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Inherited metabolic disorders (IMDs) in neonates are a diagnostic and therapeutic challenge for the neonatologist, with the priority being to rapidly flag the treatable diseases. The objective of this study was to evaluate the contribution of targeted metabolic testing for diagnosing suspected IMDs on the basis of suggestive clinical setting or family history in neonates. We conducted an observational study over five years, from January 1st, 2010 to December 31, 2014 in the neonatal intensive care unit (NICU) at Robert Debré University Hospital, Paris, France. We assessed the number of neonates for whom a metabolic testing was performed, the indication for each metabolic test and the diagnostic yield of this selected metabolic workup for diagnosing an IMD. Metabolic testing comprised at least one of the following testings: plasma, urine or cerebrospinal fluid amino acids, urine organic acids, plasma acylcarnitine profile, and urine mucopolysaccharides and oligosaccharides. 11,301 neonates were admitted at the neonatal ICU during the study period. One hundred and ninety six neonates underwent metabolic testing. Eleven cases of IMDs were diagnosed. This diagnostic approach allowed the diagnosis, treatment and survival of 4 neonates (maple syrup urine disease, propionic acidemia, carnitine-acylcarnitine translocase deficiency and type 1 tyrosinemia). In total, metabolic testing was performed for 1.7% of the total number of neonates admitted in the NICU over the study period. These included 23% finally unaffected neonates with transient abnormalities, 5.6% neonates suffering from an identified IMD, 45.4% neonates suffering from a non-metabolic identified disease and 26% neonates with chronic abnormalities but for whom no final causal diagnosis could be made. In conclusion, as expected, such a metabolic targeted workup allowed the diagnosis of classical neonatal onset IMDs in symptomatic newborns. However, this workup remained normal or unspecific for 94.4% of the tested patients. It allowed excluding an IMD in 68.4% of the tested neonates. In spite of the high rate of normal results, such a strategy seems acceptable due to the severity of the symptoms and the need for immediate treatment when available in neonatal IMDs. However, its cost-effectiveness remains low especially in a clinically targeted population in a country where newborn screening is still unavailable for IMDs except for phenylketonuria in 2019.

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterised by impaired glucose liver homeostasis and proximal renal tubular dysfunction. It is caused by pathogenic variants in SLC2A2 coding for the glucose transporter GLUT2. Main clinical features include hepatomegaly, fasting hypoglycaemia, postprandial hyperglycaemia, Fanconi-type tubulopathy occasionally with rickets, and a severe growth disorder. While treatment for renal tubular dysfunction is well established, data regarding optimal nutritional therapy are scarce. Similarly, detailed clinical evaluation of treated FBS patients is lacking. These unmet needs were an incentive to conduct the present pilot study. We present clinical findings, laboratory parameters and molecular genetic data on 11 FBS patients with emphasis on clinical outcome under various nutritional interventions. At diagnosis, the patients' phenotypic severity could be classified into two categories: a first group with severe growth failure and rickets, and a second group with milder signs and symptoms. Three patients were diagnosed early and treated because of family history. All patients exhibited massive glucosuria at diagnosis and some in both groups had fasting hypoglycaemic episodes. Growth retardation improved drastically in all five patients treated by intensive nutritional intervention (nocturnal enteral nutrition) and uncooked cornstarch with final growth parameters in the normal range. The four severely affected patients who were treated with uncooked cornstarch alone did not catch up growth. All patients received electrolytes and l-carnitine supplementation to compensate for the tubulopathy. This is one of the largest series of FBS on therapeutic management with evidence that nocturnal enteral nutrition rescues growth failure.

A patient with late-onset exercise intolerance had haploinsufficiency of SLC25A32, which encodes the human mitochondrial flavin adenine dinucleotide transporter. The patient's symptoms were highly responsive to oral supplementation with riboflavin.

Type 2 diabetes (T2D) in obese children is an emerging problem, including in Europe. Its presentation at diagnosis very often differs from that in adults.The objective of this study was to investigate the relative contributions of the two components of T2D, insulin resistance and insulin secretion, early in the history of the disease in adolescents.Six obese adolescents with T2D were included 2 months to 4.3 yr after diagnosis (five girls and one boy; median age, 15.4 yr; median body mass index, 4.4 sd). Peripheral and hepatic insulin sensitivity was evaluated with euglycemic hyperinsulinemic (40 mU/m(2).min) clamp. First-phase insulin release was evaluated after iv glucose stimulation. A graded iv glucose infusion and an arginine test were performed to measure insulin secretion.All patients showed decreased peripheral glucose uptake to the same extent. Five patients showed hepatic insulin resistance. First-phase insulin release was very low in two patients. Three patients showed an exaggerated insulin response under graded glucose infusion and preserved secretion under arginine stimulation. Three other patients, with elevated fasting plasma glucose levels, demonstrated a very low insulin response under glucose stimulation and a low insulin response under arginine stimulation.These data emphasize that together with marked insulin resistance, the failure of beta-cell function is a major component in the course of T2D in childhood.

I deficiency is the leading cause of preventable mental retardation. A number of surveys in Afghanistan show goitre prevalence rates more than 20% amongst children and women. Access to iodised salt remains low, with disparate coverage by region, despite the recent implementation of a national salt iodisation programme. The objectives were to identify whether the presence of goitre is a satisfactory marker of I deficiency and to examine the relationship between goitre and thyroid function. A case–control study was carried out in children and women of childbearing age, stratified on the presence of goitre. Adequate levels of urinary I were observed in 6·8% of all the subjects, and amongst the subjects without goitre, this figure was only 9%. The presence of goitre was significantly associated with severe urinary I deficiency; however, the difference between the cases and controls was not as great as expected. An association between the presence of goitre and elevated thyroid-stimulating hormone (TSH) levels was observed, but 14% of the children without palpable goitre also showed abnormal TSH levels.Given that the majority of subjects showed some degree of I deficiency and that children without goitre may have elevated TSH levels, the absence of goitre is an insufficient indicator to determine adequate I status. The risk of subsequent development of goitre, in the currently non-goitre population, is elevated. This suggests that short-term I supplementation should be considered independently of the presence of goitre or urinary I level, until the access to and consumption of iodised salt is generalised.

Organic acidurias comprise many various disorders. Methylmalonic aciduria (MMA) and propionic aciduria (PA) are the most frequent diseases and the two organic acidurias for which we have better knowledge of the long-term outcome. Comparing the outcome of patients born before and after 1990, it appears that better neonatal and long-term management have improved the survival rate. Less than 20% of the patients died in either the neonatal period or before the age of 10 years. However, most surviving patients showed poor nutritional status with growth retardation and about 40% present some kind of visceral or neurological impairment. The developmental outcome may have improved in MMA patients, with IQ higher than 75 in about 40% patients aged more than 4 years. Conversely, poor intellectual development is the rule in PA patterns, with 60% having an IQ less than 75 and requiring special education. Successful liver and/or renal transplantations, in a few patients, have resulted in better quality of life but have not necessarily prevented neurological and various visceral complications. These results emphasize the need for permanent metabolic follow-up whatever the therapeutic strategy.

Background: Lactate (L) and pyruvate (P) concentrations in cerebrospinal fluid (CSF) and the L/P ratio have diagnostic value in numerous primary and acquired disorders affecting the central nervous system, but age-related reference values are not available for children. Methods: We analyzed CSF and blood lactate and pyruvate concentrations and their ratio in a 4-year retrospective survey of a children’s hospital laboratory database. Reference intervals (10th–90th percentiles) were established from data on 197 hospitalized children. A recent regression modeling method was used to normalize and smooth values against age. The model equation of best fit was calculated for each variable. Results: Slight age-related variations were shown by the model, with an increase in lactate, a decrease in pyruvate, and a resulting increase in the L/P ratio with increasing age. However, the SD did not vary with age. We defined the upper limit of the reference intervals as the 90th percentiles, which from birth to 186 months of age varied continuously from 1.78 to 1.88 mmol/L (6%), 148 to 139 μmol/L (6%), and 16.9 to 19.2 (14%) for lactate, pyruvate, and the L/P ratio, respectively. At a threshold of 2 (in Z-score units), the sensitivity for a subgroup of inborn errors of metabolism (respiratory chain disorders) was 73%, 42%, and 31% for lactate, pyruvate, and the L/P ratio, respectively. Conclusions: In children, CSF lactate and pyruvate concentrations and their ratio appear to vary slightly with age. Average 90th percentile values of 1.8 mmol/L, 147 μmol/L, and 17, respectively, could be used in infants up to 24 months of age. In older children, age-adjusted reference intervals should be used, especially when values are close to the 90th percentile.

Introduction: Multiple acyl-coenzyme A dehydrogenase deficiency (MADD), also called glutaric aciduria type II, is an inherited metabolic disorder resulting from a deficiency in electron transfer flavoprotein (ETF) or of its ubiquinone oxidoreductase (ETF-QO). It usually occurs in the neonatal period or in early infancy and, very rarely, in adolescents and young adult patients. Methods: We report the case of a 55-year-old woman who developed a painful subacute myopathy. Results: Lipid accumulation was found at biopsy. MADD was confirmed by plasma acylcarnitine profile and by assessment of ETF-QO activity in muscle. Conclusions: This study demonstrates that metabolic myopathies usually found in infancy may be also diagnosed in older patients. MADD may be easily treated by riboflavin and coenzyme Q10 and therefore should be included in the differential diagnosis of adult-onset painful myopathy. Muscle Nerve 43: 444–446, 2011

Inherited metabolic disorders are the cause of a small but significant number of sudden infant deaths in infants. We report on a boy who suddenly died at 10 months of age during an acute illness. Parents declined autopsy; nevertheless, they accepted a whole body MRI, which revealed hepatomegaly with steatosis. Acylcarnitine profile of a blood sample from neonatal Guthrie screening led to the diagnosis of type 2 carnitine palmitoyltransferase deficiency. To conclude, whole body MRI is useful in the investigation of some inherited metabolic causes of sudden infant death, which might prevent future deaths in the family. It is a good alternative when autopsy is refused.

The authors report 7 years of follow-up evaluation of a patient with coenzyme Q 10 (CoQ 10 ) deficiency. Initial symptoms of exercise intolerance and hyperlactatemia improved markedly with substitutive treatment. However, CoQ 10 supplementation did not prevent the onset of a cerebellar syndrome. A switch to idebenone treatment resulted in clinical and metabolic worsening, which disappeared with subsequent CoQ 10 treatment. CoQ 10 defects may cause progressive neurologic disease despite supplementation.

OBJECTIVE To assess the prevalence of in vivo detectable abnormalities of lactate metabolism in mitochondrial disorders. DESIGN Retrospective study in a metabolic investigation unit. PATIENTS 28 patients with a respiratory chain disorder identified from biochemical or genetic analyses, or both, and 133 age matched controls. Controls were children in whom causes of secondary hyperlactataemia and/or disorders, affecting the energy pathways could be excluded. METHODS Lactate and pyruvate were measured in blood, together with other intermediary metabolism indices, before and one hour after four meals each day. Lactate and creatinine in a 24 hour urine sample collected at the same time were analysed. When basal hyperlactataemia was not evident, an intravenous glucose or pyruvate loading test was performed as a provocative test. RESULTS Abnormal lactate metabolism was found in 25 of 28 patients thus demonstrating the potential usefulness of these investigations in the diagnosis of mitochondrial diseases. Moderate lactate accumulation was present in relatively mild disease, associated with a mitochondrial DNA mutation and combined respiratory complexes deficiency. By contrast, high lactate concentrations were observed in very young children, with severe disease, isolated complex deficiency, and no apparent mitochondrial DNA defect.