Explore the vast range of titles available.

Autoimmune Polyendocrine Syndrome Type 1 (APS-I) results from mutations in the Autoimmune Regulator ( AIRE) gene and serves as a valuable model to understand autoimmunity and immune deficiency. Various studies have produced differing results on how AIRE dysfunction affects the balance of immune cell subsets in blood in humans. We conducted high-resolution whole blood immune cell subset analysis using a 36-panel mass cytometry assay in Norwegian APS-I patients ( N  = 18) and compared with age and sex-matched healthy subjects ( N  = 19). Additionally, we provide a comprehensive summary of findings from 28 other studies examining blood immune subset distributions in APS-I patients. Norwegian APS-I patients had significantly reduced numbers of B cells, which was driven by lower levels of the naïve and transitional B cell compartments. We further observed trends indicating reduced frequencies of NK cells, as well as deviations in CD16-expressing cells in several subsets in APS-I patients. Contrary to previous reports, our study did not find differences in regulatory T cell levels between APS-I patients and healthy controls. Several studies in our summary consistently reported lower frequencies of resting naïve B cells in APS-I patients and higher proportions of activated memory B cells in APS-I patients. The composition of other immune cell subsets was more diverse between studies, probably reflecting contributions by other factors like medications, ethnicity, disease complexity, insufficient sample sizes, time of sampling, ages, unique immune profiles and health conditions of the patients and controls. Future research should prioritize investigating antigen-specific responses in blood and tissues to further illuminate this complex area.

Genetic testing for monogenic diabetes is important for patient care. Given the extensive genetic and clinical heterogeneity of diabetes, exome sequencing might provide additional diagnostic potential when standard Sanger sequencing-based diagnostics is inconclusive. The aim of the study was to examine the performance of exome sequencing for a molecular diagnosis of MODY in patients who have undergone conventional diagnostic sequencing of candidate genes with negative results. We performed exome enrichment followed by high-throughput sequencing in nine patients with suspected MODY. They were Sanger sequencing-negative for mutations in the HNF1A, HNF4A, GCK, HNF1B and INS genes. We excluded common, non-coding and synonymous gene variants, and performed in-depth analysis on filtered sequence variants in a pre-defined set of 111 genes implicated in glucose metabolism. On average, we obtained 45 X median coverage of the entire targeted exome and found 199 rare coding variants per individual. We identified 0-4 rare non-synonymous and nonsense variants per individual in our a priori list of 111 candidate genes. Three of the variants were considered pathogenic (in ABCC8, HNF4A and PPARG, respectively), thus exome sequencing led to a genetic diagnosis in at least three of the nine patients. Approximately 91% of known heterozygous SNPs in the target exomes were detected, but we also found low coverage in some key diabetes genes using our current exome sequencing approach. Novel variants in the genes ARAP1, GLIS3, MADD, NOTCH2 and WFS1 need further investigation to reveal their possible role in diabetes. Our results demonstrate that exome sequencing can improve molecular diagnostics of MODY when used as a complement to Sanger sequencing. However, improvements will be needed, especially concerning coverage, before the full potential of exome sequencing can be realized.

Mitch Cohen, a skilled family physician with a passion for rural medicine, died at the age of 39 in 2011. Cohen would be overwhelmed to see the grieving patients he has left behind and the impact he has made on his community. Physicians often underestimate their influence. A listening ear, a single critical prescription, a friendly face helping to navigate uncharted territory - these are the things that physicians do daily that change peoples' lives.

Autoimmune Addison’s disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci ( P  < 5 × 10 −8 ). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA , BACH2 , PTPN22 and CTLA4 , we associate two protein-coding alterations in Autoimmune Regulator ( AIRE ) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7–4.3), P  = 9.0 × 10 −25 ) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35–41% of heritability ( h 2 ). Autoimmune Addison’s disease is a rare complex disease, which has not yet been characterized by non-biased genetic studies. Here, the authors perform the first GWAS for the disease, identifying nine loci including two coding variants in the gene Autoimmune Regulator ( AIRE ).

Abstract Objective Atypical Graves disease (GD) is a common complication in multiple sclerosis (MS) patients treated with alemtuzumab. We present epidemiological, clinical, and biochemical characteristics of alemtuzumab-induced GD. Methods Retrospective follow-up study of MS patients treated with alemtuzumab from 2014 to 2020, including clinical course of GD, pregnancy outcome, and thyroid eye disease (TED). Results We enrolled 183 of 203 patients (90%, 68% women) treated with alemtuzumab at 4 hospitals in Norway. Seventy-five (41%) developed thyroid dysfunction, of whom 58 (77%) had GD. Median time from the first dose of alemtuzumab to GD diagnosis was 25 months (range, 0-64). Twenty-four of 58 GD patients (41%) had alternating phases of hyper- and hypothyroidism. Thyrotropin receptor antibodies became undetectable in 23 of 58 (40%) and they could discontinue antithyroid drug treatment after a median of 22 (range, 2-58) months. Conversely, 26 (44%) had active disease during a median follow-up of 39 months (range, 11-72). Two patients (3%) received definitive treatment with radioiodine, 6 (10%) with thyroidectomy. Nine developed TED (16%), 7 had mild and 2 moderate to severe disease. Four patients completed pregnancy, all without maternal or fetal complications. Patients who developed GD had a lower frequency of new MS relapses and MRI lesions than those without. Conclusion GD is a very common complication of alemtuzumab treatment and is characterized by alternating hyper- and hypothyroidism. Both remission rates and the prevalence of TED were lower than those reported for conventional GD. Pregnancies were uncomplicated and GD was associated with a lower risk of subsequent MS activity.

The 22q11.2 deletion syndrome (22q11.2 del), also known as DiGeorge syndrome, is a genetic disorder with an estimated incidence of 1:3000 to 1:6000 births. These patients may suffer from affection of many organ systems with cardiac malformations, immunodeficiency, hypoparathyroidism, autoimmunity, palate anomalies, and psychiatric disorders being the most frequent. The importance of the complement system in 22q11.2 del has not been investigated. The objective of this study was to evaluate the complement system in relation to clinical and immunological parameters in patients. A national cohort of patients (n = 69) with a proven heterozygous deletion of chromosome 22q11.2 and a group of age and sex matched controls (n = 56) were studied. Functional capacity of the classical, lectin, and alternative pathways of the complement system as well as complement activation products C3bc and terminal complement complex (TCC) were accessed and correlated to clinical features. All patients in our study had normal complement activation in both classical and alternative pathways. The frequency of mannose-binding lectin deficiency was comparable to the normal population. The patients had significantly raised plasma levels of C3bc and a slight, but not significant, increase in TCC compared with controls. This increase was associated with the presence of psychiatric disorders in patients. The present study shows no complement deficiencies in 22q11.2 deletion syndrome. On the contrary, there are signs of increased complement activation in these patients. Complement activation is particularly associated with the presence of psychiatric disorders.

PurposeImmunodeficiency is one of the key features of 22q11.2 deletion syndrome (del), and it is seen in approximately 75% of the patients. The degree of immunodeficiency varies widely, from no circulating T cells to normal T cell counts. It has been hypothesized that the low number of T cells may at least in part be due to increased apoptosis of T cells. Increased spontaneous T cell apoptosis has been reported in one patient with 22q11.2del, but this has not been further investigated.MethodsA national cohort of patients with a proven heterozygous deletion of chromosome 22q11.2 diagnosed by FISH or MLPA and a group of age and sex matched controls were studied. Spontaneous and activation-induced apoptosis, in addition to FAS expression on lymphocytes, were measured using flow cytometry. Serum levels of FASL were analyzed using ELISA.ResultsThere was no increased spontaneous apoptosis in patients with 22q11.2del. Upon activation, anti-FAS-induced apoptosis was significantly increased in patients compared to those in controls, while there was no difference in activation induced cell death or activated cell autonomous death. We also found a significant increase in expression of FAS on freshly isolated lymphocytes from patients, while there was no difference in serum levels of FASL. Patients with congenital heart defects (CHD) had significantly higher serum levels of FASL compared to non-CHD patients.ConclusionWe have shown increased FAS expression on lymphocytes from patients with 22q11.2del as well as increased levels of FASL in patients with CHD. Those changes may contribute to the pathophysiology of the 22q11.2del.

Purpose Newborns with severe T-cell lymphopenia, including those with 22q11.2 deletion syndrome (DS), have low numbers of T-cell receptor excision circles (TRECs). The aim of this study was to determine a possible correlation between neonatal TRECs in 22q11.2DS and the development of different phenotypes to elucidate the prognostic value of TREC in this disease. Methods In this national survey including 46 patients with 22q11.2DS born after 2005, TREC levels were determined using stored newborn screening blood spots on filter cards. Patients were grouped into quartiles according to their TREC values, except the two infants with thymus aplasia. Results The two patients with thymic aplasia had no detectable TREC. The rest had no severe clinical immunodeficiency. There was a significant correlation between low TRECs and the proportion of patients with CD3 + CD4 + T-cells below the 5th percentile of healthy infants ( p  = 0.027) as well as the proportion with an abnormal thymus feature either no thymus or remnant thymus as observed during heart surgery ( p  = 0.022). Significantly lower TRECs ( p  = 0.019) were found in patients with cardiac defects compared to no such defects. Patients within the lowest quartile of TREC values (<71 TRECs/μL, n  = 11) had more frequent severe cardiac defects than the other quartiles ( p  = 0.010). Eight of these patients in the lowest quartile needed an operation/intervention within two weeks after birth or died because of a cardiac defect. Conclusion The low TREC values not only correlate with decreased T-cell immunity, but also with the occurrence of heart defects in the patients.

Patients with the 22q11.2 deletion syndrome display a wide phenotypic variation that is important for clinical follow-up. In this national survey of 60 patients (ages 1 to 54 years) diagnosed by Fluorescence in situ hybridization test, data were collected from medical records, a physical examination, and a semistructured interview. Ultrasound investigation of the kidneys was also performed. In addition, multiplex ligation probe amplification assay was performed to detect deletion size. Phenotypic features leading to the genetic diagnosis were noted. The patients showed a variety of organ malformations including 39 with heart anomalies. Only 20 individuals had been diagnosed with 22q11.2 DS in the first year of life. Four patients had renal and five males had genital malformations. The increased infection susceptibility (excluding otitis media) and most feeding difficulties subsided during early childhood. Speech difficulties started early and were a major problem for many patients at least until 10 years of age. Ten patients developed kyphoscoliosis in late childhood. In teenagers and adults, abnormal social behavior, learning disabilities, and psychiatric symptoms dominated. Our study which also includes adult patients emphasizes a marked change in challenges in individuals with the 22q11.2 deletion syndrome with increasing age.

Parkinson’s Disease (PD) is the fastest-growing neurological disorder and only symptomatic treatment is available. Zebrafish are ideally suited for high-throughput screening of disease modifying drugs and mechanistic studies. Mutations in PARK7 are associated with early onset familial PD, however also idiopathic PD patients without known mutations in PARK7 show altered subcellular location and levels of its protein product DJ-1 in pathological tissues. Here, we show that PARK7 -/- zebrafish already at their larval stage show a correlation between reduced number of dopaminergic neurons and motor dysfunction. Additionally, PD associated prodromal symptoms as reduced sensory function, increased sleep latency and light phase sleepiness were also observed. The 1-methyl-4-phenylpyridinium (MPP + ) exposed PD model did not reproduce similar sleep disturbances. This is the first stable genetic larval zebrafish model of Parkinson’s disease which shows both motor and non-motor symptoms together with a reduction in dopaminergic neurons. The model should therefore be highly valuable as a tool for PD related drug screening and mechanistic studies.