Mitochondrial myopathy with tRNA Leu(UUR) mutation and complex I deficiency responsive to riboflavin,☆☆

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Abstract

Deficiency of complex I (reduced nicotinamide adenine dinucleotide dehydrogenase–ubiquinone oxidoreductase) of the mitochondrial respiratory chain may be seen as a pure myopathy or as a neuromuscular disorder at presentation. Efficacy of long- term therapy for these disorders is yet to be established. We report the case of a female patient with complex I deficiency and skeletal myopathy, who has had a sustained clinical response to riboflavin during 3 years of therapy. Molecular studies found no mutations in the putative flavin mononucleotide binding site in the 51 kd subunit of complex I, but a T-to-C transition at nucleotide 3250 in the mitochondrial DNA tRNA Leu(UUR) gene was identified. This mutation has been reported in one other family in that five members had fatigue with or without muscle weakness. There were also five cases of unexplained infant deaths in that family and two cases in the family reported here. Riboflavin therapy should be attempted in all patients with complex I deficiency when the clinical presentation is one of isolated skeletal myopathy. (J Pediatr 1997;130:138-45)

Section snippets

CASE REPORTS

The proband (III-2 in Fig. 1) is the second child of nonconsanguineous Australian parents.

. Family pedigree and heteroplasmic load of the nt3250 T-to-C mutation in tissues of family members. Tissuesstudied were as follows: blood (Bl) , skeletal muscle (Mu) , fibroblasts (Fb) , liver (Li) , heart muscle (He) , and brain (Br) .

Birth weight was 3317 gm (25th to 50th percentile). Early developmental milestones were normal. The girl smiled at 2 months of age, sat independently at 5 months, and was

Muscle histochemistry, electron microscopy, and enzymology

An open muscle biopsy was performed initially on the left quadriceps. Sections of muscle were stained with hematoxylin-eosin, modified Gomori trichrome, oil red O, lactate dehydrogenase succinate dehydrogenase, and cytochrome c oxidase. Electron microscopy was also performed.

A repeated open quadriceps biopsy was performed when the patient was 2 ½ years of age for respiratory chain enzyme analysis and repeated enzyme histochemistry study. Respiratory chain complexes I (rotenone-sensitive

Muscle histochemistry and electron microscopy

A muscle biopsy performed at when the patient was 2 ½ years of age showed type I fibers to have an increase in lipid droplets. The mitochondrial stains were abnormal, with increased numbers of subsarcolemmal mitochondria in the modified Gomori trichrome, succinic dehydrogenase, and cytochrome c oxidase stains. The staining pattern was not sufficiently abnormal, however, to be called true ragged red fibers (Fig. 3).

. Histopathologic features of muscle biopsy specimen obtained when patient was

DISCUSSION

There have been only a few reports of the pure myopathic form of complex I deficiency that have been responsive to treatment. However, there has been no systematic reporting of unresponsive patients. At initial diagnosis, our patient was presumed to have an isolated complex I defect, because all other enzymes were in the normal range and no definite cytochrome c oxidase–negative fibers were found. Clinically she had an unequivocally positive response to riboflavin during a 3-year period. Some

Acknowledgements

We thank Dr. John Walsh, Department of Neurology, Royal Prince Alfred Hospital, Camperdown, for reporting on the microscopy of the muscle biopsy specimen, Prof. David Sillence, Head of Department of Clinical Genetics, Royal Alexandra Hospital for Children, Westmead, for his assistance in the photography of the muscle biopsy specimen, Dr. Xenia Dennett for her examination of postmortem muscle samples from the sibling, and Dr. Alex Kan, Department of Histopathology, Royal Alexandra Hospital for

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    Reprint requests: John Christodoulou, FRACP, PhD, University Department of Paediatrics and Child Health, New Children's Hospital, PO Box 3515, Parramatta, NSW 2132, Australia.

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