Short-chain acyl-CoA Dehydrogenase Deficiency Research Articles

Short-chain acyl-CoA dehydrogenase deficiency: from gene to cell pathology and possible disease mechanisms.

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an inherited disorder of mitochondrial fatty acid oxidation that is characterized by the presence of increased butyrylcarnitine and ethylmalonic acid (EMA) concentrations in plasma and urine. Individuals with symptomatic SCADD may show relatively severe phenotype, while the majority of those who are diagnosed through newborn screening by tandem mass spectrometry may remain asymptomatic. As such, the associated clinical symptoms are very diverse, ranging from severe metabolic or neuromuscular disabilities to asymptomatic. Molecular analysis of affected individuals has identified rare gene variants along with two common gene variants, c.511C>T and c.625G>A. In vitro studies have demonstrated that the common variants as well as the great majority of rare variants, which are missense variants, impair folding, that may lead to toxic accumulation of the encoded protein, and/or metabolites, and initiate excessive production of ROS and chronic oxidative stress. It has been suggested that this cell toxicity in combination with yet unknown factors can trigger disease development. This association and the full implications of SCADD are not commonly appreciated. Accordingly, there is a worldwide discussion of the relationship of clinical manifestation to SCADD, and whether SCAD gene variants are disease associated at all. Therefore, SCADD is not part of the newborn screening programs in most countries, and consequently many patients with SCAD gene variants do not get a diagnosis and the possibilities to be followed up during development.

Erratum to: Novel magnetic resonance imaging findings in a patient with short chain acyl CoA dehydrogenase deficiency.

Reports on magnetic resonance imaging findings in patients with short chain acyl –Coenzyme A dehydrogenase (SCAD) deficiency, an autosomal recessive disorder caused by mutations in the acyl-Coenzyme A dehydrogenase (ACADS), are limited. Many asymptomatic carriers of ACAD variants have also been described necessitating careful evaluation of clinical and biochemical findings for an accurate diagnosis. Here we report a an infant with short chain acyl –Coenzyme A dehydrogenase (SCAD) deficiency diagnosed based on the characteristic biochemical findings and confirmed by genetic testing. He presented with refractory seizures and neuro regression at 4 months of age. His metabolic work up revealed elevated butyryl carnitine in plasma and ethyl malonic acid in urine. Magnetic resonance imaging of the brain showed cortical and basal ganglia signal changes with cortical swelling. Serial scans showed progression of the lesions resulting in cystic leukomalacia with brain atrophy. Exome sequencing revealed a novel homozygous nonsense variation, c.1146C > G (p.Y382Ter) in exon ten of ACADS which was further validated by Sanger sequencing. Both parents were heterozygous carriers. Follow up at 15 months showed gross psychomotor retardation and refractory seizures despite being on optimal doses of anti-epileptic medications, carnitine and multivitamin supplementation. This report expands the phenotypic and genotypic spectrum of SCAD deficiency.

Microcephaly and developmental delay caused by short-chain acyl-CoA dehydrogenase deficiency.

Kılıç M, Şenel S, Karaer K, Ceylaner S. Microcephaly and developmental delay caused by short-chain acyl-CoA dehydrogenase deficiency. Turk J Pediatr 2017; 59: 708-710. We report a four-year-old girl who presented with intrauterine growth retardation, mild dysmorphism, cleft palate, microcephaly, developmental delay, epilepsy and recurrent lower respiratory tract infection and diagnosed short-chain acyl-CoA dehydrogenase deficiency. Metabolic evaluation and molecular analysis confirmed the diagnosis. In spite of many patients already known in literature, this is one of the rarest reports of a Turkish patient. This suggests selective metabolic screening should be done in every patient with unknown etiology of neurological disorder. Furthermore, newborn screening using tandem mass spectrometry may prevent this severe neurological impairment.

Clinical, biochemical and gene mutation characteristics of short chain acyl-coenzyme A dehydrogenase deficiency by neonatal screening

Objective: To investigate the incidence, clinical, biochemical and gene mutation characteristics of short chain acyl-coenzyme A dehydrogenase deficiency (SCADD). Method: From January, 2009 to October, 2015, a retrospective analysis of the urine organic acids and acyl-coenzyme A dehydrogenase (ACADS) gene mutation characteristics of patients diagnosed as SCADD by newborn screening using tandem mass spectrometry in Department of Genetics and Metabolism (Newborn screening Center of Zhejiang Province), Children's Hospital, Zhejiang University School of Medicine. Dietary guidance, life management and supplementation of L-carnitine were conducted, and growth and intelligence development were observed during follow-up among the SCADD patients. Result: A total of 1 430 024 neonates, seventeen cases were diagnosed with SCADD with an incidence of 1/84 117. All patients had no clinical symptoms, and intelligence and physical development were normal. Blood butylacyl-carnitine (C4) levels and the ratios increased, C4 0.713.14 μmol/L(reference value 0.03-0.48 μmol/L), C4/C2 0.07-0.23(reference value 0.01-0.04), C4/C3 0.65-2.04(reference value 0.05-0.39). Thirteen with increased urinary ethyl malonic acid (9.30-90.99 mg/g creatinine (reference value 0-6.20 mg/g creatinine )), one patient was accompanied by increased methyl succinic acid (12.33 mg/g creatinine(reference value 0-6.40 mg/g creatinine)), one subject with increased acetylglycine (3.52 mg/g creatinine(reference value 0-0.70 mg/g creatinine)). A total of 13 known mutations were detected in the ACADS gene, 1 homozygous mutation (c.1031A>G), the others are compound heterozygous mutations. One frameshift mutation (c.508_509delGC) and 12 missense mutations were detected. Common mutation were c. 1031A>G(35.3%), c. 164C>T(20.6%) and c. 991G>A(11.8%). SCADD in newborn screening program had no clinical symptoms and normal growth development after 8-42 months follow-up. Conclusion: Cases with SCADD had no clinical symptoms with an incidence of 1/84117. The c. 164C>T and c. 1031A>G may be the common mutations.

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. © 2016 by John Wiley & Sons, Inc.

PHS165 - Impact of Missing Data in Criteria of Least Consensus on Acmg Newborn Screening Recommendations for Short-Chain Acyl-Coa Dehydrogenase Deficiency

PHS165 - Impact of Missing Data in Criteria of Least Consensus on Acmg Newborn Screening Recommendations for Short-Chain Acyl-Coa Dehydrogenase Deficiency

Clinical relevance of short-chain acyl-CoA dehydrogenase (SCAD) deficiency: Exploring the role of new variants including the first SCAD-disease-causing allele carrying a synonymous mutation

Short-chain acyl-coA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation caused by ACADS gene alterations. SCADD is a heterogeneous condition, sometimes considered to be solely a biochemical condition given that it has been associated with variable clinical phenotypes ranging from no symptoms or signs to metabolic decompensation occurring early in life.A reason for this variability is due to SCAD alterations, such as the common p.Gly209Ser, that confer a disease susceptibility state but require a complex multifactorial/polygenic condition to manifest clinically.Our study focuses on 12 SCADD patients carrying 11 new ACADS variants, with the purpose of defining genotype–phenotype correlations based on clinical data, metabolite evaluation, molecular analyses, and in silico functional analyses.Interestingly, we identified a synonymous variant, c.765G>T (p.Gly255Gly) that influences ACADS mRNA splicing accuracy. mRNA characterisation demonstrated that this variant leads to an aberrant splicing product, harbouring a premature stop codon.Molecular analysis and in silico tools are able to characterise ACADS variants, identifying the severe mutations and consequently indicating which patients could benefit from a long term follow- up. We also emphasise that synonymous mutations can be relevant features and potentially associated with SCADD.

Short chain acyl-CoA dehydrogenase deficiency and short-term high-fat diet perturb mitochondrial energy metabolism and transcriptional control of lipid-handling in liver.

BackgroundThe liver is an important site of fat oxidation, which participates in the metabolic regulation of food intake. We showed previously that mice with genetically inactivated Acads, encoding short-chain acyl-CoA dehydrogenase (SCAD), shift food consumption away from fat and toward carbohydrate when tested in a macronutrient choice paradigm. This phenotypic eating behavior suggests a link between fat oxidation and nutrient choice which may involve an energy sensing mechanism. To identify hepatic processes that could trigger energy-related signals, we have now performed transcriptional, metabolite and physiological analyses in Acads-/- mice following short-term (2 days) exposure to either high- or low-fat diet.Methods and ResultsMetabolite analysis revealed 25 acylcarnitine species that were altered by diet and/or genotype. Compared to wild-type mice, phosphorylated AMP-activated protein kinase was 40 % higher in Acads-/- mice after short-term high-fat diet, indicating a low ATP/AMP ratio. Metabolite analyses in isolated liver mitochondria from Acads-/- mice during ADP-linked respiration on butyrate demonstrated a reduced oxygen consumption rate (OCR) compared to wild-type, an effect that was not observed with succinate or palmitoylcarnitine substrates. Liver transcriptomic responses in Acads-/- mice fed high- vs. lowfat diet revealed increased RXR/PPARA signaling, up-regulation of lipid handling pathways (including beta and omega oxidation), and increased mRNA expression of Nfe2l2 target genes.ConclusionsTogether, these results point to an oxidative shortage in this genetic model and support the hypothesis of a lower hepatic energy state associated with SCAD deficiency and high-fat diet.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-016-0075-0) contains supplementary material, which is available to authorized users.

Compound heterozygous mutations of ACADS gene in newborn with short chain acyl-CoA dehydrogenase deficiency: case report and literatures review.

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive mitochondrial disorder of fatty acid β-oxidation, and is associated with mutations in the acyl-CoA dehydrogenase (ACADS) gene. Recent advances in spectrometric screening for inborn errors of metabolism have helped detect several metabolic disorders, including SCADD, without symptoms in the neonate period. This allows immediate initiation of treatment and monitoring, so they remain largely symptomless metabolic disease. Here, we report a 15-month-old asymptomatic male, who was diagnosed with SCADD by newborn screening. Spectrometric screening for inborn errors of metabolism 72 hours after birth revealed an elevated butyrylcarnitine (C4) concentration of 2.25 µmol/L (normal, <0.99 µmol/L). Urinary excretion of ethylmalonic acid was also elevated, as detected by urine organic acid analysis. To confirm the diagnosis of SCADD, direct sequencing analysis of 10 coding exons and the exon-intron boundaries of the ACADS gene were performed. Subsequent sequence analysis revealed compound heterozygous missense mutations c.164C>T (p.Pro55Leu) and c.1031A>G (p.Glu344Gly) on exons 2 and 9, respectively. The patient is now growing up, unretarded by symptoms such as seizure and developmental delay.

Quantitative acylcarnitine determination by UHPLC-MS/MS--Going beyond tandem MS acylcarnitine "profiles".

Tandem MS "profiling" of acylcarnitines and amino acids was conceived as a first-tier screening method, and its application to expanded newborn screening has been enormously successful. However, unlike amino acid screening (which uses amino acid analysis as its second-tier validation of screening results), acylcarnitine "profiling" also assumed the role of second-tier validation, due to the lack of a generally accepted second-tier acylcarnitine determination method. In this report, we present results from the application of our validated UHPLC-MS/MS second-tier method for the quantification of total carnitine, free carnitine, butyrobetaine, and acylcarnitines to patient samples with known diagnoses: malonic acidemia, short-chain acyl-CoA dehydrogenase deficiency (SCADD) or isobutyryl-CoA dehydrogenase deficiency (IBD), 3-methyl-crotonyl carboxylase deficiency (3-MCC) or ß-ketothiolase deficiency (BKT), and methylmalonic acidemia (MMA). We demonstrate the assay's ability to separate constitutional isomers and diastereomeric acylcarnitines and generate values with a high level of accuracy and precision. These capabilities are unavailable when using tandem MS "profiles". We also show examples of research interest, where separation of acylcarnitine species and accurate and precise acylcarnitine quantification is necessary.

Inherited metabolic disorders in Turkish patients with autism spectrum disorders.

Autism spectrum disorders (ASDs) are a major health problem because of their high prevalence in the general population. The pathophysiology of ASD remains unclear, although genetic defects may be detected in 10-20% of affected patients. Among these cases, the prevalence of inherited metabolic disorders (IMD) has not been extensively evaluated. IMDs responsible for ASDs are usually identified via clinical manifestations such as microcephaly, dysmorphic features, convulsions, and hepatosplenomegaly. Infrequently, patients with no additional clinical symptoms suggestive of an IMD may be diagnosed as having an idiopathic ASD. High consanguinity rates have resulted in an increased prevalence of IMDs in the Turkish population. The aim of this study was to explore the benefits of systematic screening for IMD among Turkish patients with ASDs. In our study, data were retrospectively collected for 778 children with ASDs. In all cases, the metabolic investigations included an arterial blood gas analysis, serum ammonia and lactate levels, a quantitative plasma amino acid analysis, a whole blood acylcarnitine profile via tandem mass spectrometry and a urine organic acid profile. Urinary glycosaminoglycan levels and homocysteine levels were screened in selected cases; 300 of the 778 patients with ASDs whose physical and metabolic investigations were complete and met this study's criteria were enrolled. Among the 300 children with autism, IMD were diagnosed in nine patients as follows: two patients were diagnosed with phenylketonuria, and one patient was diagnosed with partial biotinidase deficiency; one patient was diagnosed with mucopolysaccharidosis type III, and one patient was diagnosed with classical homocystinuria; one patient was diagnosed with glutaric acidemia type 1, and one patient was diagnosed with short chain acyl-CoA dehydrogenase deficiency; one patient was diagnosed with argininemia, and one patient was diagnosed with L-2-hydroxyglutaric aciduria.

Brain and muscle redox imbalance elicited by acute ethylmalonic acid administration.

Ethylmalonic acid (EMA) accumulates in tissues and biological fluids of patients affected by short-chain acyl-CoA dehydrogenase deficiency (SCADD) and ethylmalonic encephalopathy, illnesses characterized by neurological and muscular symptoms. Considering that the mechanisms responsible for the brain and skeletal muscle damage in these diseases are poorly known, in the present work we investigated the effects of acute EMA administration on redox status parameters in cerebral cortex and skeletal muscle from 30-day-old rats. Animals received three subcutaneous injections of EMA (6 μmol/g; 90 min interval between injections) and were killed 1 h after the last administration. Control animals received saline in the same volumes. EMA administration significantly increased thiobarbituric acid-reactive substances levels in cerebral cortex and skeletal muscle, indicating increased lipid peroxidation. In addition, carbonyl content was increased in EMA-treated animal skeletal muscle when compared to the saline group. EMA administration also significantly increased 2’,7’-dihydrodichlorofluorescein oxidation and superoxide production (reactive species markers), and decreased glutathione peroxidase activity in cerebral cortex, while glutathione levels were decreased only in skeletal muscle. On the other hand, respiratory chain complex I-III activity was altered by acute EMA administration neither in cerebral cortex nor in skeletal muscle. The present results show that acute EMA administration elicits oxidative stress in rat brain and skeletal muscle, suggesting that oxidative damage may be involved in the pathophysiology of the brain and muscle symptoms found in patients affected by SCADD and ethylmalonic encephalopathy.

Genotype-based databases for variants causing rare diseases

Inherited diseases are the result of DNA sequence changes. In recessive diseases, the clinical phenotype results from the combined functional effects of variants in both copies of the gene. In some diseases there is often considerable variability of clinical presentation or disease severity, which may be predicted by the genotype. Additional effects may be triggered by environmental factors, as well as genetic modifiers which could be nucleotide polymorphisms in related genes, e.g. maternal ApoE or ABCA1 genotypes which may have an influence on the phenotype of SLOS individuals. Here we report the establishment of genotype variation databases for various rare diseases which provide individual clinical phenotypes associated with genotypes and include data about possible genetic modifiers. These databases aim to be an easy public access to information on rare and private variants with clinical data, which will facilitate the interpretation of genetic variants.The created databases include ACAD8 (isobutyryl-CoA dehydrogenase deficiency (IBD)), ACADSB (short-chain acyl-CoA dehydrogenase (SCAD) deficiency), AUH (3-methylglutaconic aciduria (3-MGCA)), DHCR7 (Smith–Lemli–Opitz syndrome), HMGCS2 (3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiency), HSD17B10 (17-beta-hydroxysteroid dehydrogenase X deficiency), FKBP14 (Ehlers–Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss; EDSKMH) and ROGDI (Kohlschütter–Tönz syndrome). These genes have been selected because of our specific research interests in these rare and metabolic diseases. The aim of the database was to include all identified individuals with variants in these specific genes. Identical genotypes are listed multiple times if they were found in several patients, phenotypic descriptions and biochemical data are included as detailed as possible in view also of validating the proposed pathogenicity of these genotypes. For DHCR7 genetic modifier data (maternal APOE and ABCA1 genotypes) is also included.Databases are available at http://databases.lovd.nl/shared/genes and will be updated based on periodic literature reviews and submitted reports.

The effect of long-term oral L-carnitine administration on insulin sensitivity, glucose disposal, plasma concentrations of leptin and acylcarnitines, and urinary acylcarnitine excretion in warmblood horses

Background: Insulin resistance in horses is an emerging field of interest as it is thought to be a contributing factor in the pathogenesis of many equine conditions.Objectives: The objectives of the present study were to determine the effects of long-term oral administration of L-carnitine on insulin sensitivity, glucose disposal, plasma leptin concentrations and acylcarnitine spectrum both in plasma and urine.Animals and methods: Six 3-year-old healthy warmblood geldings were used. In a double blind 2 × 2 Latin square design at a dosage of 100 mg/kg body weight (BW)/day for 28 days the effects of oral supplementation of L-carnitine (as fumarate) were assessed. Glucose disposal and insulin sensitivity were measured by means of the euglycemic-hyperinsulinemic clamp technique. Radioimmunoassays were used to determine plasma leptin and insulin concentrations. Electrospray tandem mass spectrometry was used to assess acylcarnitines both in plasma and urine. Statistical analysis was performed using a linear mixed-effects model and P values <0.05 were considered significant.Results: Long-term L-carnitine administration did not affect insulin sensitivity. Plasma leptin and free carnitine concentrations in plasma and urine increased significantly (P = 0.047 and 0.000, respectively) following L-carnitine administration as well as short-chain acylcarnitines in plasma and urinary excretion of short- and medium-chain acylcarnitines.Conclusion and clinical relevance: Given the effects of oral administration of L-carnitine further clinical study is necessary in order to assess the potential beneficial effects in equine patients suffering from metabolic myopathies such as acquired multiple acyl-CoA dehydrogenase deficiency.Impact for human medicine: The current study supports the treatment rationale of short-chain acyl-CoA dehydrogenase deficiency in humans with L-carnitine at an oral dosage of 100 mg/kg BW/day.

Complex changes in the liver mitochondrial proteome of short chain acyl-CoA dehydrogenase deficient mice

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is an autosomal recessive inborn error of metabolism that leads to the impaired mitochondrial fatty acid β-oxidation of short chain fatty acids. It is heterogeneous in clinical presentation including asymptomatic in most patients identified by newborn screening. Multiple mutations have been identified in patients; however, neither clear genotype–phenotype relationships nor a good correlation between genotype and current biochemical markers for diagnosis has been identified. The definition and pathophysiology of this deficiency remain unclear. To better understand this disorder at a global level, quantitative alterations in the mitochondrial proteome in SCAD deficient mice were examined using a combined proteomics approach: two-dimensional gel difference electrophoresis (2DIGE) followed by protein identification with MALDI-TOF/TOF and iTRAQ labeling followed by nano-LC/MALDI-TOF/TOF. We found broad mitochondrial dysfunction in SCAD deficiency. Changes in the levels of multiple energy metabolism related proteins were identified indicating that a more complex mechanism for development of symptoms may exist. Affected pathways converge on disorders with neurologic symptoms, suggesting that even asymptomatic individuals with SCAD deficiency may be at risk to develop more severe disease. Our results also identified a pattern associated with hepatotoxicity implicated in mitochondrial dysfunction, fatty acid metabolism, decrease of depolarization of mitochondria and mitochondrial membranes, and swelling of mitochondria, demonstrating that SCAD deficiency relates more directly to mitochondrial dysfunction and alteration of fatty acid metabolism. We propose several candidate molecules that may serve as markers for recognition of clinical risk associated with this disorder.

Ethylmalonic Acid Induces Permeability Transition in Isolated Brain Mitochondria

Predominant accumulation of ethylmalonic acid (EMA) in tissues and biological fluids is a characteristic of patients affected by short chain acyl-CoA dehydrogenase deficiency and ethylmalonic encephalopathy. Neurological abnormalities are frequently found in these disorders, but the mechanisms underlying the brain injury are still obscure. Since hyperlacticacidemia is also found in many affected patients indicating a mitochondrial dysfunction; in the present work, we evaluated the in vitro and ex vivo effects of EMA plus Ca(2+) on mitochondrial integrity and redox balance in succinate-supported brain organelles. We verified that the evaluated parameters were disturbed only when EMA was associated with exogenous micromolar Ca(2+) concentrations. Thus, we found that this short chain organic acid plus Ca(2+) dissipated the membrane potential and provoked mitochondrial swelling, as well as impaired the mitochondrial Ca(2+) retention capacity, resulting in a rapid Ca(2+) release and decreased NAD(P)H matrix content. In contrast, EMA was not able to stimulate mitochondrial hydrogen peroxide generation. We also observed that all these effects were prevented by the mitochondrial Ca(2+) uptake inhibitor ruthenium red and the mitochondrial permeability transition (MPT) inhibitors cyclosporin A (CsA) and ADP. Furthermore, mitochondria isolated from rat brains after in vivo intrastriatal administration of EMA was more susceptible to Ca(2+)-induced swelling, which was fully prevented by CsA and ADP. Finally, EMA significantly decreased striatal slice viability, which was attenuated by CsA. The data strongly indicate that EMA reduced the mitochondrial threshold for Ca(2+)-induced MPT reinforcing the role of this cation in EMA-induced disruption of mitochondrial bioenergetics. It is, therefore, presumed that EMA acting synergistically with Ca(2+) compromises mitochondrial energy homeostasis in the central nervous system that may explain at least in part the neurologic alterations presented by patients with abnormal levels of this organic acid.

Proteomic investigation of cultivated fibroblasts from patients with mitochondrial short-chain acyl-CoA dehydrogenase deficiency

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is a rare inherited autosomal recessive disorder with not yet well established mechanisms of disease. In the present study, the mitochondrial proteome of five symptomatic patients homozygous for missense variations in the SCAD gene ACADS was investigated in an extensive large-scale proteomic study to map protein perturbations linked to the disease.Fibroblast cultures of patient cells homozygous for either c.319C>T/p.Arg107Cys (n=2) or c.1138C>T/p.Arg380Trp (n=3) in ACADS, and healthy controls (normal human dermal fibroblasts), were studied. The mitochondrial proteome derived from these cultures was analyzed by label free proteomics using high mass accuracy nanoliquid chromatography tandem mass spectrometry (nanoLC–MS/MS).More than 300 mitochondrial proteins were identified and quantified. Thirteen proteins had significant alteration in protein levels in patients carrying variation c.319C>T in ACADS compared to controls and they belonged to various pathways, such as the antioxidant system and amino acid metabolism. Twenty-two proteins were found significantly altered in patients carrying variation c.1138C>T which included proteins associated with fatty acid β-oxidation, amino acid metabolism and protein quality control system. Three proteins were found significantly regulated in both patient groups: adenylate kinase 4 (AK4), nucleoside diphosphate kinase A (NME1) and aldehyde dehydrogenase family 4 member A1 (ALDH4A1). Proteins AK4 and NME1 deserve further investigation because of their involvement in energy reprogramming, cell survival and proliferation with relevance for SCAD deficiency and related metabolic disorders.

First case report of short-chain acyl-CoA dehydrogenase deficiency in China

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive inborn error of mitochondrial fatty acid oxidation. It caused by rare mutations as well as polymorphic susceptibility variants. We describe the case of a 1-year-old male patient who had growth and mental retardation, seizures, fever since infancy. Urinary GC/MS showed elevated levels of ethylmalonic acid. Plasma acylcarnitines on MS/MS, elevations of C4-cartinitine are consistently present. The two polymorphic susceptibility variants of SCAD gene, c.625G>A and c.322G>A, was detected. As its highly variable clinical characteristics, there is no related report in China. This report broadens the phenotype and genotype of SCAD deficiency in China and underlines the difficulty of diagnosis.

Ethylmalonic acid modulates Na+, K+‐ATPase activity and mRNA levels in rat cerebral cortex

Ethylmalonic acid (EMA) accumulates in tissues of patients affected by short-chain acyl-CoA dehydrogenase deficiency and ethylmalonic encephalopathy, illnesses characterized by variable neurological symptoms. In this work, we investigated the in vitro and in vivo EMA effects on Na(+), K(+)-ATPase (NAK) activity and mRNA levels in cerebral cortex from 30-day-old rats. For in vitro studies, cerebral cortex homogenates were incubated in the presence of EMA at 0.5, 1, or 2.5 mM concentrations for 1 h. For in vivo experiments, animals received three subcutaneous EMA injections (6 μmol g(-1); 90-min interval) and were killed 60 min after the last injection. After that, NAK activity and its mRNA expression were measured. We observed that EMA did not affect this enzyme activity in vitro. In contrast, EMA administration significantly increased NAK activity and decreased mRNA NAK expression as assessed by semiquantitative reverse transcriptase polymerase chain reaction when compared with control group. Considering the high score of residues prone to phosphorylation on NAK, this profile can be associated with a possible regulation by specific phosphorylation sites of the enzyme. Altogether, the present results suggest that NAK alterations may be involved in the pathophysiology of brain damage found in patients in which EMA accumulates.

Central nervous system pathology in an infant with short-chain acyl-CoA dehydrogenase deficiency (SCADD): evidence for abnormal neuronal migration as part of its phenotypic spectrum

Central nervous system pathology in an infant with short-chain acyl-CoA dehydrogenase deficiency (SCADD): evidence for abnormal neuronal migration as part of its phenotypic spectrum