Genotypic Spectrum and Natural History of Cavitating Leukoencephalopathies in Childhood

Zhang, Jie; Liu, Ming; Zhang, Zhongbin; Zhou, Ling; Kong, Weijing; Jiang, Yuwu; Wang, Jingmin; Xiao, Jiangxi; Wu, Ye

doi:10.1016/j.pediatrneurol.2019.01.002

Cited by 27 publications

(34 citation statements)

References 32 publications

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“…The clinical course was variable with some patients having slower progression of neurological manifestations [90,91,103] . Brain MRI and MRS findings included features of typical Leigh syndrome, white matter changes, basal ganglia changes, elevated lactate peak, infantile striatal necrosis [97] , and cavitating leukoencephalopathy [109] . Outcome was available in 34 patients; ten died at a median age of six months (range: three days to three years).…”

Section: Fdxr Deficiency (Omim #617717)mentioning

confidence: 99%

“…In a cohort of 37 children with cavitating leukoencephalopathies, three (3/37, 8.1%) were compound heterozygotes for pathogenic mutations in the NDUFV2 gene [109] . The age of onset of symptoms was 4-46 months with stable/improved clinical course and frontal predominant and deep white matter patterns on brain MRI [109] .…”

Section: Ndufv2 Deficiency (Omim #618229)mentioning

confidence: 99%

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Riboflavin metabolism: role in mitochondrial function

Balasubramaniam¹,

Yaplito‐Lee²

2020

jtgg

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Riboflavin, known as vitamin B2, a water-soluble vitamin, is an essential nutrient in vertebrates, hence adequate dietary intake is imperative. Riboflavin plays a role in a variety of metabolic pathways, serving primarily as an integral component of its crucial biologically active forms, the flavocoenzymes flavin adenine dinucleotide and flavin mononucleotide. These flavocoenzymes ensure the functionality of numerous flavoproteins including dehydrogenases, oxidases, monooxygenases, and reductases, which play pivotal roles in mitochondrial electron transport chain, β-oxidation of fatty acids, redox homeostasis, citric acid cycle, branched-chain amino acid catabolism, chromatin remodeling, DNA repair, protein folding, and apoptosis. Unsurprisingly, impairment of flavin homeostasis in humans has been linked to various diseases including neuromuscular and neurological disorders, abnormal fetal development, and cardiovascular diseases. This review presents an overview of riboflavin metabolism, its role in mitochondrial function, primary and secondary flavocoenzyme defects associated with mitochondrial dysfunction, and the role of riboflavin supplementation in these conditions.

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Section: Fdxr Deficiency (Omim #617717)mentioning

confidence: 99%

Section: Ndufv2 Deficiency (Omim #618229)mentioning

confidence: 99%

Riboflavin metabolism: role in mitochondrial function

Balasubramaniam¹,

Yaplito‐Lee²

2020

jtgg

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“…NDUFAF5 was reported to catalyze the hydroxylation of Arg-73 in NADH: Ubiquinone Oxidoreductase Core Subunit S7 (NDUFS7) and affect the biogenesis of Complex I at an early stage of assembly [40]. Mutations in NDUFAF5 were found to be related to cavitating leukoencephalopathies, lactic acidosis, classic Leigh syndrome, hyponatremia and some lethal neonatal mitochondrial diseases [41][42][43]. In our study, Co-IP assay was performed and the results proved that there was an endogenous interaction between DTX3 and NDUFAF5 in PTC cells.…”

Section: Discussionmentioning

confidence: 99%

Deltex3 inhibits Epithelial Mesenchymal Transition in Papillary Thyroid Carcinoma via promoting ubiquitination of XRCC5 to regulate the AKT signal pathway

Wang¹,

Huang²,

Liu³

et al. 2021

J. Cancer

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“…1 In addition, the MRI findings showing cavitating leukoencephalopathy affecting mainly the posterior parts of the white matter and the adjacent corpus callosum and sparing the infratentorial regions seem to be a very characteristic pattern and different from other cavitating leukoencephalopathies (table 1). 2,3,5 By protein analyses, we identified profound deficiency of subunits MT-CO1, MT-CO2, and COX4, which are integral to the assembly of complex IV. This loss of complex IV subunits in muscle may explain the deficient enzyme activity.…”

Section: Discussionmentioning

confidence: 99%

COX deficiency and leukoencephalopathy due to a novel homozygous APOPT1/COA8 mutation

et al. 2020

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ObjectiveTo describe the long-term follow-up and pathogenesis in a child with leukoencephalopathy and cytochrome c oxidase (COX) deficiency due to a novel homozygous nonsense mutation in APOPT1/COA8.MethodsThe patient was clinically investigated at 3, 5, 9, and 25 years of age. Brain MRI, repeat muscle biopsies with biochemical, morphologic, and protein expression analyses were performed, and whole-genome sequencing was used for genetic analysis.ResultsClinical investigation revealed dysarthria, dysphagia, and muscle weakness following pneumonia at age 3 years. There was clinical regression leading to severe loss of ambulation, speech, swallowing, hearing, and vision. The clinical course stabilized after 2.5 years and improved over time. The MRI pattern in the patient demonstrated cavitating leukoencephalopathy, and muscle mitochondrial investigations showed COX deficiency with loss of complex IV subunits and ultrastructural abnormalities. Genetic analysis revealed a novel homozygous mutation in the APOPT1/COA8 gene, c.310T>C; p.(Gln104*).ConclusionsWe describe a novel nonsense mutation in APOPT1/COA8 and provide additional experimental evidence for a COX assembly defect in human muscle causing the complex IV deficiency. The long-term outcome of the disease seems in general to be favorable, and the characteristic MRI pattern with cavitating leukoencephalopathy in combination with COX deficiency should prompt for testing of the APOPT1/COA8 gene.

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Genotypic Spectrum and Natural History of Cavitating Leukoencephalopathies in Childhood

Cited by 27 publications

References 32 publications

Riboflavin metabolism: role in mitochondrial function

Riboflavin metabolism: role in mitochondrial function

Deltex3 inhibits Epithelial Mesenchymal Transition in Papillary Thyroid Carcinoma via promoting ubiquitination of XRCC5 to regulate the AKT signal pathway

COX deficiency and leukoencephalopathy due to a novel homozygous APOPT1/COA8 mutation

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