Cerebellar hypoplasia in children with the carbohydrate-deficient glycoprotein syndrome

We describe seven children with the carbohydrate-deficient glycoprotein syndrome, an autosomal recessive inborn error of protein glycosylation characterised by failure to thrive, neurological dysfunction and a unique pattern of physical abnormalities. Neuroradiological investigations revealed cerebellar hypoplasia in all seven children. Two children also developed supratentorial atrophy following episodes of neurological deterioration.     

Neonatal Mass-Screening for Inborn Errors of Metabolism in Japan

This report describes the results of neonatal mass screening in Japan for PKU, maple syrup urine disease, histidinemia, homocystinuria, galactosemia, inborn errors of urea cycle metabolism and congenital hypothyroidism. The incidence of PKU is low but the incidence of histidinemia is somewhat high compared to that in the United States. Some genetic variants of each of these inborn errors of metabolism such as malignant hyperphenylalaninemia or mild form of MSUD have been detected in the neonatal screening. Clinical values of the screening for each of these in born errors of metabolism are discussed.     

Atypical phenylketonuria with “dihydrobiopterin synthetase” deficiency: Absence of phosphate-eliminating enzyme activity demonstrated in liver

An assay for the phosphate-eliminating enzyme (PEE) activity in liver was developed which required only 5–10 mg tissue. PEE catalyses the elimination of inorganic triphosphate from dihydroneopterin triphosphate, which is the second and irreversible step in the biosynthesis of tetrahydrobiopterin (BH₄). In the presence of substrate, magnesium, NADPH, and a sepiapterin reductase fraction from human liver, PEE catalysed the formation of BH₄ which was measured by HPLC and electrochemical detection. In adult human liver, a PEE activity of 1.02±0.134 U/mg protein (mean ±1 SD; n=5) was observed. In liver needle biopsy material from five patients with defective biopterin biosynthesis, no PEE activity was found (less than 2% and 6% of the control values, respectively). The presence of an endogenous inhibitor was excluded. In a patient who died without definite diagnosis and in a patient with -thalassaemia liver PEE activity was increased. Sepiapterin reductase activity was present in all cases. Results indicate that in dihydrobiopterin synthetase deficiency, the most frequent of the rare BH₄-deficient variants of hyperphenylalaninaemia, the molecular defect consists in a defect of PEE.Abbreviations PEE Phosphate eliminating enzyme - DHBS Dihydrobiopterin synthetase - HPLC High pressure liquid chromatography - BH₄ tetrahydrobiopterin     

The association between acute fatty liver of pregnancy and fatty acid oxidation disorders

Acute fatty liver of pregnancy is a relatively rare but potentially fatal liver disorder of late pregnancy. Recent advances in molecular diagnostic procedures provide evidence of a genetic basis for this condition and a link to offspring disorders in fatty acid oxidation. This relationship implies the need for genetic testing and follow-up of at-risk women and their neonates.     

Correlation between Hypoglycemia and Positive Rate of Inborn Error of Metabolism in Neonatal Intensive Care Unit

Objective

To investigate the correlation between hypoglycemia and positive rate of inborn error of metabolism (IEM) in neonatal intensive care unit.

Methods

160 patients from a neonatal intensive care unit were enrolled. Blood glucose was measured by Roche Modular chemistry. The dry blood on filter papers, collected from 160 patients, was tested by tandem mass spectrometry to detect 35 inborn errors of metabolism. Clinical follow-up of all the patients was at least in an interval of 12 months. The mean observation period was 13.5 months per child.

Findings

Based on the ROC curve, the optimal cut-off value of hypoglycemia as an indicator for screening for IEMs was projected to be 2.8 mmol/L, which yielded a sensitivity of 71.4% and a specificity of 76.5%. The patients were divided into two groups: hypoglycemia group (48 cases) and the control group (112 cases). 5(10.4%) of the 48 patients in the hypoglycemia group were positive, while only 2(1.8%) of the 112 patients in the control group were positive. The difference of the positive rate in the screening for IEMs between the two groups was significant (χ²=4.10, P<0.05); the relative risk (RR) was 5.83 (95% CI: 1.06–32.12).

Conclusion

The risk of patients with hypoglycemia suffering from IEMs was significantly higher than that of the non-hypoglycemia patients in NICU, based on cut-off value of 2.8mmol/L.     

Short-chain acyl-coenzyme A dehydrogenase deficiency

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a disorder of mitochondrial fatty acid oxidation that leads to the accumulation of butyrylcarnitine and ethylmalonic acid in blood and urine. Originally described with a relatively severe phenotype, most patients are now diagnosed through newborn screening by tandem mass spectrometry and remain asymptomatic. Molecular analysis of affected individuals has identified a preponderance of private inactivating point mutations and one common one present in high frequency in individuals of Ashkenazi Jewish ancestry. In addition, two polymorphic variants have been identified that have little affect on enzyme kinetics but impair folding and stability. Individuals homozygous for one of these variants or compound heterozygous for one of each often show an increased level of ethylmalonic acid excretion that appears not to be clinically significant. The combination of asymptomatic affected newborns and the frequent variants can cause much confusion in evaluating and treating individuals with SCADD. The long-term consequences and the need for chronic therapy remain current topics of contention and investigation.     

Intravenous ketogenic diet therapy for neonatal-onset pyruvate dehydrogenase complex deficiency

BackgroundPyruvate dehydrogenase complex (PDHC) deficiency is an inborn error of metabolism that causes lactic acidosis and neurodevelopmental changes. Five causative genes have been identified: PDHA1, PDHB, DLAT, DLD, and PDHX. Four neurological phenotypes have been reported: neonatal encephalopathy with lactic acidosis, non-progressive infantile encephalopathy, Leigh syndrome, and relapsing ataxia. Of these, neonatal encephalopathy has the worst mortality and morbidity and there is no effective treatment.Subjects and methodsWe studied two girls who were clinically diagnosed with PDHC deficiency as neonates; they were subsequently found to have PDHA1 mutations. The clinical diagnosis was based on white matter loss and a lateral ventricular septum on fetal MRI, spasticity of the lower extremities, and lactic acidosis worsening after birth. Intravenous ketogenic diets were started within 24 h after birth. The ketogenic ratio was increased until the blood lactate level was controlled, while monitoring for side effects.ResultsIn both cases, the lactic acidosis improved immediately with no apparent side effects. Both children had better developmental outcomes than previously reported cases; neither exhibited epilepsy.ConclusionsIntravenous ketogenic diet therapy is a treatment option for neonatal-onset PDHC deficiency. Further studies are needed to optimize this therapy.     

Improving the uptake of newborn screening for endocrinopathies and inborn errors of metabolism: A quality improvement initiative

IntroductionNewborn Screening (NBS) is a globally recognized essential, preventive public health program for identifying life threatening and debilitating conditions.MethodThis single centre quality improvement (QI) initiative was taken to improve the newborn screening uptake from the existing rate of 70%–100% over a period of three months in a tertiary care facility of India. A QI team was constituted to evaluate the reasons for low uptake of NBS and introduce changes in the existing system of NBS.ResultsBaseline data collection along with process mapping, and fishbone analysis were done. Problems attributing to most of the missed cases of newborns were studied using Pareto chart. Total three plan-do-study-asct (PDSA) cycles were used to fix the identified problems in order to improve the rate of NBS. The results of PDSA cycles were discussed among the team members. Frequency and percentage was computed for the collected data, after coding and entering in excel sheet. .ConclusionThe QI project on NBS successfully improved the rate of uptake of newborns for NBS from baseline to 100%.     

串联质谱与高通量测序技术在新生儿疾病筛查中的应用

目的 探讨串联质谱（tandem mass spectrometry,TMS）联合高通量测序技术（又称新一代测序技术,next generation sequencing,NGS）在新生儿疾病筛查中的应用价值。方法 依托妇幼健康服务联合体,对2015年4月至2018年5月期间常州地区出生的50844例新生儿开展TMS初筛,对初筛阳性病例运用NGS等技术进行鉴别诊断和基因诊断。结果 50844例新生儿经TMS初筛阳性650例,召回再次TMS检测结果阳性54例,对该54例病例运用NGS技术进行检测,最终确诊19例为遗传代谢病患儿,总体发病率为1/2676。结论 TMS联合NGS开展新生儿疾病筛查,能更早、更多地发现新生儿遗传性代谢疾病,从而达到早干预、早治疗的目的。