Severe central hypomyelination in an infant with mtDNA depletion caused by RRM2B gene mutations

Aims: Mitochondriopathies are an important differenzial diagnosis of infantile muscular hypotonia. Patients with combined defects of the respiratory chain enzyme complexes should undergo investigations for mtDNA depletion syndromes (MDS). Among MDS different nuclear gene defects have been associated with different clinical phenotypes. Only a few patients with RRM2B mutations have been described. We report on an infant with MDS and cerebrorenal phenotype with severe central hypomyelination, early fatal outcome, and a novel mutation of the RRM2B gene.

Patient: The girl presented with congenital deafness detected in neonatal screening programs and nephrocalcinosis found at age 2 months. At the age of 8 weeks she developed muscular hypotonia. Plasma lactate and lactate/pyruvate ratio were elevated. Urinary organic acids and plasma very long chain fatty acids were normal. Cranial MRI at the age of 10 weeks showed generalized severe hypomyelination. No lactate peak was detected on MRS. A muscle biopsy gave the diagnosis of combined deficiency of complex I, III, IV and V and histology showed ragged red fibers and accumulation of cytosolic fat globules. mtDNA content was reduced to 4% of normal. A novel mutation of the RRM2B gene was found. At the age of 3 months poor sucking and recurrent vomiting necessitated nasogastric tube feeding. Extinguished deep tendon reflexes were noted. She developed respiratory distress, focal seizures, and severe generalized hypotonia, and died at the age of 4 months.

Conclusion: As the RRM2B gene is expressed ubiquitously, the organ specific manifestations are not yet understood. Brain MRI of our patient revealed severe generalized hypomyelination. Severe generalized hypomyelination of the hemispheres, cerebellum and brainstem may illustrate the prenatal impact of energy deficiency on brain maturation. Peripheral neuropathy not yet described in association with RRM2B mutations was suggested by abolished deep tendon reflexes. More data are needed to prove whether RRM2B mutations lead to a primarily encephalomyopathic phenotype.