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Summary: A small subset of myasthenia gravis (MG) patients develop autoantibodies against muscle‐specific kinase (MuSK), which are predominantly of the immunoglobulin (Ig)G4 isotype. MuSK‐MG is strongly associated with HLA‐DRB1*14, HLA‐DRB1*16 and HLA‐DQB1*05. In this study, the possible effects of these HLA associations on MuSK IgG autoantibody or cytokine production were investigated. Samples from 80 MG patients with MuSK antibodies were studied. The disease‐associated HLA types were screened in the DNA samples. The IgG1, IgG2, IgG3 and IgG4 titres of the MuSK antibodies and the levels of interleukin (IL)‐4, IL‐6, IL‐17A and IL‐10 were measured in the sera. Comparisons were made among the groups with or without HLA‐DRB1*14, HLA‐DRB1*16 or HLA‐DQB1*05. The IgG4 titres of the MuSK antibodies were higher than those of the IgG1, IgG2 and IgG3 isotypes among the whole group of patients. DRB1*14 (+) DRB1*16 (–) patients had higher levels of IgG4 antibodies than those of DRB1*14 (–) DRB1*16 (+) patients. DRB1*14 (+) DRB1*16 (+) patients also had higher levels of IgG4 antibodies than those of DRB1*14 (–) DRB1*16 (+) and DRB1*14 (–) DRB1*16 (–) patients. Higher IL‐10 and lower IL‐17A levels were measured in DRB1*14 (+) DRB1*16 (–) patients than in DRB1*14 (–) DRB1*16 (–) patients. The higher IgG4 titres of MuSK autoantibodies in patients carrying HLA‐DRB1*14 than those in the other patients suggest a role for HLA in the production of the antibodies. The differences in IL‐10 and IL‐17A support the role of DRB1 in the etiopathogenesis of this autoimmune response. [ABSTRACT FROM AUTHOR]

Impairment of the suppressive function of regulatory T (Treg) cells has been reported in myasthenia gravis (MG). In this study, cytokine-related mechanisms that may lead to the defect of Treg were investigated in patients with anti-acetylcholine receptor antibody-positive MG (AChR + MG). Proliferation and cytokine production of responder T (Tresp) cells in response to polyclonal activation were measured in a suppression assay. The effect of interleukin (IL)-21 on suppression was evaluated in vitro in co-culture. IL-21 increased the proliferation of Tresp cells in Tresp/Treg co-cultures. Tresp cells from patients with MG secreted significantly lower levels of IL-2. In patients with MG, IL-2 levels did not change with the addition of Treg to cultures, whereas it decreased significantly in controls. In Tresp/Treg co-cultures, IL-4, IL-6 and IL-10 production increased in the presence of Treg in patients. Interferon (IFN)-γ was decreased, whereas IL-17A was increased in both patient and control groups. IL-21 inhibited the secretion of IL-4 in MG and healthy controls (HC), and IL-17A in HC only. The results demonstrated that IL-21 enhances the proliferation of Tresp cells in the presence of Treg. An effect of IL-21 mainly on Tresp cells through IL-2 is implicated. [ABSTRACT FROM AUTHOR]

Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine-Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot-Marie-Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot-Marie-Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset. [ABSTRACT FROM AUTHOR]

Rituximab (RTX) and eculizumab (ECU) are treatment options for refractory myasthenia gravis (MG), but comparative clinical data derived from real-world experience are limited. Here we describe the baseline characteristics, treatment and safety outcomes of patients with anti-acetylcholine receptor antibody-positive (AChR+) generalized myasthenia gravis (gMG) treated with ECU and/or RTX in our clinic. Patients with refractory AChR+ gMG who received more than one year of ECU or/and RTX treatment at the Department of Neurology, Istanbul Faculty of Medicine were included in this observational study. After obtaining patient consent, data were collected retrospectively from medical records. Twelve patients treated with ECU and 25 patients treated with RTX were included in the analysis. Groups were comparable with regard to demographic and clinical characteristics, including age at onset of MG, disease duration and history of thymoma. ECU was associated with significantly better outcomes compared with RTX, as measured by decreases in the mean MG activities of daily living score at 1 (p = 0024), 3 (p < 0.001), 6 (p < 0.001), and 12 (p < 0.001) months of treatment; steroid-sparing effect after 1 year of treatment (decrease in mean [standard deviation] daily prednisolone dose of -21.8 [13.5] mg vs -6.6 [9.4] mg with RTX; p < 0.001); need for rescue treatment and myasthenic crisis episodes during treatment (p < 0.001). No new safety signals were observed with either treatment. Our data provide real-world evidence supporting the use of ECU over RTX to treat refractory AChR+ gMG. [ABSTRACT FROM AUTHOR]

To describe the baseline characteristics, treatment and safety outcomes of the patients with late onset TK2 deficiency treated with deoxynucleoside monophosphates and deoxynucleoside in our clinic. Recessive mutations in the TK2 which encodes for mitochondrial thymidine kinase, cause a rare mitochondrial depletion/multiple deletions syndrome. Late-onset TK2 deficiency is very rare and usually manifests as myopathy. There was only one observational multicenter study describing the results of deoxynucleoside therapy previously. Deoxynucleoside monophosphate and deoxynucleoside therapies have not been approved yet for the treatment of thymidine kinase 2 deficiency. We administered deoxynucleoside monophosphates and deoxynucleoside to three late onset TK2-deficient patients under a compassionate use approved by FDA and Ministry of Health of Turkey. We obtained signed informed consent for the treatment from all patients. All patients underwent motor assessments using 6-minute walk test (6MWT) and Hammersmith Functional Motor Scale (HFMS). Routine laboratory test forced vital capacity (sitting and upright), FSS and BMI were also recorded. The mean age of onset was 17 years (ranges 14-24 years). The distance walked improved in all, mean baseline 6MWT distances was 153m, mean 6MWT distance was 273m after 3 months, 350m after 6 months and 398m after 12 months, 417m after 18 months of treatment. Mean FVC 1 year prior to the treatment was 41%, 37% at baseline, 44% after 3 months, 50% after 6 months and 55% 12 months and 56.6 18 months of treatment. Mean HFMS was 34.7 at baseline, 41.7 at 3th month, 47.7 at 6th month and 54 at 12th and 55.3 at 18th month of treatment. Mean FSS score was reduced by 10 points (from a baseline of 57.3) after 6 months of treatment and was unchanged at 18th month. All patients gained weight, mean BMI was 15.5 at the baseline and 21 after 12 months of treatment. No treatment related serious adverse event was observed. Our data indicates favorable and sustained clinical efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies for late onset TK2 deficiency. [ABSTRACT FROM AUTHOR]

• Multitude of DMD variants challenges the management and genetic counseling in dystrophinopathy. • Single exon deletion may accommodate pathogenic sequence variant in the probe binding site. • Co-occurrence of two mutations in the same allele may complicate phenotype associations. • Segregation assays may guide the critical evaluation of the variants' pathogenicity. • Next generation sequencing technology allows the detection of mosaicism of the sequence variant. We genetically evaluated 260 dystrophinopathy patients from Turkey. Karyotyping as an initial test in female patients, followed stepwise by multiplex ligation-dependent probe amplification and by targeted next-generation sequencing of DMD revealed definitive genetic diagnoses in 214 patients (82%), with gross deletions/duplications in 153 (59%), pathogenic sequence variants in 60 (23%), and X-autosome translocation in one. Seven of the gross and 27 of the sequence variants found novel. In silico prediction, co-segregation and transcript assays supported the pathogenic nature of the novel silent (p.Lys534=) and the splice site (c.4345–12C>G) alterations. From a total of 189 singleton cases, 154 (82%) had pathogenic alterations. From 138 of those who had maternal carrier testing, 68 out of 103 (66%) showed gross and 11 out of 35 (31%) showed small pathogenic variants. This suggests that the de novo occurrences in DMD appear approximately 2.1 times more frequently in meiotic unequal crossing-over than in uncorrected replication errors. Our study also disclosed three mothers as obligate gonadal mosaic carriers. Family-based investigation of dystrophinopathy patients is crucial for the ascertainment of novel or rare variants and also for counseling and follow-up care of the families. [ABSTRACT FROM AUTHOR]

B cells play a major role in the pathophysiology of myasthenia gravis (MG) with their ability to produce disease specific, pathogenic antibodies. However, their status during disease development and follow-up stages of the disease in the peripheral blood may need further studies to determine useful markers. In this study, we aimed to detect B cell associated factors concerning immunosuppressive treatment in generalized non-thymomatous MG patients. Although CD19+ B cell distribution did not vary among disease subgroups, expressions of both CD38 and BAFFR were altered on B cells in MG patients under immunosuppressive therapy. Serum levels of BAFF were elevated in untreated MG patients as compared to treated MG patients and healthy controls. B cell activation factors may show profound alterations due to immunosuppression. • We investigated B cell associated factors for immunosuppressive treatment in MG patients. • Expressions of CD38 and BAFFR were altered on B cells under immunosuppressive therapy. • Serum levels of BAFF were elevated in untreated patients as compared to treated patients. • B cell activation factors may show profound alterations due to immunosuppression. [ABSTRACT FROM AUTHOR]

Findings in recent epidemiological studies have implied that the frequency of myasthenia gravis (MG) may be increasing in the elderly population. Published studies of late-onset MG have disclosed some of its characteristics: males are more frequently affected, the thymus is more likely to be involuted, there is a different HLA profile and anti-striatal muscle antibodies against titin/ryanodine receptors may be present. In our MG database, there were 95 generalized non-thymomatous MG patients with disease onset ⩾50 years who first presented to our outpatient clinic during the 10 years between 2001 and 2010 and who were followed for at least 3 years. All patients were contacted by phone calls or letters. There was a marked male preponderance with male to female ratio of 1.7:1. Onset was with predominantly ocular symptoms (62%), followed by bulbar symptoms (23%) and weakness in the extremities (11%); two patients had neck weakness and 4 had mixed onset symptoms. Anti-acetylcholine receptor antibodies (AChR Ab) were present in 84%, 5% were anti-MuSK Ab positive and 11 % were double negative. Sixty-two percent had anti-titin antibodies. The disease was mild (MGFA 2) in approximately half of the patients (47%) while 6% were intubated. Fifty-seven percent (including all of the patients with MuSK MG) had MGFA postintervention status of complete stable remission/pharmacological remission/minimal manifestations at the last visit. A further 28 % were improved. The combination of prednisolone and azathioprine appeared to be superior to these agents used alone. In 15 mildly affected patients in whom azathioprine was combined with low dose prednisolone (<30 mg/day), 73% had pharmacological remission/minimal manifestations. Fifteen patients had thymectomy, but its effect could not be evaluated because of concomitant immunosuppressives. The thymus showed hyperplasia in only one-third. In this study group, LOMG appears to be a fairly benign disorder with good prognosis. [ABSTRACT FROM AUTHOR]

Oculopharyngodistal myopathy (OPDM) is a rare, adult-onset, slowly progressive hereditary vacuolar myopathy in which the weakness and atrophy affect oculofacial, pharyngeal and distal skeletal muscles. The underlying genetic defect is yet unknown. Swallowing difficulties and hoarseness due to oropharyngeal involvement are two of the most prominent features of the condition affecting the quality of life and survival of the patients. Swallowing difficulty due to cord paresis and atrophy causes aspiration, compromises respiration and cause premature death. Vocal fold injection augmentation with different types of materials is a method used to treat vocal cord paralysis, paresis, atrophy and scars. It is a safe, repeatable, practical and effective procedure and can be performed in awake patients or under general anesthesia. Here, we report the dramatic outcome after vocal cord injection augmentation in a 43 years old female patient with OPDM, evidenced by improvement in ENT examination, videolaryngostroboscopic evaluation, Voice Handicap Index (Validated in Turkish), MDVP Analysis, M.D. Anderson Dysphagia Inventory, FEES (Fiberoptic Endoscopic Evaluation of Swallowing). We examined the patient, and performed all the tests during preoperative and postoperative 1st week, 1st month and 3rd month visits. No complications occurred during or after the procedure. The method was very successful in that aspirations stopped immediately after the injection, the voice became less hoarse and speech was more understandable. Augmentation was more effective for aspiration than for voice quality. Oculopharyngodistal myopathy is a non-curable genetic disease which threatens life due to respiratory insufficiency even in ambulatory patients. Application of vocal cord injection augmentation can be a promising symptomatic therapy option to decrease or stop aspiration in patients with OPDM. A larger study with more patients and longer follow-up is ongoing. [ABSTRACT FROM AUTHOR]