An Italian case series' description of thiamine responsive megaloblastic anemia syndrome: importance of early diagnosis and treatment.

BACKGROUND: Individuals with thiamine-responsive megaloblastic anemia (TRMA) mainly manifest macrocytic anemia, sensorineural deafness, ocular complications, and nonautoimmune diabetes. Macrocytic anemia and diabetes may be responsive to high-dosage thiamine treatment, in contrast to sensorineural deafness. Little is known about the efficacy of thiamine treatment on ocular manifestations. CASES PRESENTATION: Our objective is to report data from four Italian TRMA patients: in Cases 1, 2 and 3, the diagnosis of TRMA was made at 9, 14 and 27 months. In 3 out of 4 subjects, thiamine therapy allowed both normalization of hyperglycemia, with consequent insulin suspension, and macrocytic anemia. In all Cases, thiamine therapy did not resolve the clinical manifestation of deafness. In Cases 2 and 3, follow-up showed no blindness, unlike Case 4, in which treatment was started for megaloblastic anemia at age 7 but was increased to high doses only at age 25, when the genetic diagnosis of TRMA was performed. CONCLUSIONS: Early institution of high-dose thiamine supplementation seems to prevent the development of retinal changes and optic atrophy in TRMA patients. The spectrum of clinical manifestations is broad, and it is important to describe known Cases to gain a better understanding of this rare disease.

Can obesity exacerbate hyperinsulinaemia in the presence of the mutation of an insulin receptor gene?

Insulin receptor gene (INSR) mutations are a relatively rare and diverse cause of insulin resistance (IR), typically associated with a lean phenotype. However, we present a unique case of severe obesity and Type A severe IR syndrome in a patient with a heterozygous mutation of the INSR gene. Next Generation Sequencing (NGS) analysis was conducted to identify the genetic variant. A 16-year-old girl with severe obesity (BMI-SDS +2.79) exhibited markedly elevated basal insulin levels (>800 mcU/L). Despite obesity being a known cause of hyperinsulinism, further investigation was pursued due to the severity of hyperinsulinaemia. A heterozygous nucleotide variant at the donor splicing site of intron 13 (c.2682 + 1G > A) of the INSR gene was identified. This mutation was also present in the proband's normal-weight mother and her two younger brothers with obesity. Metformin treatment provided limited benefits, but subsequent liraglutide therapy resulted in weight loss and decreased IR 3 months after initiation. Our findings suggest that obesity can exacerbate hyperinsulinaemia in individuals with an INSR gene mutation. Although INSR signalling defects play a minor role in the aetiology of IR, they should still be considered in the diagnostic pathway, particularly in severe phenotypes. Clinicians should not overlook the possibility of genetic causes in patients with obesity and IR, as they may require personalized management approaches.

The Pathogenic Diagnosis in Pediatric Diabetology: Next Generation Sequencing and Precision Therapy.

In pediatric diabetology, a precise diagnosis is very important because it allows early and correct clinical management of the patient. Monogenic diabetes (MD), which accounts for 1-6% of all pediatric-adolescent diabetes cases, is the most relevant example of precision medicine. The definitive diagnosis of MD, possible only by genetic testing, allows us to direct patients to more appropriate therapy in relation to the identified mutation. In some cases, MD patients can avoid insulin and be treated with oral hypoglycemic drugs with a perceptible impact on both the quality of life and the healthcare costs. However, the genetic and phenotypic heterogeneity of MD and the overlapping clinical characteristics between different forms, can complicate the diagnostic process. In recent years, the development of Next-Generation Sequencing (NGS) methodology, which allows the simultaneous analysis of multiple genes, has revolutionized molecular diagnostics, becoming the cornerstone of MD precision diagnosis. We report two cases of patients with clinical suspects of MD in which a genetic test was carried out, using a NGS multigenic panel, and it clarified the correct pathogenesis of diabetes, allowing us to better manage the disease both in probands and other affected family members.

Metabolic Treatment of Wolfram Syndrome.

Wolfram Syndrome (WS) is a very rare genetic disorder characterized by several symptoms that occur from childhood to adulthood. Usually, the first clinical sign is non-autoimmune diabetes even if other clinical features (optic subatrophy, neurosensorial deafness, diabetes insipidus) may be present in an early state and may be diagnosed after diabetes' onset. Prognosis is poor, and the death occurs at the median age of 39 years as a consequence of progressive respiratory impairment, secondary to brain atrophy and neurological failure. The aim of this paper is the description of the metabolic treatment of the WS. We reported the experience of long treatment in patients with this syndrome diagnosed in pediatric age and followed also in adult age. It is known that there is a correlation between metabolic control of diabetes, the onset of other associated symptoms, and the progression of the neurodegenerative alterations. Therefore, a multidisciplinary approach is necessary in order to prevent, treat and carefully monitor all the comorbidities that may occur. An extensive understanding of WS from pathophysiology to novel possible therapy is fundamental and further studies are needed to better manage this devastating disease and to guarantee to patients a better quality of life and a longer life expectancy.

NGS Analysis Revealed Digenic Heterozygous GCK and HNF1A Variants in a Child with Mild Hyperglycemia: A Case Report.

Monogenic diabetes (MD) represents a heterogeneous group of disorders whose most frequent form is maturity-onset diabetes of the young (MODY). MD is predominantly caused by a mutation in a single gene. We report a case of a female patient with suspected MD and a positive family history for diabetes and obesity. In this patient, two gene variants have been identified by next-generation sequencing (NGS): one in the Glucokinase (GCK) gene reported in the Human Gene Mutation Database (HGMD) and in the literature associated with GCK/MODY, and the other in the hepatocyte nuclear factor 1A (HNF1A) gene not previously described. The GCK variant was also identified in the hyperglycemic father, whereas the HNF1A variant was present in the mother. This new case of digenic GCK/HNF1A variants identified in a hyperglycemic subject, evidences the importance of NGS analysis in patients with suspected MD. In fact, this methodology will allow us to both increase the number of diagnoses and to identify mutations in more than one gene, with a better understanding of the genetic cause, and the clinical course, of the disease.

Cystic Fibrosis-Related Diabetes (CFRD): Overview of Associated Genetic Factors.

Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population and is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that encodes for a chloride/bicarbonate channel expressed on the membrane of epithelial cells of the airways and of the intestine, as well as in cells with exocrine and endocrine functions. A common nonpulmonary complication of CF is cystic fibrosis-related diabetes (CFRD), a distinct form of diabetes due to insulin insufficiency or malfunction secondary to destruction/derangement of pancreatic betacells, as well as to other factors that affect their function. The prevalence of CFRD increases with age, and 40-50% of CF adults develop the disease. Several proposed hypotheses on how CFRD develops have emerged, including exocrine-driven fibrosis and destruction of the entire pancreas, as well as contrasting theories on the direct or indirect impact of CFTR mutation on islet function. Among contributors to the development of CFRD, in addition to CFTR genotype, there are other genetic factors related and not related to type 2 diabetes. This review presents an overview of the current understanding on genetic factors associated with glucose metabolism abnormalities in CF.

Congenital diabetes mellitus.

Congenital diabetes mellitus is a rare disorder characterized by hyperglycemia that occurs shortly after birth. We define "Diabetes of Infancy" if hyperglycemia onset before 6 months of life. From the clinical point of view, we distinguish two main types of diabetes of infancy: transient (TNDM), which remits spontaneously, and permanent (PNDM), which requires lifelong treatment. TNDM may relapse later in life. About 50% of cases are transient (TNDM) and 50% permanent. Clinical manifestations include severe intrauterine growth retardation, hyperglycemia and dehydration. A wide range of different associated clinical signs including facial dysmorphism, deafness and neurological, cardiac, kidney or urinary tract anomalies are reported. Developmental delay and learning difficulties may also be observed. In this paper we review all the causes of congenital diabetes and all genes and syndromes involved in this pathology. The discovery of the pathogenesis of most forms of congenital diabetes has made it possible to adapt the therapy to the diagnosis and in the forms of alteration of the potassium channels of the pancreatic Beta cells the switch from insulin to glibenclamide per os has greatly improved the quality of life. Congenital diabetes, although it is a very rare form, has been at the must of research in recent years especially for pathogenesis and pharmacogenetics. The most striking difference compared to the more frequent autoimmune diabetes in children (type 1 diabetes) is the possibility of treatment with hypoglycemic agents and the apparent lower frequency of chronic complications.

The Association of Autoimmune Diseases with Type 1 Diabetes Mellitus in Children Depends Also by the Length of Partial Clinical Remission Phase (Honeymoon).

Type 1 diabetes mellitus (DM) is characterized by irreversible, autoimmune, pancreatic ß-cell destruction. During the disease, some patients experience a phase of Partial Clinical Remission (PCR) known as "honeymoon." This is a transitory period that is characterized by insulin production by residual ß cells following DM diagnosis and initiating the insulin therapy. In this study, we aimed to evaluate the influence of insulin production on immune system after the onset of diabetes, and we showed that the duration of honeymoon period could be related to the onset of other autoimmune conditions. For this retrospective study, 159 children aged between 11 and 18 years with type 1 DM were eligible. They have been diagnosed diabetes at least 10 years ago and use exogenous insulin. Our results showed that younger age at the onset of Type 1 DM in children, predicts Celiac Disease. Female sex and low HCO3 levels at the onset of DM had a high predictive value on patients who did not experience longer Partial Clinical Remission phase. Patients with higher BMI at the diagnosis of DM experienced shorter honeymoon period than the average. Smaller of our patients who diagnosed just DM have more than 297 days honeymoon period with respect to patients with one associated autoimmune disease. This may be due to a continuous and prolonged stimulation of immune system during the period of honeymoon that predispose the patient to develop other TH1 diseases. The patients who experienced more than 297 days Partial Clinical Remission seem under risk of developing one other autoimmune disease more than the patients who experienced less than 297 days Partial Clinical Remission. We have to consider that this observation is very intriguing because many protocols spring-up to try prolonging the honeymoon period in patients with autoimmune DM. If this aim is important from a metabolic point of view, long follow-ups are needed to be sure that the risk of other autoimmune diseases does not increase.