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Rare cause of high anion gap metabolic acidosis in an infant: Succinyl‐CoA:3‐ketoacid transferase deficiency

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A 10-month-old male infant was referred due to refractory metabolic acidosis. He had presented with respiratory distress after 2 days of vomiting. Past and family histories were unremarkable except for… Click to show full abstract

A 10-month-old male infant was referred due to refractory metabolic acidosis. He had presented with respiratory distress after 2 days of vomiting. Past and family histories were unremarkable except for parental consanguinity. There was no known exposure to drugs or toxins. Growth and development were normal. Upon arrival, he had severe Kussmaul breathing despite being sedated and intubated. Vital signs were: temperature 36.3 C, heart rate 167/min, respiratory rate 66/min, blood pressure 95/55 mmHg, oxygen saturation 98%. He was comatose (Infant Glasgow Coma Scale score: 6) and moderately dehydrated with otherwise unremarkable physical examination. He had severe high anion gap metabolic acidosis (blood pH 6.90, bicarbonate 2.8 mmol/L, anion gap 29.2 mmol/L) with leucocytosis (41.5 × 10/μL), hyperuricaemia (16.5 mg/dL), hyperammonaemia (163 μmol/L), normal glucose, lactate and significant ketonuria (3+ with dipstick). He was admitted to the paediatric intensive care unit with a presumptive diagnosis of organic acidaemia. Dried blood spots, plasma and urine samples were obtained and stored for future testing. He was kept nil orally and given glucose, insulin and lipid infusions to promote anabolism. Levocarnitine, biotin, hydroxycobalamin and intravenous bicarbonate were started. As acidosis was refractory, continuous venovenous hemodiafiltration (CVVH) was performed for 24 h. Blood gases, breathing pattern, ammonia normalised, ketonuria disappeared and he was extubated within 12 h of CVVH. Low-protein formula feeding was initiated. Electroencephalogram and brain magnetic resonance imaging were normal. Consciousness improved on day 5 and the patient recovered without any apparent deficits. Ketonuria did not recur during the hospital stay. He was discharged in good neurologic condition. Results of metabolic analyses on the initial critical samples were available on day 6. Unexpectedly; carnitine, acylcarnitines, amino acids and urinary acylglycines were normal. Urine organic acids were also normal except for markedly elevated ketone bodies β-hydroxybutyric acid (13 270 mmol/mol creatinine; normal range: 0–11) and acetoacetate. Organic acidaemias were thus ruled out; protein restriction, levocarnitine, biotin and hydroxycobalamin were discontinued. Disorders of ketone utilisation were suspected (Table 1). As succinyl-CoA:3-ketoacid transferase (SCOT) deficiency was the most likely culprit, sequencing of OXCT1 gene was ordered, which encodes SCOT enzyme. A previously unreported, homozygous missense variant c.424G>C (p.Ala142Pro) was detected in OXCT1 (RefSeq NM_000436.3), which is not included in gnomAD or ClinVar databases. In silico variant analysis tools Mutation Taster (NeuroCure Cluster of Excellence, Berlin, Germany), PROVEAN (J. Craig Venter Institute, CA, USA), PolyPhen-2 (Harvard University, Cambridge, MA, USA) and SIFT (Pauline Ng, Singapore) predict that this variant is likely pathogenic. Therefore, c.424G>C (p.Ala142Pro) variant in OXCT1 gene is likely to be a novel pathogenic variant (mutation) associated with SCOT deficiency, virtually confirming the diagnosis in the present case. This sequence data has been submitted to the ClinVar database under the accession number SCV000902433.

Keywords: acidosis; deficiency; metabolic acidosis; anion gap

Journal Title: Journal of Paediatrics and Child Health
Year Published: 2019

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