G.P.188: Autosomal recessive Kearns-Sayre syndrome in a girl with altered mitochondrial DNA transcription caused by RRM2B gene defect

Abstract

Kearns-Sayre syndrome (KSS) is a mitochondrial DNA (mtDNA) disorder characterized by ophthalmoplegia, ptosis, retinopathy, onset before age 20 years plus one: cardiac conduction defects, cerebellar syndrome, elevated CSF protein. KSS may affect many organs causing encephalomyopathy, sensorineural hearing loss, endocrinopathy and/or heart and renal involvement. De novo single large-scale mtDNA rearrangements are the genetic hallmark, detectable at high heteroplasmic levels. We present the first child with KSS described so far with a nuclear gene defect of RRM2B, encoding the small subunit of p53-inducible ribonucleotide reductase. In the 15 year-old girl, sensorineural hearing loss was noticed at the age of 11/2 year leading to cochlear implants at ages 2 and 6 years. Her psychomotor development was slightly retarded until the age of 10 years when muscle weakness and an atactic gait became increasingly evident. At the age of 8 years, the girl developed edema caused by a protein-loosing nephropathy. She now presents with ptosis, external ophthalmoplegia and retinitis pigmentosa. Muscle biopsy showed COX-positive and -negative ragged-red fibers, but no biochemical abnormalities of the respiratory chain complexes. Muscle mtDNA analysis revealed no single large-scale rearrangements, but multiple low-level mtDNA deletions. Nuclear gene analysis identified compound heterozygous mutations in the nuclear RRM2B gene: c.328C > T, p.Arg110Cys; c.846G > C, p.Met282Ile. Ribonucleotide reductase has a crucial role in the de novo conversion of ribonucleoside diphosphates into the corresponding deoxyribonucleoside diphosphates, and thus is essential for proper mtDNA synthesis. RRM2B mutations have been described so far only in a single adult patient with KSS. This second case, the first pediatric patient, underlines that KSS is not exclusively a sporadic mtDNA deletion/duplication disorder but rarely an autosomal recessive disease caused by nuclear encoded mtDNA transcription alteration. Kearns-Sayre syndrome (KSS) is a mitochondrial DNA (mtDNA) disorder characterized by ophthalmoplegia, ptosis, retinopathy, onset before age 20 years plus one: cardiac conduction defects, cerebellar syndrome, elevated CSF protein. KSS may affect many organs causing encephalomyopathy, sensorineural hearing loss, endocrinopathy and/or heart and renal involvement. De novo single large-scale mtDNA rearrangements are the genetic hallmark, detectable at high heteroplasmic levels. We present the first child with KSS described so far with a nuclear gene defect of RRM2B, encoding the small subunit of p53-inducible ribonucleotide reductase. In the 15 year-old girl, sensorineural hearing loss was noticed at the age of 11/2 year leading to cochlear implants at ages 2 and 6 years. Her psychomotor development was slightly retarded until the age of 10 years when muscle weakness and an atactic gait became increasingly evident. At the age of 8 years, the girl developed edema caused by a protein-loosing nephropathy. She now presents with ptosis, external ophthalmoplegia and retinitis pigmentosa. Muscle biopsy showed COX-positive and -negative ragged-red fibers, but no biochemical abnormalities of the respiratory chain complexes. Muscle mtDNA analysis revealed no single large-scale rearrangements, but multiple low-level mtDNA deletions. Nuclear gene analysis identified compound heterozygous mutations in the nuclear RRM2B gene: c.328C > T, p.Arg110Cys; c.846G > C, p.Met282Ile. Ribonucleotide reductase has a crucial role in the de novo conversion of ribonucleoside diphosphates into the corresponding deoxyribonucleoside diphosphates, and thus is essential for proper mtDNA synthesis. RRM2B mutations have been described so far only in a single adult patient with KSS. This second case, the first pediatric patient, underlines that KSS is not exclusively a sporadic mtDNA deletion/duplication disorder but rarely an autosomal recessive disease caused by nuclear encoded mtDNA transcription alteration.