J Med Genet. 2011 Oct;48(10):660-668. doi: 10.1136/jmg.2011.089995.

Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease.

Uusimaa J^#¹, Jungbluth H^#^2,³, Fratter C⁴, Crisponi G⁵, Feng L⁶, Zeviani M⁷, Hughes I⁸, Treacy EP⁹, Birks J¹⁰, Brown GK¹¹, Sewry CA⁶, McDermott M¹², Muntoni F⁶, Poulton J¹.

Author information

1: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, The Women's Centre, John Radcliffe Hospital, Oxford, UK.
2: Department of Clinical Neuroscience, King's College Hospital, London, UK.
3: Department of Paediatric Neurology - Neuromuscular Service, Evelina Children's Hospital, St Thomas' Hospital, London, UK.
4: Oxford Medical Genetics Lab, Churchill Hospital, Oxford, UK.
5: Servizio di Puericultura, Universita' di Cagliari, Italy.
6: Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.
7: Unit of Molecular Neurogenetics, "C. Besta" Neurological Institute - IRCCS Foundation, Milan, Italy.
8: Department of Paediatric Neurology, Manchester Children's Hospital, Manchester, UK.
9: National Centre for Inherited Metabolic Disease, Children's University Hospital, Dublin Republic of Ireland.
10: Centre for Statistics in Medicine, University of Oxford, UK.
11: Department of Biochemistry, University of Oxford, UK.
12: Our Lady's Hospital for Sick Children, Dublin, Ireland.
#: Contributed equally

Abstract

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.