Assessment of carnitine excretion and its ratio to plasma free carnitine as a biomarker for primary carnitine deficiency in newborns

In the Netherlands, newborns are referred by the newborn screening (NBS) Program when a low free carnitine (C0) concentration (&lt;5 μmol/l) is detected in their NBS dried blood spot. This leads to ~85% false positive referrals who all need an invasive, expensive and lengthy evaluation. We investigated whether a ratio of urine C0 / plasma C0 (RatioU:P) can improve the follow-up protocol for primary carnitine deficiency (PCD). A retrospective study was performed in all Dutch metabolic centres, using samples from newborns and mothers referred by NBS due to low C0 concentration. Samples were included when C0 excretion and plasma C0 concentration were sampled on the same day. RatioU:P was calculated as (urine C0 [μmol/mmol creatinine])/(plasma C0 [μmol/l]). Data were available for 59 patients with genetically confirmed PCD and 68 individuals without PCD. The RatioU:P in PCD patients was significantly higher (p value &lt; 0.001) than in those without PCD, median [IQR], respectively: 3.4 [1.2–9.5], 0.4 [0.3–0.8], area under the curve (AUC) 0.837. Classified for age (up to 1 month) and without carnitine suppletion (PCD; N = 12, Non-PCD; N = 40), medians were 6.20 [4.4–8.8] and 0.37 [0.24–0.56], respectively. The AUC for RatioU:P was 0.996 with a cut-off required for 100% sensitivity at 1.7 (yielding one false positive case). RatioU:P accurately discriminates between positive and false positive newborn referrals for PCD by NBS. RatioU:P is less effective as a discriminative tool for PCD in adults and for individuals that receive carnitine suppletion.</p

Exercise Stress Testing in Children with Metabolic or Neuromuscular Disorders

The role of exercise as a diagnostic or therapeutic tool in patients with a metabolic disease (MD) or neuromuscular disorder (NMD) is relatively underresearched. In this paper we describe the metabolic profiles during exercise in 13 children (9 boys, 4 girls, age 5–15 yrs) with a diagnosed MD or NMD. Graded cardiopulmonary exercise tests and/or a 90-min prolonged submaximal exercise test were performed. During exercise, respiratory gas-exchange and heart rate were monitored; blood and urine samples were collected for biochemical analysis at set time points. Several characteristics in our patient group were observed, which reflected the differences in pathophysiology of the various disorders. Metabolic profiles during exercises CPET and PXT seem helpful in the evaluation of patients with a MD or NMD

Liver transplantation in glycogen storage disease type I

Glycogen storage disease type I (GSDI), an inborn error of carbohydrate metabolism, is caused by defects in the glucose-6-transporter/glucose-6-phosphatase complex, which is essential in glucose homeostasis. Two types exist, GSDIa and GSDIb, each caused by different defects in the complex. GSDIa is characterized by fasting intolerance and subsequent metabolic derangements. In addition to these clinical manifestations, patients with GSDIb suffer from neutropenia with neutrophil dysfunction and inflammatory bowel disease. With the feasibility of novel cell-based therapies, including hepatocyte transplantations and liver stem cell transplantations, it is essential to consider long term outcomes of liver replacement therapy. We reviewed all GSDI patients with liver transplantation identified in literature and through personal communication with treating physicians. Our review shows that all 80 GSDI patients showed improved metabolic control and normal fasting tolerance after liver transplantation. Although some complications might be caused by disease progression, most complications seemed related to the liver transplantation procedure and subsequent immune suppression. These results highlight the potential of other therapeutic strategies, like cell-based therapies for liver replacement, which are expected to normalize liver function with a lower risk of complications of the procedure and immune suppression

Exercise Stress Testing in Children with Metabolic or Neuromuscular Disorders

The role of exercise as a diagnostic or therapeutic tool in patients with a metabolic disease (MD) or neuromuscular disorder (NMD) is relatively underresearched. In this paper we describe the metabolic profiles during exercise in 13 children (9 boys, 4 girls, age 5–15 yrs) with a diagnosed MD or NMD. Graded cardiopulmonary exercise tests and/or a 90-min prolonged submaximal exercise test were performed. During exercise, respiratory gas-exchange and heart rate were monitored; blood and urine samples were collected for biochemical analysis at set time points. Several characteristics in our patient group were observed, which reflected the differences in pathophysiology of the various disorders. Metabolic profiles during exercises CPET and PXT seem helpful in the evaluation of patients with a MD or NMD

Impaired Cognitive Functioning in Patients with Tyrosinemia Type I Receiving Nitisinone

ObjectiveTo examine cognitive functioning in patients with tyrosinemia type I treated with nitisinone and a protein-restricted diet.Study designWe performed a cross-sectional study to establish cognitive functioning in children with tyrosinemia type I compared with their unaffected siblings. Intelligence was measured using age-appropriate Wechsler Scales. To assess cognitive development over time, we retrieved sequential IQ scores in a single-center subset of patients. We also evaluated whether plasma phenylalanine and tyrosine levels during treatment was correlated with cognitive development.ResultsAverage total IQ score in 10 patients with tyrosinemia type I receiving nitisinone was significantly lower compared with their unaffected siblings (71 ± 13 vs 91 ± 13; P = .008). Both verbal and performance IQ subscores differed (77 ± 14 vs 95 ± 11; P < .05 and 70 ± 11 vs 87 ± 15; P < .05, respectively). Repeated IQ measurements in a single-center subset of 5 patients revealed a decline in average IQ score over time, from 96 ± 15 to 69 ± 11 (P < .001). No significant association was found between IQ score and either plasma tyrosine or phenylalanine concentration.ConclusionPatients with tyrosinemia type I treated with nitisinone are at risk for impaired cognitive function despite a protein-restricted diet

PIGO deficiency: palmoplantar keratoderma and novel mutations.

Background Several genetic defects have been identified in the glycosylphosphatidylinositol (GPI) anchor synthesis, including mutations in PIGO encoding phosphatidylinositol glycan anchor biosynthesis class O protein. These defects constitute a subgroup of the congenital disorders of glycosylation (CDG). Seven patients from five families have been reported carrying variants in PIGO that cause an autosomal recessive syndrome characterised by dysmorphism, psychomotor disability, epilepsy and hyperphosphatasemia. Methods Whole exome sequencing was performed in a boy with dysmorphism, psychomotor disability, epilepsy, palmoplantar keratoderma, hyperphosphatasemia and platelet dysfunction without a clinical bleeding phenotype. Results Two novel variants in PIGO were detected. The missense variant encoding p. His871Pro was inherited from the boy’s father while the frameshift variant encoding p. Arg604ProfsTer40 was maternally inherited. Conclusion A boy with two novel PIGO variants is reported. The skin phenotype and platelet dysfunction in this patient have not been described in previously reported patients with PIGO deficiency but it is of course uncertain whether these are caused by this disorder. The literature on PIGO deficiency is reviewed

Prediction of disease severity in multiple acyl-CoA dehydrogenase deficiency:a retrospective and laboratory cohort study

Multiple acyl-CoA dehydrogenase deficiency (MADD) is an ultra-rare inborn error of mitochondrial fatty acid oxidation (FAO) and amino acid metabolism. Individual phenotypes and treatment response can vary markedly. We aimed to identify markers that predict MADD phenotypes. We performed a retrospective nationwide cohort study; then developed an MADD-disease severity scoring system (MADD-DS3) based on signs and symptoms with weighed expert opinions; and finally correlated phenotypes and MADD-DS3 scores to FAO flux (oleate and myristate oxidation rates) and acylcarnitine profiles after palmitate loading in fibroblasts. Eighteen patients, diagnosed between 1989 and 2014, were identified. The MADD-DS3 entails enumeration of eight domain scores, which are calculated by averaging the relevant symptom scores. Lifetime MADD-DS3 scores of patients in our cohort ranged from 0 to 29. FAO flux and [U-13C]C2-, C5-, and [U-13C]C16-acylcarnitines were identified as key variables that discriminated neonatal from later onset patients (all P <.05) and strongly correlated to MADD-DS3 scores (oleate: r = −.86; myristate: r = −.91; [U-13C]C2-acylcarnitine: r = −.96; C5-acylcarnitine: r =.97; [U-13C]C16-acylcarnitine: r =.98, all P <.01). Functional studies in fibroblasts were found to differentiate between neonatal and later onset MADD-patients and were correlated to MADD-DS3 scores. Our data may improve early prediction of disease severity in order to start (preventive) and follow-up treatment appropriately. This is especially relevant in view of the inclusion of MADD in population newborn screening programs

Inborn Errors of Metabolism That Cause Sudden Infant Death:A Systematic Review with Implications for Population Neonatal Screening Programmes

BACKGROUND: Many inborn errors of metabolism (IEMs) may present as sudden infant death (SID). Nowadays, increasing numbers of patients with IEMs are identified pre-symptomatically by population neonatal bloodspot screening (NBS) programmes. However, some patients escape early detection because their symptoms and signs start before NBS test results become available, they even die even before the sample for NBS has been drawn or because there are IEMs which are not included in the NBS programmes. OBJECTIVES AND METHODS: This was a comprehensive systematic literature review to identify all IEMs associated with SID, including their treatability and detectability by NBS technologies. Reye syndrome (RS) was included in the search strategy because this condition can be considered a possible pre-stage of SID in a continuum of aggravating symptoms. RESULTS: 43 IEMs were identified that were associated with SID and/or RS. Of these, (1) 26 can already present during the neonatal period, (2) treatment is available for at least 32, and (3) 26 can currently be identified by the analysis of acylcarnitines and amino acids in dried bloodspots (DBS). CONCLUSION: We advocate an extensive analysis of amino acids and acylcarnitines in blood/plasma/DBS and urine for all children who died suddenly and/or unexpectedly, including neonates in whom blood had not yet been drawn for the routine NBS test. The application of combined metabolite screening and DNA-sequencing techniques would facilitate fast identification and maximal diagnostic yield. This is important information for clinicians who need to maintain clinical awareness and decision-makers to improve population NBS programmes