title: Homozygous variants in pyrroline-5-carboxylate reductase 2 (PYCR2) in patients with progressive microcephaly and hypomyelinating leukodystrophy.
abstract: Pyrroline-5-carboxylate reductase 2, encoded by PYCR2, is one of the three homologous enzymes that catalyze the last step of proline synthesis. Homozygous variants in PYCR2 have been reported in patients from multiple consanguineous families with hypomyelinating leukodystrophy 10 (HLD10) (MIM: 616420). Here, we report five additional patients from three families with homozygous nonsense or missense variants in PYCR2, identified through clinical exome sequencing. All patients presented with postnatally acquired microcephaly, moderate to profound global developmental delay, and failure to thrive. Brain MRI in these patients showed thin corpus callosum, delayed myelination, and generalized white-matter volume loss. Additional phenotypes that were less consistent among patients included seizures or seizure-like movements, spasticity and ataxic gait, recurrent vomiting, cortical blindness, dysmorphic features, joint contractures, and irritability. Exome sequencing identified homozygous variants in PYCR2 in the proband from each family: c.28C>T (p.(Glu10Ter)), c.796C>T (p.(Arg266Ter)), and c.577G>A (p.(Val193Met)). Subsequent targeted analyses demonstrated co-segregation of the disease with the variant in the family. Despite the metabolic role of PYCR2, routine serum metabolic test in these patients were normal. To further understand the disease etiology and functions of PYCR2, small molecule metabolomics profiling was performed in plasma from three severely affected patients. No significant changes were identified in proline biosynthesis pathway or related metabolites. Studying the clinical features and the metabolic profiles of the PYCR2-deficient patients provides a more comprehensive picture for this newly identified disorder and facilitates further research on the gene function and disease etiology. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.|Baylor Genetics, Houston, Texas.
authors.forename: Linyan
authors.initials: L
authors.lastname: Meng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Taraka
authors.initials: T
authors.lastname: Donti
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.|Baylor Genetics, Houston, Texas.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Zhiyv
authors.initials: Z
authors.lastname: Niu
authors.affiliation: Tawam Hospital, Al Ain, United Arab Emirates.
authors.forename: Aisha
authors.initials: A
authors.lastname: Al Shamsi
authors.affiliation: Tawam Hospital, Al Ain, United Arab Emirates.|Department of Pediatrics, College of Medicine and Heath Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Jozef
authors.initials: J
authors.lastname: Hertecant
authors.affiliation: Tawam Hospital, Al Ain, United Arab Emirates.|Department of Pediatrics, College of Medicine and Heath Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Fatma
authors.initials: F
authors.lastname: Al-Jasmi
authors.affiliation: Specially for Children, Austin, Texas.
authors.forename: James B
authors.initials: JB
authors.lastname: Gibson
authors.affiliation: Specially for Children, Austin, Texas.
authors.forename: Honey
authors.initials: H
authors.lastname: Nagakura
authors.affiliation: Baylor Genetics, Houston, Texas.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Baylor Genetics, Houston, Texas.
authors.forename: Weimin
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.|Baylor Genetics, Houston, Texas.
authors.forename: Christine
authors.initials: C
authors.lastname: Eng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.|Baylor Genetics, Houston, Texas.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.|Baylor Genetics, Houston, Texas.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Elsea
mesh_terms: D000293:Adolescent; D000483:Alleles; D019943:Amino Acid Substitution; D001921:Brain / Q000002:abnormalities; D002648:Child; D002675:Child, Preschool; D003062:Codon; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D057238:Growth Charts; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000175:diagnosis* / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008297:Male; D055432:Metabolomics / Q000379:methods; D008831:Microcephaly / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011762:Pyrroline Carboxylate Reductases / Q000235:genetics*; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
chemical_list: D003062:Codon; D011762:Pyrroline Carboxylate Reductases; C000620304:PYCR2 protein, human; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
keywords: PYCR2; exome sequencing; hypomyelinating leukodystrophy; proline synthesis; pyrroline-5-carboxylate reductase 2