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Abstract Background Isolated methylmalonic acidemia, an autosomal recessive disorder of propionate metabolism, is usually caused by mutations in the methylmalonyl-CoA mutase gene (mut-type). Because no universal consensus was made on whether mut-type methylmalonic acidemia should be included in newborn screening (NBS), we aimed to compare the outcome of this disorder detected by NBS with that detected clinically and investigate the influence of NBS on the disease course. Design & methods In this study, 168 patients with mut-type methylmalonic acidemia diagnosed by NBS were compared to 210 patients diagnosed after disease onset while NBS was not performed. Clinical data of these patients from 7 metabolic centers in China were analyzed retrospectively, including initial manifestations, biochemical metabolites, the responsiveness of vitamin B12 therapy, and gene variation, to explore different factors on the long-term outcome. Results By comparison of the clinically-diagnosed patients, NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12, younger age at start of treatment, lower levels of biochemical features before and after treatment, and better long-term prognosis (P

Biomimetic damping materials have emerged as promising candidates for various applications due to their ability to mimic the exceptional damping properties observed in biological systems. This review provides a comprehensive overview of recent advances in the field of biomimetic damping gel materials. The conceptual framework of biomimetic damping materials is discussed, the synthesis methods inspired by biological principles are elucidated, and key considerations in material selection are highlighted. The latest research findings on the mechanical properties, biocompatibility and practical applications of these materials are synthesized and insights into the future directions of biomimetic damping gel materials are offered.

Abstract Phenylketonuria (PKU) is the most common inherited metabolic disease in humans. Clinical screening of newborn heel blood samples for PKU is costly and time‐consuming because it requires multiple procedures, like isotope labeling and derivatization, and PKU subtype identification requires an additional urine sample. Delayed diagnosis of PKU, or subtype identification can result in mental disability. Here, plasmonic silver nanoshells are used for laser desorption/ionization mass spectrometry (MS) detection of PKU with label‐free assay by recognizing metabolic profile in dried blood spot (DBS) samples. A total of 1100 subjects are recruited and each DBS sample can be processed in seconds. This platform achieves PKU screening with a sensitivity of 0.985 and specificity of 0.995, which is comparable to existing clinical liquid chromatography MS (LC‐MS) methods. This method can process 360 samples per hour, compared with the LC‐MS method which processes only 30 samples per hour. Moreover, this assay enables precise identification of PKU subtypes without the need for a urine sample. It is demonstrated that this platform enables high‐performance and fast, low‐cost PKU screening and subtype identification. This approach might be suitable for the detection of other clinically relevant biomarkers in blood or other clinical samples.

Abstract Background cblC defect is the most common type of methylmalonic acidemia in China. Patients with late-onset form (>1 year) are often misdiagnosed due to heterogeneous symptoms. This study aimed to describe clinical characteristics and evaluate long-term outcomes of Chinese patients with late-onset cblC defect. Methods A total of 85 patients with late-onset cblC defect were enrolled. Clinical data, including manifestations, metabolites, molecular diagnosis, treatment and outcome, were summarized and analyzed. Results The age of onset ranged from 2 to 32.8 years old (median age 8.6 years, mean age 9.4 years). The time between first symptoms and diagnosis ranged from a few days to 20 years (median time 2 months, mean time 20.7 months). Neuropsychiatric symptoms were presented as first symptoms in 68.2% of cases, which were observed frequently in schoolchildren or adolescents. Renal involvement and cardiovascular disease were observed in 20% and 8.2% of cases, respectively, which occurred with the highest prevalence in preschool children. Besides the initial symptoms, the disease progressed in most patients and cognitive decline became the most frequent symptom overall. The levels of propionylcarnitine, propionylcarnitine / acetylcarnitine ratio, methylmalonic acid, methylcitric acid and homocysteine, were decreased remarkably after treatment (PA variant was the most frequent mutated allele in this cohort (25%). Except for 16 patients who recovered completely, the remaining patients were still left with varying degrees of sequelae in a long-term follow-up. The available data from 76 cases were analyzed by univariate analysis and multivariate logistic regression analysis, and the results showed that the time from onset to diagnosis (OR = 1.025, P = 0. 024) was independent risk factors for poor outcomes. Conclusions The diagnosis of late-onset cblC defect is often delayed due to poor awareness of its various and nonspecific symptoms, thus having an adverse effect on the prognosis. It should be considered in patients with unexplained neuropsychiatric and other conditions such as renal involvement, cardiovascular diseases or even multiple organ damage. The c.482G>A variant shows the highest frequency in these patients. Prompt treatment appears to be beneficial.

Abstract Background This study aimed to describe the clinical, biochemical, and molecular characteristics of Chinese patients with holocarboxylase synthetase (HLCS) deficiency, and to investigate the mutation spectrum of HCLS deficiency as well as their potential correlation with phenotype. Methods A total of 28 patients with HLCS deficiency were enrolled between 2006 and 2021. Clinical and laboratory data were reviewed retrospectively from medical records. Results Among the 28 patients, six patients underwent newborn screening, of which only one was missed. Therefore, 23 patients were diagnosed because of disease onset. Among all the patients, 24 showed varying degrees of symptoms such as rash, vomiting, seizures, and drowsiness, while only four cases remained asymptomatic nowadays. The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals. After prompt supplement of biotin, both the clinical and biochemical symptoms were dramatically resolved and nearly all patients developed normal intelligence and physique on follow-up. DNA sequencing revealed 12 known and 6 novel variants in the HLCS gene of patients. Among them, the variant of c.1522C > T was the most common. Conclusions Our findings expanded the spectrum of phenotypes and genotypes for HLCS deficiency in Chinese populations and suggested that with timely biotin therapy, patients with HLCS deficiency showed low mortality and optimistic prognosis. Newborn screening is crucial for early diagnosis, treatment, and long-term outcomes.

Background: Primary carnitine deficiency (PCD) is an autosomal recessive disease caused by mutations in the SLC22A5 gene, which encodes the organic cation transporter 2 (OCTN2). Patients with PCD may be at risk of skeletal or cardiac myopathy, metabolic decompensation, and even sudden death. This study aimed to analyze the biochemical, clinical, and genetic characteristics of PCD patients identified by newborn screening (NBS) in Shanghai.Methods: Dried blood spot (DBS) samples of newborns were analyzed through tandem mass spectrometry (MS/MS) from January 2003 to December 2021. Newborns with low free carnitine (C0) levels were recalled. Mutation in the SLC22A5 gene was analyzed on suspected positive newborns with low C0 levels after recall.Results: 1,247,274 newborns were screened by MS/MS and 40 newborns were diagnosed with PCD, therefore the incidence of PCD in Shanghai was approximately 1:31,200. The mean C0 level in newborns with PCD was 5.37 ± 1.79 μmol/L before treatment and increased to 24.45 ± 10.87 μmol/L after treatment with L-carnitine. Twenty-three different variants were identified in the SLC22A5 gene, including 8 novel variants, of which c.51C>G (p.F17L) was the most frequent (27.27%, 18/66), followed by c.1400C>G (p.S467C) (25.76%, 17/66). Almost all the screened PCD patients were asymptomatic.Conclusion: NBS via MS/MS was a quick and efficient method for the early diagnosis of PCD. The incidence of PCD in Shanghai was 1:31,200. Eight novel variants were identified, which greatly expanded the variant spectrum of SLC22A5. MS/MS combined with genetic testing could effectively improve the diagnostic accuracy of PCD.

Background: Isovaleric acidemia (IVA) is an inborn error of leucine metabolism and different approaches have been applied to its prenatal diagnosis. However, systemic application of a biochemical strategy is rare. To evaluate its reliability and validity, we conducted a retrospective study of our experience with metabolite measurement together with genetic analysis in IVA prenatal diagnosis at a single center.Methods: A total of eight pregnancies whose probands were diagnosed as IVA were referred to our center for prenatal diagnosis. Prenatal data of genetic analysis and metabolite measurement using tandem mass spectrometry (MS/MS) and gas chromatography/mass spectrometry (GC/MS) in amniotic fluid (AF) samples were retrospectively reviewed.Results: Genetic and biochemical results were both available in these eight at-risk fetuses. Among them, two fetuses had higher levels of isovalerylcarnitine (C5) and C5/acetylcarnitine (C2) in AF compared with normal reference range and, thus, were determined to be affected, both of whom were found to carry compound heterogeneous mutations according to genetic analysis. The remaining six fetuses were determined to be unaffected based on a normal AF metabolite profile, except one showed slightly elevated C5 and they were found to be carriers according to genetic analysis. However, the level of isovalerylglycine (IVG) could not be detected at all in both groups.Conclusion: The biochemical analysis, as a quick and convenient method, could be an additional reliable option for the prenatal diagnosis of IVA, especially in families with inconclusive genetic results, and can achieve a more precise diagnosis in conjunction with mutation analysis.

Objective: The present study aimed to determine the diagnostic value of prenatal chromosomal microarray analysis (CMA) for fetuses with several indications of being at high risk for various conditions. Materials and methods: This retrospective analysis included 1256 pregnancies that were prenatally evaluated due to high-risk indications using invasive CMA. The indications for invasive prenatal diagnosis mainly included ultrasound anomalies, high-risk for maternal serum screening (MSS), high-risk for non-invasive prenatal tests (NIPT), family history of genetic disorders or birth defects, and advanced maternal age (AMA). The rate of clinically significant genomic imbalances between the different groups was compared. Results: The overall prenatal diagnostic yield was 98 (7.8%) of 1256 pregnancies. Clinically significant genomic aberrations were identified in 2 (1.5%) of 132 patients with non-structural ultrasound anomalies, 36 (12.7%) of 283 with structural ultrasound anomalies, 2 (4.5%) of 44 at high-risk for MSS, 38 (26.6%) of 143 at high-risk for NIPT, 11 (3.8%) of 288 with a family history, and 7 (2.1%) of 328 with AMA. Submicroscopic findings were identified in 29 fetuses, 19 of whom showed structural ultrasound anomalies. Conclusion: The diagnostic yields of CMA for pregnancies with different indications greatly varied. CMA could serve as a first-tier test for structural anomalies, especially multiple anomalies, craniofacial dysplasia, urinary defects, and cardiac dysplasia. Our results have important implications for genetic counseling.

Abstract Background Combined methylmalonic acidemia and homocystinuria, cobalamin C type (cblC defect) is the most common inborn error of cobalamin metabolism, and different approaches have been applied to its prenatal diagnosis. To evaluate the reliability of biochemical method for the prenatal diagnosis of cblC defect, we conducted a retrospective study of our 10-year experience at a single center. Methods 248 pregnancies whose probands were diagnosed as cblC defect were referred to our center for prenatal diagnosis from January 2010 to December 2019. Prenatal data of Hcy levels determined by enzymatic cycling assay, acylcarnitine analysis using liquid chromatography tandem mass spectrometry, organic acid analysis using gas chromatography mass spectrometry, and genetic analysis by direct sequencing of 248 at-risk fetuses were retrospectively reviewed. Results For 2.0 and 16.0 μmol/L levels of Hcy AF samples, the relative errors were − 2.5% and 2.8%, respectively. The respective measurement uncertainties were 13.07% and 14.20%. For the 248 at-risk fetuses, 63 fetuses were affected and 185 fetuses were unaffected. Hcy level of 13.20 (6.62–43.30) μmol/L in 63 affected fetuses was significantly higher than that in 185 unaffected fetuses of 2.70 (0.00–5.80) μmol/L, and there was no overlap between the affected and unaffected groups. The diagnostic sensitivity and specificity of Hcy were 100% and 92.05%, respectively. The positive and negative predictive values of the combination of Hcy, propionylcarnitine (C3), ratio of C3 to acetylcarnitine (C2; C3/C2), methylmalonic acid (MMA), and methylcitric acid (MCA) were both 100%. Sixteen fetuses displayed inconclusive genetic results of MMACHC variants, in which seven fetuses were determined to be affected with elevated levels of Hcy, C3, C3/C2 and MMA, and their levels were 18.50 (6.70–43.30) μmol/L, 8.53(5.02–11.91) μmol/L, 0.77 (0.52–0.97), 8.96 (6.55–40.32) mmol/mol Cr, respectively. The remaining nine fetuses were considered unaffected based on a normal amniotic fluid metabolite profile. Conclusions Hcy appears to be another characteristic biomarker for the prenatal diagnosis of cblC defect. The combination of Hcy assay with acylcarnitine and organic acid analysis is a fast, sensitive, and reliable prenatal diagnostic biochemical approach. This approach could overcome the challenge of the lack of genetic analysis for families with at-risk cblC defect fetuses.

Abstract Background Methylmalonic acidemia is an inherited organic acid metabolic disease. It involves multiple physiological systems and has variable manifestations. The primary causative gene MMUT carries wide range of mutations, and one of them, c.1663G > A (p.A555T), is considered to be a rare type, which is seen more frequently in Asian than other populations. So far, little is known about the clinical features of patients carrying this mutation. In the present study, we aimed to define the clinical and biochemical features of the patients with this genotype. Methods Among 328 mut type methylmalonic acidemia patients from multiple hospitals in China, we collected 30 compound heterozygous patients sharing the mutation c.1663G > A (p.A555T) in the MMUT gene. Their clinical characteristics and biochemical index were described in detail and compared with methylmalonic acidemia patients without this variant. Results Most of these patients were diagnosed via newborn screening (26/30), treated in a timely manner, and kept healthy (24/30). Disease onset occurred in 7 patients. Developmental delay or intellectual impairment occurred in 4 patients. 100% of these patients (29/29) were responsive to Vitamin B12 administration. The blood propionylcarnitine, blood propionylcarnitine/acetylcarnitine ratio, urinary methylmalonic acid, urinary methylcitric acid before and after treatment in c.1663G > A (p.A555T) carrying patients were much lower than those in non-c.1663G > A (p.A555T) carrying patients. Conclusion Compared to patients with other mutations in the MMUT gene, patients with the c.1663G > A (p.A555T) mutation showed later onset, milder clinical phenotype, lighter biochemical abnormalities, better vitamin B12 responsiveness, lower morbidity, easier metabolic control, and thereby better prognosis. Newborn screening project plays an important role in early diagnosis, treatment, and prognosis of these patients.

Abstract Background This study aimed to describe the clinical and biochemical features of Chinese patients with ornithine transcarbamylase deficiency (OTCD), and to investigate the mutation spectrum of OTC gene and their potential correlation with phenotype. Methods Sixty-nine patients with OTCD were enrolled between 2004 and 2019. Clinical and laboratory data were reviewed retrospectively from medical records. Results Fifteen cases (13 males, 2 females) presented with early onset; 53 cases (21 males, 32 females) had late onset, and one female was asymptomatic. The median onset age was 1.5 years (range 1 day–56 years). Urine orotic acid levels were increased in all patients tested, while only 47.6% of patients showed decreased serum levels of citrulline. The peak plasma ammonia levels were higher in early-onset patients than in late-onset patients (P

Abstract Background Propionic acidemia (PA) is a serious metabolic disorder, and different approaches have been applied to its prenatal diagnosis. To evaluate the reliability and validity of a biochemical strategy in the prenatal diagnosis of PA, we conducted a retrospective study of our 11-year experiences at a single center. Methods We accumulated data from 78 pregnancies from 58 families referred to our center and provided prenatal diagnosis by directed genetic analysis and/or metabolite measurement using tandem mass spectrometry (MS/MS) and gas chromatography/mass spectrometry (GC/MS) of amniotic fluid (AF) samples. Results Sixty-five unaffected fetuses (83.33%) and 13 affected fetuses (16.67%) were confirmed in our study. The characteristic metabolites including propionylcarnitine (C3) level, C3/acetylcarnitine (C2) ratio and 2-methylcitric acid (2MCA) level in unaffected and affected groups showed significant differences (P 0.05).Of the 78 pregnancies, 24 fetuses were found to have either one causative pathogenic variant or were without genetic information in the proband. Three of these fetuses had elevated AF levels of C3, C3/C2 ratio, and 2MCA and, thus, were determined to be affected, while the remaining fetuses were determined to be unaffected based on a normal AF metabolite profile. Our genetic and biochemical results were highly consistent with postnatal follow-up results on all unaffected fetuses. Conclusions We conclude that a biochemical approach can serve as a fast and convenient prenatal diagnostic method for pregnancies at an increased risk for PA, which could be used in conjunction with genetic testing for precise prenatal diagnosis of this disorder. In our analysis, the characteristic metabolites C3 level, C3/C2 ratio, and 2MCA level in AF supernatant were dependable biochemical markers for diagnosis, of which the C3/C2 ratio appears to be the most reliable biochemical marker for the prenatal diagnosis of PA.

Objective: The cblC type of combined methylmalonic acidemia and homocystinuria, an inherited disorder with variable phenotypes, is included in newborn screening (NBS) programs at multiple newborn screening centers in China. The present study aimed to investigate the long-term clinical benefits of screening individual.Methods: A national, retrospective multi-center study of infants with confirmed cblC defect identified by NBS between 2004 and 2020 was conducted. We collected a large cohort of 538 patients and investigated their clinical data in detail, including disease onset, biochemical metabolites, and gene variation, and explored different factors on the prognosis.Results: The long-term outcomes of all patients were evaluated, representing 44.6% for poor outcomes. In our comparison of patients with already occurring clinical signs before treatment to asymptomatic ones, the incidence of intellectual impairment, movement disorders, ocular complications, hydrocephalus, and death were significantly different (p < 0.01). The presence of disease onset [Odd ratio (OR) 12.39, 95% CI 5.15–29.81; p = 0.000], variants of c.609G>A (OR 2.55, 95% CI 1.49–4.35; p = 0.001), and c.567dupT (OR 2.28, 95% CI 1.03–5.05; p = 0.042) were independently associated with poor outcomes, especially for neurodevelopmental deterioration.Conclusion: NBS, avoiding major disease-related events and allowing an earlier treatment initiation, appeared to have protective effects on the prognosis of infants with cblC defect.

Abstract In this study, we constructed multifunctional liposomes with preferentially mitochondria-targeted feature and gold nanoparticles-assisted synergistic photodynamic therapy. We systemically investigated the in vitro X-ray triggered PDT effect of these liposomes on HCT 116 cells including the levels of singlet oxygen, mitochondrial membrane potential, cell apoptosis/necrosis and the expression of apoptosis-related proteins. The results corroborated that synchronous action of PDT and X-ray radiation enhance the generation of cytotoxic reactive oxygen species produced from the engineered liposomes, causing mitochondrial dysfunction and increasing the levels of apoptosis.

Abstract Background PYGL mutations can cause liver phosphorylase deficiency, resulting in a glycogenolysis disorder, namely, glycogen storage disease (GSD) VI. The disease is rarely reported in the Chinese population. GSD VI is mainly characterized in untreated children by hepatomegaly, growth retardation and elevated liver transaminases. Case presentation In this study, we report two GSD VI patients with growth retardation and abnormal liver function. There was no obvious hepatomegaly for one of them. Whole exome sequencing (WES) combined with copy number variation analysis was performed. We found a novel homozygous gross deletion, c.1621-258_2178-23del, including exons 14–17 of PYGL in patient 1. The exons 14–17 deletion of PYGL resulted in an in-frame deletion of 186 amino acids. Compound heterozygous mutations of PYGL were identified in patient 2, including a novel missense mutation c.1832C > T/p.A611V and a recurrent nonsense mutation c.280C > T/p.R94X. After treatment with uncooked cornstarch (UCS) 8 months for patient 1 and 13 months for patient 2, the liver transaminases of both patients decreased to a normal range and their stature was improved. However, patient 1 still showed mild hypertriglyceridemia. Conclusions We describe two GSD VI patients and expand the spectrum of PYGL mutations. Patient 1 in this study is the first GSD VI case that showed increased transaminases without obvious hepatomegaly due to a novel homozygous gross deletion of PYGL identified through WES.

Borjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked disease caused by PHF6 mutations. Classic BFLS has been associated with intellectual disability (ID), developmental delay (DD), obesity, epilepsy, typical facial features and anomalies of fingers and toes. Endocrinological phenotypes and outcome of treatment in this condition remain to be delineated. Here we report a patient who exhibited complete growth hormone deficiency who responded to hormonal treatment but with adverse effects. Horseshoe kidney was present in this patient, which is also atypical in BFLS. A heterozygous nonsense mutation c.673C>T (p.R225X) of PHF6 gene was identified in the patient, inherited from her unaffected mother. Both the patient and her mother showed highly skewed X-inactivation. We reviewed the phenotypes of all reported BFLS cases, and summarized their endocrine presentations. This first report of an Asian patient with BFLS further delineated the genetic and phenotypic spectrum of the syndrome. The adverse effect experienced by the patient suggests caution in the use of growth hormone treatment in this condition.

Abstract Background To summarize the relationship between different MMUT gene mutations and the response to vitamin B12 in MMA. Methods This was a retrospective study of patients diagnosed with mut‐type MMA. All patients with mut‐type MMA were tested for responsiveness to vitamin B12. Results There were 81, 27, and 158 patients in the completely responsive, partially responsive, and nonresponsive groups, respectively, and the proportions of symptom occurrence were 30/81 (37.0%), 21/27 (77.8%), and 131/158 (82.9%), respectively (p A, c.2080C>T, c.1880A>G, c.1208G>A, etc. were completely responsive and with the mutations of c.1741C>T, c.1630_1631GG>TA, c.599T>C, etc. were partially responsive. The proportions of healthy/developmental delay outcomes in the three groups were 63.0%/23.5%, 33.3%/40.7%, and 13.3%/60.1%, respectively (p

PurposeTo characterize the phenotypic and genotypic variations associated with Glutaric aciduria type 1 (GA1) in Chinese patients.MethodsWe analyzed the clinical, neuroradiological, biochemical, and genetic information from 101 GA1 patients in mainland China.Results20 patients were diagnosed by newborn screening and the remaining 81 cases were identified following clinical intervention. Macrocephaly was the most common presentation, followed by movement disorders and seizures. A total of 59 patients were evaluated by brain MRI and 58 patients presented with abnormalities, with widening of the sylvian fissures being the most common symptom. The concentration of glutarylcarnitine in the blood, glutarylcarnitine/capryloylcarnitine ratio, and urine levels of glutaric acid were increased in GA1 patients and were shown to decrease following intervention. A total of 88 patient samples were available for genotyping and 74 variants within the GCDH gene, including 23 novel variants, were identified. The most common variant was c.1244-2A > C (18.4%) and there were no significant differences in the biochemical or clinical phenotypes described for patients with the four most common variants: c.1244-2A > C, c.1064G > A, c.533G > A, and c.1147C > T. Patients identified by newborn screening had better outcomes than clinical patients.ConclusionOur findings expand the spectrum of phenotypes and genotypes for GA1 in Chinese populations and suggest that an expanded newborn screening program using tandem mass spectrometry may facilitate the early diagnosis and treatment of this disease, improving clinical outcomes for patients in China.

Abstract Background Cleidocranial dysplasia (CCD) is a rare autosomal dominant disorder mainly characterized by hypoplastic or absent clavicles, delayed closure of the fontanelles, multiple dental abnormalities, and short stature. Runt-related transcription factor 2 (RUNX2) gene variants can cause CCD, but are not identified in all CCD patients. Methods In this study, we detected genetic variants in seven unrelated children with CCD by targeted high-throughput DNA sequencing or Sanger sequencing. Results All patients carried a RUNX2 variant, totally including three novel pathogenic variants (c.722_725delTGTT, p.Leu241Serfs*8; c.231_232delTG, Ala78Glyfs*82; c.909C > G, p.Tyr303*), three reported pathogenic variants (c.577C > T, p.Arg193*; c.574G > A, p.Gly192Arg; c.673 C > T, p.Arg225Trp), one likely pathogenic variant (c.668G > T, p.Gly223Val). The analysis of the variant source showed that all variants were de novo except the two variants (c.909C > G, p.Tyr303*; c.668G > T, p.Gly223Val) inherited from the patient’s father and mother with CCD respectively. Further bioinformatics analysis indicated that these variants could influence the structure of RUNX2 protein by changing the number of H-bonds or amino acids. The experimental result showed that the Gly223Val mutation made RUNX2 protein unable to quantitatively accumulate in the nucleus. Conclusions The present study expands the pathogenic variant spectrum of RUNX2 gene, which will contribute to the diagnosis of CCD and better genetic counseling in the future.

Abstract Background Pompe disease is a rare, progressive, autosomal recessive lysosomal storage disorder caused by mutations in the acid α-glucosidase gene. This is the first report of Chinese patients from the global Pompe Registry. Chinese patients enrolled in the Registry (ClinicalTrials.gov, NCT00231400) between Jan 2013 and 2 Sep 2016 with late onset Pompe disease (LOPD; presentation after 12 months of age or presentation at ≤12 months without cardiomyopathy) were included. Data analyses were descriptive. Results Of the 59 Chinese patients included, 86.4% had never received enzyme replacement therapy (ERT). The age at symptom onset and diagnosis was 14.9 (12.35) and 22.1 (10.08) years, which is younger than previous reports of LOPD patients from the rest of the world (28.4 [18.86] and 34.9 [20.03], respectively). The most common diagnosis methods were enzyme assay (79.7%) and/or DNA analysis (61.0%). Of the 36 patients diagnosed using DNA analysis, 31 had standardized variant data and among these patients the most common mutations were c.2238G > C (n = 18, 58.1%) and c.2662G > T (n = 5, 16.1%). Chinese LOPD patients appeared to have worse lung function versus patients from the rest of the world, indicated by lower forced vital capacity (37.2 [14.00]% vs. 63.5 [26.71]%) and maximal expiratory and inspiratory pressure (27.9 [13.54] vs. 51.0 [38.66] cm H2O, and 29.4 [12.04] vs. 70.5 [52.78] cm H2O). Conclusions Compared with patients from the rest of the world, Chinese patients with LOPD appeared to have younger age at symptom onset and diagnosis, lower lung function, and the majority had not received ERT. The most common mutations were c.2238G > C and c.2662G > T.

ObjectiveMedium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare inherited metabolic disorder of fatty acid β-oxidation. The present study aimed to evaluate clinical and biochemical manifestations, and the mutation spectrum of this disorder in a large cohort of Chinese patients.MethodsA total of 24 patients were enrolled, and blood acylcarnitine and urinary organic acid levels were measured by tandem mass spectrometry and gas chromatography–mass spectrometry (GC–MS), respectively. Mutations in the ACADM gene were detected by Sanger or next-generation sequencing. Clinical progression, acylcarnitine spectra, and mutations were analyzed and described in detail.ResultsAmong the 24 patients, six cases were diagnosed because of disease onset with symptoms such as vomiting, diarrhea, convulsion, and hypoglycemia; 18 patients without symptoms were diagnosed by newborn screening (NBS). All patients who accepted treatment after diagnosis developed normal intelligence and physique. The concentrations of octanoylcarnitine, the octanoylcarnitine/decanoylcarnitine ratio, and the octanoylcarnitine/acetylcarnitine ratio in the blood and urinary dicarboxylic acid concentrations were consistently elevated. Blood biomarkers failed to decrease after treatment. DNA sequencing revealed seven known and 17 novel mutations in the ACADM gene of patients. Mutation p.T150Rfs∗4 was most frequent, followed by p.R31C, p.F103Y, p.I223T, p.G362E, and c.387+1delG.ConclusionDespite biochemical abnormalities, medium-chain acyl-CoA dehydrogenase deficiency showed relatively mild clinical phenotypes with low mortality and optimistic prognoses in China. NBS is crucial for early diagnosis, treatment, and prognosis.

Improving the tribological characteristics of water-based drilling fluids by adding graphene-based lubricants has garnered attention because of the potential for a range of inorganic-material-based additives at high temperature. In this study, we constructed a green and simple adsorption approach to prepare highly dispersed graphite using a cationic surfactant for graphite modification. The findings demonstrated that the prepared graphite was highly dispersed in water and had a low sedimentation rate and small contact angle in distilled water. The concentration dosage of cetyltrimethylammonium chloride (CTAC) on graphite was 0.02 g/g. We evaluated the performance of the modified graphite as a lubricated additive in water-based drilling through a rheological study and viscosity coefficient measurement. The results showed that the viscosity coefficient of drilling fluid with 0.05% modified graphite was reduced by 67% at 180 °C. We proved that the modified graphite can significantly improve the lubrication performance of drilling fluid. Furthermore, we revealed the lubrication mechanism by analyzing the chemical structural and crystalline and morphological features of graphite through a particle size test, zeta potential test, Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRD), and scanning electron microscopy (SEM) measurements. The results indicated that the modification of graphite by CTAC only occurs through physical adsorption, without changing the crystal structure. These findings provide a reference for the development of high-performance water-based drilling fluids.

Simple copy number variations (CNVs) detected by chromosomal microarray (CMA) can result from complex structural changes. Therefore, it is necessary to characterize potential structural changes that cause pathogenic CNVs. We applied whole-genome low-coverage sequencing (WGLCS) to concurrently detect pathogenic CNVs and their associated chromosomal rearrangements in 15 patients. All the patients had an average of 2–3 pathogenic CNVs involving 1–2 chromosomes. WGLCS identified all the 34 pathogenic CNVs found by microarray. By identifying chimeric read pairs, WGLCS mapped 70 breakpoints in these patients, of which 47 were finely mapped at the nucleotide level and confirmed by subsequent PCR amplification and Sanger sequencing of the junction fragments. In 15 patients, structural rearrangements were defined at molecular level in 13 patients. In 13 patients, WGLCS reveal no additional results in two patients. In another 11 patients, WGLCS revealed new breakpoints or finely mapped the genes disrupted by breakpoints or 1–6 bp microhomology and/or short insertion (4–70 bp) in the breakpoints junctions. However, structural changes in the other two patients still remained unclear after WGLCS was performed. The structural alteration identified in the 13 patients could be divided into the following categories: (1) interstitial inverted duplication with concomitant terminal deletion (inv dup del) (P1,P4,P9,P11); (2) the product of pericentric inversion (P5); (3) ring chromosome (P8); (4) interstitial duplication and/or triplication (P6, P7); and (5) +der(22)t(11;22) (P2,P15); (6) complex structural rearrangements (P3,P12,P14). WGLCS displayed the ability to discover CNVs and define breakpoints and its disrupted genes and its surrounding sequences in one experiment at base-pair-resolution, which help us to learn more about the mechanisms of formation of observed genomic rearrangements, and in which DNA replicative/repair mechanism might contribute to the formation of complex rearrangements in 11 patients. Clear karyotype at molecular level could help provide an accurate evaluation of recurrent risk and guide prenatal diagnosis or reproductive planning.

Direct mutation analysis is the major method for glutaric acidemia I (GA-I) prenatal diagnosis, while systemic application of a biochemical strategy is rare. We describe our experiences with metabolite measurement together with mutation analysis in GA-I prenatal diagnosis at a single center over 10 years. The data of genetic analysis and metabolite measurement using gas chromatography/mass spectrometry(GC/MS) and tandem mass spectrometry(MS/MS) in amniotic fluid samples of 44 fetuses from 42 GA-I families referred to our center from 2009 to 2019 were retrospectively analyzed. Among these 44 fetuses, genetic and biochemical results were both available in 39 fetuses. Of these, 6 fetuses were judged as affected and 33 fetuses as unaffected by mutation analysis. The levels of glutarylcarnitine (C5DC), C5DC/octanoylcarnitine (C8), and glutaric acid in the supernatant of amniotic fluid from affected fetuses were significantly higher than those in unaffected fetuses [1.73μmol/L (0.89–4.19) vs. 0.16μmol/L (0.06–0.37), 26.26 (12.4–55.55) vs. 2.23 (1.04–8.44), and 103.94 mmol/mol creatinine (30.37–148.31) vs. 1.01mmol/mol creatinine (0–9.81), respectively; all P < 0.0001]. Among all families, two were found to have one causative mutation in the proband, in four pregnancies from these two families, three fetuses were judged as “unaffected” and one was judged as “affected” according to metabolites results. Postnatal follow-up showed a normal phenotype in all unaffected fetuses judged by mutation or metabolite analysis. C5DC, C5DC/C8, and glutaric acid levels in the supernatant of amniotic fluid showed significant differences and no overlap between the affected and unaffected fetuses. Biochemical strategy could be implemented as a quick and convenient method for the prenatal diagnosis of GA-I.

Abstract Background Aromatic L‐amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive inherited disorder which is characterized by neurological and vegetative symptoms. To date, only 130 patients with AADCD have been reported worldwide. Methods We demonstrated 14 previously undescribed patients together with three reportedly patients in Mainland China. Full clinical information was collected, and disease‐causing variants in the DDC gene were detected. Results The common clinical manifestation of patients, including intermittent oculogyric crises, retarded movement development, and autonomic symptoms. Notably, a patient showed bone‐density loss which have not been reported and two mildly phenotype patients improved psychomotor function after being prescribed medication. The most common genotype of Mainland Chinese AADCD is the splice‐site variant (IVS6+4A> T; c.714+4A> T), which accounts for 58.8%, followed by c.1234C>T variant. Three novel compound heterozygous variants, c. 565G>T, c.170T>C, and c.1021+1G>A, were firstly reported. It is important to recognize the milder phenotypes of the disease as these patients might respond well to therapy. Besides, we discovered that patients may presented with milder if found to be compound heterozygote or homozygote for one of the following variants c.478C>G, c.853C>T, c.1123C>T, c.387G>A, and c.665T>C. Discussion The clinical data of the cohort of 17 patients in Mainland China broaden the clinical, molecular, and treatment spectrum of aromatic L‐amino acid decarboxylase deficiency.

Abstract Background Developmental delay (DD) and intellectual disability (ID) are frequently associated with a broad spectrum of additional phenotypes. Chromosomal microarray analysis (CMA) has been recommended as a first-tier test for DD/ID in general, whereas the diagnostic yield differs significantly among DD/ID patients with different comorbid conditions. Methods To investigate the genotype-phenotype correlation, we examined the characteristics of identified pathogenic copy number variations (pCNVs) and compared the diagnostic yields among patient subgroups with different co-occurring conditions. Results This study is a retrospective review of CMA results generated from a mixed cohort of 710 Chinese patients with DD/ID. A total of 247 pCNVs were identified in 201 patients (28%). A large portion of these pCNVs were copy number losses, and the size of copy number losses was generally smaller than gains. The diagnostic yields were significantly higher in subgroups with co-occurring congenital heart defects (55%), facial dysmorphism (39%), microcephaly (34%) or hypotonia (35%), whereas co-occurring conditions of skeletal malformation (26%), brain malformation (24%) or epilepsy (24%) did not alter the yield. In addition, the diagnostic yield nominally correlated with ID severity. Conclusion Varied yields exist in DD/ID patients with different phenotypic presentation. The presence of comorbid conditions can be among factors to consider when planning CMA.

SID1 transmembrane family member 2 (Sidt2) is an integral lysosomal membrane protein. To investigate its explicit function, we generated a global Sidt2 knockout mouse model (Sidt2−/−). Compared with the littermate controls, Sidt2−/− mice exhibited a remarkable accumulation of lipid droplets in liver. First, it was observed that food consumption, hepatocyte fatty acid uptake and de novo lipogenesis, hepatocyte lipolysis, and TG secretion in the form of very low density lipoprotein were comparable between Sidt2−/− and WT mice. However, the hepatic β-oxidation of fatty acids decreased significantly as revealed by a low level of serum β-hydroxybutyrate in the Sidt2−/− mice along with normal mRNA expression of genes involved in fatty acid oxidation. In addition, the classical autophagy pathway marker proteins, p62 and LC3-II, increased in liver, along with compromised autophagic flux in primary hepatocytes, indicating a block of autophagosome maturation due to Sidt2 deficiency, which was also supported by electron microscopy image analysis both in livers and in primary hepatocytes from Sidt2−/− mice. It was concluded that Sidt2 plays an important role in mouse hepatic lipid homeostasis by regulating autophagy at the terminal stage.

Abstract Background Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are autosomal dominant developmental disorders. NS and NSML are caused by abnormalities in genes that encode proteins related to the RAS-MAPK pathway, including PTPN11, RAF1, BRAF, and MAP2K. In this study, we diagnosed ten NS or NSML patients via targeted sequencing or whole exome sequencing (TS/WES). Methods TS/WES was performed to identify mutations in ten Chinese patients who exhibited the following manifestations: potential facial dysmorphisms, short stature, congenital heart defects, and developmental delay. Sanger sequencing was used to confirm the suspected pathological variants in the patients and their family members. Results TS/WES revealed three mutations in the PTPN11 gene, three mutations in RAF1 gene, and four mutations in BRAF gene in the NS and NSML patients who were previously diagnosed based on the abovementioned clinical features. All the identified mutations were determined to be de novo mutations. However, two patients who carried the same mutation in the RAF1 gene presented different clinical features. One patient with multiple lentigines was diagnosed with NSML, while the other patient without lentigines was diagnosed with NS. In addition, a patient who carried a hotspot mutation in the BRAF gene was diagnosed with NS instead of cardiofaciocutaneous syndrome (CFCS). Conclusions TS/WES has emerged as a useful tool for definitive diagnosis and accurate genetic counseling of atypical cases. In this study, we analyzed ten Chinese patients diagnosed with NS and related disorders and identified their correspondingPTPN11, RAF1, and BRAF mutations. Among the target genes, BRAF showed the same degree of correlation with NS incidence as that of PTPN11 or RAF1.

In this paper, alkyl aliphatic hydrazine, which is different from traditional polymer fluidity improver, was synthesized from aliphatic hydrazine and cetane bromide, and evaluated as a pour point and viscosity-reducer depressant for crude oil. The evaluation results showed that alkyl aliphatic hydrazone fully reduced the pour point and viscosity of crude oil with the increase of crude oil fluidity. The viscosity reduction rate of crude oil in Jinghe oilfield was 79.6%, and the pour point was reduced by about 11.3 °C. The viscosity reduction rate of crude oil in Xinjiang Oilfield was 74.7%, and the pour point was reduced by 8.0 °C. The long alkyl chain is beneficial to the eutectic of wax in crude oil, and the polar group inhibits the crystal growth, resulting in the decrease of pour point and viscosity. The waste oil is fully recycled into oilfield chemicals.

Abstract Molecular characterization of PAH deficiency has been proven essential in establishing treatment options. We examine the diagnostic accuracy of two genetic assays to predict BH4 responsiveness: to determine whether the AV sum test or mutation-status assessment test can obviate the need for BH4 loading in Chinese patients. The overall predicted response in 346 patients was 31.65% by the AV sum test and 25.43% by the other assay; both percentages were lower than 51.06% derived from loading results in 94 patients. Responders were compound heterozygotes with definite BH4 responsive mutations, while non-responders had null/null ones; some consistently with specific mutations and genotypes. The sensitivity and specificity of the assays were 81.1% and 92.5% for the AV sum, and 82.9%, 97.3% for the other. An AV sum cutoff >2 has a positive predictive value (PPV) of 90.9%, while the presence of at least one BH4 responsive mutation has a PPV of 97.1%. The two approaches showed good concordance. Our data confirmed that the mutation-status assessment has a higher diagnostic accuracy in predicting response for Chinese patients than the AV sum test. BH4-responsiveness may be predicted or excluded from patients’ molecular characteristics to some extent, thus some patients may avoid the initial loading.

To verify the temperature sensitive failure of poly (N-isopropylacrylamide) (PNIPAM) anchored on the surface of gold nanoparticles (AuNPs), the UV-Vis spectra with temperature variations of the following aqueous solutions respectively containing AuNPs-PNIPAM, Au-PNIPAM/PNIPAM, PNIPAM, in different media (including salt, ethanol, HCl and cetyltrimethylammoniumbromide (CTAB)), were systematically determined. The results indicated that the UV-Vis spectrum of AuNPs-PNIPAM suspension hardly changed even above the Lower Critical Solution Temperature (LCST) of PNIPAM, but that of Au-PNIPAM/PNIPAM sharply increased only in absorbance intensity. A possible mechanism of the failed temperature sensitivity of PNIPAM anchored on the surface of AuNPs was proposed. Being different from free PNIPAM molecules, a strong interaction exists among PNIPAM molecules anchored on the surface of AuNPs, restraining the change in conformation of PNIPAM. The temperature sensitivity of Au-PNIPAM/PNIPAM originates from the free PNIPAM molecules rather than the anchored PNIPAM one. The changing electrostatic interaction could effectively regulate the aggregation behavior of AuNPs-PNIPAM and enhance its sensitivity to temperature.

Acid sphingomyelinase (ASMase)-deficient Niemann-Pick disease (NPD) is caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, resulting in accumulation of sphingomyelin in the lysosomes and secondary changes in cholesterol metabolism. We hypothesized that the oxidation product of cholesterol, 7-ketocholesterol (7-KC), might increase in the plasma of patients with ASMase-deficient NPD. In this study, a rapid and nonderivatized method of measurement of plasma 7-KC by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. Plasma samples from healthy subjects, patients with ASMase-deficient NPD, nonaffected ASMase-deficient NPD heterozygotes, Niemann-Pick type C (NPC) disease, glycogen storage disorder type II (GSDII), Gaucher disease (GD), mucopolysaccharidosis type II (MPSII), Krabbe disease (KD), and metachromatic leukodystrophy (MLD) were tested retrospectively. Markedly elevated 7-KC was found in patients with ASMase-deficient NPD and NPC disease that showed significant differences from ASMase-deficient NPD heterozygotes; patients with GSDII, GD, MPSII, KD, and MLD; and normal controls. The analysis of plasma 7-KC by LC-MS/MS offers the first simple, quantitative, and highly sensitive method for detection of ASMase-deficient NPD and could be useful in the diagnosis of both ASMase-deficient NPD and NPC disease.

The difference in gold nanoparticle (AuNPs) aggregation caused by different mixing orders of AuNPs, 4-mercaptophenylboronic acid (4-MPBA), and hydrogen peroxide (H2O2) has been scarcely reported. We have found that the color change of a ((4-MPBA + AuNPs) + H2O2) mixture caused by H2O2 is more sensitive than that of a ((4-MPBA + H2O2) + AuNPs) mixture. For the former mixture, the color changes obviously with H2O2 concentrations in the range of 0~0.025%. However, for the latter mixture, the corresponding H2O2 concentration is in the range of 0~1.93%. The mechanisms on the color change originating from the aggregation of AuNPs occurring in the two mixtures were investigated in detail. For the ((4-MPBA + H2O2) + AuNPs) mixture, free 4-MPBA is oxidized by H2O2 to form bis(4-hydroxyphenyl) disulfide (BHPD) and peroxoboric acid. However, for the ((4-MPBA+AuNPs) + H2O2) mixture, immobilized 4-MPBA is oxidized by H2O2 to form 4-hydroxythiophenol (4-HTP) and boric acid. The decrease in charge on the surface of AuNPs caused by BHPD, which has alarger steric hindrance, is poorer than that caused by -4-HTP, and this is mainly responsible for the difference in the aggregation of AuNPs in the two mixtures. The formation of boric acid and peroxoboric acid in the reaction between 4-MPBA and H2O2 can alter the pH of the medium, and the effect of the pH change on the aggregation of AuNPs should not be ignored. These findings not only offer a new strategy in colorimetric assays to expand the detection range of hydrogen peroxide concentrations but also assist in deepening the understanding of the aggregation of citrate-capped AuNPs involved in 4-MPBA and H2O2, as well as in developing other probes.

Objectives: To compare the response between Chinese children with growth hormone deficiency (GHD) born either small for gestational age (SGA) or appropriate for gestational age (AGA) after 4 weeks of recombinant human growth hormone (r-hGH) therapy. Methods: This was a phase IV, open-label, multicenter, interventional study (NCT01187550). Prepubertal children with GHD received open-label treatment with daily r-hGH (0.033 mg/kg) for 4 weeks. Serum levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor-binding protein 3 (IGFBP3), and metabolic markers (including fasting glucose, insulin, total cholesterol, and homeostasis model assessment of insulin resistance) were assessed at baseline and after 4 weeks of treatment, and were analyzed according to patient subgroup (SGA or AGA). Results: A total of 205 children with GHD (mean age 10.4 years; 175 AGA, 30 SGA) were included in the analysis. Mean baseline serum IGF-I and IGFBP3 standard deviation scores (SDS) across the whole patient population were lower than the population norms (mean values: -2.1 SDS for IGF-I and -1.2 SDS for IGFBP3), with no significant differences between the two patient subgroups. After 4 weeks, IGF-I and IGFBP3 levels increased by 1.0 SDS ( p < 0.001) and 0.34 SDS ( p < 0.001), respectively, but no significant differences were found between the two patient subgroups for growth-related or metabolic markers. Conclusions: For children with GHD born SGA, IGF-I and IGFBP3 are short-term biomarkers of responsiveness to treatment with growth hormone, as for children with GHD born AGA.

Sidt2 was identified as a novel integral lysosomal membrane protein recently. We generated global Sidt2 knockout mice by gene targeting. These mice have a comparatively higher random and fasting glucose concentration. Intraperitoneal and oral glucose tolerance tests in Sidt2 knockout mice indicated glucose intolerance and decreased serum insulin level. Notably, the Sidt2(-/-) mice had hypertrophic islets compared with control mice. By Western blot and immunofluorescence, Sidt2(-/-) mouse islets were shown to have increased insulin protein, which actually contained more insulin secretory granules than their controls, demonstrated by electromicroscopy. Consistent with the in vivo study, isolated islet culture from the Sidt2(-/-) mice produced less insulin when stimulated by a high concentration of glucose or a depolarizing concentration of KCl. Under electromicroscope less empty vesicles and more mature ones in Sidt2(-/-) mice islets were observed, supporting impaired insulin secretory granule release. In conclusion, Sidt2 may play a critical role in the regulation of mouse insulin secretory granule secretion.

Biliary Atresia (BA), a result from inflammatory destruction of the intrahepatic and extrahepatic bile ducts, is a severe hepatobiliary disorder unique to infancy. Early diagnosis and Kasai operation greatly improve the outcome of BA patients, which encourages the development of early screening methods. Using HPLC coupled tandem mass spectrometry, we detected primary bile acids content in dried blood spots obtained from 8 BA infants, 17 neonatal jaundice and 292 comparison infants at 3-4 days of life. Taurocholate (TC) was significantly elevated in biliary atresia infants (0.98 ± 0.62 µmol/L) compared to neonatal jaundice (0.47 ± 0.30 µmol/L) and comparison infants (0.43 ± 0.40 µmol/L), with p=0.0231 and p=0.0016 respectively. The area under receiver operating characteristic (ROC) curve for TC to discriminate BA and comparison infants was 0.82 (95% confidence interval: 0.72-0.92). A cutoff of 0.63 µmol/L produced a sensitivity of 79.1% and specificity of 62.5%. The concentrations of total bile acids were also raised significantly in BA compared to comparison infants (6.62 ± 3.89 µmol/L vs 3.81 ± 3.06 µmol/L, p=0.0162), with the area under ROC curve of 0.75 (95% confidence interval: 0.61-0.89). No significant difference was found between the bile acids of neonatal jaundice and that of comparison infants. The early increase of bile acids indicates the presentation of BA in the immediate newborn period and the possibility of TC as newborn screening marker.

BACKGROUND: Hunter syndrome (mucopolysaccharidosis type II, MPS II) is a rare disease inherited in an X-linked autosomal recessive pattern. It is the prevailing form of the mucopolysaccharidoses in China. Here we investigated mutations of IDS (iduronate 2-sulfatase) gene in 38 unrelated Chinese patients, one of which is a female. METHODS: Peripheral leucocytes were collected from the patients and the IDS gene was amplified to looking for the variations. For a female patient, the X chromosome status was analyzed by androgen receptor X-inactivation assay and the mutation impact on RNA level was further performed by reverse transcription polymerase chain reaction. RESULTS: We discovered that point mutations constituted the major form while mutations in codon p.R468 defined the largest number of patients in our cohort. Consistent with data from other ethnic groups, exons 9 and 3 had comparatively more mutations, while exon 2 had quite a few mutations unique to Chinese patients. Of the 30 different mutations identified, only 9 were novel: one was a premature termination mutation, i.e., c.196C>T (p.Gln66X); three were missense mutations, i.e., c.200T>C (p.Leu67Pro), c.215T>C (p.Leu72Pro), c.389C>T (p.Thr130Ile); one was a small deletion, i.e., c.1104_1122del19 (p.Ser369ArgfsX16); and one was a deletion that spanned both exons 8 and 9 deletion leading to gross structural changes in the IDS gene. In addition, a synonymous mutation c.879G>A (p.Gln293Gln) was identified in a female Hunter disease patient, which resulted in loss of the original splicing site, activated a cryptic splicing site upstream, leading to a 28 bp deletion and a premature termination at p. Tyr285GlufsX47. Together with concurrent skewed X-inactivation this was believed to facilitate the development of Hunter disease in this girl. CONCLUSIONS: In conclusion, the molecular analysis of IDS gene in Chinese patients confirmed the Hunter disease diagnosis and expanded the mutation and clinical spectrum of this devastating disorder.

Background Primary adrenal insufficiency (PAI) is a rare but life-threatening condition. Differential diagnosis of numerous causes of PAI requires a thorough understanding of the condition. Methods To describe the genetic composition and presentations of PAI. The following data were collected retrospectively from 111 patients with non-21OHD with defined genetic diagnoses: demographic information, onset age, clinical manifestations, laboratory findings and genetic results. Patients were divided into four groups based on the underlying pathogenesis: (1) impaired steroidogenesis, (2) adrenal hypoplasia, (3) resistance to adrenocorticotropic hormone (ACTH) and (4) adrenal destruction. The age of onset was compared within the groups. Results Mutations in the following genes were identified: NR0B1 (n=39), STAR (n=33), CYP11B1 (n=12), ABCD1 (n=8), CYP17A1 (n=5), HSD3B2 (n=4), POR (n=4), MRAP (n=2), MC2R (n=1), CYP11A1 (n=1), LIPA (n=1) and SAMD9 (n=1). Frequent clinical manifestations included hyperpigmentation (73.0%), dehydration (49.5%), vomiting (37.8%) and abnormal external genitalia (23.4%). Patients with adrenal hypoplasia typically presented manifestations earlier than those with adrenal destruction but later than those with impaired steroidogenesis (both p<0.01). The elevated ACTH (92.6%) and decreased cortisol (73.5%) were the most common laboratory findings. We generated a differential diagnosis flowchart for PAI using the following clinical features: 17-hydroxyprogesterone, verylong-chain fatty acid, external genitalia, hypertension and skeletal malformation. This flowchart identified 84.8% of patients with PAI before next-generation DNA sequencing. Conclusions STAR and NR0B1 were the most frequently mutated genes in patients with non-21OHD PAI. Age of onset and clinical characteristics were dependent on aetiology. Combining clinical features and molecular tests facilitates accurate diagnosis. [ABSTRACT FROM AUTHOR]

Rapid corrosion of steel bars in marine and complex saline environments has become a serious concern, and corrosion inhibitor for steel bar has proved to be one of the main protective measures to prevent the corrosion. In this paper, a new organic composite anti-corrosion agent (HTCI) was synthesised by hydrazine hydrate and tartaric acid for the preventing reinforced concrete from corrosion in marine engineering. The inhibition behaviors of HTCI for Q235 steel in saturated Ca(OH)2 solution with 3.0 wt.% NaCl were studied by weight loss, electrochemical measurement and surface analysis. All these techniques revealed that inhibition efficiency increased with increasing HTCI concentration and the inhibitor showed 84.37% inhibition efficiency at a concentration of 500 mg·L-1. Potentiodynamic polarization studies indicated the HTCI with mixed-type inhibitor properties. Scan analysis demonstrated that the depth of the pitting crater decreased with increasing HTCI concentration. Kinetically and thermodynamically simulated that the adsorption of HTCI on mild steel obeys Langmuir adsorption isotherm, and the mechanisms of this corrosion inhibitor were based on physical and chemical adsorption. [ABSTRACT FROM AUTHOR]