title: Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients.
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.
authors.affiliation: IRCCS Fondazione Stella Maris, Pisa, Italy.
authors.forename: Denise
authors.initials: D
authors.lastname: Cassandrini
authors.forename: Maria Roberta
authors.initials: MR
authors.lastname: Cilio
authors.forename: Marzia
authors.initials: M
authors.lastname: Bianchi
authors.forename: Mara
authors.initials: M
authors.lastname: Doimo
authors.forename: Martina
authors.initials: M
authors.lastname: Balestri
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tessa
authors.forename: Teresa
authors.initials: T
authors.lastname: Rizza
authors.forename: Geppo
authors.initials: G
authors.lastname: Sartori
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Meschini
authors.forename: Claudia
authors.initials: C
authors.lastname: Nesti
authors.forename: Giulia
authors.initials: G
authors.lastname: Tozzi
authors.forename: Vittoria
authors.initials: V
authors.lastname: Petruzzella
authors.forename: Fiorella
authors.initials: F
authors.lastname: Piemonte
authors.forename: Luigi
authors.initials: L
authors.lastname: Bisceglia
authors.forename: Claudio
authors.initials: C
authors.lastname: Bruno
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: Adele
authors.initials: A
authors.lastname: D'Amico
authors.forename: Fabiana
authors.initials: F
authors.lastname: Fattori
authors.forename: Rosalba
authors.initials: R
authors.lastname: Carrozzo
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
mesh_terms: D001126:Arginine-tRNA Ligase / Q000235:genetics*; D002531:Cerebellum / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics; D019344:Lactic Acid / Q000097:blood / Q000134:cerebrospinal fluid; D065768:Lennox Gastaut Syndrome; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008831:Microcephaly / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics; D008928:Mitochondria / Q000235:genetics; D009154:Mutation; D059906:Neuroimaging / Q000379:methods; D009849:Olivopontocerebellar Atrophies / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D011596:Psychomotor Disorders / Q000235:genetics; D012640:Seizures / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics; D013036:Spasms, Infantile / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics
chemical_list: D019344:Lactic Acid; D001126:Arginine-tRNA Ligase