Combined Malonic and Methylmalonic Aciduria Due to ACSF3 Variants Results in Benign Clinical Course in Three Chinese Patients

Introduction: Combined malonic and methylmalonic aciduria (CMAMMA) is a rare metabolic disease caused by biallelic variants in ACSF3 gene. The clinical phenotype is highly heterogeneous in this disorder, ranging from asymptomatic to severe symptoms. No cases with CMAMMA were reported in China.Materials and Methods: In this study, three Chinese pediatric patients were diagnosed with CMAMMA unexpectedly while being treated for other ailments. To better characterize CMAMMA in a Chinese population, we made a multidimensional analysis with detailed clinical phenotype, semi-quantitative detection of urine organic acid, and analysis of ACSF3 gene variants.Results: The clinical presentation of these patients is quite different; their main complaints were anemia, jaundice, or abnormal urine test, respectively. They showed no symptoms of the classic methylmalonic academia, but urine organic acid analysis showed elevated malonic acid and methylmalonic acid in all the patients repeatedly. Variants were found at four sites in ACSF3 gene. Patient 1 carried the compound heterogeneous variant c.689G> A (p.Trp230*)/c.1456G> A (p.Ala486Thr). A compound heterozygous variant c.473C> T (p.Pro158Leu)/c.1456G> A (p.Ala486Thr) was identified in patient 2. Patient 3 harbored a novel homozygous variant c.1447A> G (p.Lys483Glu).Conclusions: Three Chinese patients were diagnosed with CMAMMA caused by ACSF3 variants. Their clinical course revealed that CMAMMA can be a benign condition that does not affect individual growth and development, but severe clinical phenotype may appear when other triggers exist. This study systematically elaborates CMAMMA in a Chinese population for the first time, broadens the spectrum of gene variant, and provides a strong basis for the etiological study of this disorder.

Urine organic acids may be useful biomarkers for metabolic syndrome and its components in Korean adults

Objectives Although metabolic syndrome (MetS) and its components are defined clinically, those with MetS may have various derangements in metabolic pathways. Thus, this study aimed to evaluate the traits of urine organic acid metabolites indicating the metabolic intermediates of the pathways in the subjects with MetS. Methods This cross-sectional study included 246 men and 283 women in a hospital health check-up setting. Urine organic acid metabolites were assayed via high-performance liquid chromatography–mass spectrometry analyses. A high level of each metabolite was defined as the fifth quintile of the distribution. Results The subjects with MetS had high levels of pyruvate, α-ketoglutarate, α-ketoisovalerate, α-ketoisocaproate, formiminoglutamate, and quinolinate (odds ratios from 1.915 to 2.809 in logistic models adjusted for age and sex). Among the metabolites, pyruvate, formiminoglutamate, and quinolinate were not independent of homeostatic model assessment of insulin resistance (HOMA2-IR). Several metabolites were associated with one or more components of MetS and HOMA2-IR. Conclusions Urine organic acid metabolites in MetS are characterized in altered carbohydrate and amino acid metabolism. MetS shared some traits in insulin resistance. These findings may promote the understanding of the pathophysiology of MetS.

A Case of Potential Inborn Error of Metabolism as a Cause of Young Onset Psychosis

Introduction: Young onset psychosis has poor prognosis, and inborn errors of metabolism (IEM) can be easily missed. There is scarce information regarding IEM and young onset psychosis in Malaysia. Case Report: A 15-year-old Malay girl presented at the age of 8 years with a history of intellectual disability and neuro-regression, subsequently developing psychotic and obsessive-compulsive symptoms several years later. Organic workup revealed elevated lactate levels. Urine organic acid chromatogram revealed a moderate peak of lactate however most other investigations were normal. As MRI brain is normal and there are no neurological signs it appears less likely there is an underlying IEM-related aetiology for psychosis. Discussion: Various IEMs can be related to psychosis however the incidence is very low and quality of evidence is poor. Thus, any psychiatric presentation, particularly with suggestive clinical signs, should warrant an organic (including IEM) workup since these causes are potentially reversible with supplementation.

Succinyl-CoA: 3-Ketoacid CoA-Transferase Deficiency in a Saudi Girl

Objective: Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is a rare genetic disorder of ketone utilization and isoleucine catabolism caused by mutations in the OXCT1 gene, Case: A Saudi girl case of SCOT deficiency confirmed by genetic analysis has been reported in this study. A 5-year-old girl presented to the emergency with the first episode of severe metabolic ketoacidosis after a febrile illness. On admission, she was drowsy lethargic, and severely dehydrated needs to admit in a highly dependent area. Initial investigations were done during the crisis showed refractory severe metabolic acidosis (pH of 7.18, HCO3- of 7.4 mmol/L), normal ammonia, lactic acidosis, and urine organic acid profile revealed elevations in 3-hydroxybutyrate and acetoacetate. Genetic analysis was done by CentoMito Comprehensive (Large extended screening panel), sequencing of OXCT1 gene revealed that the proband is homozygous for the missense likely pathogenic variant c.1402C>T p.(Arg468Cys) confirming the diagnosis of SCOT deficiency. Conclusion: This is the first Saudi child with succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency case report as searched in the literature. This case highlights the importance of suspecting SCOT deficiency in the differential diagnosis of pediatric metabolic ketoacidosis in preventing life-threatening of severe Metabolic ketoacidosis

Prediction of Autoimmune Diseases by Targeted Metabolomic Assay of Urinary Organic Acids

Autoimmune diseases (ADs) are chronic disorders characterized by the loss of self-tolerance, and although being heterogeneous, they share common pathogenic mechanisms. Self-antigens and inflammation markers are established diagnostic tools; however, the metabolic imbalances that underlie ADs are poorly described. The study aimed to employ metabolomics for the detection of disease-related changes in autoimmune diseases that could have predictive value. Quantitative analysis of 28 urine organic acids was performed using Gas Chromatography-Mass Spectrometry in a group of 392 participants. Autoimmune thyroiditis, inflammatory bowel disease, psoriasis and rheumatoid arthritis were the most prevalent autoimmune diseases of the study. Statistically significant differences were observed in the tricarboxylate cycle metabolites, succinate, methylcitrate and malate, the pyroglutamate and 2-hydroxybutyrate from the glutathione cycle and the metabolites methylmalonate, 4-hydroxyphenylpyruvate, 2-hydroxyglutarate and 2-hydroxyisobutyrate between the AD group and the control. Artificial neural networks and Binary logistic regression resulted in the highest predictive accuracy scores (66.7% and 74.9%, respectively), while Methylmalonate, 2-Hydroxyglutarate and 2-hydroxybutyrate were proposed as potential biomarkers for autoimmune diseases. Urine organic acid levels related to the mechanisms of energy production and detoxification were associated with the presence of autoimmune diseases and could be an adjunct tool for early diagnosis and prediction.

MON-068 The First Case in Korea, ZC4H2 Gene Mutation in Wieacker-Wolff Syndrome with Recurrent Hypoglycemia

Wieacker-Wolff syndrome was first described in 1985 and is a rare congenital syndrome cause by ZC4H2 mutation. It is a X-linked recessive disorder characterized by congenital contracture of the feet, mental retardation, progressive neurologic muscular atrophy, scoliosis, and hypoglycemia. 9-years-old boy with brain atrophy, mental retardation, scoliosis, convulsion and exotropia visited our clinic with recurrent hypoglycemia. Hypoglycemia was developed since infant. Physical examination showed dysmorphism and no hepatomegaly. In the ‘critical sample’, ketoacidosis was present and serum levels of free fatty acid was elevated. Lactate was in the normal range. Hyperinsulinism was excluded with ‘critical sample’ and glucagon stimulation test. Combined pituitary stimulation showed no deficiency of growth hormone and cortisol, respectively. Fatty acid oxidation was excluded by serum levels of acylcarnitines and urine organic acid test. Due to the presence of multiple anomaly and under the suspicion of glycogen storage type 0, whole exome sequencing was performed and p.P154T mutation on the ZC4H2 was observed. Although Sanger sequencing is in processing yet, clinical features are very similar compare to previous cases. In summary, we reported a first Korean male with a novel ZC4H2 mutation, P154T.

High anion gap metabolic acidosis caused by D-lactate

Introduction: D-lactic acidosis is an uncommon cause of high anion gap acidosis. Materials and methods: A 35-year old woman was admitted to the emergency room with somnolence, drowsiness, dizziness, incoherent speech and drunk appearance. Her past medical history included a Roux-en-Y bypass. Point-of-care venous blood analysis revealed a high anion gap acidosis. Based on the clinical presentation, routine laboratory results and negative toxicology screening, D-lactate and 5-oxoprolinuria were considered as the most likely causes of the high anion gap acidosis. Urine organic acid analysis revealed increased lactate, but no 5-oxoproline. Plasma D-lactate was < 1.0 mmol/L and could not confirm D-lactic acidosis. What happened: Further investigation revealed that the blood sample for D-lactate was drawn 12 hours after admission, which might explain the false-negative result. Data regarding the half-life of D-lactate are, however, scarce. During a second admission, one month later, D-lactic acidosis could be confirmed with an anion gap of 40.7 mmol/L and a D-lactate of 21.0 mmol/L measured in a sample collected at the time of admission. Main lesson: The time of blood collection is of utmost importance to establish the diagnosis of D-lactic acidosis due to the fast clearance of D-lactate in the human body