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

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

J Uusimaa #  1 , H Jungbluth #  2   3 , C Fratter  4 , G Crisponi  5 , L Feng  6 , M Zeviani  7 , I Hughes  8 , E P Treacy  9 , J Birks  10 , G K Brown  11 , C A Sewry  6 , M McDermott  12 , F Muntoni  6 , J Poulton  1
Affiliations

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

J Uusimaa et al. J Med Genet. 2011 Oct.

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.

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Figures

Figure 1
Figure 1
Typical facial features associated with Reversible Infantile Respiratory Chain Deficiency due to the m.14674T>C mt-tRNAGlu mutation, Patient 3 (B, C) and Patient 4 (A). There is a myopathic facial appearance (A-C) with an elongated face and chin, bilateral ptosis, narrowed upslanting palpebral fissures and an elongated, prominent nose. Inability to bury the eyelashes completely (C) is reflective of mild facial weakness.
Figure 2
Figure 2
Brain MRI at day 26 of life of Patient 8 with a compound heterozygous mutation p. V279M, (c.G835A)/IVS11-3, C>G in TRMU gene. An abnormal high signal focus in right thalamus in T1 image (A). Brain MR spectroscopy centred on the left basal ganglia and thalamus with TE 35 showing an abnormal double peak at 1.3ppm (arrow) (B). When MRS was repeated with TE 144 this double peak at 1.3ppm inverted which is characteristic of lactate (C).
Figure 2
Figure 2
Brain MRI at day 26 of life of Patient 8 with a compound heterozygous mutation p. V279M, (c.G835A)/IVS11-3, C>G in TRMU gene. An abnormal high signal focus in right thalamus in T1 image (A). Brain MR spectroscopy centred on the left basal ganglia and thalamus with TE 35 showing an abnormal double peak at 1.3ppm (arrow) (B). When MRS was repeated with TE 144 this double peak at 1.3ppm inverted which is characteristic of lactate (C).
Figure 2
Figure 2
Brain MRI at day 26 of life of Patient 8 with a compound heterozygous mutation p. V279M, (c.G835A)/IVS11-3, C>G in TRMU gene. An abnormal high signal focus in right thalamus in T1 image (A). Brain MR spectroscopy centred on the left basal ganglia and thalamus with TE 35 showing an abnormal double peak at 1.3ppm (arrow) (B). When MRS was repeated with TE 144 this double peak at 1.3ppm inverted which is characteristic of lactate (C).
Figure 3
Figure 3
Histopathological features associated with Reversible Infantile Respiratory Chain Deficiency due to the m.14674T>C mt-tRNAGlu mutation. Transverse sections of muscle biopsies from the quadriceps of Patient 5, at 4 months of age (A-B; D-E), and from Patient 1 on follow-up biopsy at 28 years of age (C, F). Serial sections from Patient 5 stained for combined SDH-COX activity (A) show numerous COX negative fibres (blue appearance), several with reduced COX (blue/greyappearance) and only a few COX positive fibres (brown appearance); COX negative fibres have a ragged-red appearance on the Gomori trichrome stain (D) and some correspond to type 1 fibres, dark with slow myosin (B) and light on fast myosin stains (E). There is co-expression of both myosin isoforms in some fibres and several of the very atrophic fibres are type 1/slow fibres. On the repeat muscle biopsy from Patient 1 obtained at 28 years there is increased variability in fibre size, a mild increase in connective tissue on H&E (C), and marked type 2 predominance on ATPase pre-incubated at a pH of 4.6 with atrophy of type 1 fibres (F).
Figure 4
Figure 4
Histological findings in liver in Patient 8 with reversible infantile respiratory chain deficiency with acute infantile liver failure associated with a compound heterozygous mutation p. V279M, (c.G835A)/IVS11-3, C>G in TRMU gene. Liver parenchyma showng central hepatic rosette with cholestasis. Hepatocytes exhibit prominent haemosiderin and microvesicular steatosis. (Hematoxylin and Eosin)
Figure 5
Figure 5
Mutations is TRMU gene in two patients with reversible infantile respiratory chain deficiency. 3A) a heterozygous p.A10S (c.G28T) in Patient 7 and 3B, and 3C) A compound heterozygous mutation p. V279M, (c.G835A)/IVS11-3, C>G Patient 8. 3D) Multiple sequence alignment of the TRMU protein with eukaryotic homologues showing the conservation of alanine in site 10 and valine in site 279.
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