Application of live biotherapeutic products and perspective in the treatment of inherited metabolic disease / 生物工程学报

Live biotherapeutic products (LBPs) refer to the living bacteria derived from human body intestinal gut or in nature that can be used to treat the human disease. However, the naturally screened living bacteria have some disadvantages, such as deficient therapeutic effect and great divergence, which fall short of the personalized diagnosis and treatment needs. In recent years, with the development of synthetic biology, researchers have designed and constructed several engineered strains that can respond to external complex environmental signals, which speeded up the process of development and application of LBPs. Recombinant LBPs modified by gene editing can have therapeutic effect on specific diseases. Inherited metabolic disease is a type of disease that causes a series of clinical symptoms due to the genetic defect of some enzymes in the body, which may cause abnormal metabolism the corresponding metabolites. Therefore, the use of synthetic biology to design LBPs targeting specific defective enzymes will be promising for the treatment of inherited metabolic defects in the future. This review summarizes the clinic applications of LBPs and its potential for the treatment of inherited metabolic defects.

Dietary therapy for inherited metabolic diseases / 中华实用儿科临床杂志

The developments of mass spectrometry and gene detection technology and the introduction of newborn screening have led to an expanding population of patients with inherited metabolic diseases.Therapies of inherited metabolic diseases have attracted much attention.The basic principles of management in these diseases are to limite the consumption of nutrients that produce toxic products, supplement deficient substances, and increase excretion of toxic metabolites.Dietary therapy is one of the major treatments for many inherited metabolic disorders, with the starting point of limiting the intake of substrates for metabolic disorders and supplementing products of insufficient synthesis or alternative energy sources to bypass the defective pathway in order to maintain normal growth and development.With more and more special medical formula nutritional foods being put into production and use, dietary therapy become accessible and compliant.With the effective dietary therapy, many patients get clinical symptom controlled, and their quality of life has been improved.This article mainly elaborates the common inherited metabolic diseases dietary therapy.

Recent research on inherited metabolic diseases in children / 中国当代儿科杂志

With the improvement in the research level and the diagnosis and treatment technology of inherited metabolic diseases (IMD), the research on pediatric IMD in China has made great progress, but there is still some distance from the international level. Due to the vast territory of China and the uneven distribution of medical resources, the regional characteristics of IMD remain unclear in China, and there are many problems and difficulties in early diagnosis and treatment. Therefore, it is necessary to improve the understanding of pediatric IMD among pediatricians, so as to improve the diagnosis and treatment level, achieve an early identification, diagnosis, and treatment of pediatric IMD, and effectively reduce the fatality and disability rates of children with IMD. This article reviews the research progress of IMD in children in China, and analyzes the features of representative IMDs. Citation:Chinese Journal of Contemporary Pediatrics, 2022, 24(3): 326-331.

Quality evaluation of tandem mass spectrometry screening for neonatalinherited metabolic diseases in Zhejiang Province from 2009 to 2021 / 预防医学

Objective@#To evaluate the quality of tandem mass spectrometry (MSMS) screening for neonatal inherited metabolic diseases in Zhejiang Province from 2009 to 2021.@*Methods@#The data pertaining to MSMS screening for neonatal inherited metabolic diseases in Zhejiang Province from 2009 to 2021 were collected from the database created by Zhejiang Provincial Center for Neonatal Disease Screening. The percentage of MSMS screening, percentage of recall of suspected screening-positive infants and incidence of neonatal inherited metabolic diseases were analyzed retrospectively to evaluate the quality of MSMS screening for inherited metabolic diseases.@*Results@#A total of 4 706 916 newborns were screened among 8 297 039 live births by MSMS in Zhejiang Province from 2009 to 2021, and the percentage of MSMS screening increased from 5.48% to 97.54%, with a mean percentage of 56.73%. Of 46 838 suspected screening-positive infants, 45 527 infants were recalled, and the percentage of recall increased from 94.57% to 98.62%, with a mean percentage of 97.20%. A total of 1 038 infants were definitively diagnosed with inherited metabolic diseases in Zhejiang Province from 2009 to 2021, with an overall incidence rate of 1/4 535, and the incidence rates of amino acid metabolic disorder, fatty acid oxidation metabolic disorder and organic acid metabolic disorder were 1/11 767, 1/13 763 and 1\15 902, respectively. Of the 11 cities in Zhejiang Province, the highest percentage of tandem mass spectrometry screening for inherited metabolic diseases was found in Hangzhou City (83.01%), and the highest percentage of recall of suspected screening-positive infants was se en in Zhoushan City (99.08%). @*Conclusions@#A high percentage of MSMS screening for neonatal inherited metabolic diseases was observed in Zhejiang Province from 2009 to 2021; however, there was a region-specific percentage of screening, and the recall of suspected screening-positive infants remains to be improved.

Genotypes of neonatal inherited metabolic diseases in Zhejiang Provincefrom 2009 to 2021 / 预防医学

Objective@#To investigate the genotypes and prognosis of infants with definitive diagnosis of inherited metabolic diseases during neonatal screening in Zhejiang Province from 2009 to 2021, so as to provide insights into the management of birth defects.@*Methods@#The medical records of infants with definitive diagnosis of inherited metabolic diseases by tandem mass spectrometry during neonatal screening in Zhejiang Province from 2009 to 2021 were collected from the database created by Zhejiang Provincial Center for Neonatal Disease Screening. The prevalence, genotypes and prognosis of inherited metabolic diseases were analyzed. @*Results@#A total of 1 038 infants were definitively diagnosed with inherited metabolic diseases in Zhejiang Province from 2009 to 2021, with an overall incidence rate of 1/4 535. There were 400 infants with amino acid metabolic disorders (AAD), 342 infants with fatty acid oxidation metabolic disorders and 296 infants with organic acid metabolic disorders (OAD), with incidence of 1/11 767, 1/13 763 and 1\15 902, respectively. There were 32 types of diseases, including 13 types of AAD, 8 types of FAOD and 11 types of OAD identified, and phenylketonuria and tetrahydrobiopterin deficiency (PKU/BH4D), primary carnitine deficiency (PCD) and methylmalonic academia (MMA) were detected as the most common forms of AAD, FAOD and OAD, with incidence of 1/20 827, 1/24 262 and 1\49 030, respectively. A total of 789 infants received genetic testing (76.01%), and genetic testing was performed among 70.00% of infants with AAD, 83.04% of infants with FAOD and 76.01% of infants with OAD. The c.728G >A (p.R243Q) variant was the most common mutation in infants with PKU (29.17%), c.1400C>G (p.S467C) variant was the most common mutation in infants with PCD (33.46%), c.609G>A (p.W203X) variant was the most common mutation in infants with combined MMA (40.00%), and c.1663G>A (p.A555T) variant was the most common mutation in infants with MMA (17.86%). Among the 997 infants (96.05%) with successful follow-up, 973 infants (93.74%) had normal intelligence and physical developments, and 41 infants died (3.95%), including 9 deaths due to AAD, 15 deaths due to FAOD and 17 deaths due to OAD. @*Conclusions @#The incidence of PKU, PCD and MMA was high among infants with inherited metabolic diseases in Zhejiang Province from 2009 to 2021, with c.728G>A (p.R243Q), c.1400C>G (p.S467C) and c.609G>A (p.W203X) variants as common gene mutations, respectively. Most infants with inherited metabolic diseases had a favorable prognosis; however, the mortality of OAD was relatively high.

Detection of urine metabolites in patients with inherited metabolic diseases by nuclear magnetic resonance spectroscopy / 中华检验医学杂志

Objective:Nuclear magnetic resonance spectroscopy (NMR) was used to detect the species and content of metabolites in urine of patients with inherited metabolic diseases, and to explore the application value of NMR technology in the diagnosis of inherited metabolic diseases.Methods:Urine samples were collected from 20 patients with inherited metabolic diseases diagnosed in Xinhua Hospital, Shanghai Jiaotong University School of Medicine from March to June 2019, including 9 cases of methylmalonic acidemia (MMA). NMR pulse length-based concentration determination and Gas chromatography mass spectrometry (GC/MS) semi-quantitative method were used to detect the composition of metabolites in urine samples of patients with inherited metabolic diseases, and the levels of abnormal metabolites in the two methods were analyzed.Results:NMR technology can detect the levels of characteristic metabolites significantly increased in the urine of patients with MMA, isovalerinemia, glutaric acidemia, propionic acidemia, 3-methylcrotonyl-CoA carboxylase deficiency, ornithine carbamyltransferase deficiency, Citrin deficiency, Canavan disease, tyrosinemia and lysinuria protein intolerance. The average is 8 times of the upper limit of the reference value, and the highest is 545 times. Compared to GC/MS, NMR technology can detect the levels of various metabolites such as organic acids, amino acids and sugars. In 9 cases of untreated MMA,the median levels of methylmalonic acid and 3-hydroxypropionic acid in NMR [1 800 (180-12 000) and 50 (0-270) mmol/mol Cr] were higher than the reference values (0-31, 0-35). The median levels of methylmalonic acid and methylmalonic acid in GC/MS [136.56 (43.79-518.67) and 4.87 (1.52-7.52)] were higher than the reference values (0-4 and 0-0.7).Conclusions:NMR and GC/MS technologies are specific for the diagnosis of organic acidemia. The primary component detected by GC/MS is organic acid. NMR technology can break through this limitation and measure the level of various metabolites in urine, which provides a more theoretical basis for the diagnosis and research of inherited metabolic disease.

In silico analysis of the effects of disease-associated mutations of b-hexosaminidase A in Tay–Sachs disease

Tay–Sachs disease (TSD), a deficiency of b-hexosaminidase A (Hex A), is a rare but debilitating hereditary metabolic disorder. Symptoms include extensive neurodegeneration and often result in death in infancy. We report an in silico study of 42 Hex A variants associated with the disease. Variants were separated into three groups according to the age of onset: infantile (n=28), juvenile (n=9) and adult (n=5). Protein stability, aggregation potential and the degree of conservation of residues were predicted using a range of in silico tools. We explored the relationship between these properties and the age of onset of TSD. There was no significant relationship between protein stability and disease severity or between protein aggregation and disease severity. Infantile TSD had a significantly higher mean conservation score than nondisease associated variants. This was not seen in either juvenile or adult TSD. This study has established that the degree of residue conservation may be predictive of infantile TSD. It is possible that these more highly conserved residues are involved in trafficking of the protein to the lysosome. In addition, we developed and validated software tools to automate the process of in silico analysis of proteins involved in inherited metabolic diseases. Further work is required to identify the function of well-conserved residues to establish an in silico predictive model of TSD severity

Tandem mass spectrometry screening of 565 182 newborns for inherited metabolic diseases in Hunan province / 中华实用儿科临床杂志

Objective@#To investigate the prevalence, mutation characteristics and clinical outcomes of inherited metabolic diseases(IMD) by using tandem mass spectrometry screening.@*Methods@#In Hunan province, 565 182 newborns who underwent tandem mass spectrometry (MS/MS) screening for IMDs were studied, including fatty acid oxidation disorders (FAODs), amino acid disorders (AAs), and organic acidemias (OAs) between March 2013 and September 2017.For the patients with positive results, a recall screening test was performed, and the results were further confirmed by specific biochemical and genetic analysis.For all the patients with IMD, guideline-directed medical treatment was administrated, and the follow-up outcomes was evaluated.@*Results@#A total of 107 newborns were diagnosed with IMDs, with an overall prevalence of 1∶5 282, including 65 newborns with FAODs (1∶ 8 695), 29 newborns with AAs (1∶19 489), and 13 newborns with OAs (1∶43 476). The primary carnitine deficiency(PCD)(44 cases), hyperphenylalaninemia (HPA)(17 cases), short-chain acyl-CoA dehydrogenase deficiency(SCADD)(12 cases), citrine deficiency(NICCD)(6 cases) were the 4 most common IMDs in Hunan province.The hotspot mutations in SLC22A5 gene of PCD were c. 51C>G(25.3%), c.1400C>G(23.0%), and c. 760C>T(13.8%); in PAH gene of HPA were c. 728G>A (22.2%) and c. 721C>T(14.8%); in ACADS gene of SCADD was c. 1031A>G(38.9%); and in SLC25A13 gene of NICCD was c. 851_854delGTAT (50.0%), respectively.The remaining IMDs were rare, and the hotspot mutations were unclear right now.During a mean follow-up of (26.1±5.6) months, 7 patients died, 4 patients suffered an intelligent disability, whereas the remaining 96 subjects had normal physical and intelligent development.@*Conclusions@#The overall prevalence of IMDs is not fairly low in Hunan province.Newborn screening and early appropriate management can significantly improve the outcomes of these patients.

Screening, diagnosis and treatment of propionic academia / 中华实用儿科临床杂志

Propionic acidemia or propionic aciduria, is a rare autosomal recessive inherited metabolic disease.It is a metabolic disorder of branched amino acids and odd-chain fatty acids caused by propionyl-CoA carboxylase deficiency, resulting in brain, heart, liver, bone marrow or multi-organ damages leading to disabilities even death.Patients with propionic acidemia have various clinical manifestations.Most patients presented in the neonatal period or early infancy.Nonspecific clinical presentations of the patients make the clinical diagnosis difficult, a definite diagnosis relies on the blood amino acids and acylcarnitines determination, urine organic acids analysis, and gene testing.The treatment for the patients in acute and stable phase should be individualized, including L-carnitine, dietary management, symptomatic intervention and liver transplantation.If not treated timely, patients have a high risk of death and disability.Early screening, diagnosis and treatment can greatly improve the patients′ clinical outcomes.

Tandem mass spectrometry screening of 565 182 newborns for inherited metabolic diseases in Hunan province / 中华实用儿科临床杂志

Objective To investigate the prevalence,mutation characteristics and clinical outcomes of inherited metabolic diseases(IMD) by using tandem mass spectrometry screening.Methods In Hunan province,565 182 newborns who underwent tandem mass spectrometry (MS/MS) screening for IMDs were studied,including fatty acid oxidation disorders (FAODs),amino acid disorders (AAs),and organic acidemias (OAs) between March 2013 and September 2017.For the patients with positive results,a recall screening test was performed,and the results were further confirmed by specific biochemical and genetic analysis.For all the patients with IMD,guideline-directed medical treatment was administrated,and the follow-up outcomes was evaluated.Results A total of 107 newborns were diagnosed with IMDs,with an overall prevalence of 1 ∶ 5 282,including 65 newborns with FAODs (1 ∶ 8 695),29 newborns with AAs (1 ∶ 19 489),and 13 newborns with OAs (1 ∶ 43 476).The primary carnitine deficiency(PCD) (44 cases),hyperphenylalaninemia (HPA) (17 cases),short-chain acyl-CoA dehydrogenase deficiency (SCADD) (12 cases),citrine deficiency(NICCD)(6 cases) were the 4 most common IMDs in Hunan province.The hotspot mutations in SLC22A5 gene of PCD were c.51C ＞ G(25.3％),c.1400C ＞ G(23.0％),and c.760C ＞ T(13.8％);in PAH gene of HPA were c.728G ＞ A (22.2％) and c.721C ＞ T(14.8％);in ACADS gene of SCADD was c.1031A ＞ G(38.9％);and in SLC25A13 gene of NICCD was c.851_854delGTAT (50.0％),respectively.The remaining IMDs were rare,and the hotspot mutations were unclear right now.During a mean follow-up of (26.1 ± 5.6) months,7 patients died,4 patients suffered an intelligent disability,whereas the remaining 96 subjects had normal physical and intelligent devdopment.Conclusions The overall prevalence of IMDs is not fairly low in Hunan province.Newborn screening and early appropriate management can significantly improve the outcomes of these patients.

Screening, diagnosis and treatment of propionic acidemia / 中华实用儿科临床杂志

Propionic acidemia or propionic aciduria,is a rare autosomal recessive inherited metabolic disease.It is a metabolic disorder of branched amino acids and odd-chain fatty acids caused by propionyl-CoA carboxylase deficiency,resulting in brain,heart,liver,bone marrow or multi-organ damages leading to disabilities even death.Patients with propionic acidemia have various clinical manifestations.Most patients presented in the neonatal period or early infancy.Nonspecific clinical presentations of the patients make the clinical diagnosis difficult,a definite diagnosis relies on the blood amino acids and acylcarnitines determination,urine organic acids analysis,and gene testing.The treatment for the patients in acute and stable phase should be individualized,including L-carnitine,dietary management,symptomatic intervention and liver transplantation.If not treated timely,patients have a high risk of death and disability.Early screening,diagnosis and treatment can greatly improve the patients' clinical outcomes.

Analysis on neonatal screening for inherited metabolic diseases in Zhejiang Province from 1999 to 2018 / 预防医学

Objective@#To evaluate the quality of neonatal screening work for inherited metabolic diseases，to learn the incidence of inherited metabolic diseases in newborns in Zhejiang Province from 1999 to 2018，and to provide scientific basis for formulating policies for control of birth defects. @*Methods@#The neonatal screening data for inherited metabolic diseases in Zhejiang Province from 1999 to 2018 were collected from the neonatal disease screening database of Zhejiang Neonatal Disease Screening Center，including congenital hypothyroidism（CH），phenylketonuria/tetrahydrobiopterin deficiency（PKU/BH4D），congenital adrenal hyperplasia（CAH），glucose-6-phosphate dehydrogenase deficiency（G6PD）and other metabolic disorders. The related indicators，such as the screening rate，prevalence rate，recall rate for suspected positive cases，resample rate of unqualified blood slides and rate of delayed blood slides delivery，were calculated to assess the quality of neonatal screening and understand the epidemic situation of inherited metabolic diseases in Zhejiang Province. @*Results@#A total of 10 016 839 newborns were screened and the rate rised from 6.46% in 1999 to 100.62% in 2018. The recall rate for suspected positive cases had exceeded 95% since 2007. The rate of unqualified blood tablets was under 1%（0.06% in 2018）；the resample rate of unqualified blood slides had exceeded 99% since 2004；the rate of delayed blood slides delivery dropped to 0.19% in 2018. The proportion of newborns screened by tandem mass spectrometry reached 92.75% in 2018. There were 13 664 cases of inherited metabolic diseases confirmed，with 6 723 cases of CH（6.71/10 000），472 cases of PKU/BH4D（0.47/10 000），125 cases of CAH（0.38/10 000），5 644 cases of G6PD（22.19/10 000）and 700 cases of other metabolic disorders（2.13/10 000）. The highest prevalence rate of CH，PKU/BH4D，G6PD and other metabolic disorders lay in Lishui，Hangzhou，Ningbo and Quzhou，respectively，which was significantly different in cities（P<0.05）.@*Conclusion@#The neonatal screening rate for inherited metabolic diseases，recall rate for suspected positive cases and resample rate of unqualified blood slides are high，while the rate of unqualified blood slides and delayed blood slides delivery have been kept low in Zhejiang Province. The prevalence of CH is above and PKU/BH4D is below the national average.

A New Integrated Newborn Screening Workflow Can Provide a Shortcut to Differential Diagnosis and Confirmation of Inherited Metabolic Diseases

PURPOSE: We developed a new workflow design which included results from both biochemical and targeted gene sequencing analysis interpreted comprehensively. We then conducted a pilot study to evaluate the benefit of this new approach in newborn screening (NBS) and demonstrated the efficiency of this workflow in detecting causative genetic variants. MATERIALS AND METHODS: Ten patients in Group 1 were diagnosed clinically using biochemical assays only, and 10 newborns in Group 2 were diagnosed with suspected inherited metabolic disease (IMD) in NBS. We applied NewbornDiscovery (SD Genomics), an integrated workflow design that encompasses analyte-phenotype-gene, single nucleotide variant/small insertion and deletion/copy number variation analyses along with clinical interpretation of genetic variants related to each participant's condition. RESULTS: A molecular genetic diagnosis was established in 95% (19/20) of individuals. In Group 1, 13 and 7 of 20 alleles were classified as pathogenic and likely pathogenic, respectively. In Group 2, 11 and 6 of 17 alleles with identified causative variants were pathogenic and likely pathogenic, respectively. There were no variants of uncertain significance. For each individual, the NewbornDiscovery and biochemical analysis results reached 100% concordance, since the single newborn testing negative for causative genetic variant in Group 2 showed a benign clinical course. CONCLUSION: This integrated diagnostic workflow resulted in a high yield. This approach not only enabled early confirmation of specific IMD, but also detected conditions not included in the current NBS.

Hypermethioninemia caused by deficient activity of methionine adenosyltransferase / 临床儿科杂志

Objective To investigate the clinical and molecular genetic characteristics of hypermethioninemia caused by methionine adenosyltransferase deficiency. Methods The clinical data and related gene analysis of hypermethioninemia caused by methionine adenosyltransferase deficiency in 3 children were retrospectively analyzed. The core pedigree analysis was carried out. Results Three children (2 boys and 1 girl) aged from 5 months to 3 years, were from 3 unrelated families. All of them had no family history. One case was found in neonatal screening. One case was onset with pathological jaundice at 1 month old. Another case was found due to tremor and growth retardation at 2 years old. Blood amino acid ester acyl carnitine spectrum analysis showed that all of them had significantly elevated levels of methionine at 134.50-790.67 μmol/L. All children had MAT1A mutation in methionine adenosyltransferase gene. One case was heterozygous mutations with third exon c.274T>C and seventh exon c.895C>T mutation; one case had sixth exon c.757G>A homozygous mutation; and another case had seventh exon c.791G>A homozygous mutation. The core pedigree analysis showed that the mutations were from theirs parents respectively. Conclusions For children with neurologic impairment, methionine metabolic disorders should be considered. Blood amino acids and gene analysis are important methods for confirmation of the diagnosis. Neonatal screening is an effective way to detect this disease.

Progress of fructose-1, 6-bisphosphatase deficiency / 国际儿科学杂志

Fructose-1,6-bisphosphatase(FBPase) deficiency is a rare inherited metabolic disease,which is an autosomal recessive metabolic disorder.Affected patients usually present with metabolic crisis including severe hypoglycemia and metabolic acidosis.Each attack occurred with a similar sequence.The triggering factors are removed and then clinical status is improved dramatically.As patients are usually symptomless in the plateau stage,it is often misdiagnosed.Metabolite assay in blood and urine is very useful for the diagnosis of FBPase deficiency.FBPase is a key enzyme in gluconeogenesis.Deficiency of FBPase impairs the formation of glucose from all precursors.FBP1 gene mutation contributes to the disease.More than 30 mutation types have been reported.There is no specific treatment.Early diagnosis and appropriate life-style can prevent repetitive metabolic derangements,improving life quality of these children and ensuring successful pregnancy.

Attention to guide breast feeding for sickness infants / 中华实用儿科临床杂志

Breast milk is best nutrition source for infants. However,human breast feeding is ceased or changed as formula feeding during disease or disease treatment. Now,the important significance of breast feeding for infants with preterm,diarrhea,jaundice,allergy,genetic disease and congenital cleft palate are analyzed,and feeding program is pro-vided,which can help mothers continue breast feeding and let the infants get nutritional support and protection from breast feeding. By breast feeding,it may improve children rehabilitation growth and development.

The clinical and genetic findings of childhood cystinuria / 临床儿科杂志

Objective To explore the clinical features and genetic etiology of children with cystinuria with onset of kidney stone. Methods The clinical data of 3 children with cystinuria with onset of kidney stone and the gene analysis results of SLC3A1 and SLC7A9 by PCR sequencing were retrospectively analyzed.Results Three male children were from three unrelated families, kidney stone were presented in 2 cases at 1 year old and 1 case at 14 years old. The blood amino acid spectrum was normal in all 3 cases, while the free carnitine were decreased. The urinary amino acid spectrum indicated that cystine, ornithine, arginine,and threonine increased.Gene analysis confirmed that 1 case had homozygous mutations of SLC7A9 gene c.325G>A, and his parents were carriers of c.325G>A heterozygous mutation;other 2 cases had heterozygous mutations of SLC3A1 gene, c.1365delG and c.1113C>A heterozygous mutation in one case, and c.1897_1898insTA and c.1093C>T heterozygous mutation in one case, and their parents were heterozygous mutation carriers. After treatment with potassium citrate and L-carnitine, the conditions were improved in all cases. Conclusions Inherited metabolic disease should be considered for children with kidney stone. Urine amino acid analysis and gene detection are important methods for the diagnosis of cystinuria.

Clinical analysis of inherited metabolic diseases in the neonatal intensive care unit / 中华实用儿科临床杂志

Objective To study the clinical characteristics of inherited metabolic disease(IMD) in the neonatal intensive care unit and to improve the ability of early diagnosis of the disease.Methods A total of 5 590 newborns were hospitalized in the Neonatal Intensive Care Unit (NICU),Fujian Maternity and Children Hospital between January 2012 and April 2015,and 340 neonates who were suspected of IMD consecutively were recruited.Tandem mass spectrometry and gas chromatography-tandem mass spectrometry were used to diagnose IMD.A retrospective study of analyzing the clinical characteristics of the patients of IMD in the NICU was conducted.Results Fifteen neonates were diagnosed as IMD,among whom methylmalonic academia,maple syrup urine disease,hyperphenylalaninemia,citrin deficiency,propionic acidemia,glutaric academia,ornithine transcarbamylase deficiency and primary carnitine deficiency were 5,2,2,2,1,1,1 and 1,respectively.Sixty-six point seven percent (10/15 cases) of IMD onset in the first week after birth were severe.Clinical presentations include the nervous was severe,digestive system and respiratory system symptoms,such as poor response,coma,lethargy,dystonia,convulsion,shortness of breath,dyspnea,milk refusal,diarrhea,jaundice,and so on.The main early manifestations were anorexia,lethargy,seizures and shortness of breath,which were nonspecific.Conclusions Clinical manifestations of IMD are nonspecific.The earlier onset of the disease is more serious,and early tandem mass spectrometry and gas phase chromatography-mass spectrometry are useful for early diagnosis and may guide early clinical intervention.

Screening of Urinary Organic Acid in Children with High Risk of Inherited Metabolic Diseases / 中国康复理论与实践

Objective To explore the application of gas chromatography mass spectrometry (GC/MS) in children with high risk of inher-ited metabolic disease. Methods From March, 2010 to November, 2015, 119 children suspected with inherited metabolic disease were in-cluded. The urinary organic acid was detected with GC/MS, and related diseases were screened. Results Seventeen children (14.29%) were positive with inherited metabolic disease, in which 16 cases (94.12%) manifested with development retardation. 20 children (16.81%) were probable positive. Conclusion GC/MS is effective in screening children with high risk of inherited metabolic disease, which can provide ba-sis for further diagnosis.

A Population-Based Genomic Study of Inherited Metabolic Diseases Detected Through Newborn Screening

BACKGROUND: A newborn screening (NBS) program has been utilized to detect asymptomatic newborns with inherited metabolic diseases (IMDs). There have been some bottlenecks such as false-positives and imprecision in the current NBS tests. To overcome these issues, we developed a multigene panel for IMD testing and investigated the utility of our integrated screening model in a routine NBS environment. We also evaluated the genetic epidemiologic characteristics of IMDs in a Korean population. METHODS: In total, 269 dried blood spots with positive results from current NBS tests were collected from 120,700 consecutive newborns. We screened 97 genes related to NBS in Korea and detected IMDs, using an integrated screening model based on biochemical tests and next-generation sequencing (NGS) called NewbornSeq. Haplotype analysis was conducted to detect founder effects. RESULTS: The overall positive rate of IMDs was 20%. We identified 10 additional newborns with preventable IMDs that would not have been detected prior to the implementation of our NGS-based platform NewbornSeq. The incidence of IMDs was approximately 1 in 2,235 births. Haplotype analysis demonstrated founder effects in p.Y138X in DUOXA2, p.R885Q in DUOX2, p.Y439C in PCCB, p.R285Pfs*2 in SLC25A13, and p.R224Q in GALT. CONCLUSIONS: Through a population-based study in the NBS environment, we highlight the screening and epidemiological implications of NGS. The integrated screening model will effectively contribute to public health by enabling faster and more accurate IMD detection through NBS. This study suggested founder mutations as an explanation for recurrent IMD-causing mutations in the Korean population.