GAD65 Research Articles

9185 Pembrolizumab-Induced New-Onset Type 1 Diabetes Mellitus: A Case Report

Abstract Disclosure: D. Teng: None. T.L. Connelly: None. M. Ahmad: None. R. Saeed: None. Introduction: Immune checkpoint inhibitors are becoming essential in the treatment of various cancers. Pembrolizumab is a monoclonal antibody that binds PD-1 receptors, thereby enabling an anti-tumor response by preventing T-cell suppression. Common side effects associated with pembrolizumab include thyroid disorders, hepatitis, pneumonitis, and acute kidney injury, among others. We describe an interesting case of a woman presenting with diabetic ketoacidosis (DKA) in the setting of pembrolizumab-associated new-onset type 1 diabetes mellitus, which was reported at 0.1% during initial clinical trials but is now being increasingly recognized as a complication of immune checkpoint therapy. Case Description: The patient is a 70-year-old female with past medical history notable for stage IIIA vulvar squamous cell carcinoma initially diagnosed and treated in 2017, with recurrence in 2022 and in 2023, at which point pembrolizumab therapy was initiated. Approximately one month after her first dose, the patient presented to the emergency department with palpitations, nausea, non-bloody vomiting, polydipsia, and non-bloody diarrhea. On arrival, the patient’s vital signs were as follows: 97.2 °F, BP 128/74 mmHg, heart rate 80 bpm, respiratory rate 18 per minute, and SpO2 100% on room air. No acute findings were noted on physical exam. Initial blood work was notable for: pH 7.146, lactate 2.4 mmol/L, bicarbonate 8 mmol/L, anion gap 37 mmol/L, creatinine 1.59 mg/dL, glucose 563 mg/dL, C-peptide 0.16 ng/mL, HbA1c 6.9%, and WBC 18.8 B/L with neutrophilic predominance. Urinalysis was notable for 4+ glucose and 4+ ketones. The patient was admitted to the progressive care unit and DKA protocol was initiated including the administration of IV fluids, insulin infusion, and electrolyte replacement. Additional blood work was unrevealing, including insulin autoantibodies <0.4 U/mL, negative islet cell IgG cytoplasmic autoantibodies, and negative anti-GAD65 antibodies. The patient was eventually discharged with outpatient Endocrinology follow-up. Discussion: Immunotherapy is quickly redefining the standard of care in the treatment of several types of malignancies through the leveraging of the body’s immune defense apparatus. Pembrolizumab prevents the deactivation of T-cells via the PD-1/PD-L1 pathway. Unfortunately, this also predisposes non-cancerous cells to autoimmune destruction by these T-cells. It is proposed that such is the mechanism by which pancreatic beta islet cells are destroyed in the setting of pembrolizumab use, thereby resulting in a rapid reduction in insulin production capability. New-onset type 1 diabetes complicated by DKA is potentially life-threatening, and so we believe this case highlights the need for both pre-treatment counseling as well as follow-up screening following initiation of pembrolizumab therapy. Presentation: 6/2/2024

Spectrum of neurological manifestations, existence of diabetes mellitus, and 5-year mortality and cancer association outcomes in a cohort of Omani patients with positive anti- GAD autoimmunity

ABSTRACT Objectives There is scarce data in the literature concerning the anti-GAD65 antibodies (GAD-Abs) autoimmunity in the Omani population. Methods Retrospective cohort study included GAD-Abs positive patients (n = 444) presented to a tertiary referral center in Oman from January 2005 until January 2018, with a five-year follow-up to study the cancer association and mortality outcomes. Results Out of 444 patients, 27 patients (6.1%) showed GAD-Abs related neurological disorders. Adult age group was significantly associated with more GAD-Abs related neurological manifestations compared to pediatric and adolescents age group (p = 0.045). There was no association between the presence or absence of neurological manifestations with diabetes mellitus nor the titer level of GAD-Abs. Refractory status epilepticus and stiff person syndrome were the main causes of death in patients with neurological manifestations over five years and none of them found to have associated cancer. Conclusion The GAD-Abs autoimmunity represents a spectrum of neurological manifestations with variable severity and outcome among Omanis with positive GAD-Abs testing. The results of this study will serve as a platform for future studies to address the impact of GAD-Abs autoimmunity on the morbidity, mortality and treatment efficacy in the Omani population.

Autoantibodies against beta cells to predict early insulin requirements in pediatric patients with clinically diagnosed type 2 diabetes.

Autoimmunity has emerged as a probable disease modifier in patients with clinically diagnosed type 2 diabetes mellitus (T2DM), that is, patients who have insulin resistance, obesity, and other cardiovascular risk factors, suggesting that the presence of glutamic acid decarboxylase (anti-GAD65), islet antigen 2 (anti-IA2), and zinc transporter 8 (anti-Zn8T) antibodies could have deleterious effects on beta cell function, causing failure and earlier requirement for insulin treatment. To evaluate anti-GAD65, anti-IA2 and anti-Zn8T as predictors of early insulin requirement in adolescents with a clinical diagnosis of T2DM. This was a case-control study in patients with clinically diagnosed with T2DM (68 cases and 64 controls with and without early insulin dependence respectively), male and female, aged 12-18 years. Somatometry, blood pressure, glucose, insulin, C-peptide, glycated hemoglobin A1c, and lipid profiles were assessed. ELISA was used to measure anti-GAD65, anti-IA2, and anti-Zn8T antibodies. Descriptive statistics, Pearson's χ 2 test, Student's t test, and logistic regression was performed. P < 0.05 was considered statistically significant. There were 132 patients (53.8% female), with a mean age was 15.9 ± 1.3 years, and there was a disease evolution time of 4.49 ± 0.88 years. The presence of anti-GAD65, anti-IA2, and anti-Zn8T positivity was found in 29.5%, 18.2%, and 15.9%, respectively. Dividing the groups by early or no insulin dependence showed that the group with insulin had a higher frequency of antibody positivity: anti-GAD65 odds ratio (OR): 2.42 (1.112-5.303, P = 0.026); anti-IA2: OR: 1.55 (0.859-2.818, P = 0.105); and anti-Zn8T: OR: 7.32 (2.039-26.279, P = 0.002). Anti-GAD65 positivity was high in our study. Anti-GAD65 and anti-Zn8T positivity showed a significantly depleted beta cell reserve phenotype, leading to an increased risk of early insulin dependence.

Pediatric Case of Autoimmune Cerebellitis with Positive Anti-GAD Antibodies and Accidental Finding of Roth Spots

Abstract We present a pediatric case of autoimmune cerebellitis, which was distinguished by the presence of positive anti-glutamic acid decarboxylase (anti-GAD) antibodies. The patient, a young child, presented with a four-day history of progressively worsening headaches, coupled with persistent vomiting. These symptoms prompted immediate medical evaluation. Initial computed tomography (CT) imaging revealed a hypodense area in the left cerebellum and mild hydrocephalus, indicating fluid accumulation in the brain. Subsequent magnetic resonance imaging (MRI) provided more detailed visualization, confirming the diagnosis of acute cerebellitis, which was characterized by bilateral enlargement of the cerebellum and an associated mass effect that exerted pressure on the adjacent brain structures. The medical team initiated a comprehensive treatment regimen that included antibiotics to address any potential bacterial infection, antivirals to counter possible viral etiologies, immunoglobulin therapy to modulate the immune response, and corticosteroids to reduce inflammation. The patient responded well to this treatment protocol, with follow-up imaging showing a significant reduction in cerebellar swelling and overall improvement in clinical symptoms. The detection of elevated anti-GAD antibodies, along with anti-thyroglobulin antibodies, indicated an autoimmune origin of the cerebellitis. This autoimmune response can lead to the body’s immune system mistakenly attacking healthy brain tissue. Moreover, the incidental finding of a Roth spot, a retinal hemorrhage with a white center, during a routine eye examination suggested potential systemic involvement, possibly indicating a broader immune-mediated condition.

Exploring the diverse phenotypes of anti-GAD 65 encephalitis, diagnosis and treatment challenges

Objectives. To present two cases of anti-glutamic acid decarboxylase 65 (anti-GAD65) antibody encephalitis with different clinical phenotypes. Introduction. Anti-glutamic acid decarboxylase 65 antibody encephalitis (GAD-65 AE) is a rare pathology with a high potential for severity, having multiple forms of presentation and multiple differential diagnoses. This presentation aims to exemplify the strong clinical heterogeneity that is associated with this clinical entity by putting forth two cases that were treated in our clinic, each representing a separate clinical phenotype of this pathology. Material and methods. We analyzed two cases from our clinic of autoimmune encephalitis with positive anti-GAD65 antibodies and compared the cases with the data from the literature regarding clinical presentation, differential diagnosis, treatment, and evolution. Content. The first case presented is a woman aged 71 (66 at onset) presenting with progressive cerebellar ataxia. She was diagnosed with GAD-65 AE based on clinical presentation and positive anti-GAD65 antibodies titer. She was initially treated with methylprednisolone pulse therapy and received four such courses in the first year after diagnosis, resulting in a slowing of the progression of the neurological deficit. During the COVID19 pandemic, treatment was paused and her neurological status resumed its decline, and she also developed insulin-dependent diabetes mellitus. Starting in 2021, treatment was continued, having received one course of IVIg and one course of plasma exchange in our clinic. Eventually, the treatment was switched to Mycophenolate mofetil but her status continues to decline. The second case is about a 32 years old woman, with a history of recurrent seizures and progressive memory decline that started at 28 years. She was diagnosed 11 months after the onset with limbic encephalitis with anti-GAD65 antibodies, left temporal focal epilepsy with nocturnal seizures and mild cognitive decline. She was treated with corticotherapy and IgG. She was discharged home with antiepileptic treatment with no recurring seizures, but a slow cognitive decline. She had two relapses at distance from the onset, the first one with status epilepticus and the second one with focal seizures and a generalized seizure. She developed type I diabetes with positive anti-pancreatic islet antibodies. After the first relapse, immunosuppressive therapy with Mycophenolate mofetil was initiated. The evolution was good and under immunosuppression she had only one episode of seizures in the context of a COVID-19 infection. Conclusions. Autoimmune encephalitis with positive GAD antibodies presents a very diverse clinical picture, as we can see in the presented cases.

Characterization of Anti-GAD65-Associated Neurological Syndromes: Clinical Features and Antibody Titers.

Anti-GAD65 antibodies are associated with several neurological phenotypes. Antibody titers are increasingly recognized as useful in diagnosis and prognosis. To describe a Portuguese cohort of patients with anti-GAD65-associated neurological syndromes. Retrospective analysis of all patients with positive anti-GAD65 antibodies and associated neurological syndromes followed in a tertiary referral center. Nineteen anti-GAD65 antibody-positive neurological patients were identified, 62.3% female, with a mean age of onset of 56.0 (SD = 13.3) years. Comorbid autoimmune disorders were present in seven patients. Six patients had limbic encephalitis (31.6%), four had epilepsy (21.1%), four had cerebellar ataxia (21.1%), and three had stiff-person syndrome (15.8%). Two patients presented with isolated cognitive dysfunction (executive and mnesic) in the absence of other neurological symptoms. The mean follow-up time was 24.0 (14.0-42.0) months, at the end of which the mean modified Rankin Scale (mRS) value was 2.0 (1.0-4.0). Screening for malignancies was negative in all patients. Serum quantitative analysis was carried out in 18 patients, 10 of whom showed titers above previously defined cut-off points (>10,000 IU/L for ELISA and >20 mmol/L for RIA). Quantitative CSF analysis was performed in nine patients, with four showing above-threshold titers. There was no association between anti-GAD65 levels and clinical phenotype or the final mRS values. High-dose intravenous methylprednisolone and oral prednisolone were the most common acute and chronic treatment regimens, respectively. Anti-GAD65 antibodies are associated with varied neurological syndromes, and antibody titers alone should not be used to exclude a disease.

Immune checkpoint inhibitors and immune mediated diabetes mellitus: Meta-review of case reports.

e14606 Background: Use of Immune checkpoint inhibitors (ICIs) is an increasingly popular antitumor immunotherapy targeting immunoreceptors on T lymphocytes, enhancing the anti-neoplastic immune response. ICIs are becoming first line therapy options for non-small cell lung cancer and gastric adenocarcinoma and can be used as second line for variety of others. Various endocrinologic adverse events have been reported with use of ICIs. Of these, new onset Type-1 diabetes mellitus (T1DM) is of particular interest given its significant morbidity and noted frequency of 1-5% of patients who receive ICIs. There is limited consolidated information about symptomatic presentations, risk factors, and demographics of patients developing Type 1 DM in relation to ICI use. We performed a systematic review of published case reports to identify commonalities between patient disease presentation, ICI use, and development of immune-mediated diabetes mellitus. Methods: A comprehensive systemic literature search from PubMed Web Science, CINAHL, and Google Scholars was performed identifying case reports showing development of new onset diabetes mellitus in patients using immune checkpoint inhibitors. Descriptive analysis was performed to better identify characteristics and presentation of patients. Results: Based on our parameters, 130 reports with 149 cases were included. Primary tumors among the patients comprised lung cancer (34.9%) and melanoma (31.5%). Amongst all the cases, about 88% of the patients were treated with anti-PD-1 (program cell death) receptor, with nivolumab alone (34.9%) and pembrolizumab alone (26.2%) being the most common agents. Cases were more commonly found to be males (61.7%) and of Asian (36.6%) or North American (35.6%) background. Patient ages ranged from 14-95 with a mean of 62.3. Presentation most commonly started after the third cycle (13.4%) and was noted to occur between 1-50 doses. Diabetic Ketoacidosis was diagnosed in 69.8% of individuals, and the average presenting blood glucose was 611 mg/dl with an HbA1c of 8.2%. Autoantibody data was largely missing; however, anti-GAD antibodies were noted to be present in 29.5% of cases. 34.2% of patients had coexisting endocrinopathies with thyroiditis being the most common, occurring in 20% of patients. 1.3% of patients did not survive the initial hospitalizations, with the vast majority (95.3%) remaining on insulin and a select few (2%) were eventually able to discontinue insulin. Conclusions: New onset diabetes is a rare but a potential life-threatening metabolic urgency. Thus, it is paramount that clinicians maintain close monitor of blood glucose and endocrine function when a cancer patient who recently started ICIs gets admitted for hyperglycemia. Further research is warranted to understand onset of diabetes mellitus at molecular level.

Frequency of C-peptide and antibody levels (anti GAD, Islet cell antibodies, insulin auto antibodies) in children of Pakistan with Type-1 diabetes.

The autoimmune mechanism in T1DM causes gradual loss of pancreatic β-cell, which progresses to hyperglycemia and ultimate reliance on consistent insulin therapy. T1DM has been the commonest type of diabetes in children and this study will help in refining indulgent towards the problem and its pathophysiology in our people. The objective was to find out the prevalence of C-peptide and antibody levels (anti GAD, ICA, IAA and IA2) in children and adolescents of Pakistan with T1DM. We conducted this cross-sectional study at Department of Pediatric Endocrinology, National Institute of Child Health, Karachi between August 2019 to February 2020 and included 98 children who had T1DM for more than one month. Subjects whose GFR was <30ml/min were omitted from the study. Among those registered subjects, C-peptide, human islet cell antibody (ICA), insulin auto antibodies (IAA) and anti-glutamic acid decarboxylase were assessed. Demographical and laboratorial facts were noted on a pre-constructed proforma. There were 77(78.3%) cases who had level of C-peptide <0.8 and anti-GAD was found in 47(48%) subjects. 35(35.7%) cases found positive for IA2 .and 7(7.1%) patients had insulin auto antibodies positive while ICA was negative in total 98(100%) subjects. Children with T1 DM possessed increased levels of anti-GAD antibodies, insulin autoantibodies and anti (IA2) but islet cells antibodies were negligible in our population when checked at a point of time. C-peptide may be normal in some, but its level declines with long duration of diabetes in children.

The significance of precise diabetes diagnosis: a case of euglycemic diabetic ketoacidosis induced by the introduction of empagliflozin with simultaneous reduction of insulin dosage

Euglycemic diabetic ketoacidosis (euDKA) is a rare but severe metabolic complication of diabetes mellitus characterised by elevated anion gap metabolic acidosis despite normal or mildly elevated blood glucose levels. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as effective antidiabetic medications, yet their use is associated with an increased risk of euDKA, especially when coupled with insulin dose reduction. We present the case of a 50-year-old male with a 20-year history of diabetes mellitus, initially managed with insulin and metformin, who developed euDKA following the introduction of empagliflozin and sitagliptin alongside a reduction in insulin therapy. Despite normoglycaemia the patient exhibited symptoms of ketoacidosis, including chronic fatigue, polydipsia, and polyuria. Diagnostic workup revealed metabolic acidosis, elevated inflammatory markers, acute kidney injury and ketonuria. Subsequent specialised laboratory tests confirmed type 1 diabetes mellitus (T1DM) with the presence of anti-glutamic acid decarboxylase (anti-GAD) antibodies and the absence of C-peptide secretion. Management involved fluid therapy, intravenous insulin and glucose administration. This case underscores the diagnostic challenges of euDKA and emphasises the importance of differentiating between T1DM and T2DM, as management strategies vary significantly. Patient education on insulin therapy and injection techniques is crucial to prevent complications such as improper insulin delivery and dose reduction, which can precipitate euDKA. In conclusion, clinicians should be vigilant for euDKA in patients on SGLT2 inhibitors, particularly when insulin dose reduction is involved. Comprehensive patient education and accurate differentiation between diabetes types are essential for timely diagnosis and optimal management, thereby reducing the risk of severe complications.

Antibody-positive autoimmune encephalitis and paraneoplastic neurological syndrome: A Swedish case series.

This study aimed to explore the clinical characteristics and temporal disease course of patients with autoimmune encephalitis (AE) and paraneoplastic neurological syndrome (PNS) in Sweden. Thirty-seven antibody-positive AE and PNS cases were identified in the Healthcare region Mid Sweden between 2015 and 2019. Clinical data were collected through a retrospective review of electronic health records. Patients were divided into three subgroups based on antibody type: neuronal surface antibodies (NSAbs), onconeural antibodies, and anti-GAD65 antibodies. Nineteen patients had NSAbs, 11 onconeural antibodies, and seven anti-GAD65 antibodies. Anti-LGI1 and anti-NMDAR were the most frequently detected NSAbs, with anti-NMDAR cases having an older-than-expected age distribution (median age 40, range 17-72). Only 11 of 32 (30%) of patients had findings suggesting encephalitis on initial MRI, but 28 of 31 (90%) had pathological findings on initial cerebrospinal fluid analysis. All patients but one had abnormal EEG findings. Median time to immunotherapy was comparable among the three subgroups, whereas patients with anti-LGI1, anti-CASPR2, and anti-IgLON5 had an eightfold longer time to immunotherapy than anti-NMDAR and anti-GABA-B (p=.0016). There was a seasonal variation in onset for patients with non-tumor-related NSAbs and anti-GAD65 antibodies, with most patients (72%) falling ill in spring or summer. Swedish patients with AE and PNS had similar clinical characteristics as previously described cohorts from other geographical regions except for anti-NMDAR encephalitis, with older onset than expected. The onset of non-tumor-related AE occurred predominantly in the warm seasons, and AE with a more insidious onset was associated with delayed treatment initiation.

Clinical and Laboratory Characteristics of MODY Cases, Genetic Mutation Spectrum and Phenotype-genotype Relationship

Maturity onset diabetes of the young (MODY) occurs due to mutations in genes involved in pancreatic beta cell function and insulin secretion, has heterogeneous clinical and laboratory features, and account for 1-5% of all diabetes cases. The prevalence and distribution of MODY subtypes vary between countries. The aim of this study was to evaluate the clinical and laboratory characteristics, mutation distribution, and phenotype-genotype relationship in a large case series of pediatric Turkish patients genetically diagnosed with MODY. MODY cases from 14 different pediatric endocrinology departments were included. Diagnosis, treatment, follow-up data, and results of genetic analysis were evaluated. A total of 224 patients were included, of whom 101 (45%) were female, and the mean age at diagnosis was 9.4±4.1 years. Gene variant distribution was: 146 (65%) GCK; 43 (19%) HNF1A; 8 (3.6%) HNF4A, 8 (3.6%) KLF11 and 7 (3.1%) HNF1B. The remaining 12 variants were: PDX (n=1), NEUROD1 (n=3), CEL (n=1), INS (n=3), ABCC8 (n= 3) and KJNC11 (n=1). Of the cases, 197 (87.9%) were diagnosed with incidental hyperglycemia, 16 with ketosis (7%) and 7 (3%) with diabetic ketoacidosis (DKA), while 30% presented with classical symptoms of diabetes. Two-hundred (89%) had a family history of diabetes. Anti-GAD antibody was detected in 13 cases, anti-islet antibody in eight and anti-insulin antibody in four. Obesity was present in 16. Distribution of therapy was: 158 (71%) diet only; 23 (11%) intensive insulin treatment; 17 (7.6%) sulfonylureas; 10 (4.5%) metformin; and 6 (2.7%) insulin and oral anti-diabetic treatment. This was the largest genetically diagnosed series from Turkey. The most common gene variants were GCK and HNF1A with much lower proportions for other MODY types. Hyperglycemia was the most common presenting symptom while 11% of patients had diabetes-associated autoantibodies and 7% were obese. The majority of patients received dietary management only.

Utility of Fasting C-Peptide for the Diagnostic Differentiation of Patients with Type 1, Type 2 Diabetes, MODY, and LADA.

The prevalence of obesity has increased in patients with type 1 diabetes (T1D) and latent autoimmune diabetes of the adult (LADA), limiting the use of clinical features such as the body mass index for its differentiation with type 2 diabetes (T2D). Additionally, some patients with maturity-onset diabetes of the young (MODY) or LADA are misdiagnosed as having T2D. The evaluation of autoantibodies and genetic testing are not fully available. We aimed to evaluate the utility of a widely available and less expensive diagnostic tool such as C-peptide to differentiate between T1D, T2D, MODY, and LADA. Our study included 38 patients with T1D, 49 with T2D, 13 with MODY, and 61 with LADA. We recorded anthropometric measurements, biochemical profiles, and antidiabetic treatment and determined C-peptide, anti-GAD65, and anti-IA2 antibodies. C-peptide concentration differed significantly among populations (T1D: 0.2 ng/mL; T2D: 2.4 ng/mL; MODY: 1.14 ng/mL; LADA: 1.87 ng/mL). Through a ROC curve, we observed that the C-peptide cut-off point of 0.95 ng/mL allows differentiation between T1D and T2D (sensitivity 82%, specificity 77%); 0.82 ng/mL between T1D and LADA (sensitivity 82%, specificity 77%); and 1.65 ng/mL between T2D and MODY (sensitivity 72%, specificity 72%). C-peptide is useful for the diagnostic differentiation of patients with type 1, type 2 diabetes, MODY, and LADA.

Relapsing Anti-GAD65-Associated Encephalitis Responsive to Thymoma Resection, Radiation, and Immunomodulatory Therapy.

Herein we describe a case of relapsing anti-GAD65-associated encephalitis which was responsive to the combination of thymoma resection, external beam radiotherapy, and immunomodulatory therapy. The case illustrates the value of remaining vigilant for the possibility of paraneoplastic syndromes in the context of anti-GAD65 antibodies and thymoma. It also illustrates that tumor-directed therapies may offer additional benefit beyond immunomodulatory therapy alone.

Nystagmus and Imbalance as the Presenting Symptoms of AntiGad Antibody Syndrome in A 67-Year-Old Female

Autoimmune encephalitis is a serious condition that causes brain inflammation, usually mediated by antibodies to various neuronal antigens [1]. One of the many antigens that may generate an immune response and cause this type of inflammation is the glutamic acid decarboxylase enzyme (GAD). AntiGAD (glutamic acid decarboxylase) antibodies are targeted against the GAD enzyme that converts glutamate to GABA, which is the nervous system’s primary inhibitory neurotransmitter [2]. With the body’s primary inhibitory neurotransmitter compromised, anti-GAD antibody syndrome is a rare type of autoimmune encephalitis that results in various symptoms related to prolonged excitation, such as seizures or nystagmus [3]. We present a rare case of autoimmune encephalitis caused by significantly elevated Anti-GAD antibody, with concomitant rheumatoid arthritis in the hands/wrists; symptoms of downbeat nystagmus, diplopia, headaches, and joint pain are improved with rituximab and IVIG infusion, following an unsuccessful treatment with oral prednisone.

P-32 A Seckel syndrome patient exhibited with metabolic problems

Abstract Introduction Seckel syndrome is a disease with nine distinct phenotypes that is inherited autosomally recessively and is caused by DNA damage on chromosomes 3, 13, and 18. It is also known as 'bird-headed dwarfism' due to the disease's characteristic phenotypic features, microcephaly and dwarfism. In addition to mental retardation, other possible complications include bilateral optic atrophy, strabismus, hearing difficulties, micrognathia, microdontia, hypodontia, malocclusion of the mandible, scoliosis, bone anomalies, hematological, endocrinological, genitourinary, neurological anomalies (epilepsy, etc.), and cancers. Presented here is a patient with metabolic dysfunction who has been diagnosed with Seckel's syndrome. Clinical Case A male patient, age 22, was admitted to the endocrinology outpatient clinic for regulation of hyperglycemia. The patient's medical history included diabetes of type 2 since 2021, hypothyroidism, mental retardation, and hepatosteatosis. His parents were related as first cousins. One of the patient's two brothers has been diagnosed with Seckel syndrome. On his physical examination, his temperature was 36.1°C, his blood pressure was 92/61 mmHg, his heart rate was 76 beats per minute, his height was 125 cm, his weight was 19 kg, and his BMI was 12 kg/m2. Microcephaly, hypodontia, and micrognotia were observed. The patient was using insulin glargin 32 units, insulin aspart 2×18 units, metformin 500mg once day, and levothyroxine sodium 50mcg. In blood glucose follow-ups, the highest was 304 mg/dl and the lowest was 127 mg/dl, whereas Hba1c was 7.5% and c-peptide was 2.44 ng/ml. Anti-GAD, anti-islet cell, anti-TPO, and antithyroglobulin antibodies were negative. Insulin glargine was changed to 34 units, and insulin aspart was changed to 2×20 units. Due to mental retardation and hypodontia, it was discovered that the patient could not pay attention to his diet, could hardly eat solid foods, and was provided primarily liquids, particularly sugar-sweetened, flavored, and carbonated soft drinks. The patient was referred to the dental polyclinic and dietitian, while the family was monitored at the genetics polyclinic. Conclusion Follow-up care for patients with Seckel syndrome should include routine metabolic screening. Due to the patient's mental cooperation and dietary habits resulting from dental anomalies, metabolic control may be challenging. To ensure metabolic homeostasis in these patients, a multidisciplinary approach is necessary, involving the patient, his or her family, in multidisciplinary setting.

Anti-glutamic acid decarboxylase antibodies-associated cerebellar ataxia: A treatable ataxia

Abstract Background: Anti-glutamate decarboxylase 65 antibody-associated cerebellar ataxia (anti-GAD65Ab-associated CA) is the most widely studied immune-mediated CA. There are few case series evaluating the clinical, radiological, treatment profile, and outcome of anti-GAD65Ab-associated CA. Objective: To study the clinical, radiological profile, associated neoplasm, treatment outcome, and prognosis in patients diagnosed with anti-GAD65Ab-associated CA. Methods: A retrospective descriptive analysis of a cohort of patients diagnosed with anti-GAD65Ab-associated CA was performed and analyzed. Results: Thirteen patients were selected for the analysis with female predominance (70%). The mean age at presentation was 47.5 ± 11.1 years (range, 29–65 years), and the median duration of the symptoms was 4 months. All 13 patients (100%) had gait ataxia. Ten patients had limb ataxia along with gait ataxia (75%). Seven patients had cerebellar dysarthria (54%). Four patients (31%) had gaze-evoked jerky nystagmus. Five patients (39%) were diagnosed with type 2 diabetes mellitus, and one patient had hypothyroidism in addition to type 2 diabetes mellitus. Brain magnetic resonance imaging was normal in seven (54%) patients, and pure cerebellar atrophy was observed in six patients. One patient was detected with a colon neoplasm. All 13 patients received intravenous methylprednisolone, followed by oral steroids over 3 months. Six patients (50%) received plasma exchange along with intravenous methylprednisolone. Favorable outcomes (modified Rankin scale score ≤2) were observed in five patients and poor outcomes in two; six patients were lost to follow-up after the first admission. Conclusion: Anti-GAD65Ab-associated CA presents as subacute to chronic progressive CA with a favorable outcome with immunotherapy. Anti-GAD antibodies should be assessed in serum or cerebrospinal fluid in patients presenting subacute to chronic sporadic CA. The occurrence of a systemic neoplasm is rare in anti-GAD65Ab-associated CA.

Stiff-person syndrome

Stiff-person syndrome is a rare autoimmune disorder manifested by stiffness in the trunk and proximal limb muscles and painful muscle spasms in them. The disease is associated with the production of glutamate decarboxylase autoantibodies, an enzyme converting glutamate into gamma-aminobutyric acid. An increase of anti-GAD antibody serum levels above 10.000 IU/mL is specific for stiff-person syndrome. Our own clinical observation of a patient diagnosed with stiff-person syndrome is presented.

A Case of Stiff Person Syndrome Treated Using Intrathecal Baclofen

Introduction: Stiff Person Syndrome is a rare autoimmune neurological disorder with chronic muscle spasms leading to chronic pain and debilitation. Case Report: We describe a case of a 57-year-old man with the history of Diabetes mellitus type 1 diagnosed 15 years back with high-titer positive anti-GAD antibodies and poorly controlled blood sugar levels under highly dosed insulin treatment. Discussion: Intrathecal baclofen showed a marked improvement for the relief of spasticity with the choice of a baclofen pump for similar patients.

Probable Anti-Glutamate Decarboxylase 65 (Gad65) Antibody-Associated Cerebellar Ataxia. Clinical Case Report and Literature Review

Introduction. As more information about cerebellar ataxia induced by anti- GAD65 antibodies is accumulated, cerebellar dysfunction is increasingly associated with autoimmune causes. The prevalence of other neurological syndromes associated with anti- GAD65 antibodies has been estimated, but the occurrence of cerebellar ataxia of the same cause has not yet been reported. The clinical presentation and management of anti-GAD65 antibodies induced cerebellar ataxia are currently known only from single cases and small series reports.&#x0D; Case report. We present a clinical case of a 52-year-old woman who was admitted to the hospital due to dizziness, impaired coordination, occasional choking, and slurred speech. Diagnostic procedures were performed, in which anti-GAD65 antibodies and atrophic changes in the upper parts of the cerebellum were detected on brain MRI, which led to a possible diagnosis of anti-GAD65 antibody-associated cerebellar ataxia.&#x0D; Discussion and literature review. Patients tend to be women in their 60s with clinical symptoms such as gait and posture ataxia. Most patients present with nystagmus, dysarthria, and limb ataxia. To make the diagnosis, it is crucial to detect high titers of anti-GAD65 antibodies, do intrathecal anti-GAD65 antibody synthesis, and perform a brain MRI, which may reveal atrophy of the cerebellum as the disease progresses. Corticosteroids are one of the recommended treatment methods, which were effective in our case. Maintenance therapy is essential to prevent relapse of the disease.

Microvascular Disease Associates with Larger Osteocyte Lacunae in Cortical Bone in Type 2 Diabetes Mellitus.

Clinical studies indicate that microvascular disease (MVD) affects bone microstructure and decreases bone strength in type 2 diabetes mellitus (T2D). Osteocytes are housed in small voids within the bone matrix and lacunae and act as sensors of mechanical forces in bone. These cells regulate osteoclastic bone resorption and osteoblastic bone formation as well as osteocytic perilacunar remodeling. We hypothesized that MVD changes morphometric osteocyte lacunar parameters in individuals with T2D. We collected iliac crest bone biopsies from 35 individuals (10 female, 25 male) with T2D with MVD (15%) or without MVD (21%) with a median age of 67 years (interquartile range [IQR] 62-72 years). The participants were included based on c-peptide levels >700 pmol L-1, absence of anti-GAD65 antibodies, and glycated hemoglobin (HbA1c) levels between 40 and 82 mmol mol-1 or 5.8% and 9.7%, respectively. We assessed osteocyte lacunar morphometric parameters in trabecular and cortical bone regions using micro-computed tomography (micro-CT) at a nominal resolution of 1.2 μm voxel size. The cortical osteocyte lacunar volume (Lc.V) was 7.7% larger (p = 0.05) and more spherical (Lc.Sr, p < 0.01) in the T2D + MVD group. Using linear regression, we found that lacunar density (Lc.N/BV) in trabecular but not cortical bone was associated with HbA1c (p < 0.05, R 2 = 0.067) independently of MVD. Furthermore, Lc.V was larger and Lc.Sr higher in the center than in the periphery of the trabecular and cortical bone regions (p < 0.05). In conclusion, these data imply that MVD may impair skeletal integrity, possibly contributing to increased skeletal fragility in T2D complicated by MVD. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.