Rare Antagonistic Leptin Variants and Severe, Early-Onset Obesity.

Hormone absence or inactivity is common in congenital disease, but hormone antagonism remains controversial. Here, we characterize two novel homozygous leptin variants that yielded antagonistic proteins in two unrelated children with intense hyperphagia, severe obesity, and high circulating levels of leptin. Both variants bind to the leptin receptor but trigger marginal, if any, signaling. In the presence of nonvariant leptin, the variants act as competitive antagonists. Thus, treatment with recombinant leptin was initiated at high doses, which were gradually lowered. Both patients eventually attained near-normal weight. Antidrug antibodies developed in the patients, although they had no apparent effect on efficacy. No severe adverse events were observed. (Funded by the German Research Foundation and others.).

Understanding the Genetics of Early-Onset Obesity in a Cohort of Children From Qatar.

CONTEXT: Monogenic obesity is a rare form of obesity due to pathogenic variants in genes implicated in the leptin-melanocortin signaling pathway and accounts for around 5% of severe early-onset obesity. Mutations in the genes encoding the MC4R, leptin, and leptin receptor are commonly reported in various populations to cause monogenic obesity. Determining the genetic cause has important clinical benefits as novel therapeutic interventions are now available for some forms of monogenic obesity. OBJECTIVE: To unravel the genetic causes of early-onset obesity in the population of Qatar. METHODS: In total, 243 patients with early-onset obesity (above the 95% percentile) and age of onset below 10 years were screened for monogenic obesity variants using a targeted gene panel, consisting of 52 obesity-related genes. RESULTS: Thirty rare variants potentially associated with obesity were identified in 36 of 243 (14.8%) probands in 15 candidate genes (LEP, LEPR, POMC, MC3R, MC4R, MRAP2, SH2B1, BDNF, NTRK2, DYRK1B, SIM1, GNAS, ADCY3, RAI1, and BBS2). Twenty-three of the variants identified were novel to this study and the rest, 7 variants, were previously reported in literature. Variants in MC4R were the most common cause of obesity in our cohort (19%) and the c.485C>T p.T162I variant was the most frequent MC4R variant seen in 5 patients. CONCLUSION: We identified likely pathogenic/pathogenic variants that seem to explain the phenotype of around 14.8% of our cases. Variants in the MC4R gene are the commonest cause of early-onset obesity in our population. Our study represents the largest monogenic obesity cohort in the Middle East and revealed novel obesity variants in this understudied population. Functional studies will be required to elucidate the molecular mechanism of their pathogenicity.

Managing Severe Hypoglycaemia in Patients with Diabetes: Current Challenges and Emerging Therapies.

Hypoglycaemia is common in patients with diabetes mellitus and is a limiting factor for achieving adequate glycaemic control. In the vast majority of cases, hypoglycaemia develops due to the imbalance between food intake and insulin injections. As recurrent hypoglycaemia leads to significant morbidity and mortality, the recognition and immediate treatment of hypoglycaemia in diabetic patients is thus important. In the last 20 years, the introduction of improved insulin analogues, insulin pump therapy, continuous glucose monitoring (CGM), and sensor-augmented pump therapy have all made significant improvements in helping to reduce and prevent hypoglycaemia. In terms of treatment, the American Diabetes Association recommends oral glucose as the first-line treatment option for all conscious patients with hypoglycaemia. The second line of treatment (or first line in unconscious patients) is the use of glucagon. Novel formulations of glucagon include the nasal form, the Gvoke HypoPen which is a ready-to-deliver auto-injector packaged formulation and finally a glucagon analogue, Dasiglucagon. The Dasiglucagon formulation has recently been approved for the treatment of severe hypoglycaemia. It is a ready-to-use, similar to endogenous glucagon and its potency is also the same as native glucagon. It does not require reconstitution before injection and therefore ensures better compliance. Thus, significant improvements including development of newer insulin analogues, insulin pump therapy, continuous glucose monitoring (CGM), sensor-augmented pump therapy and novel formulations of glucagon have all contributed to reducing and preventing hypoglycaemia in diabetic individuals. However, considerable challenges remain as not all patients have access to diabetes technologies and to the newer glucagon formulations to help reduce and prevent hypoglycaemia.

Severe Growth Hormone Deficiency in an Indian Boy Caused By a Novel 6 kb Homozygous Deletion Spanning the GH1 Gene.

Growth disorders resulting in extreme short stature are often a result of deficiency in growth hormone released from the pituitary gland or defective growth hormone releasing receptor. Genetic defects in the GH1 and GHRHR genes account for around 11.1-20% of extreme short stature cases, resulting in a rare condition called Isolated Growth Hormone Deficiency. We describe the characterization of a GH1 genetic defect discovered in a 3-year-old male patient with extreme short stature, developmental failure and undetectable serum levels of growth hormone. There is a familial history of short stature with both parents being short. Whole genome sequencing of the patient DNA revealed a large novel 6 kb homozygous deletion spanning the entire GH1 gene in the patient. While the deletion was homozygous in the subjects, it was found in a heterozygous state in the parents. Thus we report a novel homozygous deletion including the GH1 gene leading to Isolated Growth Hormone Deficiency- Type 1A associated with extreme short stature.

Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi-Bickel Syndrome.

Fanconi−Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized by the accumulation of glycogen mainly in the liver. It is inherited in an autosomal recessive manner due to mutations in the SLC2A2 gene. SLC2A2 encodes for the glucose transporter GLUT2 and is expressed in tissues that are involved in glucose homeostasis. The molecular mechanisms of dysglycemia in FBS are still not clearly understood. In this study, we report two cases of FBS with classical phenotypes of FBS associated with dysglycemia. Genomic DNA was extracted and analyzed by whole-genome and Sanger sequencing, and patient PBMCs were used for molecular analysis. One patient had an exonic SLC2A2 mutation (c.1093C>T in exon 9, R365X), while the other patient had a novel intronic SLC2A2 mutation (c.613-7T>G). Surprisingly, the exonic mutation resulted in the overexpression of dysfunctional GLUT2, resulting in the dysregulated expression of other glucose transporters. The intronic mutation did not affect the coding sequence of GLUT2, its expression, or glucose transport activity. However, it was associated with the expression of miRNAs correlated with type 1 diabetes mellitus, with a particular significant overexpression of hsa-miR-29a-3p implicated in insulin production and secretion. Our findings suggest that SLC2A2 mutations cause dysglycemia in FBS either by a direct effect on GLUT2 expression and/or activity or, indirectly, by the dysregulated expression of miRNAs implicated in glucose homeostasis.

Sib-pair subgroup familial type 1 diabetes mellitus in children in the state of Qatar.

BACKGROUND: Type 1 diabetes is the most common type of diabetes mellitus (DM) in children. It can be sporadic in onset or cluster in families, which comprises parent-offspring and sib-pair subgroups. The risk of developing DM in first-degree relatives of affected individuals is 8-15 fold higher. There is limited data about familial DM from the Gulf region. This study aims to describe the clinical, biochemical and genetic characteristics of sib-pair familial type 1 diabetes in Qatar. METHODS: Every child with DM following up at Sidra Medicine was recruited. Data was collected regarding clinical features, family history, type 1 diabetes autoantibodies and whole genome sequencing was performed. Genetic analysis for MODY genes and HLA association analysis was conducted. RESULTS: 44 families with sib-pair familial diabetes were identified. Of these, 2 families had 4 affected siblings and 5 families had 3 affected siblings. The majority are of Qatari ethnicity and the most common autoantibody was GAD65. The most common age of onset in the proband was 5-9 years while it was 10-14 years in subsequent siblings. The occurrence of DKA & HbA1c levels were lower in the second affected sibling. No relevant MODY gene variants were found. HLA analysis found 15 variants in at least 50% of the subjects. Most common were HLA-F*01*01*01G, HLA- DPA1*01*03*01G, HLA- DRB3*02*02*01G, HLA- E*01*01*01G & DRB4*03*01N. CONCLUSIONS: The prevalence of sib-pair diabetes is 3.64%. The second affected siblings were older. MODY is unlikely and Class I and II HLA genes was present in sib-pair diabetes.

Understanding the Mechanism of Dysglycemia in a Fanconi-Bickel Syndrome Patient.

Fanconi-Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized mainly by the accumulation of glycogen in the liver and kidney. It is inherited as an autosomal recessive disorder caused by mutations in the SLC2A2 gene, which encodes for GLUT2. Patients with FBS have dysglycemia but the molecular mechanisms of dysglycemia are still not clearly understood. Therefore, we aimed to understand the underlying molecular mechanisms of dysglycemia in a patient with FBS. Genomic DNA was isolated from a peripheral blood sample and analyzed by whole genome and Sanger sequencing. CRISPR-Cas9 was used to introduce a mutation that mimics the patient's mutation in a human kidney cell line expressing GLUT2 (HEK293T). Mutant cells were used for molecular analysis to investigate the effects of the mutation on the expression and function of GLUT2, as well as the expression of other genes implicated in dysglycemia. The patient was found to have a homozygous nonsense mutation (c.901C>T, R301X) in the SLC2A2 gene. CRISPR-Cas9 successfully mimicked the patient's mutation in HEK293T cells. The mutant cells showed overexpression of a dysfunctional GLUT2 protein, resulting in reduced glucose release activity and enhanced intracellular glucose accumulation. In addition, other glucose transporters (SGLT1 and SGLT2 in the kidney) were found to be induced in the mutant cells. These findings suggest the last loops (loops 9-12) of GLUT2 are essential for glucose transport activity and indicate that GLUT2 dysfunction is associated with dysglycemia in FBS.

Type 2 Diabetes Mellitus in a 7 Year Old Girl.

Type 2 diabetes is a chronic disease due to insulin resistance resulting in hyperglycemia. The prevalence of type 2 diabetes is increasing worldwide in the pediatric population. In the pediatric population, type 2 diabetes typically develops around adolescence; however, patients with a younger age of onset are now being reported. Earlier onset of type 2 diabetes is associated with a more aggressive course of disease and earlier comorbidities, although data on this is limited. We report a child from Qatar with type 2 diabetes that was diagnosed at 7 years of age, along obesity with a BMI of 26.8 kg/m2. Elevated liver enzymes, c-peptide, and insulin levels were observed along with fatty liver on an ultrasound. The child had severe acanthosis nigricans with increased appetite. There was a positive family history for type 2 diabetes. Testing for type 1 diabetes autoantibodies, monogenic obesity, and monogenic diabetes screening was negative. This is the second youngest child reported to have type 2 diabetes. Accurate diagnosis, early reporting, and long-term follow-up of such cases is necessary to bring more attention to the subgroup of type 2 diabetes in very young patients.

A Novel Homozygous MC2R Variant Leading to Type-1 Familial Glucocorticoid Deficiency.

Context: Type 1 familial glucocorticoid deficiency (FGD) (OMIM #607397) is a rare autosomal recessive disorder due to mutations in melanocortin-2-receptor (MC2R) gene encoding the G protein-coupled adrenocorticotropic (ACTH) transmembrane receptor. Objective: The aim of the study is to describe 2 siblings born to a healthy consanguineous family presenting with clinical and biochemical features of FGD, harboring a novel homozygous MC2R variant. Methods: Both patients are siblings born at term via normal delivery with normal birth weights. The first sibling presented with symptoms of hypoglycemia, repeated episodes of infections starting from 2 days of age. At 18 months of age, low serum cortisol was found, and he was started on hydrocortisone replacement therapy. The second sibling developed hypoglycemia on day 1 after birth, investigations revealed low serum sodium and cortisol levels and was also commenced on hydrocortisone treatment. Whole exome sequencing (WES) and in vitro functional studies on cell line transfected with wild-type and mutant plasmid clones were undertaken. Results: WES revealed a novel homozygous missense mutation c.326T>A, p.Leu109Gln in the MC2R gene. In-silico prediction tools predicted the effect of this mutation to be deleterious. In vitro study using HEK293 cells transfected with MC2R wild-type and mutant clones showed a defect in protein expression and cAMP generation when stimulated with ACTH. Conclusion: Homozygous semiconserved p.Leu109Gln mutation disrupts cAMP production and MC2R protein expression leading to ACTH resistance. This study provides additional evidence that this novel pathogenic variant in MC2R results in FGD phenotypes.

The epidemiology, clinical, biochemical, immunological and radiological features of youth onset type 2 diabetes mellitus in the state of Qatar.

Objectives: To describe the epidemiology, clinical, biochemical, immunological and radiological aspects of youth with type 2 diabetes. Methods: Patients under 18 year of age with type 2 diabetes were recruited from 2018 to 2020, clinical data collected, autoantibodies (GAD65, IAA, IA2 and ZnT8), insulin, ALT and c-peptide were measured. Hepatic ultrasound was performed for assessment of non-alcoholic fatty liver disease (NAFLD). Results: 104 patients were identified. The incidence in 2020 and prevalence per 100,000 was 2.51 and 23.7, respectively. The age of onset was between 8.5 and 18 years with 74% of the patients being of Qatari nationality. Males were more affected than females (1.5/1). Overweight/obesity was present in 98% of all the patients, a positive family history (either both parents or a single parent) in 71% and maternal gestational diabetes mellitus (GDM) in 60% of patients. More than 90% of the patients had acanthosis nigricans. 5 patients had 1 autoantibody positivity and hepatic ultrasound detected evidence of NAFLD in majority of patients. Conclusion: Obesity, maternal GDM and family history of diabetes were the key risk factors for the development of type 2 diabetes. Autoantibody positivity may be present in youth type 2 diabetes. As youth type 2 diabetes is associated with early onset microvascular and macrovascular complications, these findings have important social and health budget implications for Qatar. Tackling the burden of maternal GDM and childhood obesity and building programmes for early detection and intervention, are therefore, essential to reduce the risk of future complications.

Case Report: Hepatic Adenomatosis in a Patient With Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a genetic disorder caused by the lack of expression of genes on the paternally inherited chromosome region 15q11.2-q13. It is a multisystem disorder that is characterized by severe hypotonia with poor suck and feeding difficulties in early infancy, followed in early childhood by excessive eating and gradual development of morbid obesity. The incidence of type 2 diabetes mellitus is high, particularly in obese patients. Non-alcoholic fatty liver disease has also been reported in some patients with PWS. Liver adenomatosis is a benign vascular lesion of the liver, defined by the presence of >10 adenomas, in the otherwise healthy liver parenchyma. We report the first case of a patient with PWS with severe obesity, type 2 diabetes mellitus, and non-alcoholic fatty liver who also developed liver adenomatosis, review the pediatric literature on liver adenomatosis, and discuss the potential underlying mechanisms.

Homozygous Insulin Promotor Gene Mutation Causing Permanent Neonatal Diabetes Mellitus and Childhood Onset Autoantibody Negative Diabetes in the Same Family.

PURPOSE: To report a family with a homozygous INS promotor gene mutation causing permanent neonatal diabetes mellitus (PNDM) in one sibling and autoantibody negative childhood onset diabetes in another sibling. CASE PRESENTATION: Patient 1 is a 12-year-old girl born at term with low birth weight to a consanguineous family, diagnosed with PNDM at 26 days of life. She presented with ketoacidosis and has a severe course of disease with high insulin requirement. Patient 2 is a 9-year-old girl born at term with normal weight, who presented with ketoacidosis at 2 years of age. Both subjects have negative type 1 autoantibodies. On genetic testing, a mutation in the promoter region of INS gene c.-331 C>G was found in homozygous state in both subjects and in a heterozygous state in parents. CONCLUSION: Homozygous INS gene promotor mutations may present with either PNDM or later onset autoantibody negative diabetes in childhood. This suggests that homozygous INS gene promotor mutations show marked heterogeneity in clinical presentation within individuals in the same family. The pathophysiology of this is not well known but could be related to a number of factors, including the position of the variant, penetrance, other associated genetic defects, HLA etc. Premarital screening and genetic counselling is recommended for highly consanguineous families to reduce occurrence of such conditions.

Maturity-onset diabetes of the young (MODY) due to PDX1 mutation in a sib-pair diabetes family from Qatar.

Maturity-onset diabetes of young (MODY) is an autosomal dominant genetic disorder that causes insulin deficiency without autoimmunity. We present the first family with pancreatic duodenal homeobox 1 (PDX1) mutation causing diabetes from Qatar. Routine genetic screening of all antibody-negative diabetic patients with diabetes should be offered to avoid misdiagnosis.

Clinical features, epidemiology, autoantibody status, HLA haplotypes and genetic mechanisms of type 1 diabetes mellitus among children in Qatar.

To describe the clinical features, epidemiology, autoantibody status, HLA haplotypes and genetic mechanisms of type 1 diabetes mellitus (T1DM). Patients (0-18 years) with diabetes were recruited. Clinical data was collected, autoantibodies and c-peptide were measured. Whole Genome Sequencing was performed. Genomic data analysis was compared with the known genes linked with T1DM and HLA alleles were studied. 1096 patients had one or more antibody positivity. The incidence of T1DM in 2020 was 38.05 per 100,000 children and prevalence was 249.73. GADA was the most common autoantibody followed by IAA. Variants in GSTCD, SKAP2, SLC9B1, BANK1 were most prevalent. An association of HLA haplotypes DQA1*03:01:01G (OR = 2.46, p value = 0.011) and DQB1*03:02:01G (OR = 2.43, p value = 0.022) was identified. The incidence of T1DM in Qatar is the fourth highest in the world, IA2 autoantibody was the most specific with some patients only having ZnT8 or IA2 autoantibodies thus underlining the necessity of profiling all 4 autoantibodies. The genes associated with T1DM in the Arab population were different from those that are common in the Caucasian population. HLA-DQ was enriched in the Qatari patients suggesting that it can be considered a major risk factor at an early age.

The Epidemiology and Genetic Analysis of Children With Idiopathic Type 1 Diabetes in the State of Qatar.

CONTEXT: Idiopathic type 1 diabetes is characterized by the absence of autoantibodies and the underlying mechanisms are not clear. OBJECTIVE: We aimed to study the epidemiology, describe the clinical characteristics, and report results of genetic studies in pediatric patients with idiopathic type 1 diabetes. METHODS: This was a prospective study of type 1 diabetes patients attending Sidra Medicine from 2018 to 2020. Autoantibodies (GAD65, IAA, IA-2A, and ZnT8) were measured and genetic testing was undertaken in patients negative for autoantibodies to rule out monogenic diabetes. Demographic and clinical data of patients with idiopathic type 1 diabetes were compared with patients with autoimmune type 1 diabetes. RESULTS: Of 1157 patients with type 1 diabetes, 63 were antibody-negative. Upon genome sequencing, 4 had maturity onset diabetes of the young (MODY), 2 had Wolfram syndrome, 1 had H syndrome, and 3 had variants of uncertain significance in MODY genes; 53 patients had idiopathic type 1 diabetes. The most common age of diagnosis was 10 to 14 years. C-peptide level was low but detectable in 30 patients (56.6%) and normal in 23 patients (43.4%) The average body mass index was in the normal range and 33% of the patients had a history of diabetic ketoacidosis (DKA). CONCLUSION: Four percent of the children had idiopathic type 1 diabetes. There were statistically significant differences in the C-peptide level and insulin requirement between the 2 groups. DKA was less common in the idiopathic group. Mutations in MODY genes suggest the importance of autoantibody testing and genetic screening for known causes of monogenic diabetes in idiopathic type 1 diabetes. The mechanism of idiopathic type 1 diabetes is unknown but could be due to defects in antibody production or due to autoantibodies that are not yet detectable or discovered.

The prevalence, immune profile, and clinical characteristics of children with celiac disease and type 1 diabetes mellitus in the state of Qatar.

OBJECTIVES: Children with antibody positive type 1 diabetes mellitus (type 1 diabetes) are at an increased risk of developing celiac disease (CD) which suggests a common autoimmune basis with both high-risk human lymphocyte antigen (HLA) and non-HLA factors playing a role in the pathophysiology. We aim to describe the prevalence, immune profile, and clinical characteristics of children with CD who have type 1 diabetes mellitus in Qatar. METHODS: All children (aged 0-18 years) attending a regional diabetes clinic with antibody positive type 1 diabetes were screened for CD. Measurement of tissue transglutaminase IgA and IgG as well as anti-endomysial antibody, was done, clinical details about the birth history, family history of diabetes and CD, age of onset, and ethnicity were collected. RESULTS: Out of the 1,325 children with antibody positive type 1 diabetes, 54 were identified to have CD on screening and then confirmed on small bowel biopsy. The prevalence of CD in the type 1 diabetes childhood population in Qatar is 4.07%. CD and type 1 diabetes were more prevalent in the Qatari children (n=32) as compared to non-Qatari (n=22) and occurred mostly in the age group 6-10 years. The most common type 1 diabetes antibodies in children with CD were glutamic acid decarboxylase and insulin autoantibody. Twelve subjects were asymptomatic for CD symptoms and picked up only on screening. CONCLUSIONS: The prevalence of CD in children with type 1 diabetes in Qatar is comparable to reports from around the world. Many children were asymptomatic and thus routine screening is recommended.

Epidemiology, genetic landscape and classification of childhood diabetes mellitus in the State of Qatar.

AIMS/INTRODUCTION: To study the epidemiology, genetic landscape and causes of childhood diabetes mellitus in the State of Qatar. MATERIALS AND METHODS: All patients (aged 0-18 years) with diabetes mellitus underwent biochemical, immunological and genetic testing. American Diabetes Association guidelines were used to classify types of diabetes mellitus. The incidence and prevalence of all the different types of diabetes mellitus were calculated. RESULTS: Total number of children with diabetes mellitus was 1,325 (type 1 n = 1,096, ≥1 antibody; type 2 n = 104, type 1B n = 53; maturity onset diabetes of the young n = 20; monogenic autoimmune n = 4; neonatal diabetes mellitus n = 10;, syndromic diabetes mellitus n = 23; and double diabetes mellitus n = 15). The incidence and prevalence of type 1 diabetes were 38.05 and 249.73 per 100,000, respectively, and for type 2 were 2.51 and 23.7 per 100,000, respectively. The incidence of neonatal diabetes mellitus was 34.4 per 1,000,000 live births, and in indigenous Qataris the incidence was 43.6 per 1,000,000 live births. The prevalence of type 1 diabetes and type 2 diabetes in Qatari children was double compared with other nationalities. The prevalence of maturity onset diabetes of the young in Qatar was 4.56 per 100,000. CONCLUSIONS: This is the first prospective and comprehensive study to document the epidemiology and genetic landscape of childhood diabetes mellitus in this region. Qatar has the fourth highest incidence of type 1 diabetes mellitus, with the incidence and prevalence being higher in Qatari compared with non-Qatari. The prevalence of type 2 diabetes mellitus is also higher in Qatar than in Western countries. The incidence of neonatal diabetes mellitus is the second highest in the world. GCK is the most common form of maturity onset diabetes of the young, and a large number of patients have type 1B diabetes mellitus.

Case Report: Phenotype-Gene Correlation in a Case of Novel Tandem 4q Microduplication With Short Stature, Speech Delay and Microcephaly.

We describe a sporadic case of a pure, tandem, interstitial chromosome 4q duplication, arr[hg19] 4q28.1q32.3 (127,008,069-165,250,477) x3 in a boy born at 36 weeks of gestation. He presented with microcephaly (head circumference <1st percentile), short stature (height <2nd percentile) and poor weight gain (weight <3rd percentile). Hypospadias and horseshoe shaped kidneys were also revealed following a urinary tract ultrasound. Biochemical analysis revealed normal growth hormone and thyroid hormone levels. While gross and fine motor skill development was in line with his age, speech delay was observed. This patient adds to a group of more than 30 cases of pure 4q tandem duplication with common and differing phenotypic presentations. Using a retrospective analysis of previous case studies alongside the current case and bioinformatics analysis of the duplicated region, we deduced the most likely dosage sensitive genes for some of the major phenotypes in the patient. The positive predictive value (PPV) was calculated for each gene and phenotype and was derived by comparing the previously reported patients who have gene duplications and an associated phenotype versus those who had the gene duplications but were unaffected. Thus, the growth retardation phenotype may be associated with NAA15 duplication, speech delay with GRIA2 and microcephaly with PLK4 duplication. Functional studies will help in confirming the observations and elucidating the mechanisms. However, our study highlights the importance of analysing case reports with pure duplications in defining phenotype-gene relationships and in improving our knowledge of the function of precise chromosomal regions.

Somatostatin analogues for the treatment of hyperinsulinaemic hypoglycaemia.

Hyperinsulinaemic hypoglycaemia (HH) is a biochemical finding of low blood glucose levels due to the dysregulation of insulin secretion from pancreatic ß-cells. Under normal physiological conditions, glucose metabolism is coupled to ß-cell insulin secretion so that blood glucose levels are maintained within the physiological range of 3.5-5.5 mmol/L. However, in HH this coupling of glucose metabolism to insulin secretion is perturbed so that insulin secretion becomes unregulated. HH typically occurs in the neonatal, infancy and childhood periods and can be due to many different causes. Adults can also present with HH but the causes in adults tend to be different. Somatostatin (SST) is a peptide hormone that is released by the delta cells (δ-cells) in the pancreas. It binds to G protein-coupled SST receptors to regulate a variety of location-specific and selective functions such as hormone inhibition, neurotransmission and cell proliferation. SST plays a potent role in the regulation of both insulin and glucagon secretion in response to changes in glucose levels by negative feedback mechanism. The half-life of SST is only 1-3 min due to quick degradation by peptidases in plasma and tissues. Thus, a direct continuous intravenous or subcutaneous infusion is required to achieve the therapeutic effect. These limitations prompted the discovery of SST analogues such as octreotide and lanreotide, which have longer half-lives and therefore can be administered as injections. SST analogues are used to treat different forms of HH in children and adults and therapeutic effect is achieved by suppressing insulin secretion from pancreatic ß-cells by complex mechanisms. These treatments are associated with several side effects, especially in the newborn period, with necrotizing enterocolitis being the most serious side effect and hence SS analogues should be used with extreme caution in this age group.

A SLC16A1 Mutation in an Infant With Ketoacidosis and Neuroimaging Assessment: Expanding the Clinical Spectrum of MCT1 Deficiency.

The solute carrier family 16 member 1 (SLC16A1) gene encodes for monocarboxylate transporter 1 (MCT1) that mediates the movement of monocarboxylates, such as lactate and pyruvate across cell membranes. Inactivating recessive homozygous or heterozygous mutations in the SLC16A1 gene were described in patients with recurrent ketoacidosis and hypoglycemia, a potentially lethal condition. In the brain where MCT1 is highly localized around axons and oligodendrocytes, glucose is the most crucial energy substrate while lactate is an alternative substrate. MCT1 mutation or reduced expression leads to neuronal loss due to axonal degeneration in an animal model. Herein, we describe a 28 months old female patient who presented with the first hypoglycemic attack associated with ketoacidosis starting at the age of 3 days old. Whole exome sequencing (WES) performed at 6 months of age revealed a c.218delG mutation in exon 3 in the SLC16A1 gene. The variant is expected to result in loss of normal MCT1 function. Our patient is amongst the youngest presenting with MCT1 deficiency. A detailed neuroimaging assessment performed at 18 months of age revealed a complex white and gray matter disease, with heterotopia. The threshold of blood glucose to circumvent neurological sequelae cannot be set because it is patient-specific, nevertheless, neurodevelopmental follow up is recommended in this patient. Further functional studies will be required to understand the role of the MCT1 in key tissues such as the central nervous system (CNS), liver, muscle and ketone body metabolism. Our case suggests possible neurological sequelae that could be associated with MCT1 deficiency, an observation that could facilitate the initiation of appropriate neurodevelopmental follow up in such patients.