title: Pontocerebellar hypoplasia type 1: clinical spectrum and relevance of EXOSC3 mutations.
abstract: OBJECTIVE
  Pontocerebellar hypoplasia with spinal muscular atrophy, also known as PCH1, is a group of autosomal recessive disorders characterized by generalized muscle weakness and global developmental delay commonly resulting in early death. Gene defects had been discovered only in single patients until the recent identification of EXOSC3 mutations in several families with relatively mild course of PCH1. We aim to genetically stratify subjects in a large and well-defined cohort to define the clinical spectrum and genotype-phenotype correlation.
  
  
  METHODS
  We documented clinical, neuroimaging, and morphologic data of 37 subjects from 27 families with PCH1. EXOSC3 gene sequencing was performed in 27 unrelated index patients of mixed ethnicity.
  
  
  RESULTS
  Biallelic mutations in EXOSC3 were detected in 10 of 27 families (37%). The most common mutation among all ethnic groups was c.395A>C, p.D132A, responsible for 11 (55%) of the 20 mutated alleles and ancestral in origin. The mutation-positive subjects typically presented with normal pregnancy, normal birth measurements, and relative preservation of brainstem and cortical structures. Psychomotor retardation was profound in all patients but lifespan was variable, with 3 subjects surviving beyond the late teens. Abnormal oculomotor function was commonly observed in patients surviving beyond the first year. Major clinical features previously reported in PCH1, including intrauterine abnormalities, postnatal hypoventilation and feeding difficulties, joint contractures, and neonatal death, were rarely observed in mutation-positive infants but were typical among the mutation-negative subjects.
  
  
  CONCLUSIONS
  EXOSC3 mutations account for 30%-40% of patients with PCH1 with variability in survival and clinical severity that is correlated with the genotype.
authors.affiliation: Institute of Human Genetics, Medical Faculty, University Hospital Aachen, Germany. srudnik-schoeneborn@ukaachen.de
authors.forename: Sabine
authors.initials: S
authors.lastname: Rudnik-Schöneborn
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Jen
authors.forename: Gunnar
authors.initials: G
authors.lastname: Houge
authors.forename: Pavel
authors.initials: P
authors.lastname: Seeman
authors.forename: Alena
authors.initials: A
authors.lastname: Puchmajerová
authors.forename: Luitgard
authors.initials: L
authors.lastname: Graul-Neumann
authors.forename: Ulrich
authors.initials: U
authors.lastname: Seidel
authors.forename: Rudolf
authors.initials: R
authors.lastname: Korinthenberg
authors.forename: Janbernd
authors.initials: J
authors.lastname: Kirschner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Seeger
authors.forename: Monique M
authors.initials: MM
authors.lastname: Ryan
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Maja
authors.initials: M
authors.lastname: Steinlin
authors.forename: Laszlo
authors.initials: L
authors.lastname: Sztriha
authors.forename: Jaume
authors.initials: J
authors.lastname: Colomer
authors.forename: Christoph
authors.initials: C
authors.lastname: Hübner
authors.forename: Knut
authors.initials: K
authors.lastname: Brockmann
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: Manuel
authors.initials: M
authors.lastname: Schiff
authors.forename: Andreas
authors.initials: A
authors.lastname: Holzinger
authors.forename: Peter
authors.initials: P
authors.lastname: Barth
authors.forename: William
authors.initials: W
authors.lastname: Reardon
authors.forename: Michael
authors.initials: M
authors.lastname: Yourshaw
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.forename: Thomas
authors.initials: T
authors.lastname: Eggermann
authors.forename: Klaus
authors.initials: K
authors.lastname: Zerres
mesh_terms: D000293:Adolescent; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004576:Electromyography; D063326:Exosome Multienzyme Ribonuclease Complex / Q000235:genetics*; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D009849:Olivopontocerebellar Atrophies / Q000150:complications / Q000235:genetics* / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C571397:EXOSC3 protein, human; D016601:RNA-Binding Proteins; D063326:Exosome Multienzyme Ribonuclease Complex