Expanding the genotypic spectrum of PYCR2 and a common ancestry in Thai patients with hypomyelinating leukodystrophy 10

Abstract

PYCR2 pathogenic variants lead to an autosomal recessive hypomyelinating leukodystrophy 10 (HLD10), characterized by global developmental delay, microcephaly, facial dysmorphism, movement disorder, and hypomyelination. This study identified the first two unrelated Thai patients with HLD10. Patient 1 harbored the novel compound heterozygous variants, c.257T>G (p.Val86Gly) and c.400G>A (p.Val134Met), whereas patient 2 possessed the homozygous variant, c.400G>A (p.Val134Met), in PYCR2. Haplotype analysis revealed that the two families' members shared a 2.3 Mb region covering the c.400G>A variant, indicating a common ancestry. The variant was estimated to age 1450 years ago. Since the c.400G>A was detected in three outof four mutant alleles and with a common ancestry, this variant might be common in Thai patients. We also reviewed the phenotype and genotype of all 35 previously reported PYCR2 patients and found that majorities of cases were homozygous with a consanguineous family history, except patient 1 and another reported case who were compound heterozygous. All patients had microcephaly and developmental delay.Hypotonia and peripheral spasticity were common. Hypomyelination or delayed myelination was a typical radiographic feature. Here, we report the first two Thai patients with HLD10 with the novel PYCR2 variants expanding the genotypic spectrum and suggest that the c.400G>A might be a common mutation in Thai patients.

Novel pyrroline-5-carboxylate reductase 2 (PYCR2) mutation in an Iranian patient with hypomyelinating leukodystrophy: findings of molecular and in silico investigations

“…Lossof-function mutations in PYCR2 gene result in HLD10, which is identified by hypomyelination, global growth delay, microcephaly, facial dysmorphism, axial hypotonia, and movement disability. It has also been described that these patients could not survive for a long time [9,11,16]. HLDs are a class of rare hereditary neuropathies that their related genes can be determined through latest nucleotide sequencing approaches such as NGS technologies; however, no specific therapeutic method has been developed yet [17].…”

“…Depletion in PYCR2 has been shown to cause neurodegeneration results where all cases were from a consanguineous family. Moreover, they noted that loss of PYCR2 in an in vitro design resulted in incremented susceptibility to apoptosis under oxidative stress [16].…”

Exploring metabolic alterations in PYCR2 deficiency: Unveiling pathways and clinical presentations of hypomyelinating leukodystrophy 10

“…After the first report of Nakayama et al,around 40 patients have been reported so far (Aaltio et al, 2024;Afroze & Mercimek-Andrews, 2020;Hosseini & Ghelichi-Ghojogh, 2023;Manaspon et al, 2021;Meng et al, 2017;Nakayama et al, 2015;Zaki et al, 2016). There was an adult patient from a Chinese case report, while all others were under the age of 20 (Xie et al, 2021).…”

Mutation in PYCR2 gene and hypomyelinating leukodystrophy in children: a case report study

“…The disorder is caused by alterations in the PYCR2 gene (OMIM *616406), which encodes the mitochondrial enzyme, pyrroline-5-carboxylate reductase 2, which converts pyrroline-5-carboxylate to proline. Proline is an essential amino acid for the CNS and connective tissue function 2 .…”