Trends in endogenous insulin secretion capacity and anti-islet autoantibody titers in two childhood-onset slowly progressive insulin-dependent diabetes mellitus cases.

Slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) is a subtype of type 1 diabetes. Although SPIDDM is not rare among Japanese children, there are few reports on endogenous insulin secretory capacity and anti-pancreatic islet autoantibodies in pediatric SPIDDM. We followed the trends in endogenous insulin secretory capacity and anti-pancreatic islet autoantibody titers in two pediatric SPIDDM cases over several years. Case 1 developed insulin deficiency eight months after diabetes diagnosis; as her insulinoma-associated antibody test result was positive, insulin therapy was initiated. Fourteen months after the diagnosis, she tested positive for glutamic acid decarboxylase autoantibodies (GADA) and was diagnosed with SPIDDM. Case 2 was mildly positive for GADA at the onset of diabetes, but became a high titer during the course of the disease. Fourteen months after the diagnosis of diabetes, he became mildly insulin deficient, and insulin therapy was initiated. However, his insulin secretory capacity was preserved for 60 mo after the onset. SPIDDM is generally indistinguishable from type 2 diabetes at diagnosis; therefore, repeated evaluation of the insulin secretory capacity and anti-islet autoantibodies facilitates early diagnosis and appropriate treatment, especially in nonobese children with type 2 diabetes.

Stiff Person Syndrome and Brittle Type 1 Diabetes: Report of 2 Cases.

Background/Objective: Stiff person syndrome (SPS) and type 1 diabetes (T1D) are heterogeneous disorders characterized by antibodies (Abs) against glutamic acid decarboxylase (GAD). Case Report: We describe 2 patients with T1D and autoimmune thyroid disease who presented with muscle rigidity and intermittent spasms that affected gait and with elevated circulating anti-GAD titers. Classic SPS and stiff limb syndrome were diagnosed, respectively. Muscle spasms resolved with immunotherapy and muscle relaxants in both patients, and the ability to ambulate without an assistive device was restored in 1 patient. Patients also had brittle diabetes with high glycemic variability, requiring the use of flash glucose monitoring with an insulin pump and a second-generation basal insulin analog, respectively. Discussion: GAD Ab-associated syndromes include SPS, T1D, and other endocrinopathies. The clinical heterogeneity implies variable susceptibility of γ-aminobutyric acid-ergic neurons and pancreatic beta cells to anti-GAD or other autoantibodies. Conclusion: Our case series represent the heterogeneity in natural history, clinical course, and response to therapy in patients with Abs against GAD-spectrum disorders.

Improved fermentative gamma-aminobutyric acid production from glucose by the inactivation of respiratory chain components NDH-I and Cytbo3 in Escherichia coli.

Gamma-aminobutyric acid (GABA), which is synthesized from l-glutamic acid via glutamate decarboxylase (Gad), is used as food, supplements, and biodegradable plastics. Our previous study demonstrated an Escherichia coli mutant (ΔΔ) strain, lacking type I NADH dehydrogenase (NDH-I) and cytochrome bo3 oxidase (Cytbo3), produced 7 g/L glutamic acid on MS1 glucose-minimal medium. In this study, the ΔΔ strain was used for improving GABA production. A plasmid (pMBL19-gadB') expressing a mutated E. coli GadB (Glu89Gln/Δ452-466), retaining activity at neutral pH, was introduced into the ΔΔ strain and its parent strain (W1485). The ΔΔ strain carrying pMBL19-gadB' exhibited a twofold increase in GABA production compared to the W1485 strain carrying pMBL19-gadB'. Deleting the C-terminal (Δ471-511) of GadC antiporter in the ΔΔ strain further improved GABA yield by 1.5 g/L when cultured in MS1 glucose-minimal medium. On the other hand, a large amount of glutamic acid produced by the ΔΔ strain was not fully converted to GABA, likely due to the inhibition of GadB activity by the accumulation of acetic acid. Although there is room for improvement, these results indicate the efficacy of the ΔNDH-IΔCytbo3 double mutation in augmenting GABA production.

A Case of Type 2 Diabetes Mellitus Revealed Transient Positivity of Glutamic Acid Decarboxylase (GAD) Antibodies Following Immunoglobulin Administrations.

Glutamic acid decarboxylase (GAD) antibodies are frequently measured in diabetes care as islet-associated autoantibodies that are useful in the diagnosis of type 1 diabetes. However, GAD antibodies derived from other persons may contaminate immunoglobulin preparations, and there have been cases of transiently positive GAD antibodies after intravenous immunoglobulin (IVIg) in patients who were originally negative for GAD antibodies. Clinicians may be unaware of such contamination and misdiagnose some cases as type 1 instead of type 2 diabetes mellitus based on positivity for GAD antibodies. Herein, we present a case of type 2 diabetes mellitus that revealed transiently positive GAD antibodies following immunoglobulin administrations. A 68-year-old woman with a medical history of diabetes mellitus was admitted to our hospital for the treatment of Guillain-Barré syndrome, and IVIg was started on the day of admission. Blood tests on admission revealed negative for GAD antibodies but showed weak positivity on day one after IVIg. Afterward, GAD antibodies turned negative on day 72. Immunoglobulin preparations were revealed to have a high concentration of GAD antibodies. Based on changes in GAD antibody titers and all negativity for anti-insulinoma-associated antigen-2 (IA-2), insulin, and zinc transporter 8 (ZnT8) antibodies, the patient was diagnosed with type 2 diabetes mellitus rather than slowly progressive type 1 diabetes mellitus (SPIDDM). This case demonstrates that it is important for the medical clinician to be aware of the possible presence of GAD antibodies in immunoglobulin preparations and to measure antibody titers before and after their use for diagnosing the type of diabetes mellitus.

IT-DEX and B cell depletion in a child with anti-GAD 65 autoimmune encephalitis presenting as NORSE: A case report.

New-onset refractory status epilepticus (NORSE) is a devastating clinical condition that often leads to severe disability. Intrathecal dexamethasone (IT-DEX) has been reported to improve refractory status epilepticus. We present an 11-year-old female with anti-GAD 65 encephalitis presenting as NORSE who had minimal response to standard anti-seizure medications and first-line immunotherapies. The patient received 6 doses of IT-DEX in conjunction with rituximab which correlated with subsequent decreased neuroinflammation, reduced seizure burden and aided in weaning anesthetic infusions. Our case with literature review suggests IT-DEX may be utilized as an early intervention in those with refractory status epilepticus from various etiologies.

New onset diabetic ketoacidosis in a renal transplant recipient.

Post-transplant diabetes mellitus (PTDM) is a well-known solid organ transplant complication, which can be related to immunosuppressants, particularly tacrolimus. We report an unusual presentation of PTDM with diabetic ketoacidosis (DKA). This is unique as PTDM typically resembles Type 2 DM, whereas DKA is associated with Type 1 DM and has rarely been reported as a complication of tacrolimus. A 38-year-old African American male on LCP-tacrolimus presented four months post kidney transplant with vomiting, weakness, poor appetite, and polyuria. Labs demonstrated hyperglycemia, ketonuria, and high anion gap metabolic acidosis. He was nonobese and had no personal or family history of Type 2 DM. DKA was suspected to be secondary to tacrolimus-induced pancreatic beta cell damage worsened by supratherapeutic tacrolimus levels. Latent autoimmune diabetes in adults (LADA) was diagnosed when further testing showed insulinopenia, low C-peptide, and anti-glutamic acid decarboxylase (GAD) autoantibodies. He required 120-units of subcutaneous insulin daily. Our literature review revealed only 16 other tacrolimus-induced DKA cases. No cases reported anti-GAD positivity and most showed beta cell toxicity reversibility with tacrolimus tapering or substitution. Our patient was early post-transplant with leukocytopenia, so tacrolimus was not exchanged. This unusual PTDM case may have resulted from both autoimmune and tacrolimus-induced beta cell destruction. Physicians should be aware of new onset LADA post-transplantation and tacrolimus toxicity leading to DKA, even in patients without traditional risk factors. Anti-GAD antibody screening in patients on tacrolimus who develop PTDM may identify patients less likely to recover beta cell function with immunosuppression augmentation which requires careful monitoring.

High glutamic acid decarboxylase antibody titers may be associated with a decline in ß-cell function over time and future insulin deficiency in latent autoimmune diabetes in adults.

AIMS: Latent autoimmune diabetes in adults (LADA) is characterized by positive islet-associated autoantibodies including glutamic acid decarboxylase antibody (GADA), and gradual decline in insulin secretion, progressing to insulin dependency. This cross-sectional study aimed to determine whether GADA by enzyme-linked immunosorbent assay (GADA-ELISA) titer of ≥180 U/mL could be associated with decline in ß-cell function in participants with LADA. METHODS: Sixty-three participants with LADA were recruited and an association between insulin secretion capacity and disease duration was investigated. Insulin peptide-specific inflammatory immunoreactivity was investigated to determine the disease's activity. RESULTS: There was a significant inverse correlation between disease duration and C-peptide index in participants with GADA-ELISA titer of ≥180 U/mL (Spearman's r (rs) = -0.516, p < 0.01). The positivity rate of insulin peptide-specific inflammatory immunoreactivity was significantly higher in those with ≥180 U/mL than in those with <180 U/mL (p < 0.05). In participants with human leukocyte antigen (HLA)-DRB1*04:05, a significant inverse correlation was observed between disease duration and C-peptide index in those with ≥180 U/mL (rs = -0.751, p < 0.01). CONCLUSIONS: GADA-ELISA titer of ≥180 U/mL, especially with HLA-DRB1*04:05, might reflect higher disease activity and may be associated with decline in ß-cell function over time and future insulin dependency in LADA.

Posttraumatic epilepsy: Integrating clinical, inflammatory, and genetic profiles in traumatic brain injury patients.

OBJECTIVE: This study aims to assess the clinical, inflammatory, and genetic profiles of traumatic brain injury (TBI) patients over a 2-year follow-up period, focusing on the development of posttraumatic epilepsy (PTE). METHODS: Fifty-nine patients with acute TBI were recruited in the emergency unit of a hospital in Brazil. Clinical data and blood samples were collected after 10 days of hospitalization for posterior genetic profile (Apolipoprotein E- ApoE and Glutamic Acid Descarboxylase-GAD sequencing) analyses. A subset of 19 patients were assessed for cytokine markers (mRNA expression). The development of PTE was investigated for two years following TBI. Statistical analyses including univariate analysis, multiple correspondence analysis, and Mann-Whitney test were performed. RESULTS: Analysis revealed an association between severe TBI and requirement for neurosurgery and polytrauma (p<0.05), as well as the development of PTE over a two-year follow-up period (p<0.05). Multiple correspondence analysis identified two distinct profiles associated with PTE and Non-PTE outcomes. The PTE profile showed a higher prevalence of the ApoE genotype E3/E3 and GAD1 SNP (rs769391) genotype AA in our study, while the Non-PTE profile showed a higher presence of E3/E4. mRNA expression analysis demonstrated acute elevated levels of TNF-α in the PTE group as compared to Non-PTE patients (6.70±1.53 vs 5.31 ±0.33, p<0.01). SIGNIFICANCE: Our findings underscore the multifactorial nature of aspects potentially contributing to PTE. It is unlikely that any single factor might in isolation have a strong causative influence over the development of epilepsy after TBI. Our results provide a suggestion of potential clustering that might be relevant as prognostic factors for PTE.

Case report: Strong GAD antibody positivity and type 1 diabetes-HLA-susceptible haplotype-DRB1*04:05-DQB1*04:01 in a Japanese patient with immune checkpoint inhibitor-induced type 1 diabetes.

Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment; however, they can lead to immune-related adverse events, including immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM). While fulminant T1DM is common in East Asia, ICI-T1DM has predominantly been reported in Western countries. In this report, we present the case of a 66-year-old Japanese man with type 2 diabetes mellitus undergoing dialysis for diabetic nephropathy. The patient was diagnosed with left upper lobe lung cancer, and treatment with nivolumab and ipilimumab was initiated. After 48 days, the patient experienced impaired consciousness and difficulty moving. His blood glucose levels were 815 mg/dL, and metabolic acidosis was detected, leading to a diagnosis of diabetic ketoacidosis. The patient was subsequently treated with continuous intravenous insulin. However, his C-peptide levels rapidly depleted, and new-onset ICI-T1DM was diagnosed. Although most Japanese patients with ICI-T1DM test negative for glutamic acid decarboxylase (GAD) antibodies, this case exhibited a strong positivity. Thus, we reviewed the literature on 15 similar Japanese cases, revealing a mean HbA1c level at onset of 8.7% and a mean time from ICI administration to onset of 9.7 weeks, which was shorter than that in GAD-negative cases. Moreover, human leukocyte antigen typing revealed five cases of DRB1*04:05-DQB1*04:01, including the present case, and one case of DRB1*09:01-DQB1*03:03, both of which were susceptible to T1DM haplotypes. These findings suggest that GAD antibody positivity may be associated with acute onset and disease progression in some cases of Japanese patients with ICI-T1DM. Given that the prediction of new-onset ICI-T1DM is challenging, monitoring GAD antibody levels might be useful. However, further studies with large sample sizes and validation across different racial and ethnic populations are warranted.

From lab bench to hope: a review of gene therapies in clinical trials for Parkinson's disease and challenges.

Parkinson's disease (PD) is a chronic neurological disorder that is identified by a characteristic combination of symptoms such as bradykinesia, resting tremor, rigidity, and postural instability. It is the second most common neurodegenerative disease after Alzheimer's disease and is characterized by the progressive loss of dopamine-producing neurons in the brain. Currently, available treatments for PD are symptomatic and do not prevent the disease pathology. There is growing interest in developing disease-modifying therapy that can reduce disease progression and improve patients' quality of life. One of the promising therapeutic approaches under evaluation is gene therapy utilizing a viral vector, adeno-associated virus (AAV), to deliver transgene of interest into the central nervous system (CNS). Preclinical studies in small animals and nonhuman primates model of PD have shown promising results utilizing the gene therapy that express glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF), aromatic L-amino acid decarboxylase (AADC), and glutamic acid decarboxylase (GAD). This study provides a comprehensive review of the current state of the above-mentioned gene therapies in various phases of clinical trials for PD treatment. We have highlighted the rationale for the gene-therapy approach and the findings from the preclinical and nonhuman primates studies, evaluating the therapeutic effect, dose safety, and tolerability. The challenges associated with gene therapy for heterogeneous neurodegenerative diseases, such as PD, have also been described. In conclusion, the review identifies the ongoing promising gene therapy approaches in clinical trials and provides hope for patients with PD.

Prediction of future insulin-deficiency in glutamic acid decarboxylase autoantibody enzyme-linked immunosorbent assay-positive patients with slowly-progressive type 1 diabetes.

AIMS/INTRODUCTION: This study aimed to identify risk factors that contribute to the progression of slowly-progressive type 1 diabetes by evaluating the positive predictive value (PPV) of factors associated with the progression to an insulin-dependent state. MATERIALS AND METHODS: We selected 60 slowly-progressive type 1 diabetes patients who tested positive for glutamic acid decarboxylase autoantibodies (GADA) at diagnosis from the Japanese Type 1 Diabetes Database Study. GADA levels in these patients were concurrently measured using both radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: Compared with the non-progressor group (fasting C-peptide [F-CPR] levels maintained ≥0.6 ng/mL), the progressor group showed a younger age at diagnosis, lower body mass index (BMI), lower F-CPR levels and a higher prevalence of insulinoma-associated antigen-2 autoantibodies (IA-2A). The PPV of RIA-GADA increased from 56.3 to 70.0% in the high titer group (≥10 U/mL), and further increased to 76.9, 84.2, 81.0 and 75.0% when combined with specific thresholds for age at diagnosis <47 years, BMI <22.6 kg/m2, F-CPR <1.41 ng/mL and IA-2A positivity, respectively. In contrast, the PPV of ELISA-GADA (71.8%) remained the same at 73.1% in the high titer group (≥180 U/mL), but increased to 81.8, 82.4 and 79.0% when evaluated in conjunction with age at diagnosis, BMI and F-CPR level, respectively. CONCLUSIONS: Our findings show that, unlike RIA-GADA, ELISA-GADA shows no association between GADA titers and the risk of progression to an insulin-dependent state. The PPV improves when age at diagnosis, BMI and F-CPR levels are considered in combination.

Distribution of gamma-aminobutyric acid immunoreactivity in the brain of the Siberian sturgeon (Acipenser baeri): Comparison with other fishes.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system (CNS) of vertebrates. Immunohistochemical techniques with specific antibodies against GABA or against its synthesizing enzyme, glutamic acid decarboxylase (GAD) allowed characterizing GABAergic neurons and fibers in the CNS. However, studies on the CNS distribution of GABAergic neurons and fibers of bony fishes are scant and were done in teleost species. With the aim of understanding the early evolution of this system in bony vertebrates, we analyzed the distribution of GABA-immunoreactive (-ir) and GAD-ir neurons and fibers in the CNS of a basal ray-finned fish, the Siberian sturgeon (Chondrostei, Acipenseriformes), using immunohistochemical techniques. Our results revealed the presence and distribution of GABA/GAD-ir cells in different regions of the CNS such as olfactory bulbs, pallium and subpallium, hypothalamus, thalamus, pretectum, optic tectum, tegmentum, cerebellum, central grey, octavolateralis area, vagal lobe, rhombencephalic reticular areas, and the spinal cord. Abundant GABAergic innervation was observed in most brain regions, and GABAergic fibers were very abundant in the hypothalamic floor along the hypothalamo-hypophyseal tract and neurohypophysis. In addition, GABA-ir cerebrospinal fluid-contacting cells were observed in the alar and basal hypothalamus, saccus vasculosus, and spinal cord central canal. The distribution of GABAergic systems in the sturgeon brain shows numerous similarities to that observed in lampreys, but also to those of teleosts and tetrapods.

Co-existence of anti-glutamic acid decarboxylase-65 and anti-sry-like high-mobility group box receptor antibody-associated autoimmune encephalitis: A rare case report.

Autoimmune encephalitis (AE) has been increasingly recognized in children. An 11-year-old Saudi boy presented with prodromal symptoms of fever and headache followed by behavioral changes, cognitive impairment, and focal seizures. Cerebrospinal fluid (CSF) analysis showed pleocytosis. Brain magnetic resonance imaging showed T2/fluid-attenuated inversion recovery hyperintensities involving the temporal, parietal and frontal lobes. Electroencephalography revealed diffuse encephalopathy and electrographic seizures. AE was suspected; intravenous methylprednisolone and immunoglobulin were administered. Autoantibodies against glutamic acid decarboxylase-65 were detected in his serum and CSF and against Sry-like high- mobility group box 1 in his serum only. The patient was diagnosed with seropositive AE and favorably responded to intensive immunosuppressive therapy.

Latent Autoimmune Diabetes in Adults: A Case Report.

Latent autoimmune diabetes in adults (LADA) is a slow progressive autoimmune destruction of pancreatic beta cells. This condition tends to manifest during adulthood, often around 35 years of age. While LADA can initially be managed by oral medications, eventually the patient will require insulin. We report a case of a 34-year-old woman who was initially treated for type 2 diabetes mellitus but was later diagnosed with LADA.

Developmental exposure to methylmercury alters GAD67 immunoreactivity and morphology of endothelial cells and capillaries of midbrain and hindbrain regions of adult rat offspring.

INTRODUCTION: Methylmercury (MeHg) is an environmental contaminant that is of particular concern in Northern Arctic Canadian populations. Specifically, organic mercury compounds such as MeHg are potent toxicants that affect multiple bodily systems including the nervous system. Developmental exposure to MeHg is a major concern, as the developing fetus and neonate are thought to be especially vulnerable to the toxic effects of MeHg. The objective of this study was to examine developmental exposure to low doses of MeHg and effects upon the adult central nervous system (CNS). The doses of MeHg chosen were scaled to be proportional to the concentrations of MeHg that have been reported in human maternal blood samples in Northern Arctic Canadian populations. METHOD: Offspring were exposed to MeHg maternally where pregnant Sprague Dawley rats were fed cookies that contained MeHg or vehicle (vehicle corn oil; MeHg 0.02 mg/kg/body weight or 2.0 mg/kg/body weight) daily, throughout gestation (21 days) and lactation (21 days). Offspring were not exposed to MeHg after the lactation period and were euthanized on postnatal day 450. Brains were extracted, fixed, frozen, and sectioned for immunohistochemical analysis. A battery of markers of brain structure and function were selected including neuronal GABAergic enzymatic marker glutamic acid decarboxylase-67 (GAD67), apoptotic/necrotic marker cleaved caspase-3 (CC3), catecholamine marker tyrosine hydroxylase (TH), immune inflammatory marker microglia (Cd11b), endothelial cell marker rat endothelial cell antigen-1 (RECA-1), doublecortin (DCX), Bergmann glia (glial fibrillary acidic protein (GFAP)), and general nucleic acid and cellular stains Hoechst, and cresyl violet, respectively. Oxidative stress marker lipofuscin (autofluorescence) was also assessed. Both male and female offspring were included in analysis. Two-way analysis of variance (ANOVA) was utilized where sex and treatment were considered as between-subject factors (p* <0.05). ImageJ was used to assess immunohistochemical results. RESULTS: In comparison with controls, adult rat offspring exposed to both doses of MeHg were observed to have (1) increased GAD67 in the cerebellum; (2) decreased lipofuscin in the locus coeruleus; and (3) decreased GAD67 in the anterior CA1 region. Furthermore, in the substantia nigra and periaqueductal gray, adult male offspring consistently had a larger endothelial cell and capillary perimeter in comparison to females. The maternal high dose of MeHg influenced RECA-1 immunoreactivity in both the substantia nigra and periaqueductal gray of adult rat offspring, where the latter neuronal region also showed statistically significant decreases in RECA-1 immunoreactivity at the maternal low dose exposure level. Lastly, males exposed to high doses of MeHg during development exhibited a statistically significant increase in the perimeter of endothelial cells and capillaries (RECA-1) in the cerebellum, in comparison to male controls. CONCLUSION: Findings suggest that in utero and early postnatal exposure to MeHg at environmentally relevant doses leads to long-lasting and selective changes in the CNS. Exposure to MeHg at low doses may affect GABAergic homeostasis and vascular integrity of the CNS. Such changes may contribute to neurological disturbances in learning, cognition, and memory that have been reported in epidemiological studies.

The Prognosis of Glutamic Acid Decarboxylase Antibodies in Women With Hyperglycemia in Pregnancy.

CONTEXT: We recently reported that the presence of glutamic acid decarboxylase antibodies (GADA) was not associated with large-for-gestational-age infants in women with hyperglycemia in pregnancy (HIP). OBJECTIVE: We explored the association between the presence of GADA and other HIP-related adverse pregnancy outcomes. METHODS: This observational prospective study, conducted at a university hospital in a suburb of Paris, France, included 1182 consecutive women with HIP measured for GADA at HIP care initiation between 2012 and 2017. Post hoc analyses for outcomes included gestational weight gain, insulin therapy, cesarean delivery, hypertensive disorders, small-for-gestational-age infant, prematurity, and neonatal hypoglycemia. RESULTS: Of the 1182 women studied, 87 (7.4%) had positive (≥ 1 IU/mL) GADA. Although socioeconomic, clinical, and biological characteristics were similar across women in the positive and negative GADA groups, higher fasting plasma glucose values during early HIP screening were observed in the former (5.5 ± 1.5 vs 5.2 ± 0.7 mmol/L respectively, P < .001). At HIP care initiation, fructosamine levels were higher in women with positive GADA (208 ± 23 vs 200 ± 18 µmol/L; P < .05). In the homeostatic model assessment, insulin resistance (HOMA-IR) and beta secretion (HOMA-B) rates were similar in both groups. Gestational weight gain and the rates of all adverse outcomes were similar in both groups except for cesarean delivery (18.4 and 27.3% for positive and negative GADA, respectively; adjusted odds ratio 0.49 [95% CI, 0.26-0.92], P = .026). CONCLUSION: Universal measurement of GADA in women with HIP highlighted that 7.4% had positive GADA. No association was observed between GADA and HIP-related adverse pregnancy outcomes, except a lower risk of cesarean delivery.

Efgartigimod beyond myasthenia gravis: the role of FcRn-targeting therapies in stiff-person syndrome.

Stiff-person syndrome (SPS) is a rare autoimmune neurological disorder characterized by high titers of antibodies against glutamic acid decarboxylase (GAD) causing impaired GABAergic inhibitory neurotransmission. To date, there is not a defined therapy for such condition, but immunomodulating therapies, such as plasma exchange, intravenous immunoglobulins, and rituximab, have been widely used in clinical practice. However, the efficacy and tolerability of these treatments is not well established. Efgartigimod, a new neonatal Fc receptor (FcRn) blocker, is a human IgG1 antibody Fc fragment engineered with increased affinity for FcRn binding, leading to a reduction in IgGs levels, including pathogenic IgG autoantibody showing promising results in neurological autoimmune disorders and has been approved for the treatment of AChR-seropositive generalized myasthenia gravis (MG). In this study, we report and describe the first data on treatment with efgartigimod in three patients affected by both AChR-seropositive generalized MG and anti-GAD-seropositive SPS. Patients were followed since the start of efgartigimod and for the whole treatment period (12 weeks). MG symptoms were assessed with the "MG activity of daily living score" and the Quantitative Myasthenia Gravis score, while SPS ones were assessed with the "SPS activity of daily living score"; muscle strength was assessed with the Medical Research Council Sum score; the overall disability from MG and SPS was assessed by the modified Rankin Scale. All patients showed an improvement in symptoms of both SPS and MG after 2 cycles of treatment. Our data suggest that efgartigimod may be considered as a candidate drug for SPS and other autoantibody-mediated neurological disorders.

Imeglimin Improved Plasma Glucose Levels in Patients With Latent Autoimmune Diabetes of Adults: Report of 2 Cases.

Imeglimin has not been well studied as an oral agent for the treatment of latent autoimmune diabetes of adults (LADA). We treated 2 cases of LADA with imeglimin. The case 1 patient was originally diagnosed with type 2 diabetes (T2D) at age 50 years and was treated with sulfonylurea, biguanide, canagliflozin, imeglimin, and dulaglutide. Before imeglimin, his glycated hemoglobin A1c (HbA1c) change was 94.0 mmol/mol (8.6%) in November 2022, but it dropped to 71.0 mmol/mol (6.5%) in May 2023 after imeglimin was added. The case 2 patient was originally diagnosed with T2D when she was aged 48 years. She was treated with vildagliptin, biguanide, luseogliflozin, and imeglimin. Her HbA1c before imeglimin was 92.9 mmol/mol (8.5%) in January 2023, which decreased to 75.4 mmol/mol (6.9%) in July 2023 after imeglimin was added. Although imeglimin has not been approved for treating type 1 diabetes and LADA, adding imeglimin to the current medication was effective in improving and controlling the patients' plasma glucose.