m.8993T>G-Associated Leigh Syndrome with Hypocitrullinemia on Newborn Screening

Abstract

Citrulline is among the metabolites measured by expanded newborn screening (NBS). While hypocitrullinemia can be a marker for deficiency of proximal urea cycle enzymes such as ornithine transcarbamylase (OTC), only a handful of state newborn screening programs in the United States officially report a low citrulline value for further work-up due to low positive predictive value. We report a case of a male infant who was found to have hypocitrullinemia on NBS. After excluding proximal urea cycle disorders by DNA sequencing, his NBS result was felt to be a false positive. At 4 months of age, he developed poor feeding, failure to thrive, apnea and infantile spasms with a progression to intractable seizures, as well as persistent hypocitrullinemia. He was diagnosed with Leigh syndrome due to a maternally inherited homoplasmic m.8993T>G mutation in the ATPase 6 gene. His mother, who had previously been diagnosed with cerebral palsy, was concurrently diagnosed with neuropathy, ataxia, and retinitis pigmentosa (NARP) due to heteroplasmy of the same mutation. She had progressive muscle weakness, ataxia, and speech dyspraxia. The m.8993T>G mutation causes mitochondrial ATP synthase deficiency and it is hypothesized to undermine the synthesis of citrulline by CPS1. In addition to proximal urea cycle disorders, the evaluation of an infant with persistent hypocitrullinemia should include testing for the m.8993T>G mutation and other disorders that cause mitochondrial dysfunction.

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)

“…The blot was probed with anti-SMVT antibody and expression was normalized relative to b-actin istic unique to patients with the m.8993T>G mutation, seen in 90% of patients, as opposed to less than 20% for other respiratory chain deficiencies (Rabier et al 1998). These findings are sufficiently convincing to consider hypocitrullinemia as a useful biochemical marker for the m.8993T>G mutation and, more generally, as a marker of impaired oxidative phosphorylation in the enterocyte (Rabier et al 1998;Parfait et al 1999;Debray et al 2010;Henriques et al 2012;Mori et al 2014).…”

“…Persistent hypocitrullinemia has previously been reported in 13 patients with the m.8993T>G variant (Rabier et al 1998;Parfait et al 1999;Enns et al 2006;Debray et al 2010;Henriques et al 2012;Mori et al 2014). In an additional report, a female patient who was prenatally diagnosed with apparently mild ornithine transcarbamylase (OTC) deficiency succumbed during an acute febrile encephalopathic illness at 6 months of age, with neuroimaging suggestive of Leigh syndrome.…”

Utility of specific amino acid ratios in screening for pyruvate dehydrogenase complex deficiencies and other mitochondrial disorders associated with congenital lactic acidosis and newborn screening prospects

“…For subjects in Table 1, we also evaluated other amino acids and amino acid ratios (Supplementary Table S4) reported to discriminate primary MtDs from PDCD, 25 including citrulline which can be low in several primary MtDs such as MELAS 34 and mitochondrial ATP synthase deficiency 35 . Mean concentrations of citrulline in DBS and blood AA were higher in subjects with MtD (2 and 4) compared to those with PDCD (1, 3, and 5) consistent with others 25 …”

Mitochondria and Eye

“…Small pigment retinal defects have been identified in a 4-year-old female with a COX deficiency [87]. In addition, because of the mutation m.8993 T > GG retinitis pigmentosa has been identified in patients with Leigh syndrome [88].…”