As the general and the age-adjusted populations of Istanbul in 2010 were 13.255.685 and 2.347.300 respectively, the calculated corresponding 'estimated prevalences' of most suggestive s-IBM in the Istanbul area were 0.679 X 10(-6) and 3.834 X 10(-6). Since Istanbul receives heavy migration from all regions of Turkey and ours is the only muscle pathology laboratory in Istanbul, projection of these figures to the Turkish population was considered to be reasonable and an estimate of the prevalence of s-IBM in Turkey was obtained. The calculated 'estimated prevalence' of s-IBM in Turkey is lower than the previously reported rates from other countries. The wide variation in the prevalence rates of s-IBM may reflect different genetic, immunogenetic or environmental factors in different populations.

Introduction: In the demyelinating form of Charcot-Marie-Tooth disease, median motor conduction velocity (MCV) was noted to be around 20 m/s in peripheral myelin protein 22 (PMP22) duplications, in contrast to higher MCVs in connexin 32 gene (Cx32) mutations and lower MCVs in the demyelinating form of myelin protein zero gene (MPZ) mutations., Methods: Nerve conduction studies were performed in 64 families with both common and rare mutations., Results: Mean MCV of the median nerve was 20 ± 5 m/s in PMP22 duplications, 34 ± 6 m/s in Cx32 mutations, 20 ± 9 m/s in KIAA1985 (SH3TC2) mutations, and 11 ± 8 m/s in MPZ mutations. Conduction was generally uniform; however, conduction blocks were present in 1 patient each with the MPZ mutation and PMP22 duplication, both with unusual phenotypes., Conclusion: Our results confirm those of the other investigators. Electrophysiological results of the rare KIAA1985 (SH3TC2) mutation reveal that their MCVs span a broad range and that conduction is uniform., (Copyright © 2010 Wiley Periodicals, Inc.)

Object: Local administration of insulin-like growth factor-I (IGF-I) has been shown to increase the rate of axon regeneration in crush-injured and freeze-injured rat sciatic nerves. Local administration of platelet-rich plasma (PRP) has been also shown to have a measurable effect on facial nerve regeneration after transection in a rat model. The objective of the study was to compare the effects of locally administered IGF-I and PRP on the parameters of the Sciatic Function Index (SFI), sensory function (SF), axon count, and myelin thickness/axon diameter ratio (G-ratio) in a rat model of crush-injured sciatic nerves., Methods: The right sciatic nerve of Wistar albino rats (24 animals) was crushed using a Yasargil-Phynox aneurysm clip for 45 minutes. All animals were randomly divided into 3 groups: Group 1 (control group) was treated with saline, Group 2 was treated with IGF-I, and Group 3 was treated with PRP. Injections were performed using the tissue expander's injection port with a connecting tube directed at the crush-injured site. Functional recovery was assessed with improvement in the SFI. Recovery of sensory function was using the pinch test. Histopathological examination was performed 3 months after the injury., Results: The SFI showed an improved functional recovery in the IGF-I-treated animals (Group 2) compared with the saline-treated animals (Group 1) 30 days after the injury. In IGF-I-treated rats, sensory function returned to the baseline level significantly faster than in saline-treated and PRP-treated rats as shown in values between SF-2 and SF-7. The G-ratios were found to be significantly higher in both experimental groups than in the control group., Conclusions: This study suggests that the application of IGF-I to the crush-injured site may expedite the functional recovery of paralyzed muscle by increasing the rate of axon regeneration.

Objective: To investigate the activation of different complement pathways in myasthenia gravis (MG) subtypes., Subjects and Methods: Levels of complement breakdown products for different complement pathways were measured using ELISA in sera of acetylcholine receptor antibody (AChR-Ab)-positive (n = 21), muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive (n = 23) and seronegative generalized MG patients (n = 21) and healthy controls (n = 22). Levels of factor Bb (FBb), the breakdown product of factor B, and C4d, the breakdown product of C4, were measured to evaluate the activity of the alternative and classical complement pathways, respectively. Serum iC3b levels were analyzed to assess total complement activity. The results were expressed as OD values., Results: MuSK-Ab-positive MG patients had a significantly higher mean concentration of serum FBb (0.638) than other MG subtypes (0.446 for AChR-Ab-positive, 0.537 for seronegative MG patients) and healthy controls (0.434) (p = 0.045). Mean serum iC3b (1.549-1.780) and C4d (0.364-0.395) levels were comparable among the groups., Conclusion: Our results suggest that MuSK-Ab-positive MG patients might have a complement-activating serum factor and the alternative complement pathway might be involved in the pathogenesis of the disease., (Copyright © 2011 S. Karger AG, Basel.)

Therapeutic use of botulinum toxin type A (BT/A) is well known, effective, and safe. Iatrogenic botulism that presents with generalized weakness, dysphagia, and respiratory distress is a rare but significant complication in BT/A treatment. In this study, we report 4 patients who developed iatrogenic botulism after receiving therapeutic doses of BT/A for spasticity and blepharospasm. One patient was placed in intensive care unit, but consequently, every patient recovered fully. The cause of BT/A as an adverse effect is most likely hematological spread of the toxin.

A group of clinicians from across Europe experienced in the use of botulinum toxin type A for the treatment of spasticity following acquired brain injury gathered to develop a consensus statement on best practice in managing adults with spasticity. This consensus table summarizes the current published data, which was collated following extensive literature searches, their assessment for level of evidence and discussion among the whole group. Published information is supplemented by expert opinion based on clinical experience from 16 European countries, involving 28 clinicians, who treat an average of approximately 200 patients annually, representing many thousand spasticity treatments with botulinum toxin per year.

Background: Videothoracoscopic thymectomy is an alternative surgical procedure for patients with nonthymomatous myasthenia gravis. The aim of this study is to present our experience and to analyze the factors contributing to the operative morbidity., Methods: Ninety myasthenia gravis patients were operated through right-sided videothoracoscopy from June 2002 to September 2006. Prospective data recording was performed. Surgeon-related conversion to open surgery, length of the operation, chest tube duration time, duration of hospital stay, amount of drainage, pain score, and complications were evaluated. Factors contributing to longer operation time and longer postoperative stay were studied., Results: The mean length of chest tube duration and postoperative hospital stay was 26.7 +/- 18.6 hours and 2.2 days +/- 1.1 days respectively. Visual analogue scale (VAS) values for pain evaluation were 2.0 +/- 1.4. Surgeon-related open conversion occured in two patients (2.2%). Body mass index (BMI) was the sole significant factor for longer operation time. (23.04 +/- 2.93 versus 25.61 +/- 2.70 (p = 0.001). The amount of pyridostigmine was the only significant factor for longer hospital stay (213.3 +/- 101.5 mg versus 270. 0 +/- 122.6 mg (p = 0.044)., Conclusions: This study demonstrates the right-sided videothoracoscopy is a safe procedure. The only contributing factors were: BMI >25.61 for longer operation time, and pyridostigmine level >270 mg for duration of postoperative stay.

Purpose of Review: The purpose of this review is to help neurologists understand new concepts in hereditary neuropathies, from the clinician's point of view, in the molecular era after the burst of information regarding peripheral nerve biology., Recent Findings: Recent studies have focused on understanding the pathomechanisms involved in hereditary neuropathies. In the past year identification of new genes has slowed down since scientists have concentrated more on the function of genes causing Charcot-Marie-Tooth disease and Schwann cell-axon interactions to reveal the molecular cell biology of the disease. Animal models for the most common subtypes of human Charcot-Marie-Tooth disease are now available., Summary: Rapid advances in the molecular genetics and cell biology of hereditary neuropathies have highlighted the great genetic complexity of Charcot-Marie-Tooth disease. The evolution from a simple clinical classification to a complex molecular one has not facilitated our understanding of the disease. Moreover, the new molecular classification is not simple to use as different mutations of the same gene produce a range of phenotypes. The clinicians have to look for specific clinical and electrophysiological clues to direct the patient to appropriate genetic testing.

GTPases of the Rho subfamily are widely involved in the myelination of the vertebrate nervous system. Rho GTPase activity is temporally and spatially regulated by a set of specific guanine nucleotide exchange factors (GEFs). Here, we report that disruption of frabin/FGD4, a GEF for the Rho GTPase cell-division cycle 42 (Cdc42), causes peripheral nerve demyelination in patients with autosomal recessive Charcot-Marie-Tooth (CMT) neuropathy. These data, together with the ability of frabin to induce Cdc42-mediated cell-shape changes in transfected Schwann cells, suggest that Rho GTPase signaling is essential for proper myelination of the peripheral nervous system.

To assess the involvement of polymorphisms in genetic susceptibility to myasthenia gravis (MG), this study analyzed four polymorphisms of interferon (IFN)-gamma, interleukin (IL)-10, and IL-12 genes in 115 patients and 204 healthy controls (HC). IFNG +874T carriers were less frequent in MG, in patients with anti-acetylcholine receptor (AChR) (63%) and anti-titin (56.2%) antibodies compared with HC (p = 0.01 for all, OR: 0.5, 0.5, and 0.4, respectively). The presence of thymoma was also associated with lower frequency of IFNG +874T allele (p = 0.018, OR = 0.34). At IL10, -2763A allele was found to be slightly more frequent in MG and in patients with anti-AChR than in HC group (p = 0.05, OR = 1.7, p = 0.036, OR = 1.83). However, these associations did not remain significant after correction for multiple comparisons. IL12B allele distribution was not different among groups. These data suggest that some cytokine gene polymorphisms may contribute to susceptibility to or antibody production in MG. These findings need to be replicated in further studies.

We investigated the manifestations of CMT4C disease in a genetically homogeneous group of patients homozygous for the recently identified Gypsy founder mutation p.Arg1109X in SH3TC2. We observed a surprising degree of variation in age at onset, rate of progression, extent and severity of motor and sensory involvement, scoliosis, and cranial nerve involvement, suggesting that the phenotypic spectrum of CMT4C disease is much broader than the classical diagnostic criteria. Phenotype similarity in first degree relatives and increasing heterogeneity in more distantly related subjects point to the involvement of genetic modifiers, possibly variants in the genes encoding protein partners interacting with SH3TC2.

The decrement pattern at low rates of repetitive nerve stimulation in myasthenia gravis (MG) is characterized by a decrease of compound muscle action potential size within the first 4-5 responses. With subsequent stimuli, compound muscle action potential size either increases or does not change. Following an observation that the pattern of decrement might be different in patients with Lambert-Eaton myasthenic syndrome (LEMS), we retrospectively studied traces from eight LEMS patients and 14 patients with seropositive generalized MG, calculating decrement percent from first to fourth and from first to ninth compound muscle action potential. In the LEMS patients, compound muscle action potential amplitude decreased progressively from first to ninth stimulus at 2, 3 or 5Hz in all traces but one. In contrast, MG patients demonstrated the expected improvement after the initial decrement in all traces except one. In the evaluation of patients suspected of having myasthenia gravis, the finding of progressive decrement pattern at low rates of repetitive nerve stimulation may alert the electromyographer to the possibility of Lambert-Eaton syndrome and prompt the performance of further electrodiagnostic tests.

Genetic susceptibility to myasthenia gravis (MG) is reported frequently and varies depending on the clinical presentation of the patients. HLA-DQ genotyping was performed in 132 patients using polymerase chain reaction and sequence-specific oligonucleotide hybridizations in the Turkish population for the first time in this study. Antibody positivities against acetylcholine receptor and titin were 81 and 27%, respectively. Sixty-five percent of the patients had disease onset before 40 years of age (EOMG). Overall distribution of DQA1*0103 (odds ratio (OR): 0.5) and DQB1*0502 (OR: 1.9) alleles was different in patients and an ethnically matched healthy control group. Among the subgroups, DQB1*02 was significantly more frequent in EOMG (OR: 1.8), in women with MG (OR: 2.4), and in women with EOMG (OR: 2.8), whereas DQA1*0102 and DQB1*502 (OR: 2.3 for both) were increased and DQA1*0103 (OR: 0.04) was decreased in men with MG. Seropositivity was associated with both DQA1*03 (OR: 12.1) and DQB1*0302 (OR: 14.2) in the patient group. DQA1*02 (OR: 4.9) was associated with the presence of anti-titin antibodies, whereas DQA1*0101 (OR: 3.7) and *0102 (OR: 2.9) were more frequent in patients without this antibody. The presence of thymoma in MG was positively associated with DQB1*0301 (OR: 2.8), and DQB1*02 (OR: 0.3) was significantly less frequent in this group. The HLA-DQ associations in subgroups of MG suggest that the heterogeneity of the disease may be influenced by different genes or even by different alleles. DQ alleles have proved to be relatively informative polymorphisms in studying MG.

A 34-year-old woman was admitted to our emergency room with a high fever, abdominal pain, dyspnea and confusion. High fever and abdominal pain had first occured after a cystocele operation 5 months earlier. Later, congestive heart failure with mural thrombus formation, peripheral polyneuropathy and ischemic cerebrovascular accident were identified in clinical follow-ups, and multiple arterial and venous thromboses were seen on cranial and abdominal magnetic resonance imaging angiography. The patient's symptoms improved with anticoagulant treatment. Antiphospholipid syndrome with elevated serum anticardiolipin IgG levels was diagnosed, and ischemic peripheral polyneuropathy with axonal degeneration was determined by sural nerve biopsy. In antiphospholipid syndrome, elevated anticardiolipin antibodies appear to be the most common acquired blood protein defect causing thrombosis. Disseminated vascular thrombosis in catastrophic antiphospholipid syndrome can result in multiorgan failure with increased morbidity and mortality. It rarely occurs secondary to various infections as in the case of our patient, who suffered postoperative intraabdominal infection. It is important to note that peripheral nervous system involvement is rare in antiphospholipid syndrome.

Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology. CMT4C is inherited as an autosomal recessive trait and has been mapped to a 13-cM linkage interval on chromosome 5q23-q33. By homozygosity mapping and allele-sharing analysis, we refined the CMT4C locus to a suggestive critical region of 1.7 Mb. We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy. We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution. In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state. The CMT4C gene is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR domains that are likely involved in the formation of protein complexes.

The concept of Dejerine-Sottas disease, which corresponds to presumed recessive demyelinating neuropathies with onset in infancy, remains controversial. To learn more on the subject, we performed a clinico-pathological and molecular genetic study in 15 unrelated patients with the Dejerine-Sottas phenotype seen over a 16 year period. There were 12 females and 3 males, born to asymptomatic parents. Study of the PMP22, P0 and Egr2 genes was performed in all cases and 14 underwent a nerve biopsy. First manifestations of neuropathy occurred before 3 years of age in all patients. An inherited disorder was suspected in 10 patients, because of their family history and/or disclosure of a molecular genetic defect in 4 of them. One patient had a recessively transmitted homozygous point mutation (Arg157Trp) of the PMP22 gene. A heterozygous duplication of the 17p11.2-12 segment was detected in one offspring of a consanguineous marriage. One patient carried a "de novo" heterozygous Ser72Leu substitution in the PMP22. A heterozygous double mutation of the P0 gene including a "de novo" Val42 deletion and an Ala221Thr substitution, maternally inherited, were found in an apparently sporadic case. No mutation of the Egr2 gene was identified. A neuropathy with focally folded myelin sheaths (CMT4B) was diagnosed in the nerve biopsy specimens of two patients. In five patients, the clinico-pathological findings along with the absence of an identified mutation suggested the diagnosis of chronic inflammatory demyelinating polyneuropathy of infantile onset. Our findings illustrate the genetic heterogeneity of cases with identified mutations, the scarcity of cases with "demonstrated" recessive transmission and the likelihood of early acquired chronic inflammatory demyelinating polyneuropathy in several patients.

Precipitation of spike and wave (SW) discharges in some epileptic patients by eye closure (EC) has rarely been reported. To disclose the clinical characteristics and classification of syndromes of epileptic patients with SW discharges induced by EC, we investigated 10 patients (1 M, 9 F) showing this peculiar EEG feature. The patients aged between 9-39 years (mean 20.6 +/- 9.058), underwent short-term (1-3.5 hr) video-EEG investigations in order to document the appearance of the SW discharges within 3 seconds of the act of EC, in at least two occasions. Clinical analysis showed that 5 female patients who had the syndrome of juvenile myoclonic epilepsy (JME) had a later onset of epilepsy (13-15 years) than the 3 patients (3 girls) with eyelid myoclonia with absences (EMA) (3-8 years of age at onset). The remaining 2 patients who were diagnosed as childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE) according to the international classification, did not show photosensitivity on the video-EEG. All but one of the 5 JME patients had experienced myoclonic seizures in intermittent photic stimulation (IPS) at the time of EC, associated with multiple spike and wave discharges. Two of the 3 EMA patients exhibited typical absences with eyelid myoclonia during the act of EC. The high rate of family history of epilepsy in first degree relatives of our patients was an outstanding feature, which could have future implications in research of the genetic basis of epilepsy patients with ECS.

The existence of recessive transmission of Dejerine-Sottas disease, a severe demyelinating neuropathy of childhood, has been questioned, because only heterozygous mutations of the myelin proteins P0 or PMP22 genes have been identified in virtually all patients with this phenotype. We report on a family with 3 affected children with this phenotype, born to clinically and electrophysiologically unaffected parents. All 3 children carried a previously unknown homozygous missense point mutation (Arg157Trp) of the PMP22 gene. The parents were heterozygous for the same mutation. These findings demonstrate the occurrence of recessive transmission in this setting.

We examined 26 spinal muscular atrophy type III (SMA III) patients with SMNt deletions, searching for possible segmental distribution of muscle weakness. In those with disease duration of < or = 11 years, the weakest muscles were upper lumbar innervated ones in the lower extremities. In the upper extremities, early involvement of triceps muscle suggested the possibility of lower cervical (C7) onset. Electrophysiologically, weaker muscles had a more severe reduction in the recruitment pattern, particularly in the lower extremities. However, severe reduction in recruitment was sometimes also observed in clinically strong muscles. In patients with disease duration of > or = 16 years and regardless of disease duration, in those with disease onset at < or = 3 years of age, weakness and severe electrophysiological changes were more widespread. These findings may suggest a progression in muscle weakness with time. When compared to 12 patients with Becker muscular dystrophy (BMD), early stage SMA III with weak iliopsoas-strong gluteus maximus stood in contrast to BMD with weak gluteus maximus-strong iliopsoas.