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Published on: May 19, 2019
Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease
J Uusimaa1, H Jungbluth2,3, C Fratter4
1Nuffield Department of Obstetrics and Gynaecology, University of Oxford, The Women's Centre, John Radcliffe Hospital, Oxford, UK.
Insights
Reversible infantile respiratory chain deficiency has diverse genetic causes beyond known mitochondrial mutations. Mutations in the nuclear TRMU gene are implicated, offering diagnostic advances for pediatricians.
Area of Science:
- Mitochondrial Medicine
- Pediatric Neurology
- Genetics
Background:
- Reversible infantile cytochrome c oxidase deficiency, also known as benign COX deficiency, is linked to specific mitochondrial tRNA(Glu) mutations.
- This condition presents in infancy with hypotonia, feeding issues, and lactic acidosis, often showing remarkable recovery but residual myopathy.
Purpose of the Study:
- To investigate genetic defects underlying infantile reversible cytochrome c oxidase deficiency.
- To identify novel genetic causes beyond the previously identified m.14674T>C and m.14674T>G mt-tRNA(Glu) mutations.
Main Methods:
- Studied eight patients from seven families with clinical features of reversible infantile cytochrome c oxidase deficiency.
- Performed molecular genetic analyses of both mitochondrial DNA and nuclear candidate genes.
Main Results:
- The m.14674T>C mutation was found in four families; the m.14674T>G mutation was absent.
- Pathogenic mutations in the nuclear TRMU gene were identified in two families, a novel association.
- One family's genetic cause remained unidentified.
Conclusions:
- Benign COX deficiency is better termed 'reversible infantile respiratory chain deficiency' due to its genetic heterogeneity.
- Mutations in the TRMU gene are a significant cause in patients lacking mt-tRNA(Glu) mutations.
- Molecular diagnosis is crucial for pediatric neurologists and intensivists to predict prognosis and guide respiratory support.
Objectives:
Homoplasmic maternally inherited, m.14674T>C or m. 14674T>G mt-tRNA(Glu) mutations have recently been identified in reversible infantile cytochrome c oxidase deficiency (or 'benign COX deficiency'). This study sought other genetic defects that may give rise to similar presentations.
Patients:
Eight patients from seven families with clinicopathological features of infantile reversible cytochrome c oxidase deficiency were investigated.
Methods:
The study reviewed the diagnostic features and performed molecular genetic analyses of mitochondrial DNA and nuclear encoded candidate genes.
Results:
Patients presented with subacute onset of profound hypotonia, feeding difficulties and lactic acidosis within the first months of life. Although recovery was remarkable, a mild myopathy persisted into adulthood. Histopathological findings in muscle included increased lipid and/or glycogen content, ragged-red and COX negative fibres. Biochemical studies suggested more generalised abnormalities than pure COX deficiency. Clinical improvement was reflected by normalisation of lactic acidosis and histopathological abnormalities. The m.14674T>C mt-tRNA(Glu) mutation was identified in four families, but none had the m. 14674T>G mutation. Furthermore, in two families pathogenic mutations were also found in the nuclear TRMU gene which has not previously been associated with this phenotype. In one family, the genetic aetiology still remains unknown.
Conclusions:
Benign COX deficiency is better described as 'reversible infantile respiratory chain deficiency'. It is genetically heterogeneous, and patients not carrying the m.14674T>C or T>G mt-tRNA(Glu) mutations may have mutations in the TRMU gene. Diagnosing this disorder at the molecular level is a significant advance for paediatric neurologists and intensive care paediatricians, enabling them to select children with an excellent prognosis for continuing respiratory support from those with severe mitochondrial presentation in infancy.
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