Cross-sectional multicenter study of patients with urea cycle disorders in the United States

Inherited urea cycle disorders comprise eight disorders (UCD), each caused by a deficiency of one of the proteins that is essential for ureagenesis. We report on a cross-sectional investigation to determine clinical and laboratory characteristics of patients with UCD in the United States. The data used for the analysis was collected at the time of enrollment of individuals with inherited UCD into a longitudinal observation study. The study has been conducted by the Urea Cycle Disorders Consortium within the Rare Diseases Clinical Research Network (RDCRN) funded by the National Institutes of Health. One-hundred eighty-three patients were enrolled into the study. Ornithine transcarbamylase (OTC) deficiency was the most frequent disorder (55%), followed by argininosuccinic aciduria (16%) and citrullinemia (14%). Seventy-nine percent of the participants were white (16% Latinos), and 6% were African American. Intellectual and developmental disabilities were reported in 39% with learning disabilities (35%) and half had abnormal neurological examination. Sixty-three percent were on a protein restricted diet, 37% were on Na-phenylbutyrate and 5% were on Na-benzoate. Forty-five percent of OTC deficient patients were on l-citrulline, while most patients with citrullinemia (58%) and argininosuccinic aciduria (79%) were on l-arginine. Plasma levels of branched-chain amino acids were reduced in patients treated with ammonia scavenger drugs. Plasma glutamine levels were higher in proximal UCD and in neonatal type disease. The RDCRN allows comprehensive analyses of rare inherited UCD, their frequencies and current medical practices.     

串联质谱联合气相色谱-质谱检测遗传性代谢病

目的 应用串联质谱检测干血滤纸片中的氨基酸和酰基肉碱谱,联合气相色谱-质谱技术检测尿液中有机酸谱,对遗传性代谢病进行筛查和诊断.方法 留取4981例临床疑似遗传性代谢病儿童的干血滤纸片、尿或尿滤纸片,利用串联质谱仪检测血中氨基酸和酰基肉碱,利用气相色谱-质谱仪检测尿中有机酸,部分患儿结合相关酶活性测定及基因突变分析进行诊断.结果 在4981例患儿中共诊断319例(6.4%)24种遗传代谢病,其中氨基酸代谢病155例(48.6%),8种疾病;有机酸血症150例(47.0%),10种疾病;脂肪酸13氧化代谢病14例(4.4%),6种疾病.结论 串联质谱对氨基酸和脂肪酸代谢病的诊断具有特异性,气相色谱-质谱对有机酸血症的诊断具有特异性,部分氨北基酸代谢病需要这2种技术联合应用才能诊断.     

Fits of laughter (gelastic epilepsy) with a tumour of the floor of the third ventricle

Summary A patient with fits of laughter due to a tumorous alteration (hyperplasia) of the floor of the third ventricle is described with electroencephalographic findings indicative of focal epilepsy (complex partial seizures = psychomotor fits). The laughter is interpreted as an inborn emotional expression with structural substrate in the hypothalamus and neighboring brain. With structures remaining intact functional disorders in this area can cause epileptic phenomena with participation of the limbic system.In cooperation with the Deutsche Forschungsgemeinschaft     

Successful living-related liver transplantation for familial hypercholesterolemia in the Middle East

Familial hypercholesterolemia (FH) is an autosomal dominant inherited metabolic disorder resulting in advanced vascular atherosclerosis and premature death, primarily from coronary artery disease. The primary defect is a mutation in the gene encoding for the plasma LDL receptor located on the short arm of chromosome 19. Liver transplantation is currently the most effective method of treating this disorder. Living-related liver transplantation (LRLT) has become an excellent modality for treating children, including those with inherited metabolic diseases. In this paper, we describe the first report of a LRLT for familial hypercholesterolemia and review FH and the role of liver transplantation.     

Somatic mosaicism in inborn errors of immunity: Current knowledge,challenges, and future perspectives

Inborn errors of immunity (IEI) are a diverse group of monogenic disorders of the immune system due to germline variants in genes important for the immune response. Over the past decade there has been increasing recognition that acquired somatic variants present in a subset of cells can also lead to immune disorders or ‘phenocopies’ of IEI. Discovery of somatic mosaicism causing IEI has largely arisen from investigation of seemingly sporadic cases of IEI with predominant symptoms of autoinflammation and/or autoimmunity in which germline disease-causing variants are not detected. Disease-causing somatic mosaicism has been identified in genes that also cause germline IEI, such as FAS, and in genes without significant corresponding germline disease, such as UBA1 and TLR8. There are challenges in detecting low-level somatic variants, and it is likely that the extent of the somatic mosaicism causing IEI is largely uncharted. Here we review the field of somatic mosaicism leading to IEI and discuss challenges and methods for somatic variant detection, including diagnostic approaches for molecular diagnoses of patients.     

The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease

Background: Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups (“clinical niches”) have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes.

Methods: Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included.

Findings: Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches.

Conclusions: Several clinical niches have been identified that harbor patients at increased risk of NP-C.     

Preliminary Investigation of Microbiome and Dietary Differences in Patients with Phenylketonuria on Enzyme Substitution Therapy Compared to Traditional Therapies

BackgroundPhenylketonuria (PKU) is an inborn error of metabolism that impairs the function of the enzyme phenylalanine hydroxylase. Historical treatment includes limiting dietary phenylalanine (Phe) consumption while supplementing with medical food; however, this treatment has been associated with complications, such as nutritional deficiencies and disruptions in the gut microbiota.ObjectiveThe study aim was to compare dietary and gut microbiome differences between adult patients on a traditional PKU diet with those receiving the enzyme substitution therapy Palynziq on a liberalized diet while controlling blood Phe levels to <600 μmol/L (to convert to mg/dL divide by 60.5).DesignA cross-sectional study was conducted comparing patients on a traditional Phe-restricted diet with patients receiving Palynziq eating a liberalized diet.Participants/settingSix patients eating a traditional Phe-restricted diet with medical food and 6 patients on Palynziq eating a liberalized diet without medical food intake for more than 3 years were selected from the University of Kentucky Metabolic Clinic from August to December 2019.Main outcome measuresNutrient intake from 3-day diet records and fecal microbiome taxonomic abundances were analyzed.Statistical analysisMann-Whitney U tests were used for dietary data analysis. Differential abundance analysis for microbiome taxa and pathway data was done using DESeq2 analysis.ResultsDietary data showed patients receiving Palynziq consumed a lower percent of kilocalories from total protein and lower amounts of most micronutrients, but consumed greater amounts of intact protein and cholesterol (P < .05). Microbiome data revealed a greater abundance of the phylum Verrucomicrobia and genus Lachnobacterium in the Traditional group and a greater abundance of the genus Prevotella in the Palynziq group (P < .05). Pathway analysis depicted greater enrichment in carotenoid and amino acid metabolism pathways in the Traditional group (P < .05). Protein (% kcal), dietary fiber (g), fat (% kcal), linolenic acid (% Dietary Reference Intakes), and age were correlated with the underlying microbial community structure for both groups combined.ConclusionsPatients with PKU treated with Palynziq on a liberalized diet manifest significant differences in diet composition compared with those treated with traditional Phe-restricted diets. Several of these dietary differences may affect the microbiome architecture.     

探讨2002-2011年十年间广州市儿童医院先天性唇腭裂患儿住院汇总分析

目的:总结汇总先天性唇腭裂住院救治经验和统计分析方法。方法:应用临床资料收集,病案汇总方法逐年月份统计,并将广州市户籍人口患病数从中提取。结果:10年间在广州市儿童医院住院救治的先天性唇腭裂病人无1例死亡,均治愈出院,分年间住院率从2002年到2009年分别是:2.21;2.44;2.30;2.41;2.42;2.66;2.50;2.38。在2010年和2011年分别是1.95和1.75,与前述各年比较呈明显下降趋势;10年间先天性唇腭裂病儿广州户籍人口率分别是:30.84;33.88;30.57;32.68;27.40;32.54;33.13;33.29;23.44;25.30。患者就医手术年龄不等,最小出生3天,最大12岁。<6月手术者占16.9%;6月～1周岁者占39%。即1周岁以前手术病儿超过55%,占超半数以上。结论:先天性唇腭裂是出生缺陷病儿最常见的病种,产前筛查常难避免,生后及早适时矫治均可治愈。提倡产前诊断,住院分娩,一旦发现及早确立手术方案,对治愈患儿减少后遗症有益。