title: PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive.
abstract: A study was undertaken to characterize the clinical features of the newly described hypomyelinating leukodystrophy type 10 with microcephaly. This is an autosomal recessive disorder mapped to chromosome 1q42.12 due to mutations in the PYCR2 gene, encoding an enzyme involved in proline synthesis in mitochondria.
  
  
  
  From several international clinics, 11 consanguineous families were identified with PYCR2 mutations by whole exome or targeted sequencing, with detailed clinical and radiological phenotyping. Selective mutations from patients were tested for effect on protein function.
  
  
  
  The characteristic clinical presentation of patients with PYCR2 mutations included failure to thrive, microcephaly, craniofacial dysmorphism, progressive psychomotor disability, hyperkinetic movements, and axial hypotonia with variable appendicular spasticity. Patients did not survive beyond the first decade of life. Brain magnetic resonance imaging showed global brain atrophy and white matter T2 hyperintensities. Routine serum metabolic profiles were unremarkable. Both nonsense and missense mutations were identified, which impaired protein multimerization.
  
  
  
  PYCR2-related syndrome represents a clinically recognizable condition in which PYCR2 mutations lead to protein dysfunction, not detectable on routine biochemical assessments. Mutations predict a poor outcome, probably as a result of impaired mitochondrial function. Ann Neurol 2016;80:59-70.
authors.affiliation: Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Center, Cairo, Egypt.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.affiliation: Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rockefeller University, New York, NY.|Division of Pediatric Genetics, Children's Hospital at Montefiore, Bronx, NY.
authors.forename: Gifty
authors.initials: G
authors.lastname: Bhat
authors.affiliation: Pediatric Neurology, Institute of Child Health, Children Hospital, Lahore, Pakistan.
authors.forename: Tipu
authors.initials: T
authors.lastname: Sultan
authors.affiliation: Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Center, Cairo, Egypt.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Issa
authors.affiliation: Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rockefeller University, New York, NY.
authors.forename: Hea-Jin
authors.initials: HJ
authors.lastname: Jung
authors.affiliation: Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rockefeller University, New York, NY.
authors.forename: Esra
authors.initials: E
authors.lastname: Dikoglu
authors.affiliation: Cairo University Children's Hospital, Division of Neurology and Metabolic Disease, Cairo, Egypt.
authors.forename: Laila
authors.initials: L
authors.lastname: Selim
authors.affiliation: Cairo University Children's Hospital, Division of Neurology and Metabolic Disease, Cairo, Egypt.
authors.forename: Imam
authors.initials: I
authors.lastname: G Mahmoud
authors.affiliation: Department of Medical Molecular Genetics, Human Genetics and Genome Research Division, National Research Center, Cairo, Egypt.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Abdel-Hamid
authors.affiliation: Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Center, Cairo, Egypt.
authors.forename: Ghada
authors.initials: G
authors.lastname: Abdel-Salam
authors.affiliation: Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rockefeller University, New York, NY.
authors.forename: Isaac
authors.initials: I
authors.lastname: Marin-Valencia
authors.affiliation: Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rockefeller University, New York, NY.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D059472:Exome / Q000235:genetics; D005183:Failure to Thrive / Q000150:complications* / Q000235:genetics*; D005260:Female; D005347:Fibroblasts; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008831:Microcephaly / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D061251:Primary Cell Culture; D011762:Pyrroline Carboxylate Reductases / Q000096:biosynthesis / Q000235:genetics*; D013577:Syndrome; D014162:Transfection; D055815:Young Adult; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
chemical_list: D018389:Codon, Nonsense; D011762:Pyrroline Carboxylate Reductases; C000620304:PYCR2 protein, human; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase