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PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive
Author(s) -
Zaki Maha S.,
Bhat Gifty,
Sultan Tipu,
Issa Mahmoud,
Jung HeaJin,
Dikoglu Esra,
Selim Laila,
G. Mahmoud Imam,
AbdelHamid Mohamed S.,
AbdelSalam Ghada,
MarinValencia Isaac,
Gleeson Joseph G.
Publication year - 2016
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24678
Subject(s) - microcephaly , failure to thrive , missense mutation , hypotonia , global developmental delay , exome sequencing , compound heterozygosity , genetics , leukodystrophy , nonsense mutation , intellectual disability , psychomotor retardation , medicine , biology , mutation , pathology , gene , disease , phenotype , alternative medicine
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