Low Plasma Citrulline Guiding the Diagnosis of a Mitochondrial Disorder.

Abstract

A 3-month-old male presented with generalized seizures in the setting of a viral upper respiratory tract infection. The newborn screen (NBS) collected at 27 hours of life was normal. Initial evaluation was notable for lactic acidosis (lactate 4.1 mmol/L, reference interval [RI] 0.5–2.2 mmol/L; bicarbonate 12 mmol/L, RI 18–28 mmol/L). Cerebrospinal fluid analysis was normal. Brain magnetic resonance imaging (MRI) revealed T2 hyperintensities involving bilateral deep gray nuclei and upper brainstem regions suggestive of genetic or metabolic etiologies. Diffuse lactate elevation was also observed by magnetic resonance spectroscopy, consistent with a diagnosis of Leigh syndrome (LS, OMIM# 256000). Due to concerns for LS, a metabolic evaluation was obtained. The plasma amino acid (PAA) profile was notable for reduced citrulline (3 µmol/L, RI 7–47 µmol/L) in the context of normal glutamine (444 µmol/L, RI 285–832 µmol/L), leading to an abnormal plasma glutamine/citrulline ratio (148, RI <25). Given normal plasma ammonia and glutamine, a proximal urea cycle defect was unlikely. Low citrulline is also observed with short intestinal length and impaired intestinal absorption; however, the patient did not exhibit abnormal bowel function. Urine organic acid (UOA) analysis revealed elevated propionate metabolites (i.e., propionylglycine and methylcitrate) along with lactate, ketones, and tricarboxylic acid cycle metabolites (Fig.1). 3-Hydroxyisovaleric acid was normal, while 3-hydroxypropionic acid and 3-methylcrotonylglycine were not detected. The plasma acylcarnitine (PAC) profile was notably normal. Given the clinical and biochemical presentation, mitochondrial complex V deficiency mitochondrial type 1 (MC5DM1) caused by variants in MT-ATP6 (OMIM# 500015) was highly suspected (1, 2). Subsequent mitochondrial genome analysis of the proband’s blood revealed a pathogenic variant (m.8993T>G) in MT-ATP6 at 96% heteroplasmy, confirming a diagnosis of MC5DM1.