Short-chain acyl-CoA Dehydrogenase Deficiency Research Articles

Prevalence and Mutation Analysis of Short-Chain acyl-CoA Dehydrogenase Deficiency Detected by Newborn Screening in Hefei, China.

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation with highly variable biochemical and genetic characteristics. The present study aimed to estimate the prevalence and genetic characteristics of SCADD in newborns identified through screening. A total of 782,930 newborns were screened for SCADD in Hefei Neonatal Screening Center from January 2016 to December 2023. The blood samples from newborns were measured by tandem mass spectrometry (MS/MS). The suspected SCADD neonates were rechecked using next-generation gene sequencing for diagnosis. Sanger sequencing was used to verify the mutation site for patients with SCADD and their parents. A total of 21 SCADD cases were confirmed, with an incidence rate of 1/37,282. Genetic mutations were identified in all 21 cases, including 15 cases of compound heterozygous variation and 6 cases of homozygous variation. Twenty-one different mutation types and forty-two mutation sites were discovered, with the most frequent mutation being c.1031A>G, accounting for 21.43% (9/42), followed by c.1130C>T, accounting for 16.67% (7/42). Our findings expand the SCADD mutational spectra. c. 1031A>G and c.1130C>T are the common mutation sites for SCADD genes in newborns. SCADD diagnosed through NBS is primarily a benign condition, and early diagnosis is not necessarily essential.

Butyrylcarnitine Elevation in Newborn Screening: Reducing False Positives and Distinguishing between Two Rare Diseases through the Evaluation of New Ratios.

One of the main challenges of newborn screening programs, which screen for inherited metabolic disorders, is cutting down on false positives (FPs) in order to avoid family stresses, additional analyses, and unnecessary costs. False positives are partly caused by an insubstantial number of robust biomarkers in evaluations. Another challenge is how to distinguish between diseases which share the same primary marker and for which secondary biomarkers are just as highly desirable. Focusing on pathologies that involve butyrylcarnitine (C4) elevation, such as short-chain acylCoA dehydrogenase deficiency (SCADD) and isobutyrylCoA dehydrogenase deficiency (IBDD), we investigated the acylcarnitine profile of 121 newborns with a C4 increase to discover secondary markers to achieve two goals: reduce the FP rate and discriminate between the two rare diseases. Analyses were carried out using tandem mass spectrometry with whole blood samples spotted on filter paper. Seven new biomarkers (C4/C0, C4/C5, C4/C5DC\C6OH, C4/C6, C4/C8, C4/C14:1, C4/C16:1) were identified using a non-parametric ANOVA analysis. Then, the corresponding cut-off values were found and applied to the screening program. The seven new ratios were shown to be robust (p < 0.001 and p < 0.01, 0.0937 < ε2 < 0.231) in discriminating between FP and IBDD patients, FP and SCADD patients, or SCADD and IBDD patients. Our results suggest that the new ratios are optimal indicators for identifying true positives, distinguishing between two rare diseases that share the same primary biomarker, improving the predictive positive value (PPV) and reducing the false positive rate (FPR).

Long-term prognosis of fatty-acid oxidation disorders in adults: Optimism despite the limited effective therapies available.

Fatty-acid oxidation disorders (FAODs) are recessive genetic diseases. We report here clinical and paraclinical data from a retrospective study of 44 adults with muscular FAODs from six French reference centers for neuromuscular or metabolic diseases. The study cohort consisted of 44 adult patients: 14 with carnitine palmitoyl transferase 2 deficiency (32%), nine with multiple acyl-CoA deficiency (20%), 13 with very long-chain acyl-CoA dehydrogenase deficiency (30%), three with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (7%), and five with short-chain acyl-CoA dehydrogenase deficiency (11%). Disease onset occurred during childhood in the majority of patients (59%), with a mean age at onset of 15 years (range = 0.5-35) and a mean of 12.6 years (range = 0-58) from disease onset to diagnosis. The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness. Episodes of rhabdomyolysis were frequent (84%), with a mean creatinine kinase level of 68,958 U/L (range = 660-300,000). General metabolic complications were observed in 58% of patients, respiratory manifestations in 18% of cases, and cardiological manifestations in 9% of cases. Fasting acylcarnitine profile was used to orient genetic explorations in 65% of cases. After a mean follow-up of 10 years, 33% of patients were asymptomatic and 56% continued to display symptoms after exercise. The frequency of rhabdomyolysis decreased after diagnosis in 64% of cases. A standardized register would complete this cohort description of muscular forms of FAODs with exhaustive data, making it possible to assess the efficacy of therapeutic protocols in real-life conditions and during the long-term follow-up of patients.

Analysis of screening results for genetic metabolic diseases among 352 449 newborns from Changsha

To retrospectively analyze the screening results for genetic metabolic diseases among newborns from Changsha in order to determine the prevalence of single diseases and their mutational spectrum. 352 449 neonates born from January 2016 to December 2021 in Changsha were subjected to tandem mass spectrometry. Suspected cases were further analyzed by biochemical and genetic testing. Among the 352 449 newborns, 6 170 were positive for the screening, which yielded a positive rate of 1.75%. 5 437 cases were recalled, and 92 were confirmed, with the overall prevalence being 1∶3 831 and positive predictive value of 1.69%. Eighteen genetic metabolic diseases were detected among the 92 children, including 33 amino acid metabolic disorders, among which 20 were phenylalanine hydroxylase deficiency (60.60%). 17 cases had organic acid metabolic disorders, among which 4 were 2-methyl-dehydrogenase deficiency (23.50%). 42 had fatty acid metabolic disorders, among which 27 (64.30%) were primary carnitine deficiency and 12 were short-chain acyl-CoA dehydrogenase deficiency (28.60%). In total 90 genetic variants were identified, with the most common ones including c.51C>G, c.1400C>G, c.760C>T, c.1031A>G and c.1165A>G. The common neonatal genetic metabolic diseases in Changsha include primary carnitine deficiency, phenylalanine hydroxylase deficiency and short-chain acyl-CoA dehydrogenase deficiency. The preliminary delineation of mutational spectrum for genetic metabolic diseases in Changsha can facilitate early diagnosis and intervention, so as to improve the quality of newborn population.

Riboflavin ameliorates pathological cardiac hypertrophy and fibrosis through the activation of short-chain acyl-CoA dehydrogenase

Short-chain acyl-CoA dehydrogenase (SCAD), the rate-limiting enzyme for fatty acid β-oxidation, has a negative regulatory effect on pathological cardiac hypertrophy and fibrosis. FAD, a coenzyme of SCAD, participates in the electron transfer of SCAD-catalyzed fatty acid β-oxidation, which plays a crucial role in maintaining the balance of myocardial energy metabolism. Insufficient riboflavin intake can lead to symptoms similar to short-chain acyl-CoA dehydrogenase (SCAD) deficiency or flavin adenine dinucleotide (FAD) gene abnormality, which can be alleviated by riboflavin supplementation. However, whether riboflavin can inhibit pathological cardiac hypertrophy and fibrosis remains unclear. Therefore, we observed the effect of riboflavin on pathological cardiac hypertrophy and fibrosis. In vitro experiments, riboflavin increased SCAD expression and the content of ATP, decreased the free fatty acids content and improved PE-induced cardiomyocytes hypertrophy and AngⅡ-induced cardiac fibroblasts proliferation by increasing the content of FAD, which were attenuated by knocking down the expression of SCAD using small interfering RNA. In vivo experiments, riboflavin significantly increased the expression of SCAD and the energy metabolism of the heart to improve TAC induced pathological myocardial hypertrophy and fibrosis in mice. The results demonstrate that riboflavin improves pathological cardiac hypertrophy and fibrosis by increasing the content of FAD to activate SCAD, which may be a new strategy for treating pathological cardiac hypertrophy and fibrosis.

Identification of two Iranian siblings with cerebrotendinous xanthomatosis: a case report

BackgroundCerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disorder that leads to multisystem involvement. It is caused by mutations in the CYP27A1 gene which encodes the mitochondrial enzyme sterol 27-hydroxylase.Case presentationHerein we describe two affected CTX siblings with symptoms including seizures, severe diarrhea (steatorrhea), vomiting, and developmental motor delay, which was initially misdiagnosed as Short-Chain acyl-CoA dehydrogenase (SCAD) deficiency. However, to identify the possible genetic cause(s) of the disease, whole exome sequencing (WES) was performed. It was confirmed that these patients carried a nonsense variant (c.808C > T; p.Arg270Ter) of the CYP27A1 gene. The variant in the CYP27A1 gene was classified as pathogenic.ConclusionWe report rare cases of CTX with a novel mutation and summarize the clinical and molecular pathogenesis of this disease. Genetic analysis should be used as the conclusive method for CTX diagnosis because of the multisystem involvement and the lack of specific symptoms. The variant in these patients expands the molecular and phenotypic basis of a variant in CTX.

Acylglycine Analysis by Ultra‐Performance Liquid Chromatography‐Tandem Mass Spectrometry (UPLC‐MS/MS)

Quantitative analysis of urine acylglycines has shown to be a highly sensitive and specific method with proven clinical utility for the diagnosis of several inherited metabolic disorders including: medium chain acyl-CoA dehydrogenase deficiency, multiple acyl-CoA dehydrogenase deficiency, short chain acyl-CoA dehydrogenase deficiency, 3-methylcrotonyl-CoA carboxylase deficiency, 2-methylbutyryl-CoA dehydrogenase deficiency, isovaleric acidemia, propionic academia, and isobutyryl-CoA dehydrogenase deficiency. Here, a method that is currently performed using ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) is described. © 2023 Wiley Periodicals LLC. Basic Protocol: Urinary acylglycine analysis by UPLC-MS/MS Support Protocol 1: Quality control preparation Support Protocol 2: Internal standard (ISTD) preparation Support Protocol 3: Standard (STD)/calibrator preparation.

Incidence and genetic variants of inborn errors of metabolism identified through newborn screening: A 7-year study in eastern coastal areas of China.

The incidence of inborn errors of metabolism (IEM) varies across countries and areas. Currently, there are no studies on IEM using newborn screening (NBS) in eastern coastal areas of China. We aimed to estimate the incidence and genetic variants of IEM and understand the spectrum of diseases caused by IEM and variants among them in this area. The NBS performed by tandem mass spectrometry (MS/MS) from 2016 to 2021 was retrospectively reviewed. Heel blood was collected from all newborns 72 h after birth. Targeted massively parallel sequencing was performed for genetic analysis. Among 245,194 newborns, 95 were diagnosed with IEM, the overall incidence observed was-IEM: 1/2581; amino acid metabolism disorder: 1/4715; organic acid metabolism disorder: 1/11676; and fatty acid metabolism disorder: 1/11145. The incidence of different IEM was in the range of 1/245194 to 1/6452. Phenylketonuria (PKU, 1/7211) was the most common IEM, followed by methylmalonic acidemia (MMA, 1/27244), short-chain acyl-CoA dehydrogenase deficiency (SCADD, 1/30649), and citrin deficiency (CD, 1/35028). For genetic variants, the common hotspot variants found were-PAH gene for PKU: c.728G > A, c.442-1G > A, c.611A > G, c.721C > T; PTS gene for non-classical PKU: c.259C > T; MMACHC gene for MMA: c.658_660delAAG, c.609G > A; MMUT gene for MMA: c.1663G > A; ACADS gene for SCADD: c.1031A > G and c.1130C > T; and SLC25A13 gene for CD: c.1638_1660dup, c.852_855del. This study displayed the diseases and varied spectrum of IEM in eastern coastal areas of China. Implementing NBS for IEM by MS/MS combined with massively parallel sequencing can offer an improved plan for NBS to detect IEM.

Development of a Universal Second-Tier Newborn Screening LC-MS/MS Method for Amino Acids, Lysophosphatidylcholines, and Organic Acids.

First-tier MS-based newborn screening by flow injection analysis can have high presumptive positive rates, often due to isomeric/isobaric compounds or poor biomarker specificity. These presumptive positive samples can be analyzed by second-tier screening assays employing separations such as liquid chromatography-mass spectrometry (LC-MS/MS), which increases test specificity and drastically reduces false positive referrals. The ability to screen for multiple disorders in a single multiplexed test simplifies workflows and maximizes public health laboratories' resources. In this study, we developed and validated a highly multiplexed second-tier method for dried blood spots using a hydrophilic interaction liquid chromatography (HILIC) column coupled to an MS/MS system. The LC-MS/MS method was capable of simultaneously detecting second-tier biomarkers for maple syrup urine disease, homocystinuria, methylmalonic acidemia, propionic acidemia, glutaric acidemia type 1, glutaric acidemia type 2, guanidinoacetate methyltransferase deficiency, short-chain acyl-CoA dehydrogenase deficiency, adrenoleukodystrophy, and Pompe disease.

Diverse and unselected adults with clinically relevant ACADS variants lack evidence of metabolic disease.

The clinical significance of Short-chain acyl CoA dehydrogenase deficiency (SCADD), caused by biallelic variation in the ACADS gene, is contested. Clinically ascertained individuals have a range of reported metabolic and physical symptoms. Conversely, individuals identified through newborn screening remain overwhelmingly asymptomatic. Two common ACADS variants, c.511C > T (p.Arg171Trp) and c.625G > A (p.Gly209Ser) are known to reduce enzymatic activity with undetermined clinical correlate. We applied a genome-first approach to evaluate the prevalence and clinical consequences of ACADS variants in an ancestrally diverse and unselected patient population. We used exome sequence data linked to electronic health records (EHRs) to identify clinically relevant ACADS variants, and estimate their prevalence and clinical implications in 27,447 ancestrally diverse and unrelated adults from the BioMe Biobank in New York, NY. We extracted International Classification of Diseases, ninth (ICD-9) and tenth (ICD-10) revision codes corresponding to eight SCADD-associated phenotypes relevant to adults from participants' EHRs. Phenotypes included intellectual disability, behavioral disorders with onset in childhood, epilepsy or seizure disorders, hypoglycemia, muscle weakness, metabolic acidosis, fatty liver, and a diagnosis of SCADD or disorder of fatty acid oxidation. We performed manual chart reviews for individuals homozygous for rare pathogenic variants. Multivariate logistic regression was used to determine the association between clinically relevant ACADS variants and phenotypes of interest. 1 in 10,000 BioMe participants were homozygous for rare pathogenic variants (PVs) in ACADS, 1 in 20 were homozygous or presumed compound heterozygous for common variants (CVs), and 1 in 300 harbored both a PV and a CV. Of the 2035 variant positive individuals, none had a documented diagnosis of SCADD. We identified five PV/PV positive individuals, none of whom had evidence of symptomatic SCADD on manual chart review. CV/CV positive and CV/PV positive individuals did not have increased odds of any of the eight ACADS phenotypes evaluated compared to variant negative individuals (OR for CV/CV 0.99, 95% CI 0.86-1.1, p = .88; OR for CV/PV OR 1.49, 95% CI 0.87-2.6, p = .15). The prevalence of clinically relevant ACADS variants in an unselected population was higher than previously reported SCADD prevalence of 1 in 35,000 in the United States. Clinically relevant variants in ACADS were not associated with evidence of metabolic disease in a large and ancestrally diverse adult population. These findings support the assertion that SCADD is more likely a biochemical entity without clinical correlate, in particular when caused by one or more common variants.

Expanded newborn screening for inherited metabolic disorders by tandem mass spectrometry in a northern Chinese population.

Tandem mass spectrometry (MS/MS) has been developed as one of the most important diagnostic platforms for the early detection and screening of inherited metabolic disorders (IMDs). To determine the disease spectrum and genetic characteristics of IMDs in Suqian city of Jiangsu province in the northern Chinese population, dried blood spots from 2,04,604 newborns, were assessed for IMDs by MS/MS from January 2016 to November 2020. Suspected positive patients were diagnosed through next-generation sequencing (NGS) and validated by Sanger sequencing. One hundred patients with IMDs were diagnosed, resulting in an overall incidence of 1/2,046, of which 56 (1/3,653), 22 (1/9,300), and 22 (1/9,300) were confirmed amino acids disorders (AAs), organic acids disorders (OAs), fatty acid oxidation disorders (FAODs) positive cases, respectively. The highest incidence of IMDs is phenylalanine hydroxylase deficiency (PAHD) (45 cases), with a total incidence of 1:4,546. Hot spot mutations in phenylalanine hydroxylase (PAH)-related genes are c.158G > A (24.44%), c.728G > A (16.67%), c.611A > G (7.78%), and c.331C>T (7.78%). The related hot spot mutation of the MMACHC gene is c.609G > A (45.45%). Short-chain acyl-CoA dehydrogenase deficiency (SCAD)-related ACADS gene hotspot mutations are c.164C > T (33.33%) and c.1031A > G (33.33%). Our work indicated that the overall incidence of IMDs is high, and the mutations in PAH, ACADS, and MMACHC genes are the leading causes of IMDs in Suqian city. The incidence of AAs in Suqian city is higher than in other Chinese areas. The disease spectrum and genetic backgrounds were elucidated, contributing to the treatment and prenatal genetic counseling of these disorders in this region.

Disease spectrum analysis of children with inherited metabolic diseases detected by gas chromatography-mass spectrometry of urinary organic acids

Objective: To investigate the spectrum of amino acid, organic acid, and fatty acid oxidative metabolic diseases in children diagnosed by detecting urinary organic acid levels using gas chromatography-mass spectrometry. Methods: From January 2005 to December 2021, clinical data of 2 461 children diagnosed with inherited metabolic diseases (IMD) by gas chromatography-mass spectrometry, in combination with tandem mass spectrometry and genetic testing in Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were retrospectively analyzed. Results: Among 2 461 children, 1 446 were male and 1 051 were female. A total of 32 types of IMD were detected among 2 461 patients, which included 10 amino acid disorders in 662 cases (26.9%), 6 common diseases were hyperphenylalaninemia, citrin deficiency, ornithine carbamoyltransferase deficiency, maple syrup urine disease, alkaptonuria, and tyrosinemia-I, 17 types of organic acidemias in 1 683 cases (68.4%), 6 common diseases were methylmalonic acidemia, propionic acidemia, valeric acidemia-type Ⅰ, isovaleric acidemia, 3-methylcrotonyl-CoA carboxylase deficiency and multiple carboxylase deficiency and 5 fatty acid β oxidative defects in 116 cases (4.7%), 2 common diseases were multiple acyl-CoA dehydrogenase deficiency and short-chain acyl-CoA dehydrogenase deficiency). Conclusion: Among the diseases diagnosed by analyzing urinary organic acid profiling with gas chromatography-mass spectrometry, the most common are organic acidemias, followed by amino acid disorders and fatty acid oxidation defects.

Clinical characteristics and related gene mutations of infants with short-chain acyl-CoA dehydrogenase deficiency by neonatal screening in Beijing.

To investigate the clinical characteristics of infants with short-chain acyl-CoA dehydrogenase deficiency (SCADD) and related gene mutations in Beijing. The acylcarnitine levels in the blood samples of 100 603 neonates in Beijing during August 2014 and March 2022 were measured by tandem mass spectrometry (MS/MS). The suspected SCADD neonates were rechecked by MS/MS, urine gas chromatography-mass spectrometry (GC/MS) and next-generation sequencing (NGS) for diagnosis. The clinical, biochemical and gene mutation characteristics of infants with SCADD were analyzed; the growth and intellectual development of these patients were observed regularly. Among 100 603 live births, the elevated C4 concentration or elevated C4/C3 ratio were detected in the initial screening from 196 neonates, and 131 were recalled. Five cases of SCADD were diagnosed with an incidence rate of 4.97/100 000 (1/20 121). There was no significant abnormality in clinical manifestations, however, the blood butyrylcarnitine (C4) level and the ratio of C4 to propionylcarnitine (C3) were raised in all diagnosed cases. Urinary organic acids were analyzed in 4 cases, all of whom had increased ethyl malonate acid levels. Seven mutations were detected in the ACADS gene, all of which were known missense mutations. One patient had homozygous mutation, and the others showed compound heterozygous mutations. No clinical symptoms were observed, and the physical and intellectual development was normal in all patients at a median age of 33 (4-40) months during follow-up. The incidence rate of SCADD was 1/20 121 in Beijing. Neonates with early diagnosis and without clinical symptoms usually have good prognosis.

Screening for newborn fatty acid oxidation disorders in Chongqing and the follow-up of confirmed children.

To investigate the incidence, clinical characteristics, gene mutations and prognosis of fatty acid oxidation disorders (FAOD) in newborns in Chongqing. Blood samples were collected from 35 374 newborns for screening of FAOD in the Neonatal Screening Center of Women and Children's Hospital of Chongqing Medical University from July 2020 to February 2022. The acylcarnitine spectrum was detected by tandem mass spectrometry, the positive children in primary screening were recalled within 2 weeks, and the diagnosis of FAOD was confirmed by urine organic acid measurement, blood biochemistry testing and genetic analysis. The confirmed children were given early intervention, treatment and followed-up. Among 35 374 newborns, there were 267 positive children in primary screening, with a positive rate of 0.75%. Five children with FAOD were diagnosed by gene detection, with an incidence rate of 1/7075. Among them, there were 3 cases of primary carnitine deficiency (PCD, 1/11 791), 1 case of short-chain acyl-CoA dehydrogenase deficiency (SCADD, 1/35 374) and 1 case of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, 1/35 374). The c.1400C>G and c.338G>A were the common mutations of SLC22A5 gene in 3 children with PCD, while c.621G>T was a novel mutation. There were no clinical manifestations during the follow-up period in 2 children with supplementation of L-carnitine. Another child with PCD did not follow the doctor's advice of L-carnitine treatment, and had acute attack at the age of 6 months. The child recovered after treatment, and developed normally during the follow-up. The detected ACADS gene mutations were c.417G>C and c.1054G>A in child with SCADD, who showed normal intelligence and physical development without any clinical symptoms. The mutations of ACADVL gene were c.1349G>A and c.1843C>T in child with VLCADD, who showed acute attack in the neonatal period and recovered after treatment; the child was fed with milk powder rich in medium-chain fatty acids and had normal development during the follow-up. The incidence of FAOD in Chongqing area is relatively high. PCD is the most common type, and the clinical phenotype of VLCADD is serious. After early diagnosis through neonatal screening, standardized treatment and management is followed, most of FAOD children can have good prognosis.

Spectrum Analysis of Inherited Metabolic Disorders for Expanded Newborn Screening in a Central Chinese Population.

Neonatal inherited metabolic disorders (IMDs) are closely associated with early neonatal death and abnormal growth and development. Increasing attention has been paid to IMDs because of their high incidence and diversity. However, there are no reports about the incidence of IMDs in Changsha, China. Therefore, we retrospectively analyzed the screening results of neonates to evaluate the characteristics of IMDs in the area. From January 2016 to December 2020, 300,849 neonates were enrolled for expanded newborn screening by tandem mass spectrometry in the Neonatal Disease Screening Center of the Changsha Hospital for Maternal & Child Health Care. Newborns with mild initial results were recalled for repeated tests; if the second test was still positive, the patient was referred for confirmatory tests. A total of 71 confirmed cases were identified in our study, with an incidence rate of 1:4,237. There were 28 cases of amino acid metabolic disorders, representing 39.44% of the IMDs diagnosed, with an incidence rate of 1:10,745. Twelve newborns were diagnosed with organic acid metabolic disorders, accounting for 16.66% of IMDs, with an incidence rate of 1:25,071. There were 31 cases of fatty acid oxidation disorders, representing 43.05% of IMDs, with an incidence rate of 1:9,705. Overall, 14 types of IMDs were found in Changsha. The most common disorders in the region were primary carnitine deficiency, hyperphenylalaninemia and short-chain acyl-CoA dehydrogenase deficiency. Their incidence rate is respectively 1:13,675, 1:16,714 and 1:42,978. The mutations in PAH, SLC22A5, and ACADS are the leading causes of IMDs in this area. This study demonstrates the importance of utilizing MS/MS in IMD screening for early diagnosis and treatment. This strategy may be used for prenatal genetic counseling to avoid irreversible growth and intellectual development disorders in children.

Selective screening for inborn errors of metabolism by tandem mass spectrometry at Sohag University Hospital, Egypt

BackgroundInborn errors of metabolism (IEMs) comprise a group of inherited diseases that can have devastating consequences and cause irreversible damage to different body systems and even lead to death. Newborn screening helps in the presymptomatic diagnosis of many medical disorders including IEMs. Early diagnosis and management of IEMs helps reduce morbidity and mortality. ObjectiveThis study aimed to estimate the prevalence of IEMs among at-risk children and contribute toward early diagnosis and management in order to minimize morbidity and mortality. MethodsThis prospective study was conducted at the Pediatrics and Neonatology Department, Sohag University Hospital, Egypt. The study enrolled 308 participants suspected of having IEMs. Cases were included based on the presence of any of the following: unexplained convulsions, persistent metabolic acidosis, persistent hypoglycemia, disturbed consciousness, delayed milestones, or family history of previous sibling death with IEMs or sibling death with a history suggestive of IEMs. All participants in the study were subjected to metabolic screening by tandem mass spectrometry (MS/MS). ResultsOut of 308 neonates, 93 (30.2%) were diagnosed with IEMs. The most common diagnosis was phenylketonuria, followed by glutaric aciduria type 1 and maple syrup urine disease (43%, 19.4%, and 14%, respectively). Five patients had Canavan disease, four had medium-chain acyl CoA dehydrogenase deficiency, three had congenital lactic acidosis, two had methylmalonic acidemia, and two had primary carnitine deficiency. Propionic acidemia, isovaleric acidemia, homocystinuria, short-chain acyl CoA dehydrogenase deficiency, B-ketothiolase deficiency, and ketone body utilization defect were diagnosed in one patient each. Most patients improved (73.1%) following proper specific management. ConclusionWe recommend newborn screening for IEMs using MS/MS, which may help with the early diagnosis and management of this group of disorders.

Healing of a Chronic Pressure Injury in a Patient Treated With Medical Cannabis for Pain and Sleep Improvement: A Case Report

A small body of evidence suggests medical cannabis may facilitate wound healing, but the exact mechanism of this effect is unclear. This case report describes a patient with a pressure injury (PI) who received cannabis oil treatment for pain management and sleep improvement. A 37-year-old woman with multiminicore disease, scoliosis, short-chain acyl-CoA dehydrogenase deficiency, and epilepsy presented to the Neurology Centre of Toronto with chronic pain and sleep disturbance, including difficulty initiating and maintaining sleep. She also had a 5-year history of a PI between her right iliac crest and right rib cage that had progressively worsened. The patient received a medical cannabis oil protocol that used a combination of cannabidiol and tetrahydrocannabinol. Cannabis oil was effective in treating pain and sleep difficulties. Unexpectedly, during the first 2 weeks of treatment, the PI started to heal and was almost completely closed at the 2-month follow-up. Although it is unknown if the observed healing of this refractory PI was indirectly or directly related to the cannabidiol and tetrahydrocannabinol treatment, the potential relationships among pain, sleep disturbance, cannabis treatment, and healing should be explored.

Screening and follow-up results of fatty acid oxidative metabolism disorders in 608 818 newborns in Jining, Shandong province.

To investigate the incidence and gene mutation characteristics of fatty acid oxidative metabolism disorders in Jining area of Shandong province , and to evaluate the therapeutic effect. Blood samples of newborns were collected in Jining of Shandong province between July 14, 2014 and December 31, 2019. Tandem mass spectrometry was used to determine the levels of carnitine and acylcarnitine in the blood to screen for fatty acid oxidative metabolism disorder. For newborns with positive screening result, blood DNA was analyzed by MassARRAY and high-throughput sequencing, then verified by Sanger sequencing. The diagnosed children were given early intervention and treatment, and followed up. Forty-two children with fatty acid oxidative metabolism disorders were screened out of 608 818 newborns, with an incidence rate of 1/14 496. Primary carnitine deficiency (16 cases, 38.10%) and short-chain acyl-CoA dehydrogenase deficiency (16 cases, 38.10%) were the most common, followed by very long-chain acyl-CoA dehydrogenase deficiency (6 cases, 14.29%), medium-chain acyl-CoA dehydrogenase deficiency (4 cases, 9.53%). In children with primary carnitine deficiency, c.1400C>G (p.S467C) and c.51C>G were the most common in mutations; and c.278C>T (p.S93L), c.1049T >C (p.L350P), c.572A>G (p.K191R), c.431T>C (p.L144P) were newly discovered mutations. Ten children with carnitine replacement therapy showed normal development during the follow-up. In 6 children without carnitine replacement treatment, hypoglycemia developed during the neonatal period in 1 case, in whom the creatine kinase was increased, and the intellectual and language development delayed in the later period; the other 5 children developed normally during the follow-up period. The gene mutations c.1031A>G (p.E344G) and c.164C>T (p.P55L) were common in children with short-chain acyl-CoA dehydrogenase deficiency, and the children developed normally during the follow-up. In children with very long-chain acyl-CoA dehydrogenase deficiency, the c.1349G>A was common in gene mutations; and c.488T>A , c.1228G>T (p.D410Y), c.1276G>A (p.A426T), c.1522C>T (p.Q508*), c.1226C>T (p.T409M) were newly discovered mutations. Three children treated with milk powder rich in medium-chain fatty acids had normal development during the follow-up. The other 3 cases with combined carnitine reduction were treated with levocarnitine and milk powder enriched of medium-chain fatty acids, 1 case developed normally during the follow-up, 1 case died of acute illness at the age of and 1 case had acute illness and recovered after treatment, and developed normally during the follow-up. c.449_452del (p.T150Rfs*4) was the most common gene mutation in children with medium-chain acyl-CoA dehydrogenase deficiency, and c. 718A>G (p.M240V) was a newly discovered mutation. All children received low-fat diet, and hunger and fatigue were avoided; 1 child was supplemented with L-carnitine, and the other 3 children were not treated with drugs, and all of them developed normal during the follow-up. Primary carnitine deficiency and short-chain acyl-CoA dehydrogenase deficiency are the most common fatty acid oxidative metabolism disorders in Jining area. There are gene hotspot mutations and new discovered gene mutations in patients. Patients with early diagnosis and treatment through neonatal screening have a good prognosis.

Neonatal Screening on Tandem Mass Spectrometry as a Powerful Tool for the Reassessment of the Prevalence of Underestimated Diseases in Newborns and Their Family Members: A Focus on Short Chain Acyl-CoA Dehydrogenase Deficiency.

Early detection of disabling diseases, prior to clinical manifestations, is the primary goal of newborn screening (NS). Indeed, the required number of core and secondary conditions selected for screening panels is increasing in many countries. Furthermore, newborn screening can lead to diagnosis of maternal diseases such as vitamin B12 deficiency or 3-MethylcrotonylCoA-carboxylase deficiency (3MCC). NS became mandatory in Sicily in December 2017. Here we report NS data collected between December 2017 and April 2020. Our results show that tandem mass spectrometry is a powerful tool for discovery of underestimated disease in newborns and their family members. Our panel included short chain acyl-CoA dehydrogenase deficiency (SCADD). Here, we report that results of our investigation led to reassessment of SCADD prevalence in our population. The infant and adult patients diagnosed in our study had previously not shown overt symptoms.

Effects of genetic variations in Acads gene on the risk of chronic obstructive pulmonary disease.

Short-chain acyl-CoA dehydrogenase (SCAD), encoded by the Acads gene, functions in the mitochondrial β-oxidation of saturated short-chain fatty acids. SCAD deficiency results in mitochondrial dysfunction, which is one underlying biological mechanism of chronic obstructive pulmonary disease (COPD) pathogenesis. In this case-control study, we aimed to examine the effects of Acads gene polymorphisms on the susceptibility to COPD. A total of 16 tagging single-nucleotide polymorphisms (SNPs) in Acads gene region was identified and genotyped in 646 unrelated ethnic Chinese Han individuals including 279 patients with COPD and 367 healthy controls, their allelic and genotypic associations with COPD were determined by different genetic models. Furthermore, we estimated the linkage disequilibrium and haplotypes from these tested variants and determined the effects of haplotypes on the risk of COPD. The allelic and genotypic frequencies of SNPs rs2239686 and rs487915 in Acads gene were significantly different between COPD patients and controls, no statistically significant results were observed for other SNPs. Minor alleles A of rs2239686 and T of rs487915 were associated with a decreased pulmonary function and an increased COPD risk in a dominant manner. Functional analysis indicated that the risk allele A of rs2239686 could increase Acads expressions and the intracellular reactive oxygen species content. Haplotype analysis revealed that the haplotypes CTCCT in block 2 (rs3794216-rs3794215-rs34491494-rs558314-rs7312316) as well as GC in block 3 (rs2239686-rs487915) were protective against COPD, while haplotypes CTCGC in block 2 and AT in block 3 exhibited significant associations with the increased susceptibility to COPD. Our results suggest that Acads gene could potentially be a risk factor of COPD and thus its genetic variants might be as genetic biomarkers to predict the COPD susceptibility.