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

TitlePYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive.
Publication TypeJournal Article
Year of Publication2016
AuthorsZaki, MS, Bhat, G, Sultan, T, Issa, M, Jung, H-J, Dikoglu, E, Selim, L, Mahmoud, IG, Abdel-Hamid, MS, Abdel-Salam, G, Marin-Valencia, I, Gleeson, JG
JournalAnn Neurol
Date Published2016 07
KeywordsAdolescent, Child, Child, Preschool, Codon, Nonsense, Exome, Failure to Thrive, Female, Fibroblasts, Gene Expression, Genetic Predisposition to Disease, Genotype, Humans, Infant, Male, Microcephaly, Mutation, Missense, Phenotype, Primary Cell Culture, Pyrroline Carboxylate Reductases, Syndrome, Transfection, Young Adult

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.

Alternate JournalAnn. Neurol.
PubMed ID27130255
PubMed Central IDPMC4938747
Grant ListU54 HG003067 / HG / NHGRI NIH HHS / United States
P30 NS047101 / NS / NINDS NIH HHS / United States
RC2 NS070477 / NS / NINDS NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
P01 HD070494 / HD / NICHD NIH HHS / United States
R01 NS098004 / NS / NINDS NIH HHS / United States