An infant presenting with life-threatening acute metabolic decompensations with hypoglycaemia, marked lactic acidosis and hyperammonaemia due to TANGO2 deficiency

Abstract

A female infant was the third child of non-consanguineous parents. She has had six acute metabolic decompensations requiring retrieval to the pediatric intensive care unit. Episodes are triggered by vomiting and start with hypoglycemia and then progress to severe acidosis (pH <7.0), lactic acidosis (up to16 mmol/L), hyperammonemia (up to 850umol/L) and coagulopathy with the first at 3.5 months of age. She required ventilatory support with recovery being dependent on re-establishing normal feeds. Her highest CK was 248 U/l. Urine organic acids showed marked ketoacidosis, dicarboxylic acids and lactate. In contrast, acylcarnitines showed a pattern suggestive of VLCAD deficiency. Transferrin isoforms were normal but she had a mildly elevated aglyco Apo C-III with normal mono- and disialo-Apo C-III. She has been treated with a low fat diet, medium chain triglycerides and overnight feeds. Several vomiting episodes have been aborted with ondansetron avoiding hypoglycemia. Her progress is better than her older twin siblings at the same age. These twins, a boy and a girl, presented with global developmental delay at 9 months, seizures, hypoglycemia with lactic acidosis and recurrent rhabdomyolysis with CK up to 97,500 U/l. Brain MRI in both showed generalized cerebral atrophy. The female twin developed hypertrophic cardiomyopathy. The twins died at 22 and 24 months of age. A mitochondrial disorder was suspected but whole exome sequencing showed homozygous mutations in the TANGO2 gene which is expressed in the Golgi and cytoplasm. Mutations are hypothesised to cause endoplasmic reticulum and Golgi disruption and stress.L6124788662016-10-07 <br />