Congenital adrenal hyperplasia (CAH) is caused by mutations in cytochrome P450 side chain cleavage enzyme (CYP11A1 and old name, SCC). Errors in cholesterol side chain cleavage by the mitochondrial resident CYP11A1 results in an inadequate amount of pregnenolone production. This study was performed to evaluate the cause of salt-losing crisis and possible adrenal failure in a pediatric patient whose mother had a history of two previous stillbirths and loss of another baby within a week of birth. CAH can appear in any population in any region of the world. The study was conducted at Memorial University Medical Center and Mercer University School of Medicine. The patient was admitted to Pediatric Endocrinology Clinic due to salt-losing crisis and possible adrenal failure. The patient had CAH, an autosomal recessive disease, due to a novel mutation in exon 5 of the CYP11A1 gene, which generated a truncated protein of 286 amino acids compared with wild-type protein that has 521 amino acids (W286X). Although unrelated, both parents are carriers. Mitochondrial protein import analysis of the mutant CYP11A1 in steroidogenic MA-10 cells showed that the protein is imported in a similar fashion as observed for the wild-type protein and was cleaved to a shorter fragment. However, mutant’s activity was 10% of that obtained for the wild-type protein in non-steroidogenic COS-1 cells. In a patient of Mexican descent, a homozygous CYP11A1 mutation caused CAH, suggesting that this disease is not geographically restricted even in a homogeneous population.Learning points:Novel mutation in CYP11A1 causes CAH;This is a pure population from Central Mexico;Novel mutation created early truncated protein.

SummaryCholesterol transport into the mitochondria is required for synthesis of the first steroid, pregnenolone. Cholesterol is transported by the steroidogenic acute regulatory protein (STAR), which acts at the outer mitochondrial membrane prior to its import. Mutations in the STAR protein result in lipoid congenital adrenal hyperplasia (CAH). Although the STAR protein consists of seven exons, biochemical analysis in nonsteroidogenic COS-1 cells showed that the first two were not essential for pregnenolone synthesis. Here, we present a patient with ambiguous genitalia, salt-lossing crisis within two weeks after birth and low cortisol levels. Sequence analysis of the STAR, including the exon–intron boundaries, showed the complete deletion of exon 1 as well as more than 50 nucleotides upstream of STAR promoter. Mitochondrial protein import with the translated protein through synthesis cassette of the mutant STAR lacking exon 1 showed protein translation, but it is less likely to have synthesized without a promoter in our patient. Thus, a full-length STAR gene is necessary for physiological mitochondrial cholesterol transport in vivo.Learning points: STAR exon 1 deletion caused lipoid CAH.Exon 1 substitution does not affect biochemical activity.StAR promoter is responsible for gonadal development.

Type 1 diabetes is classified into two types by the American Diabetes Association; type 1A diabetes is the immune-mediated form and type 1B the non-immune mediated form of the disease, both leading to β-cell destruction and absolute insulin deficiency.It is estimated that approximately 1.5 million people in the US have type 1A diabetes. The incidence of type 1 diabetes is increasing worldwide at a rate of 3-5 % each year. Strikingly, it has doubled in each of the last two decades, children less than five years of age being the most commonly affected group. It was previously thought that the concordance rate for monozygotic twins with type 1 diabetes was relatively low (<50 %); however, following a cohort of monozygotic twins for longer than 50 years, the concordance rate for type 1 diabetes development is 66 %.A recent analysis of these long-term twin data indicates that there is no age at which an initially discordant monozygotic twin is no longer at risk, with some developing type 1 diabetes in the fourth and fifth decades of life. 17The major genetic determinant of type 1 diabetes is conferred by genes in the human leukocyte antigen (HLA) complex, which is divided into three regions: class I, II, and III. Alleles of the class II genes, DQ and DR (and to a lesser extent DP), are the most important determinants of type 1 diabetes. These major histocompatibility complex (MHC) class II molecules are expressed on antigen-presenting cells (macrophages, dendritic cells, and B cells) and present antigens to CD4+ T lymphocytes.DQ2 and DQ8 alleles are strongly associated with type 1 diabetes and more than 90 % of people with type 1A diabetes possess one or both of these genes, compared with 40 % of the US population in general.18 AbstractType 1 diabetes is a chronic autoimmune disease resulting from the immune destruction of insulin-producing β-cells in pancreatic islets.It is now a predicable disease in humans with the measurement of islet autoantibodies. Despite the ability to assess disease risk, there is no cure for type 1 diabetes and treatment requires lifelong insulin administration. Individuals with type 1 diabetes are at risk of long-term complications of the disease and the development of concomitant autoimmune disorders. Our understanding of the immunology of diabetes has increased greatly over the last decade at a basic science level, with translation to type 1 diabetes patients. Therapies are emerging to prevent beta cell destruction in these patients. This article centres around our current understanding of the immunology of type 1 diabetes, with a focus on immune intervention for the prevention and ultimate cure of the disease.

2016-12-23T18:49:38

No abstract