Hyperammonemic crisis in a child with ATP synthase deficiency caused by mtDNA mutation m.8851T>C

Life-threatening hyperammonemia is uncommon in patients with mitochondrial disorders (MDs).When present, it is usualy due to TMEM70 deficiency [1] and only rarely is it noted in other MDs [2]. Hyperammonemia was documented in patients with Barth syndrome [2], maternally inherited Leigh syndrome (MILS) [3], pyruvate dehydrogenase deficiency [4], pyruvate carboxylase deficiency [5], complex III deficiency caused by UQCRC2 deficiency [6], and patients with CoQ deficiency [7]. Here we present a fatal outcome due to newly documented hyperammonemia in a previously reported girl with ATP synthase deficiency caused by mutation m.8851TNC in mitochondrialMTATP6 [8]. The 5.5-year-old girl with moderate developmental delay, microcephaly, ataxia, epilepsy and Leigh syndrome manifested severe metabolic disturbance and an altered level of consciousness during a febrile viral infection. Metabolic acidosis (base deficit -15.1 mmol/L, controls ± 2), elevated cerebrospinal fluid (CSF) lactate (7.23 mmol/L, controls b 2.1), creatine kinase (14.76 μkat/L, controls b 2.27) andmarkedly elevated ammonia (269 μmol/L, controls b 60)were detected. Liver transaminases were elevated only marginally; there was no coagulopathy and toxicology testswere negative. Following infusion therapy, normal levels of amino acids in both serum and CSF were measured 12 h after the first hyperammonemia observation. Excretion of orotic acid in urinewas not increased. Lactate and ammonia levels normalized rapidly on i.v. glucose infusion and bicarbonate therapy. Nevertheless, lethargy and decreased level of consciousness persisted. The girl died 10th day after the onset of fever. The autopsy revealed brain oedema and other findings consistent with diagnosis of Leigh syndrome. Mild cardiomyopathy was an additional pathological feature. We present another case of a patient with severe hyperammonemia andATP synthase deficiency. Hyperammonemia is not a commonfinding in patients with MDs, but if observed, ATP synthase deficiency should be taken into consideration, in particular TMEM70 deficiency, MILS syndrome and ATP synthase deficiency caused by mutation m.8851TNC. We further emphasize the importance of regular blood ammonia measurement in patients with MDs during any stress bearing conditions.