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TRAPPC9 deficiency is an autosomal recessive disorder mainly associated with intellectual disability (ID), microcephaly, and obesity. Previously, TRAPPC9 deficiency has not been associated with biochemical abnormalities.Exome sequencing was performed in 3 individuals with ID and dysmorphic features. N-Glycosylation analyses were performed in the patients' blood samples to test for possible congenital disorder of glycosylation (CDG). TRAPPC9 gene, TRAPPC9 protein expression, and N-glycosylation markers were assessed in patient fibroblasts. Complementation with wild-type TRAPPC9 and immunofluorescence studies to assess TRAPPC9 expression and localization were performed. The metabolic consequences of TRAPPC9 deficiency were evaluated using tracer metabolomics.All 3 patients carried biallelic missense variants in TRAPPC9 and presented with an N-glycosylation defect in blood, consistent with CDG type I. Extensive investigations in patient fibroblasts corroborated TRAPPC9 deficiency and an N-glycosylation defect. Tracer metabolomics revealed global metabolic changes with several affected glycosylation-related metabolites.We identified 3 TRAPPC9 deficient patients presenting with ID, dysmorphic features, and abnormal glycosylation. On the basis of our findings, we propose that TRAPPC9 deficiency could lead to a CDG (TRAPPC9-CDG). The finding of abnormal glycosylation in these patients is highly relevant for diagnosis, further elucidation of the pathophysiology, and management of the disease.

Background Hyperinsulinemic hypoglycemia (HI) is the most frequent cause of recurrent hypoglycemia in children. Despite diagnostic and therapeutic advances, it remains an important cause of morbidity, leading to neurological complications, such as psychomotor retardation and epilepsy. Patients with diffuse drug-unresponsive HI manifest neurological impairment and neurobehavioral problems, even though surgically treated with a near-total pancreatectomy. Based on the analogies between HI and GLUT1 deficiency, both presenting with neuroglycopenia and lack of alternative cerebral energy sources, we administered a ketogenic diet (KD) in three drug-unresponsive GCK-HI patients with the aim of preserving neurodevelopment and avoiding the need of a near-total pancreatectomy. They presented recurrent symptomatic hypoglycemia, intellectual disability and refractory epilepsy. Patients were treated with classical KD for 79, 27 and 18 months, respectively. Results All patients became asymptomatic in a few days and showed an important improvement of the alert state. Epilepsy disappeared and no appearance of novel hypoglycemic lesions was detected with a brain MRI. Cognitive and adaptive abilities rapidly improved and normalized. IQ rose significantly from 81 to 111 (p = 0.04) in patient 1, from 82 vs 95 (p = 0.04) in patient 2, from 60 to 90 (p = 0.04) in patient 3. Conclusions We demonstrated the safety and efficacy of KD in the treatment of drug-unresponsive GCK-HI at a short and long-term. The neuroprotective effects of KD determined the recovery from epilepsy and intellectual disabilities and averted the need of a near-total pancreatectomy. All patients and their families reported an improvement of physical and psychosocial well-being, with a substantial improvement of their quality of life. These results might change the course and the quality of life of these patients and their families, having a relevant impact on human lives. Therefore, KD might be considered the elective treatment in unresponsive forms of GCK-HI.

Context: Single Large Scale Mitochondrial DNA (mtDNA) Deletions (SLSMDs), causing Pearson Syndrome (PS) and Kearns-Sayre Syndrome (KSS) are multisystemic diseases with multiple endocrine involvements. Adreno-cortical axis has not been systematically investigated in SLSMDs and so far, only 12 patients with adrenal insufficiency have been reported. Objective: To evaluate the involvement of adrenal axis and progression of adrenal insufficiency in SLSMDs patients. Methods: We enrolled, in a longitudinal monocentric study a large cohort of 18 patients with SLSMDs. All were systematically evaluated with adrenocorticotrophic hormone (ACTH), basal cortisol and ACTH stimulation tests at high (HDT) and low (LDT) doses to explore adrenal axis function. Results: At baseline, adrenal function was impaired in 67% of PS and 50% of KSS; of the 39% of patients with normal baseline function, all PS patients and 83% of KSS patients developed adrenal abnormalities during the follow-up. Response to HDT and LDT identified 4 types of adrenal function: normal, subclinical type I and II and Adrenal Insufficiency (AI). LDT resulted more sensitive than HDT to identify subclinical AI. Based on these results, we elaborated a diagnostic process to assess adreno-cortical axis in patients with SLSMDs, proving its utility as screening and diagnostic tool. Conclusion: We showed that adrenal insufficiency is a relevant part of clinical spectrum in SLSMDs. Basal and after-stimulus assessment of adrenal axis should be early and regularly investigated. Our proposed diagnostic process could help in early diagnosis, treatment and monitoring any degree of adrenal abnormalities.

Patients with hereditary fructose intolerance need to follow a life-long fructose dietary and drug restriction to prevent symptoms of intoxication. Concerns about vaccines administration have been manifested overtime, for the risk of a life-threatening acute intoxication. For this reason, at Ospedale Pediatrico Bambino Gesù we performed a deepen research from open sources, datasheets and Pharmaceutical Companies informations from the most common Italian and European vaccines, which are carried out in infancy and childhood. As a safe threshold of 2.4 mg/kg/dose was recently established for oral and parenteral (other than i.v.) route, the manuscript clarifies the safe administration of majority of vaccines in patients with hereditary fructose intolerance.

Methylcitric acid (MCA) analysis has been mainly utilized for the diagnosis of propionate disorders or as a second-tier test in newborn screening, but its utility for patients monitoring still needs to be established. We explored the potential contribution of MCA in the long-term management of organic acidurias. We prospectively evaluated plasma MCA and its relationship with disease biomarkers, clinical status, and disease burden in 22 patients, 13 with propionic acidemia (PA) and nine with methylmalonic acidemia (MMA) on standard treatment and/or after transplantation. Samples were collected at scheduled routine controls or during episodes of metabolic decompensation (MD), 10 patients were evaluated after transplantation (six liver, two combined liver and kidney, 2 kidney). MCA levels were higher in PA compared to MMA and its levels were not influenced by the clinical status (MD vs well state). In MMA, MCA was higher in elder patients and, along with fibroblast growth factor 21 (FGF21) and plasma methylmalonic acid, negatively correlated with GFR. In both diseases, MCA correlated with ammonia, glycine, lysine, C3, and the C3/C2, C3/C16 ratios. The disease burden showed a direct correlation with MCA and FGF21, for both diseases. All transplanted patients showed a significant reduction of MCA in comparison to baseline values, with some differences dependent on the type of transplantation. Our study provided new insights in understanding the disease pathophysiology, showing similarities between MCA and FGF21 in predicting disease burden, long-term complications and in evaluating the impact of organ transplantation.

A potential role of dietary lipids in the management of hepatic glycogen storage diseases (GSDs) has been proposed, but no consensus on management guidelines exists. The aim of this study was to describe current experiences with dietary lipid manipulations in hepatic GSD patients. An international study was set up to identify published and unpublished cases describing hepatic GSD patients with a dietary lipid manipulation. A literature search was performed according to the Cochrane Collaboration methodology through PubMed and EMBASE (up to December 2018). All delegates who attended the dietetics session at the IGSD2017, Groningen were invited to share unpublished cases. Due to multiple biases, only data on GSDIII were presented. A total of 28 cases with GSDIII and a dietary lipid manipulation were identified. Main indications were cardiomyopathy and/or myopathy. A high fat diet was the most common dietary lipid manipulation. A decline in creatine kinase concentrations (n = 19, P

Congenital hyperinsulinism (HI) is a life-threatening condition characterized by severe and recurrent episodes of hypoglycaemia due to defects in key genes involved in regulating insulin secretion. The delay in diagnosis and inappropriate management of HI lead to high risk of permanent hypoglycemic brain injury. The management of HI is challenging as each form of HI (focal, diffuse, and atypical) requires its own therapeutic strategy. In HI diagnostic work-up, integrated PET/CT scan is currently the first-line imaging technique allowing to differentiate between diffuse and focal form and, in the latter case, to localize the focus within the pancreas with high precision. Only in focal HI partial pancreatectomy is the treatment of choice and a curative surgical treatment means a real chance of transforming patient’s lives and HI patient’s future. The aim of this review is to discuss the role of PET/CT imaging in HI scenario, its technical advantages and limitations and how successful surgery is strongly dependent on accurate preoperative assessment (genetic analysis and PET/CT scan). A multidisciplinary approach in HI diagnosis and treatment inside a single team (involving different expertise) allows to manage children safely and properly, supporting their families in an organized care network.

A large number of inborn errors of metabolism present with hypoglycemia. Impairment of glucose homeostasis may arise from different biochemical pathways involving insulin secretion, fatty acid oxidation, ketone bodies formation and degradation, glycogen metabolism, fructose and galactose metabolism, branched chain aminoacids and tyrosine metabolism, mitochondrial function and glycosylation proteins mechanisms. Historically, genetic analysis consisted of highly detailed molecular testing of nominated single genes. However, more recently, the genetic heterogeneity of these conditions imposed to perform extensive molecular testing within a useful timeframe via new generation sequencing technology. Indeed, the establishment of a rapid diagnosis drives specific nutritional and medical therapies. The biochemical and clinical phenotypes are critical to guide the molecular analysis toward those clusters of genes involved in specific pathways, and address data interpretation regarding the finding of possible disease-causing variants at first reported as variants of uncertain significance in known genes or the discovery of new disease genes. Also, the trio’s analysis allows genetic counseling for recurrence risk in further pregnancies. Besides, this approach is allowing to expand the phenotypic characterization of a disease when pathogenic variants give raise to unexpected clinical pictures. Multidisciplinary input and collaboration are increasingly key for addressing the analysis and interpreting the significance of the genetic results, allowing rapidly their translation from bench to bedside.

The Ketogenic Diet (KD) is a high-fat, low-carbohydrate diet that has been utilized as the first line treatment for contrasting intractable epilepsy. It is responsible for the presence of ketone bodies in blood, whose neuroprotective effect has been widely shown in recent years but remains unclear. Since glutathione (GSH) is implicated in oxidation-reduction reactions, our aim was to monitor the effects of KD on GSH brain levels by means of magnetic resonance spectroscopy (MRS). MRS was acquired from 16 KD patients and seven age-matched Healthy Controls (HC). We estimated metabolite concentrations with linear combination model (LCModel), assessing differences between KD and HC with t-test. Pearson was used to investigate GHS correlations with blood serum 3-B-Hydroxybutyrate (3HB) concentrations and with number of weekly epileptic seizures. The results have shown higher levels of brain GSH for KD patients (2.5 ± 0.5 mM) compared to HC (2.0 ± 0.5 mM). Both blood serum 3HB and number of seizures did not correlate with GSH concentration. The present study showed a significant increase in GSH in the brain of epileptic children treated with KD, reproducing for the first time in humans what was previously observed in animal studies. Our results may suggest a pivotal role of GSH in the antioxidant neuroprotective effect of KD in the human brain.

Hyperinsulinemic hypoglycemia (HI) is the most common cause of hypoglycemia in children. Impairment of cellular pathways involved in insulin secretion from pancreatic β-cells, broadly classified as channelopathies and metabolopathies, have been discovered in the past two decades. The increasing use of NGS target panels, combined with clinical, biochemical and imaging findings allows differentiating the diagnostic management of children with focal forms, surgically curable, from those with diffuse forms, more conservatively treated with pharmacological and nutritional interventions. Specific approaches according to the subtype of HI have been established and novel therapies are currently under investigation. Despite diagnostic and therapeutic advances, HI remains an important cause of morbidity in children, still accounting for 26-44% of permanent intellectual disabilities, especially in neonatal-onset patients. Initial insult from recurrent hypoglycemia in early life greatly contributes to the poor outcomes. Therefore, patients need to be rapidly identified and treated aggressively, and require at follow-up a complex and regular monitoring, managed by a multidisciplinary HI team. This review gives an overview on the more recent diagnostic and therapeutic tools, on the novel drug and nutritional therapies, and on the long-term neurological outcomes.

Objectives To evaluate the role of next generation sequencing in genetic diagnosis of pediatric patients with persistent hypoglycemia. Study design Sixty-four patients investigated through an extensive workup were divided in 3 diagnostic classes based on the likelihood of a genetic diagnosis: (1) single candidate gene (9/64); (2) multiple candidate genes (43/64); and (3) no candidate gene (12/64). Subsequently, patients were tested through a custom gene panel of 65 targeted genes, which included 5 disease categories: (1) hyperinsulinemic hypoglycemia, (2) fatty acid-oxidation defects and ketogenesis defects, (3) ketolysis defects, (4) glycogen storage diseases and other disorders of carbohydrate metabolism, and (5) mitochondrial disorders. Molecular data were compared with clinical and biochemical data. Results A proven diagnosis was obtained in 78% of patients with suspicion for a single candidate gene, in 49% with multiple candidate genes, and in 33% with no candidate gene. The diagnostic yield was 48% for hyperinsulinemic hypoglycemia, 66% per fatty acid-oxidation and ketogenesis defects, 59% for glycogen storage diseases and other carbohydrate disorders, and 67% for mitochondrial disorders. Conclusions This approach provided a diagnosis in ~50% of patients in whom clinical and laboratory evaluation did not allow identification of a single candidate gene and a diagnosis was established in 33% of patients belonging to the no candidate gene class. Next generation sequencing technique is cost-effective compared with Sanger sequencing of multiple genes and represents a powerful tool for the diagnosis of inborn errors of metabolism presenting with persistent hypoglycemia.

Hereditary tyrosinemia type 1 (HT1) is characterized by severe progressive liver disease and renal tubular dysfunction. Kidney involvement is characterized by hypophosphatemic rickets and Fanconi syndrome. Different animal models were useful to investigate the pathophysiology of the disease and the effects of NTBC therapy on liver and kidney function. NTBC has revolutionized the prognosis of HT1 and its acute and chronic effects on renal tubular function have been proved, with normalization of tubular function within a few weeks, particularly hypophosphatemia and proteinuria. NTBC therapy is highly effective in improving renal function both at short and long-term. However, its efficacy critically depends on the age at start of treatment with normal outcome in patients diagnosed at birth by newborn screening.

Hereditary tyrosinemia type 1 (HT1) is characterized by severe progressive liver disease and renal tubular dysfunction. Kidney involvement is characterized by hypophosphatemic rickets and Fanconi syndrome. Different animal models were useful to investigate the pathophysiology of the disease and the effects of NTBC therapy on liver and kidney function. NTBC has revolutionized the prognosis of HT1 and its acute and chronic effects on renal tubular function have been proved, with normalization of tubular function within a few weeks, particularly hypophosphatemia and proteinuria. NTBC therapy is highly effective in improving renal function both at short and long-term. However, its efficacy critically depends on the age at start of treatment with normal outcome in patients diagnosed at birth by newborn screening.

Background Hereditary tyrosinemia type 1 (HT1) is characterized by severe progressive liver disease and renal tubular dysfunction. NTBC therapy has revolutionized the management of HT1 but its effect on renal tubular function has so far been poorly investigated. The aim of this study was to describe the early effect of NTBC on renal tubular disease in patients with HT1. Methods Five HT1 patients (age between 5 and 53 months) with different types of presentation were evaluated before and during the first 2 weeks of therapy with NTBC in a retrospective case analysis for phosphate metabolism and renal tubular function. Results Before starting NTBC therapy, all children manifested signs of renal dysfunction which included hypophosphatemia, acidosis, reduced phosphate reabsorption, aminoaciduria, glycosuria (Fanconi syndrome), and variable degree of proteinuria. Some patients also presented increased urinary calcium/creatinine ratio and raised fractional excretion of sodium. Starting of NTBC therapy resulted in the rapid normalization of plasma phosphate within one week from its initiation in majority of patients and in all patients during the second week of therapy. TmP/GFR normalized in 48 h, while the other markers of renal dysfunction showed an improving trend over 2 weeks. Conclusions NTBC is an efficient treatment for renal tubular dysfunction in HT1, allowing the return to normal function within a few weeks. Its early effect on renal tubular cells appeared to be very rapid, particularly in normalizing plasma phosphate and TmP/GFR. In our series of patients, the TmP/GFR resulted as the most reliable index of tubular function.

Dihydrolipoamide dehydrogenase (DLD, E3) is a flavoprotein common to pyruvate, α-ketoglutarate and branched-chain α-keto acid dehydrogenases. We found two novel DLD mutations (p.I40Lfs*4; p.G461E) in a 19 year-old patient with lactic acidosis and a complex amino- and organic aciduria consistent with DLD deficiency, manifesting progressive exertional fatigue. Muscle biopsy showed mitochondrial proliferation and lack of DLD cross-reacting material. Riboflavin supplementation determined the complete resolution of exercise intolerance with the partial restoration of the DLD protein and disappearance of mitochondrial proliferation in the muscle. Morphological and functional studies support the riboflavin chaperon-like role in stabilizing DLD protein with rescue of its expression in the muscle.

Objective: Congenital hyperinsulinism (CHI) requires rapid diagnosis and treatment to avoid irreversible neurological sequelae due to hypoglycaemia. Aetiological diagnosis is instrumental in directing the appropriate therapy. Current diagnostic algorithms provide a complete set of diagnostic tools including (i) biochemical assays, (ii) genetic facility and (iii) state-of-the-art imaging. They consider the response to a therapeutic diazoxide trial an early, crucial step before proceeding (or not) to specific genetic testing and eventually imaging, aimed at distinguishing diffuse vs focal CHI. However, interpretation of the diazoxide test is not trivial and can vary between research groups, which may lead to inappropriate decisions. Objective of this report is proposing a new algorithm in which early genetic screening, rather than diazoxide trial, dictates subsequent clinical decisions. Patients, Methods and Results: Two CHI patients weaned from parenteral glucose infusion and glucagon after starting diazoxide. No hypoglycaemia was registered during a 72-h continuous glucose monitoring (CGMS), or hypoglycaemic episodes were present for no longer than 3% of 72-h. Normoglycaemia was obtained by low–medium dose diazoxide combined with frequent carbohydrate feeds for several years. We identified monoallelic, paternally inherited mutations in KATP channel genes, and 18F-DOPA PET-CT revealed a focal lesion that was surgically resected, resulting in complete remission of hypoglycaemia. Conclusions: Although rare, some patients with focal lesions may be responsive to diazoxide. As a consequence, we propose an algorithm that is not based on a ‘formal’ diazoxide response but on genetic testing, in which patients carrying paternally inherited ABCC8 or KCNJ11 mutations should always be subjected to 18F-DOPA PET-CT.

Background Glycogen storage disease type III (GSDIII) is caused by mutations of AGL gene with debranching enzyme deficiency. Patients with GSDIII manifest fasting hypoglycemia, hepatomegaly, hepatopathy, myopathy, and cardiomyopathy. We report on an 18‐year‐old boy with a profound growth retardation (

Congenital hyperinsulinism (CHI) is a genetic disorder characterized by profound hypoglycemia related to an inappropriate insulin secretion. It is a heterogeneous disease classified into two major subgroups: "channelopathies" due to defects in ATP-sensitive potassium channel, encoded by ABCC8 and KCNJ11 genes, and "metabolopathies" caused by mutation of several genes (GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) and involved in different metabolic pathways. To elucidate the genetic etiology of CHI in the Italian population, we conducted an extensive sequencing analysis of the CHI-related genes in a large cohort of 36 patients: Twenty-nine suffering from classic hyperinsulinism (HI) and seven from hyperinsulinism-hyperammonemia (HI/HA). Seventeen mutations have been found in fifteen HI patients and five mutations in five HI/HA patients. Our data confirm the major role of ATP-sensitive potassium channel in the pathogenesis of Italian cases (~70%) while the remaining percentage should be attributed to other. A better knowledge of molecular basis of CHI would lead to improve strategies for genetic screening and prenatal diagnosis. Moreover, genetic analysis might also help to distinguish the two histopathological forms of CHI, which would lead to a clear improvement in the treatment and in genetic counseling.

OBJECTIVE The ATP-sensitive K+ channel (KATP) controls insulin secretion from the islet. Gain- or loss-of-function mutations in channel subunits underlie human neonatal diabetes and congenital hyperinsulinism (HI), respectively. In this study, we sought to identify the mechanistic basis of KATP-induced HI in two probands and to characterize the clinical course. RESEARCH DESIGN AND METHODS We analyzed HI in two probands and characterized the course of clinical treatment in each, as well as properties of mutant KATP channels expressed in COSm6 cells using Rb efflux and patch-clamp methods. RESULTS We identified mutation V290M in the pore-forming Kir6.2 subunit in each proband. In vitro expression in COSm6 cells supports the mutation resulting in an inactivating phenotype, which leads to significantly reduced activity in intact cells when expressed homomerically, and to a lesser extent when expressed heteromerically with wild-type subunits. In one heterozygous proband, a fluoro-DOPA scan revealed a causal focal lesion, indicating uniparental disomy with loss of heterozygosity. In a second family, the proband, homozygous for the mutation, was diagnosed with severe diazoxide–unresponsive hypersinsulinism at 2 weeks of age. The patient continues to be treated successfully with octreotide and amlodipine. The parents and a male sibling are heterozygous carriers without overt clinical HI. Interestingly, both the mother and the sibling exhibit evidence of abnormally enhanced glucose tolerance. CONCLUSIONS V290M results in inactivating KATP channels that underlie HI. Homozygous individuals may be managed medically, without pancreatectomy. Heterozygous carriers also show evidence of enhanced glucose sensitivity, consistent with incomplete loss of KATP channel activity.

Background/Aim: Visceral adipose tissue plays a pivotal role in the pathogenesis of metabolic syndrome. Several investigations refer to the physiology of subcutaneous and visceral adipose tissue of adult obese subjects, focusing on the characterization of adipose-derived stem cells and their differentiation capacity. To date, no study has been carried out on visceral adipose tissue of children, the main limitation being the amount of fat tissue available. The aim of this investigation was to establish a method to successfully isolate adipose progenitor cells from very small specimens of omental fat obtained from children undergoing abdominal surgery. Methods: A previously described procedure employed to extract adipose progenitors from large amounts of lipoaspirate was modified. 0.5-cm3 specimens of omental fat were collected from 13 children and 2 newborns. Primary, secondary and higher passaged adipocytic progenitor cell cultures were established. Immunophenotyping of the generated lines was carried out by flow cytometry analysis. Differentiation experiments concerning the adipogenic phenotype were conducted. Results: A feasible method for isolating adipose progenitors from pediatric specimens of omental fat was established. Cells showed a fibroblast-like appearance consistent with that of mesenchymal stem cells obtained from bone marrow. The mesenchymal phenotype was confirmed by the surface antigenic profile of these cells. Cells also underwent adipogenic differentiation in vitro. Conclusion: The availability of progenitor primary cell lines from omental adipose tissue of children may allow future investigations aimed at unraveling whether fetal programming of adipogenesis is responsible for the pathogenesis of the metabolic syndrome that develops during adulthood in subjects, born with low birth weight, typically showing central fat redistribution.

Adipose tissue is involved in the regulation of glucose and lipid metabolism, energy balance, inflammation and immune response. Abdominal obesity plays a key role in the development of insulin resistance because of the high lipolytic rate of visceral adipose tissue and its secretion of adipocytokines. Low birth weight subjects are prone to central redistribution of adipose tissue and are at high risk of developing metabolic syndrome, type 2 diabetes and cardiovascular disease. Intrauterine adipogenesis may play a key role in the fetal origin of the pathogenesis of metabolic syndrome, type 2 diabetes and cardiovascular disease. Therefore, knowledge of the behavior of visceral adipose tissue-derived stem cells could provide a greater understanding of the metabolic risk related to intrauterine growth retardation, with potential clinical implications for the prevention of long-term metabolic alterations.

Background Congenital hyperinsulinism (CHI) is the most frequent cause of hypoglycemia in children. In addition to increased peripheral glucose utilization, dysregulated insulin secretion induces profound hypoglycemia and neuroglycopenia by inhibiting glycogenolysis, gluconeogenesis and lipolysis. This results in the shortage of all cerebral energy substrates (glucose, lactate and ketones), and can lead to severe neurological sequelae. Patients with CHI unresponsive to medical treatment can be subjected to near-total pancreatectomy with increased risk of secondary diabetes. Ketogenic diet (KD), by reproducing a fasting-like condition in which body fuel mainly derives from beta-oxidation, is intended to provide alternative cerebral substrates such ketone bodies. We took advantage of known protective effect of KD on neuronal damage associated with GLUT1 deficiency, a disorder of impaired glucose transport across the blood-brain barrier, and administered KD in a patient with drug-unresponsive CHI, with the aim of providing to neurons an energy source alternative to glucose. Methods A child with drug-resistant, long-standing CHI caused by a spontaneous GCK activating mutation (p.Val455Met) suffered from epilepsy and showed neurodevelopmental abnormalities. After attempting various therapeutic regimes without success, near-total pancreatectomy was suggested to parents, who asked for other options. Therefore, we proposed KD in combination with insulin-suppressing drugs. Results We administered KD for 2 years. Soon after the first six months, the patient was free of epileptic crises, presented normalization of EEG, and showed a marked recover in psychological development and quality of life. Conclusions KD could represent an effective treatment to support brain function in selected cases of CHI.

Fetal growth restriction is associated with an increased risk of developing insulin resistance and type 2 diabetes in adulthood. In addition, 10-20% of children born small for gestational age (SGA) do not achieve a normal final height. The purpose of this study was to investigate insulin sensitivity and endocrine status in SGA children, compared with that in children born appropriate for gestational age (AGA). Furthermore, within the SGA group, we aimed to relate postnatal growth to anthropometric, biochemical, and endocrine parameters. Eighty-two SGA children (with a mean age of 8.6 +/- 3.5 yr) and 53 short-AGA children (with a mean age of 9.3 +/- 3.3 yr) were studied. A case-control study was carried out in 26 SGA and 26 short-AGA subjects. For each SGA subject, we selected a short-AGA child matched for sex, age (within 1 yr), pubertal status, body mass index (within 0.5 kg/m(2)), and height (within 0.25 z-score). Children's statures were corrected for their midparental height, and SGA children were subdivided into 2 groups: catch-up growth (CG) group (children with corrected height with at least 0 z-score); and non-CG (NCG) group (subjects with corrected height with less than 0 z-score). Comparing SGA with short-AGA subjects, no significant differences in fasting insulin, fasting glucose/insulin ratio, homeostasis assessment model for insulin resistance, and homeostasis assessment model-beta-cell values were observed. SGA children showed significantly reduced levels of glucose (4.4 +/- 0.6 vs. 4.9 +/- 0.6 mM, P < 0.0001), total cholesterol (160.1 +/- 28.8 vs. 171.8 +/- 28.5 mg/dl, P = 0.02), and high-density-lipoprotein cholesterol (53.3 +/- 12.1 vs. 58 +/- 11.4 mg/dl, P = 0.02). The analysis of the subjects selected for the case-control study confirmed that SGA children did not have significant differences in the indices of insulin sensitivity but showed significantly lower glucose levels (4.4 +/- 0.7 vs. 4.9 +/- 0.4 mM, P < 0.005). Subdividing the SGA group into CG (n = 25) and NCG (n = 57) children, we found that NCG children showed significantly higher levels of TSH (2.5 +/- 1.3 vs. 1.9 +/- 0.6 mU/liter, P = 0.002). Our data indicate that SGA children do not have altered insulin sensitivity when compared with auxologically identical AGA subjects but show a significant reduction of glucose concentrations. Whether the lower glucose levels are attributable to an early phase of augmented insulin sensitivity, as previously reported in animal models, has to be established. The finding of higher TSH concentrations in SGA children with blunted CG suggests that intrauterine reprogramming might involve thyroid function, which, in turn, might affect postnatal growth and cholesterol metabolism, eventually increasing the risk of cardiovascular disease.

Background: Hepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data. Methods. Via questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications. Results: Early treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (, SCOPUS: ar.j, info:eu-repo/semantics/published

The lysosomal acid lipase (LAL) is the enzyme responsible of the hydrolysis of cholesteryl esters and triglycerides within endo-lysosomes. Loss of enzyme activity leads to accumulation of cholesteryl esters and triglycerides in the lysosome of most tissues. The complete deficiency of LAL is responsible of Wolman disease (WD), a severe systemic disease manifesting in the first days of life with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, jaundice, anemia, and thrombocytopenia. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition which may be genetically determined or secondary to infections, malignancies, immune deficiencies, and rheumatologic disorders. So far, some inborn errors of metabolism have been associated with HLH (e.g., lysinuric protein intolerance, Gaucher’s disease), and it has been anecdotally described in three WD patients, without any specific pathogenetic hypothesis. Here, we report on a WD patient, showing clear clinical, biochemical, and histological features indicative of HLH. We discuss the pathophysiological role of cholesteryl ester-induced inflammasome activation in macrophages, leading to a secondary HLH. Conclusion: This case indicates that WD can cause secondary HLH and suggests that a careful metabolic workup should be performed when facing to a pediatric patient with HLH.

Aims: To investigate (a) the prevalence of insulin resistance in children with intrauterine growth retardation (IUGR); (b) whether catch-up growth is associated with a higher risk of insulin resistance; (c) the insulin-like growth factor (IGF) system status. Methods: 49 children with IUGR aged 9.1 ± 3.3 years underwent anthropometric measurements, and assessment of insulin resistance and IGF system parameters. A fasting glucose/insulin ratio (G/I) Results: 11/49 (22%) children had a G/I Conclusions: (a) Children with IUGR have a high prevalence of reduced insulin sensitivity; (b) postnatal catch-up growth is related to intrauterine growth and actual nutritional status; (c) insulin sensitivity status is not related to postnatal growth but to liver function; (d) IGF system is normal and not related to the insulin resistance parameters during childhood.

Objective Refeeding syndrome can occur in several contexts of relative malnutrition in which an overaggressive nutritional support is started. The consequences are life threatening with multiorgan impairment, and severe electrolyte imbalances. During refeeding, glucose-involved insulin secretion causes abrupt reverse of lipolysis and a switch from catabolism to anabolism. This creates a sudden cellular demand for electrolytes (phosphate, potassium, and magnesium) necessary for synthesis of adenosine triphosphate, glucose transport, and other synthesis reactions, resulting in decreased serum levels. Laboratory findings and multiorgan impairment similar to refeeding syndrome also are observed in acute thiamine deficiency. The aim of this study was to determine whether thiamine deficiency was responsible for the electrolyte imbalance caused by tubular electrolyte losses. Methods We describe two patients with leukemia who developed acute thiamine deficiency with an electrolyte pattern suggestive of refeeding syndrome, severe lactic acidosis, and evidence of proximal renal tubular dysfunction. Results A single thiamine administration led to rapid resolution of the tubular dysfunction and normalization of acidosis and electrolyte imbalance. This demonstrated that thiamine deficiency was responsible for the electrolyte imbalance, caused by tubular electrolyte losses. Conclusions Our study indicates that, despite sharing many laboratory similarities, refeeding syndrome and acute thiamine deficiency should be viewed as separate entities in which the electrolyte abnormalities reported in cases of refeeding syndrome with thiamine deficiency and refractory lactic acidosis may be due to renal tubular losses instead of a shifting from extracellular to intracellular compartments. In oncologic and malnourished patients, individuals at particular risk for developing refeeding syndrome, in the presence of these biochemical abnormalities, acute thiamine deficiency should be suspected and treated because it promptly responds to thiamine administration.

Familial hypercholesterolemia is an autosomal codominant disorder associated with markedly elevated plasma concentration of LDL-cholesterol and increased cardiovascular risk. Homozygous patients have rapid development of atherosclerosis with death from cardiovascular disease even in childhood. Life-long recurrent apheresis to reduce plasma LDL-cholesterol is considered the gold standard for treatment. Liver transplantation can be curative for this condition, but is usually only considered after the development of cardiovascular disease. We report a 5.5-yr-old child initially misdiagnosed with heterozygous familial hypercholesterolemia and treated by low-fat diet only. In view of persistent hypercholesterolemia and development of xanthomatosis, new molecular studies indicated the presence of two different mutations in the LDL receptor gene, with one being a deletion of two exons not identifiable with standard sequencing analysis. Recurrent plasma apheresis in combination with statins lowered, but did not normalize plasma LDL-cholesterol levels. It caused progressive reduction of the size of xanthomas and prevented the development of vascular complications. After two yr, liver transplantation normalized LDL-cholesterol levels and completely resolved the skin lesions. Preemptive liver transplantation is a definitive cure of familial homozygous hypercholesterolemia and might be more effective if performed before development of vascular complications.

CONTEXT: Use of growth hormone (GH) therapy to promote growth in short children born small for gestational age (SGA) was recently approved in the United States and Europe, but there is still disagreement about the magnitude of effectiveness of GH. OBJECTIVE: To determine the impact of GH therapy on adult height in short SGA children by a meta-analysis of randomized, controlled trials (RCTs). METHODS: We performed a systematic review of controlled studies using as data sources the Cochrane Central Register of Controlled Trials, Medline, and the bibliographic references from all retrieved articles describing RCTs up to November 2008. A meta-analysis of all RCT studies conducted up to the achievement of adult height was performed. Inclusion criteria were birth weight and/or length below −2 SD score (SDS), initial height less than −2 SDS, and GH dose range of 33 to 67 μg/kg per day. Adult height SDS and overall height gain SDS were the primary outcome measures. RESULTS: Four RCTs (391 children) met the inclusion criteria. The adult height of the GH-treated group significantly exceeded controls by 0.9 SDS. Mean height gain was 1.5 SDS in treated versus 0.25 SDS in untreated SGA subjects. No significant difference in adult height was observed between the 2 GH dose regimens. CONCLUSIONS: GH therapy seems to be an effective approach to partially reduce the adult height deficit in short SGA children. However, the response to therapy is highly variable, and additional studies are needed to identify the responders.

The biologic effects of insulin-like growth factor-1 (IGF-1) are mediated by specific cell surface receptors. IGF-1 binding to the extracellular α-subunits activates the tyrosine kinase intrinsic to