A novel mutation of the RRM2B gene in an infant with early fatal encephalomyopathy, central hypomyelination, and tubulopathy

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Abstract

A baby-girl with congenital deafness was admitted at the age of 8 weeks for lack of head control, truncal hypotonia and echodense kidneys. At the age of 10 weeks cranial MRI showed a normal brain structure, generalized mild hypomyelination but no lactate peak on 1H MR spectroscopy. A combined defect of respiratory chain enzyme complexes I, III, IV and V and severe depletion of mitochondrial DNA was found in skeletal muscle tissue. Genetic analysis revealed a novel mutation c.368T>C (p.Phe123Ser) in the RRM2B gene in the expressed maternal allele. The paternal allele was present in genomic DNA, but was not expressed as mature mRNA.

Introduction

The incidence of mitochondrial encephalomyopathies in childhood is around 1 in 5000–11,000 live births. Mitochondrial disease can be caused by genetic defects of mitochondrial DNA (mtDNA) or of nuclear genes encoding proteins of the respiratory chain enzyme complexes. More recently mitochondrial DNA (mtDNA) depletion syndromes (MDS) have been described as a subgroup, characterized by a reduction in mtDNA copy number. As neither the age of onset nor the severity of disease is predicted by the degree of mtDNA depletion, the term “mitochondrial DNA replication and repair disorders” (MRRDS) would probably be more appropriate. MtDNA replication is exclusively regulated by nuclear genes, encoding nucleotide supply as well as the mtDNA replication process. Since mtDNA encodes proteins of respiratory chain complexes I, III, IV and V, depletion of mtDNA leads to combined deficiencies of those enzyme complexes. MtDNA content in affected tissues of severe cases may be less than 5% of controls and up to 30% in milder affected patients [1], [2]. Plasma lactate levels may range from normal to marked primary lactic acidosis.

Among the mtDNA depletion syndromes different nuclear gene defects have been associated with different clinical phenotypes: e.g., the hepatocerebral syndrome may be caused by mutations in POLG, DGUOK, SUCLG1, SUCLA2, PEO1 and MPV17, while TK2 is known to cause a myopathic phenotype [3], [4], [5], [6], [7], [8], [9]. The latest gene to be identified among the group of mtDNA depletion syndromes is RRM2B, which encodes the p53-controlled R2 subunit of the ribonucleotide reductase. This enzyme plays a crucial role in de novo nucleotide synthesis. So far only 14 patients with RRM2B mutations with focus on biochemical and molecular data have been reported [10], [11], [12], [13]. All patients had myopathy and primary lactic acidosis. Data on CNS involvement and findings on cranial imaging are limited. Nine infants died before 4 months of age.

We report on an infant with early fatal MDS with central hypomyelination, proximal tubulopathy and nephrocalcinosis, and a novel mutation of the RRM2B gene.

Section snippets

Patients and methods

The girl was born to non-consanguineous Caucasian, healthy parents after an uneventful pregnancy and delivery (38 + 6 weeks of gestation; birth weight 3345 g, length 51 cm, head circumference 32.5 cm). Neonatal hearing test revealed congenital deafness, later confirmed by brainstem evoked response audiometry (BERA). Lack of head control, truncal hypotonia and nephrocalcinosis on routine ultrasound lead to admission to our hospital at the age of 8 weeks. At that time she fixed and focused but showed a

Results

Functional investigation of intact mitochondria from unfrozen muscle tissue by radiochemical substrate oxidation showed a reduced activity of nearly all measurements, the reactions creating larger amounts of reduced redox equivalents (NADH, FADH2) were predominantly reduced. Activities of complexes I, III, IV, and V were severely decreased while citrate synthase and complex II were in the upper normal range (Table 1). Determination of the mtDNA content in the patient muscle revealed a decrease

Discussion

Mitochondrial encephalomyopathies are an important differential diagnosis of infantile muscular hypotonia. Patients with combined defects of the respiratory chain enzyme complexes, but preserved activity of complex II, should undergo further investigations for mtDNA depletion. The clinical phenotype and pattern of organ involvement needs to be assessed thoroughly as it may provide important clues for molecular analysis of the various genes involved in mtDNA replication [3], [4], [5], [6], [7],

Conclusion

As the RRM2B gene is expressed ubiquitously, the organ specific manifestations are not fully understood to date. Maybe the very short lifespan observed in most patients with RRM2B mutations masks further organ involvement. As illustrated by the very small cohort of reported patients the only consistent phenotype is early onset myopathy, while renal involvement is variable. MRI data of RRM2B patients are limited and our patient was the first to show generalized hypomyelination. Our patient with

Conflict of interest

Nothing to report.

Acknowledgment

Funded by the Oesterreichische Nationalbank-Jubiläumsfonds Grant No. 12568 and the Vereinigung zur Pädiatrischen Forschung und Fortbildung Salzburg.

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