PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive

• Published in: Annals of neurology 2016-07, Vol.80 (1), p.59-70
• Main Authors: Zaki, Maha S., Bhat, Gifty, Sultan, Tipu, Issa, Mahmoud, Jung, Hea-Jin, Dikoglu, Esra, Selim, Laila, G. Mahmoud, Imam, Abdel-Hamid, Mohamed S., Abdel-Salam, Ghada, Marin-Valencia, Isaac, Gleeson, Joseph G.
• Format: Article
• Language: English
• Subjects: Adolescent; Child; Child, Preschool; Codon, Nonsense; Exome - genetics; Failure to Thrive - complications; Failure to Thrive - genetics; Female; Fibroblasts; Gene Expression; Genetic Predisposition to Disease - genetics; Genotype; Humans; Infant; Male; Microcephaly - complications; Microcephaly - diagnosis; Microcephaly - genetics; Mutation; Mutation, Missense; Phenotype; Primary Cell Culture; Proteins; Pyrroline Carboxylate Reductases - biosynthesis; Pyrroline Carboxylate Reductases - genetics; Syndrome; Transfection; Young Adult
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.24678

Objective 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. Methods 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. Results 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. Interpretation 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