An Exploratory Study of Cognitive Involvement in Hereditary Transthyretin Amyloidosis.

OBJECTIVES: Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis is an autosomal dominant disorder caused by mutations of the transthyretin (TTR) gene. The mutant ATTRv protein causes a systemic accumulation of amyloid fibrils in various organs. TTR is an important protein in the central nervous system physiology for the maintenance of normal cognitive process during aging, amidated neuropeptide processing, and nerve regeneration. The neuroprotective effect of transthyretin has been widely documented in animal models. Cognitive consequences of the mutant TTR in hereditary ATTRv amyloidosis patients remain still to be elucidated. We designed this study to investigate the cognitive involvement in ATTRv amyloidosis. METHODS: Detailed neuropsychological tests and cranial MRIs were performed. Biomarkers including amyloid beta 1-42, total tau, and phosphorylated tau were investigated in the cerebrospinal fluid samples. RESULTS: Median age of the cohort was 52 years (ranges 34-72). Neuropsychological assessment results were compatible with impaired executive functions (in all patients except one with only bilateral carpal tunnel syndrome, long-term visual and long-term verbal memory (severe in four patients and moderate in one). Visuospatial judgment and perception were impaired in six. Mean cerebrospinal fluid Aß1-42 (pg/ml) was 878.0 ± 249.5 in patients with cortical atrophyin MRI whereas 1210.0 ± 45.9 in patients without any cortical atrophy. Cranial MRI showed cortical atrophy in six patients (6/10). CONCLUSION: Our data showed the significance of the TTR protein in cognitive functions and highlighted the importance of the close follow-up of cognitive functions in ATTRv amyloidosis patients.

Late-onset generalized myasthenia gravis: clinical features, treatment, and outcome.

Late-onset myasthenia gravis (LOMG) is a unique MG subgroup. More information is needed on its subgroups such as non-thymomatous generalized LOMG. We evaluated the effect of demographic, clinical, and serological factors as well as different immunosuppressive modalities on outcome in generalized non-thymomatous LOMG with onset ≥ 50 years. Myasthenia Gravis Foundation of America (MGFA) Clinical Classification, MGFA postintervention score (MGFA PIS) and MG Composite scores were obtained to define the severity of disease and clinical outcome. In 95 patients with generalized non-thymomatous LOMG, 60 (63%) were men, 45 (47%) had mild disease, 80 (84%) were anti-AChR, and 56 (61%) were anti-titin positive. In those who received immunosuppressives and provided the clinical scores (84 patients), 50 (60%) had favorable outcome (MGFA PIS categories of complete stable remission, pharmacological remission and minimal manifestations) at the end of 3 years. Use of prednisone + azathioprine had significantly positive effect on outcome. The presence of anti-titin antibodies had no significant effect on severity and outcome. Five anti-MuSK-positive patients had favorable outcome. In conclusion, the presence of neither anti-titin nor anti-MuSK antibodies points to unfavorable outcome. Prednisone and azathioprine combination has beneficial effects in non-thymomatous generalized LOMG.

Prompt Response to Prednisone Predicts Benign Course in MuSK-MG.

BACKGROUND: The difficult course of patients with myasthenia gravis (MG) with anti-muscle-specific tyrosine kinase antibodies (MuSK) has been emphasized. However, no clear information is available on patients who have a benign course. METHODS: This study was aimed at comparing patients with favorable (minimal manifestations [MM] or better) and unfavorable outcomes to determine whether excellent response to corticosteroid (CS) treatment within 3 months (good response-3 months) has any predictive effect on the prognosis. RESULTS: Forty-six percent of 46 patients had a favorable outcome at year 3 and 54% at final follow-up. The major finding of this study was its high predictive value with good response-3 months. Those with good response-3 months had significantly more favorable outcome as compared to those without at year 3. The positive predictive value of good response-3 months was high (89% at year 3 and 84% at final follow-up). The negative predictive value diminished from 85% at year 3 to 67% at final follow-up due to increasing number of patients improving in the long run. Overall, 33% of the patients had a benign course with good response-3 months and no major exacerbations until the end of follow-up. CONCLUSIONS: Excellent response to CSs within 3 months appears to predict a favorable outcome in MuSK-MG.

Muscle magnetic resonance imaging in spinal muscular atrophy type 3: Selective and progressive involvement.

INTRODUCTION: In this study we sought to identify magnetic resonance imaging (MRI) signs of selective muscle involvement and disease progression in patients with spinal muscular atrophy type 3b (SMA3b). METHODS: Twenty-five patients with genetically confirmed SMA3b underwent MRI on a 1.5-Tesla MR scanner. RESULTS: MRI showed significantly more severe involvement of the iliopsoas than of the gluteus maximus muscles, and more severe involvement of the triceps brachii than of the biceps brachii muscles. The quadriceps femoris muscles were severely involved. The deltoid, adductor longus, portions of the hamstrings, gracilis, sartorius, and rectus abdominis muscles were well preserved. We found a significant positive correlation between MRI changes and disease duration for gluteus maximus and triceps brachii. Follow-up MRIs of 4 patients showed disease progression. CONCLUSIONS: This study confirms the pattern of selective muscle involvement suggested by previous studies and further refines muscle MRI changes in SMA3b. Progressive muscle involvement is implicated. Muscle Nerve 55: 651-656, 2017.

Genetic heterogeneity within the HLA region in three distinct clinical subgroups of myasthenia gravis.

This study aims to investigate genetic susceptibility to early-onset and late-onset anti-acetylcholine receptor antibody positive myasthenia gravis (EOMG and LOMG) and anti-muscle specific kinase antibody positive MG (MuSK-MG) at genome-wide level in a single population. Using a custom-designed array and imputing additional variants and the classical HLA alleles in 398 patients, we detected distinct associations. In EOMG, rs113519545 in the HLA class I region (OR=5.71 [3.77-8.66], P=2.24×10(-16)), HLA-B*08:01 (OR=7.04 [3.95-12.52], P=3.34×10(-11)) and HLA-C*07:01 (OR=2.74 [1.97-3.81], P=2.07(-9)), in LOMG, rs111256513 in the HLA class II region (OR=2.22 [1.59-3.09], P=2.48×10(-6)) and in MuSK-MG, an intronic variant within HLA-DQB1 (rs68081734, OR=5.86, P=2.25×10(-14)) and HLA-DQB1*05:02 (OR=8.56, P=6.88×10(-13)) revealed the most significant associations for genome-wide significance. Differential genetic susceptibility within the HLA to EOMG, LOMG and MuSK-MG has been established in a population from Turkey.

Regulatory function of CD4+CD25++ T cells in patients with myasthenia gravis is associated with phenotypic changes and STAT5 signaling: 1,25-Dihydroxyvitamin D3 modulates the suppressor activity.

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.

Differential Cytokine Changes in Patients with Myasthenia Gravis with Antibodies against AChR and MuSK.

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.

The association of PTPN22 R620W polymorphism is stronger with late-onset AChR-myasthenia gravis in Turkey.

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.

Association of HLA-DRB1∗14, -DRB1∗16 and -DQB1∗05 with MuSK-myasthenia gravis in patients from Turkey.

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.