Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported. CASE PRESENTATION: We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness. CONCLUSION: KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.

Assessment of the Clinical Impact of a Liver-Specific, BCAA-Enriched Diet in Major Liver Surgery.

BACKGROUND: The relationship between nutrition and liver disease is relevant for the outcome after surgery. Patients with liver cirrhosis characteristically show protein-energy malnutrition with decreased levels of branched-chain amino acids (BCAA) and increased levels of aromatic amino acids. MATERIALS AND METHODS: We conducted a prospective controlled clinical trial including 57 patients after liver transplantation or major liver resection surgery in order to test the effect of early postoperative nutrition on the outcome and nutrition profile of these patients. The test group received a dietetic program composed of ingredients naturally rich in BCAA (BCAA group), and the control group received standard hospital meals. Patient survival, liver function tests, subjective well-being, and a nutritional status including amino acid profiles were analyzed immediately and 14 days after major liver surgery (secondary end points). General health and well-being were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (primary end point). RESULTS: In-depth analysis of amino acid profiles was performed for patients undergoing liver resection (n = 21) and liver transplantation (n = 36). Interestingly, amino acid profiles did not correlate with body mass index or the Model for End-Stage Liver Disease score. Patients scheduled for liver transplantation showed significantly lower levels of BCAA pretransplant compared to patients undergoing liver resection. Patients in the liver resection subgroup were more likely to benefit from the BCAA cuisine in terms of significantly higher food intake and subjective rating. The clinical liver function tests, however, did not show statistical difference between the BCAA group and the control group in the examination period of 14 days. CONCLUSION: Our specifically designed BCAA-enriched diet resulted in greater patient satisfaction and compliance with nutrition. A larger trial or longer-term follow-up may be required to identify an effect on survival, recovery, surgical complications, protein profiles, and amino acid profiles.

Pregnancy management and outcome in patients with four different tetrahydrobiopterin disorders.

INTRODUCTION: Inborn errors of tetrahydrobiopterin (BH4) biosynthesis or recycling are a group of very rare neurometabolic diseases. Following growing awareness and improved availability of drug treatment the number of patients with BH4 disorders reaching adulthood is constantly increasing. Pregnancy care of patients with these disorders is therefore a new challenge for clinicians. METHODS: This retrospective study summarises for the first time clinical and biochemical monitoring data of 16 pregnancies in seven women with different disorders of BH4 metabolism and evaluates treatment regimens before and during pregnancy in relation to the obstetrical outcome and paediatric follow-up. RESULTS: Worsening of pre-existing neurological symptoms or occurrence of new symptoms during pregnancy was not observed in most of the cases. Treatment regimens remained mostly unchanged. Pregnancies were not complicated by disease-specific features. Organ abnormalities, miscarriage, prematurity, IUGR and chromosomal changes were occasionally reported, without showing any association with the standard drug treatment for BH4 deficiencies. CONCLUSION: Although our data on 16 pregnancies in seven patients did not present any association of standard drug treatment with an increased rate of pregnancy complications, abnormal obstetrical or paediatric outcome, an intensive clinical and biochemical supervision by a multidisciplinary team before, during and after the pregnancy in any BH4 deficiency is essential since available data on pregnancies in patients with BH4 deficiencies is limited.

Decreased Urinary Sodium-to-urinary Creatinine Ratio Identifies Sodium Depletion in Pediatric Acute Gastroenteritis.

UNLABELLED: In acute gastroenteritis (AG) fecal losses may cause depletion of sodium (NaD) which may not be recognized because of normal plasma Na (pNa) concentrations. We studied the incidence of this state of normonatremic sodium depletion (NNaD) and the suitability of the urinary Na/urinary creatinine ratio (uNa/uCr) for diagnosing NNaD. PATIENTS: 16 AG- and 16 healthy control children aged 0.8-15.0 years. METHODS: Prospective cross sectional pilot study. Measurements of Na, K and creatinine in plasma (p) and urine (u). Calculation of uNa/uCr Ratio, fractional excretion of Na (FENa) and uNa/uK ratio as the hitherto best known parameters of prerenal Na depletion, respectively. RESULTS: pNa concentrations were normal in 15/16 AG patients (93.8%) with only one subnormal value of 133 mmol/L, and a mean value of 137.9±2.3 mmol/L not different from the normal control group (139.4±2.2 mmol/L). Also, mean uNa concentrations and uNa/uK ratios did not differ between both groups. However, uNa/uCr ratios were below normal in 13/16 AG children (81.3%) but normal in all healthy controls with a significantly lower mean value in the AG group (12.6±8.8 vs. 31.2±8.3 mmol/mmol; p<0.0001). Similarly, 14/16 AG patients (87.5%) had a decreased FENa<0.5% with a mean FENa value significantly lower than in controls (0.36±0.28% vs. 0.95±0.26%, p<0.0001). The good agreement between FENa and uNa/uCr results was also reflected by a high correlation coefficient of r=0.9333. CONCLUSIONS: The majority of AG patients was found to have NNaD as determined by uNa/uCr and FENa. Calculation of uNa/uCr may be useful for diagnosing NNaD in AG.

Ketogenic diets in patients with inherited metabolic disorders.

Ketogenic diets (KDs) are diets that bring on a metabolic condition comparable to fasting, usually without catabolism. Since the mid-1990s such diets have been widely used in patients with seizures/epilepsies, mostly children. This review focuses on the use of KDs in patients with various inherited metabolic disorders (IMD). In glucose transporter type 1 deficiency syndrome (GLUT1-DS) and pyruvate dehydrogenase complex (PDHc) deficiency, KDs are deemed the therapy of choice and directly target the underlying metabolic disorder. Moreover, in other IMD, mainly of intermediary metabolism such as glycogen storage diseases and disorders of mitochondrial energy supply, KDs may ameliorate clinical symptoms and laboratory parameters. KDs have also been used successfully to treat symptoms such as seizures/epilepsy in IMD, e.g. in urea cycle disorders and non-ketotic hyperglycinemia. As a note of caution, catabolism may cause the condition of patients with IMD to deteriorate and should thus be avoided during KDs. For this reason, careful monitoring (clinical, laboratory and apparatus-supported) is warranted. In some IMDs specific macronutrient supply is critical. Therefore, in cases of PDHc deficiency the carbohydrate intake tolerated without lactate increase and in urea cycle disorders the protein tolerance should be determined. Considering this, it is particularly important in patients with IMD that the use of KDs be individualized and well documented.

Sports in LCHAD Deficiency: Maximal Incremental and Endurance Exercise Tests in a 13-Year-Old Patient with Long-Chain 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency (LCHADD) and Heptanoate Treatment.

Exercise and subsequent catabolism is a potential trigger for creatine kinase (CK) concentration increase (rhabdomyolysis) in patients with LCHADD, therefore we evaluated the clinical and biochemical stability under physical exertion conditions at the age of 13 years in a currently 14-year-old LCHADD patient treated with heptanoate.LCHADD was diagnosed during first decompensation at age 20 months. In the following 2 years, the patient had several episodes of rhabdomyolysis. Heptanoate 0.5-1 g/kg/day was started at 4 years, with no further CK elevations since. He is clinically stable, has retinopathy without vision impairment or polyneuropathy. Maximal incremental and endurance exercise tests were performed to evaluate both clinical and metabolic stability during and after exertion.Physical fitness was adequate for age (maximum blood lactate 7.0 mmol/L, appropriate lactate performance curve, maximum heart rate of 196 bpm, maximum power 139 Watt = 2.68 Watt/kg body weight). There were no signs of clinical (muscle pain, dark urine) or metabolic derangement (stable CK, acyl carnitine profiles, blood gas analyses) - neither after maximal incremental nor endurance exertion.This case illustrates that both under maximal incremental and endurance exertion, clinical and biochemical parameters remained stable in this currently 14-year-old LCHADD patient receiving heptanoate treatment.

Chromosomal microaberrations in patients with epilepsy, intellectual disability, and congenital anomalies.

Epilepsy is a common finding in patients with chromosomal macro- and micro-rearrangements but only few aberrations show a constant pattern of seizures. DNA array-based studies have reported causative copy number variations (CNVs) in 5-30% of patients with epilepsy with or without co-morbidities. The interpretation of many of the detected CNVs remains challenging. In order to identify CNVs carrying epilepsy-related genes we investigated 43 children with various patterns of epileptic seizures, intellectual disability (ID), and minor dysmorphism, using the Illumina® Infinium Human1M-DuoV1 array. In three patients we found likely causative de novo CNVs, i.e. deletions in 1q41q42.12 (3.4 Mb) and 19p13.2 (834 kb), and a mosaic two-segment duplication in 17p13.2 (218 kb) and 17p13.1 (422 kb). In six additional patients there were aberrations (a deletion in one and duplications in five patients) with uncertain clinical consequences. In total, the finding of causative chromosomal micro-rearrangements in 3 out of 43 patients (7%) and potentially causative CNVs in 6 additional patients (14%) with epilepsy and ID but without major malformations confirms the power of DNA arrays for the detection of new disease-related genetic regions.

Severe anemia in 3 toddlers with gastric lactobezoar.

BACKGROUND: Anemia in toddlers may result from many disorders including excessive feeding with cow's milk. Another sequel of age-inadequate cow's milk nutrition may be gastric lactobezoar (GLB), a dense lump of coagulated milk and mucus in the stomach. PATIENTS: 3 toddlers presented with a history of excessive intake of full cream cow's milk, abdominal distension, vomiting, dehydration, fatigue, marked pallor and tachycardia. DIAGNOSTIC WORKUP: Diagnostic imaging revea-led large GLBs as the likely origin of the abdominal symptoms. Laboratory evaluation showed severe anemia with depleted iron stores and signs of protein catabolism. Non-cow's milk-induced causes of anemia including defects of erythropoiesis, hemoglobin structure, RBC-enzymes and blood coagulation, hemolysis, immune disorders, infection, inflammation, extraintestinal hemorrhage, nephropathy were - according to the available data - unlikely to cause the anemia in our patients. Thus their anemia is thought to be due to age-inadequate cow's milk nutrition leading to 1) low intake, decreased absorption/bioavailability and increased intestinal loss of iron, and 2) GLB which induced blood loss following mechanical irritation of the gastric mucosa and vomiting causing high gastric pH and decrease in duodenal iron absorption. CONCLUSION: The anemia in our patients is due to both exaggerated feeding with cow's milk and adverse effects of GLBs. This hypothesis is supported by the finding that, after erythrocyte transfusion, iron substitution, age-adapted nutrition and GLB-dissolution, the anemia did not recur. We propose to include GLB in the differential diagnosis of anemia in cow's milk fed small children.

Mutation analysis in 54 propionic acidemia patients.

Deficiency of propionyl CoA carboxylase (PCC), a dodecamer of alpha and beta subunits, causes inherited propionic acidemia. We have studied, at the molecular level, PCC in 54 patients from 48 families comprised of 96 independent alleles. These patients of various ethnic backgrounds came from research centers and hospitals in Germany, Austria and Switzerland. The thorough clinical characterization of these patients was described in the accompanying paper (Grünert et al. 2012). In all 54 patients, many of whom originated from consanguineous families, the entire PCCB gene was examined by genomic DNA sequencing and in 39 individuals the PCCA gene was also studied. In three patients we found mutations in both PCC genes. In addition, in many patients RT-PCR analysis of lymphoblast RNA, lymphoblast enzyme assays, and expression of new mutations in E.coli were carried out. Eight new and eight previously detected mutations were identified in the PCCA gene while 15 new and 13 previously detected mutations were found in the PCCB gene. One missense mutation, p.V288I in the PCCB gene, when expressed in E.coli, yielded 134% of control activity and was consequently classified as a polymorphism in the coding region. Numerous new intronic polymorphisms in both PCC genes were identified. This study adds a considerable amount of new molecular data to the studies of this disease.

Propionic acidemia: neonatal versus selective metabolic screening.

BACKGROUND: Whereas propionic acidemia (PA) is a target disease of newborn screening (NBS) in many countries, it is not in others. Data on the benefit of NBS for PA are sparse. STUDY DESIGN: Twenty PA patients diagnosed through NBS were compared to 35 patients diagnosed by selective metabolic screening (SMS) prompted by clinical findings, family history, or routine laboratory test results. Clinical and biochemical data of patients from 16 metabolic centers in Germany, Austria, and Switzerland were evaluated retrospectively. Additionally, assessment of the intelligent quotient (IQ) was performed. In a second step, the number of PA patients who have died within the past 20 years was estimated based on information provided by the participating metabolic centers. RESULTS: Patients diagnosed through NBS had neither a milder clinical course regarding the number of metabolic crises nor a better neurological outcome. Among NBS patients, 63% were already symptomatic at the time of diagnosis, and <10% of all patients remained asymptomatic. Among all PA patients, 76% were found to be at least mildly mentally retarded, with an IQ <69. IQ was negatively correlated with the number of metabolic decompensations, but not simply with the patients' age. Physical development was also impaired in the majority of patients. Mortality rates tended to be lower in NBS patients compared with patients diagnosed by SMS. CONCLUSION: Early diagnosis of PA through NBS seems to be associated with a lower mortality rate. However, no significant benefit could be shown for surviving patients with regard to their clinical course, including the number of metabolic crises, physical and neurocognitive development, and long-term complications.

Epilepsy in patients with propionic acidemia.

Propionic acidemia (PA) is an autosomal recessively inherited defect of propionyl-CoA carboxylase with an incidence of approximately 1:50 000. There are few reports on the occurrence of EEG findings and development of epilepsy in patients with PA. Retrospectively, the data of 17 patients with PA from one Italian and four Austrian centers were evaluated concerning EEG findings and the development of epilepsy. Nine patients showed a disturbance of background activity, as well as epileptiform discharges. All nine patients with pathological EEG discharges developed seizures compatible with the definition of symptomatic epilepsy. Five of these nine patients showed fever induced seizures at the beginning. Two of them suffered from symptomatic absence epilepsy. Six of the nine patients with seizures were treated with antiepileptic drugs (AED), which were tolerated without side-effects. Four patients showed photosensitivity, which so far has never been reported in PA. We hypothesize that patients with PA are prone to cortical dysfunction caused by one or several pathological metabolites - leading to changes in background and epileptiform activity with a high manifestation rate of clinical seizures.

Stroke-like episodes in propionic acidemia caused by central focal metabolic decompensation.

Propionic acidemia caused by propionyl-CoA carboxylase deficiency frequently leads to neurologic complications. Herein we report an eleven-year-old patient with propionic acidemia having three stroke-like episodes during a period of 13 months characterized by acute reversible hemiplegia and vegetative symptoms like bradycardia or drowsiness. No biochemical signs of severe metabolic decompensation were detectable in plasma. At all three episodes, EEG was not indicative for status epilepticus, but in the acute episode it showed slowing of background activity emphasized on one side. MRI revealed reversible hyperintensities in cortical grey matter and basal ganglia. During the third episode a lumbar puncture was done in parallel with venous puncture. Concentrations of glutamine (902 micromol/L), glycine (24 micromol/L) and alanine (78 micromol/L) were elevated in CSF. In plasma glycine (1 859 micromol/L) and alanine (608 micromol/L) concentrations were also elevated, whereas the glutamine (458 micromol/L) concentration was normal. CSF/plasma ratios were elevated for glutamine (1.97) and alanine (0.13) and normal for glycine (0.01). We assume that the stroke-like episodes in our patient may be caused by an acute focal cerebral metabolic decompensation, which is detectable by unspecific changes in MRI and by measuring amino acids and lactate in CSF versus plasma.

Peripheral neuropathy as the sole initial finding in three children with infantile metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is a progressive white matter disease caused by arylsulfatase A deficiency. Demyelination in the nervous system is detected by cerebral magnetic resonance imaging (MRI) and neurophysiological studies. We present three children with infantile MLD, who had difficulties in standing and walking with absent reflexes. Protein levels in cerebral spinal fluid (CSF) were elevated and nerve conduction studies revealed slowing down of motor nerve conduction velocity. Initial cerebral MRIs showed no white matter changes. Consecutively, all three children developed clinical symptoms of neurodegenerative disease. Follow-up MRI and arylsulfatase A testing led to diagnosis of MLD. We conclude, that in young children who present with an acute/subacute demyelinating polyneuropathy, MLD is a differential diagnosis.

3-Heptanone as a potential new marker for valproic acid therapy.

Breath gas samples from 27 patients with epilepsy (17 male and 10 female patients; mean age: 9.7 years, median age: 8.2 years, SD: ±4.2 years) were screened via proton transfer reaction mass spectrometry. The patients were treated with valproic acid (VPA) therapy, and blood samples for determination of VPA concentrations were surveyed. All patients showed significantly elevated concentrations of 3-heptanone (C(7)H(14)O) in exhaled breath gas (mean: 14.7 ppb, median: 13.8 ppb SD: ±5.7 ppb). In human breath, several hundred different volatile organic compounds can be detected. In breath of patients with valproic acid monotherapy, an increased concentration of 3-heptanone was measured. The objective of this study was to investigate if serum VPA concentrations correlate with 3-heptanone concentrations in exhaled breath. In conclusion, 3-heptanone in breath gas is significantly elevated in patients treated with the valproic acid, but does not correlate significantly with the VPA concentrations in serum or the daily dose of this drug.

Breath acetone-aspects of normal physiology related to age and gender as determined in a PTR-MS study.

The present study was performed to determine the variations of breath acetone concentrations with age, gender and body-mass index (BMI). Previous investigations were based on a relatively small cohort of subjects (see Turner et al 2006 Physiol. Meas. 27 321-37). Since exhaled breath analysis is affected by considerable variation, larger studies are needed to get reliable information about the correlation of concentrations of volatiles in breath when compared with age, gender and BMI. Mixed expiratory exhaled breath was sampled using Tedlar bags. The concentrations of a mass-to-charge ratio (m/z) of 59, attributed to acetone, were then determined using proton transfer reaction-mass spectrometry. Our cohort, consisting of 243 adult volunteers not suffering from diabetes, was divided into two groups: one that fasted overnight prior to sampling (215 volunteers) and the other without a dietary control (28 volunteers). In addition, we considered a group of 44 healthy children (5-11 years old).The fasted subjects' concentrations of acetone ranged from 177 ppb to 2441 ppb, with an overall geometric mean (GM) of 628 ppb; in the group without a dietary control, the subjects' concentrations ranged from 281 ppb to 1246 ppb with an overall GM of 544 ppb. We found no statistically significant shift between the distributions of acetone levels in the breath of males and females in the fasted group (the Wilcoxon-Mann-Whitney test yielded p = 0.0923, the medians being 652 ppb and 587 ppb). Similarly, there did not seem to be a difference between the acetone levels of males and females in the group without a dietary control. Aging was associated with a slight increase of acetone in the fasted females; in males the increase was not statistically significant. Compared with the adults (a merged group), our group of children (5-11 years old) showed lower concentrations of acetone (p < 0.001), with a median of 263 ppb. No correlation was found between the acetone levels and BMI in adults. Our results extend those of Turner et al's (2006 Physiol. Meas. 27 321-37), who analyzed the breath of 30 volunteers (without a dietary control) by selected ion flow tube-mass spectrometry. They reported a positive correlation with age (but without statistical significance in their cohort, with p = 0.82 for males and p = 0.45 for females), and, unlike us, arrived at a p-value of 0.02 for the separation of males and females with respect to acetone concentrations. Our median acetone concentration for children (5-11 years) coincides with the median acetone concentration of young adults (17-19 years) reported by Spanel et al (2007 J. Breath Res. 1 026001).

Amino acids in CSF and plasma in hyperammonaemic coma due to arginase1 deficiency.

UNLABELLED: We report the CSF and plasma amino acid concentrations and their ratios in a male patient with arginase1 deficiency with an unusual early presentation at 34 days of age. He developed hyperammonaemic coma (ammonia >400 µmol/L; normal <90 µmol/L) on postnatal day 35. CSF and plasma concentrations were assayed by ion-exchange chromatography on day 36. Arginine was increased both in plasma (971 µmol/L; controls (mean ± 2SD) 50 ± 42) and in CSF (157 µmol/L; controls 19 ± 8.6), resulting in a normal CSF/plasma ratio of 0.16 (controls 0.41 ± 0.26). Interestingly, glutamine was disproportionately high in CSF (3114 µmol/L; controls 470 ± 236) but normal in plasma (420 µmol/L; controls 627 ± 246); the ratio exceeded unity (7.4; controls 0.76 ± 0.31). The CSF/plasma ratios of most neutral amino acids were elevated but not those of the imino- and of the dibasic amino acids lysine and ornithine. The mechanism leading to the increase of most neutral amino acids in brain is not known. CONCLUSION: A normal glutamine in plasma does not exclude an increased concentration in CSF; it could be useful to ascertain by MRS that a high CSF glutamine concentration truly reflects a high concentration in brain tissue for better understanding its pathogenesis.

Chronic immune stimulation correlates with reduced phenylalanine turnover.

Neuropsychiatric symptoms like mood changes and depression are common in patients with chronic inflammatory disorders such as infections, autoimmune diseases or cancer. The pathogenesis of these symptoms is still unclear. Pro-inflammatory stimuli interfere not only with the neural circuits and neurotransmitters of the serotonergic, but also with those of the adrenergic system. The pro-inflammatory cytokine interferon-gamma stimulates the biosynthesis of 5,6,7,8-tetrahydrobiopterin (BH4), which is cofactor for several aromatic amino acid monooxygenases and thus is strongly involved in the biosynthesis of the neurotransmitter serotonin and the catecholamines dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). In macrophages, interferon-gamma also triggers the high output of reactive oxygen species, which can destroy the oxidation-labile BH4. Recent data suggest that oxidative loss of BH4 in chronic inflammatory conditions can reduce the biosynthesis of catecholamines, which may relate to disturbed adrenergic neurotransmitter pathways in patients.

Effect of valproic acid treatment on body composition, leptin and the soluble leptin receptor in epileptic children.

PURPOSE: The aim of the study was to determine the influence of valproic acid (VPA) treatment on leptin, the soluble leptin receptor (sOB-R), the sOB-R/leptin ratio, body composition and insulin resistance in epileptic children. METHODS: A cross-sectional cohort study was conducted at the Medical University Innsbruck, Austria. Children >6 years with idiopathic epilepsy and antiepileptic drug therapy since at least six months were eligible. Leptin concentration, the sOB-R, the sOB-R/leptin ratio, body composition and glucose homeostasis were determined. RESULTS: 87 children (median [range] age 12.8 years [6.0-18.6]) were on treatment with VPA, 55 (12.3 years [6.4-18.3]) on other AEDs, comprising the non-VPA group. VPA-treated children had higher leptin concentrations, body-mass-index standard-deviation score (SDS), body fat (each p<0.001), serum insulin concentrations (p=0.014) and homeostasis model assessment (HOMA) index (p=0.009), as well as a lower sOB-R/leptin ratio (p<0.001) when compared to the non-VPA group. Overweight VPA-treated children showed lower sOB-R concentrations and a lower sOB-R/leptin ratio (each p<0.001) as well as higher body fat and leptin levels (each p<0.001) compared to lean VPA-treated children. CONCLUSION: VPA monotherapy was associated with higher body weight, body fat and serum leptin concentrations as well as impaired glucose homeostasis. Low sOB-R concentrations and a low sOB-R/leptin ratio in overweight VPA-treated patients might contribute to disturbances in glucose homeostasis and to the development of the metabolic syndrome in these children later in life.