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Journal of Inherited Metabolic Disease

, Volume 36, Issue 1, pp 43–53 | Cite as

Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients

  • Denise Cassandrini
  • Maria Roberta Cilio
  • Marzia Bianchi
  • Mara Doimo
  • Martina Balestri
  • Alessandra Tessa
  • Teresa Rizza
  • Geppo Sartori
  • Maria Chiara Meschini
  • Claudia Nesti
  • Giulia Tozzi
  • Vittoria Petruzzella
  • Fiorella Piemonte
  • Luigi Bisceglia
  • Claudio Bruno
  • Carlo Dionisi-Vici
  • Adele D’Amico
  • Fabiana Fattori
  • Rosalba Carrozzo
  • Leonardo Salviati
  • Filippo M. Santorelli
  • Enrico BertiniEmail author
Original Article

Abstract

Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been associated with early onset encephalopathy with signs of oxidative phosphorylation defects classified as pontocerebellar hypoplasia 6. We describe clinical, neuroimaging and molecular features on five patients from three unrelated families who displayed mutations in RARS2. All patients rapidly developed a neonatal or early-infantile epileptic encephalopathy with intractable seizures. The long-term follow-up revealed a virtual absence of psychomotor development, progressive microcephaly, and feeding difficulties. Mitochondrial respiratory chain enzymes in muscle and fibroblasts were normal in two. Blood and CSF lactate was abnormally elevated in all five patients at early stages while appearing only occasionally abnormal with the progression of the disease. Cerebellar vermis hypoplasia with normal aspect of the cerebral and cerebellar hemispheres appeared within the first months of life at brain MRI. In three patients follow-up neuroimaging revealed a progressive pontocerebellar and cerebral cortical atrophy. Molecular investigations of RARS2 disclosed the c.25A>G/p.I9V and the c.1586+3A>T in family A, the c.734G>A/p.R245Q and the c.1406G>A/p.R469H in family B, and the c.721T>A/p.W241R and c.35A>G/p.Q12R in family C. Functional complementation studies in Saccharomyces cerevisiae showed that mutation MSR1-R531H (equivalent to human p.R469H) abolished respiration whereas the MSR1-R306Q strain (corresponding to p.R245Q) displayed a reduced growth on non-fermentable YPG medium. Although mutations functionally disrupted yeast we found a relatively well preserved arginine aminoacylation of mitochondrial tRNA. Clinical and neuroimaging findings are important clues to raise suspicion and to reach diagnostic accuracy for RARS2 mutations considering that biochemical abnormalities may be absent in muscle biopsy.

Keywords

Lactic Acidosis Intractable Epilepsy Epileptic Encephalopathy Culture Skin Fibroblast Lactate Peak 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This research was supported in part by grants from the Italian Ministry of Heath, the Telethon Foundation Onlus (Mitocon Project GUP09004 to EB and GGP09207 to LS) Fondazione CARIPARO, Padova (to LS), the European Commission projects FP7 LeukoTreat (to EB), and EUROBFNS (to MRC) and grant from the University of Padova to GS.

Conflict of interest

None.

Supplementary material

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Copyright information

© SSIEM and Springer 2012

Authors and Affiliations

  • Denise Cassandrini
    • 1
  • Maria Roberta Cilio
    • 2
    • 8
  • Marzia Bianchi
    • 2
  • Mara Doimo
    • 3
  • Martina Balestri
    • 2
  • Alessandra Tessa
    • 1
  • Teresa Rizza
    • 2
  • Geppo Sartori
    • 4
  • Maria Chiara Meschini
    • 2
  • Claudia Nesti
    • 1
  • Giulia Tozzi
    • 2
  • Vittoria Petruzzella
    • 5
  • Fiorella Piemonte
    • 2
  • Luigi Bisceglia
    • 6
  • Claudio Bruno
    • 7
  • Carlo Dionisi-Vici
    • 9
  • Adele D’Amico
    • 2
  • Fabiana Fattori
    • 2
  • Rosalba Carrozzo
    • 2
  • Leonardo Salviati
    • 3
  • Filippo M. Santorelli
    • 1
  • Enrico Bertini
    • 2
    Email author
  1. 1.IRCCS Fondazione Stella MarisPisaItaly
  2. 2.Department of Neurosciences, Unit of Molecular Medicine for Neuromuscular and Neurodegenerative DisordersBambino Gesù Children’s Research HospitalRomeItaly
  3. 3.Department of PediatricsUnit of Clinical GeneticsPadovaItaly
  4. 4.Department of BiochemistryUniversity of PaduaPaduaItaly
  5. 5.Department of Biochemistry and Medical BiologyUniversity of BariBariItaly
  6. 6.Medical Genetics, IRCCS Casa Sollievo della SofferenzaFoggiaItaly
  7. 7.Neuromuscular Unit, IRCCS G. GasliniGenoaItaly
  8. 8.Department of NeurologyUniversity of CaliforniaSan FranciscoUSA
  9. 9.Department of PediatricsBambino Gesù HospitalRomeItaly

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