Recessive mutations in NDUFA2 cause mitochondrial leukoencephalopathy

Abstract

Deficiencies of mitochondrial respiratory chain complex I frequently result in leukoencephalopathy in young patients, and different mutations in the genes encoding its subunits are still being uncovered. We report 2 patients with cystic leukoencephalopathy and complex I deficiency with recessive mutations in NDUFA2, an accessory subunit of complex I. The first patient was initially diagnosed with a primary systemic carnitine deficiency associated with a homozygous variant in SLC22A5, but also exhibited developmental regression and cystic leukoencephalopathy, and an additional diagnosis of complex I deficiency was suspected. Biochemical analysis confirmed a complex I deficiency, and whole-exome sequencing revealed a homozygous mutation in NDUFA2 (c.134A>C, p.Lys45Thr). Review of a biorepository of patients with unsolved genetic leukoencephalopathies who underwent whole-exome or genome sequencing allowed us to identify a second patient with compound heterozygous mutations in NDUFA2 (c.134A>C, p.Lys45Thr; c.225del, p.Asn76Metfs*4). Only 1 other patient with mutations in NDUFA2 and a different phenotype (Leigh syndrome) has previously been reported. This is the first report of cystic leukoencephalopathy caused by mutations in NDUFA2.

Cavitating and tigroid‐like leukoencephalopathy in a case of NDUFA2‐related disorder

“…Consistent with the MRI findings of our case, the two children reported by Perrier et al showed confluent T2‐hyperintense and cystic changes of supratentorial white matter without involvement of basal ganglia . In contrast to the cases by Perrier et al, our case had an involvement of the corpus callosum, a tigroid‐like pattern of the deep white matter, and restriction of the DWI‐signal.…”

“…Although MRI images were not available, the pattern of neuroimaging abnormalities of the first reported patient with NDUFA2 defect appears to be different compared to the present case and the two other cases reported by Perrier et al This first case with NDUFA2 defect indeed showed an early‐onset of demyelination of cortico‐spinal tracts and subacute necrotizing encephalomyelopathy, as observed in Leigh syndrome . Consistent with the MRI findings of our case, the two children reported by Perrier et al showed confluent T2‐hyperintense and cystic changes of supratentorial white matter without involvement of basal ganglia . In contrast to the cases by Perrier et al, our case had an involvement of the corpus callosum, a tigroid‐like pattern of the deep white matter, and restriction of the DWI‐signal.…”

“…4 In three out of the four cases, evidence for increased lactate was detected by measurements of lactate in blood or in brain by MRSI. Although MRI images were not available, the pattern of neuroimaging abnormalities of the first reported patient with NDUFA2 defect appears to be different compared to the present case and the two other cases reported by Perrier et al 4,5 This first case with NDUFA2 defect indeed showed an early-onset of demyelination of cortico-spinal tracts and subacute necrotizing encephalomyelopathy, as observed in Leigh syndrome. 4 Consistent with the MRI findings of our case, the two children reported by Perrier et al showed confluent T2-hyperintense and cystic changes of supratentorial white matter without involvement of basal ganglia.…”

“…Biallelic mutations in NDUFA2 have been described in three patients exhibiting an early-onset progressive neurodegenerative disorder. [4][5][6] We here report NDUFA2related disorder in a further female patient presenting with cavitating and tigroid-like leukoencephalopathy.…”

“…Prior to this report, biallelic variants in NDUFA2 were described in only three children, presenting with Leigh syndrome or cystic leukodystrophy. 4,5 The clinical, biochemical and genetic findings of these three cases are summarized in Table 1 and compared with the case herein presented. All cases showed developmental delay and regression, although in at least two cases the loss of developmental skills was followed by either stabilization or regaining of some skills.…”