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.

Prolonged survival in a patient with a novel pyrroline‐5‐carboxylase reductase 2 genetic variant

“…Hypomyelinating leucodystrophies (HLD) are clinically overlapping, genetically heterogeneous disorders. Homozygous variants in the PYCR2 gene (pyrroline-5-carboxylase reductase 2) cause HLD10 [1,2]: failure to thrive, microcephaly, dysmorphisms, progressive psychomotor disability, axial hypotonia with limb spasticity, death within the first decade [3].…”

NGS Technologies as a Turning Point in Rare Disease Research , Diagnosis and Treatment

“…This is yet another illustrative example of phenotype expansion. PYCR2 , in turn, which is a mitochondrial enzyme that catalyzes the final step of proline biosynthesis and reduces pyrroline-5-carboxylate (P5C) to L-proline, was found to be involved in the development of hypomyelinating leukodystrophy 10 [ 133 ].…”

Pyrroline-5-Carboxylate Reductase 2 Deficiency: A New Case and Review of the Literature

“…The PYCR2 p.Arg266* variant has been reported in the five nonrelated Egyptian families and a Moroccan family. 4,5 This variant could be a founder variant in the north African population.…”

“…We listed demographics, birth history, detailed clinical features including dysmorphic features, skeletal and ophthalmological features of 25 patients with pyrroline-5-carboxylate reductase 2 deficiency in Supplemental Table 1. [3][4][5][6] Twelve PYCR2 variants in 18 families were identified and 7 of them (58%) were missense and 5 of them (42%) were truncating. Eight patients had a homozygous known p.Arg266* variant in PYCR2.…”

“…Pyrroline-5-carboxylate reductase 2 deficiency is classified as hypomyelinating leukodystrophy-10 (OMIM#616420) by Nakayama et al 3 Delayed myelination, demyelination, cerebral atrophy, thin corpus callosum, and cerebellar atrophy in brain MRI were also reported in patients. [4][5][6] Hypomyelination and delayed myelination have a similar appearance on a single MRI. The diagnosis of hypomyelination requires another MRI at least 6 months apart from the first MRI to see if myelin content has been increasing.…”