PYCR2 – Hypomyelinating Leukodystrophy 10

Autosomal recessive variants in PYCR2 cause Hypomyelinating Leukodystrophy 10, a white-matter disorder marked by CNS hypomyelination, postnatal microcephaly, and global developmental delay. Initial linkage in two consanguineous families and whole-exome sequencing in a single proband established a homozygous nonsense mutation in PYCR2 as disease-causing (PMID:25865492). Subsequent reports have now described at least 11 affected individuals across five unrelated families, including a recurrent c.400G>A (p.Val134Met) founder variant in Thai patients (1 proband (PMID:37228935); 2 probands (PMID:34037307); 5 probands (PMID:27860360); 3 probands (PMID:38709052)).

All patients exhibit autosomal recessive inheritance with both missense and loss-of-function allele classes. Documented variants include nonsense (e.g., c.28C>T (p.Gln10Ter)), splice-site and frameshift alleles, and recurrent missense changes such as c.400G>A (p.Val134Met) and c.355C>T (p.Arg119Cys) (PMID:27860360; PMID:33771508). The c.400G>A variant shows a 2.3 Mb shared haplotype suggesting a ~1,450-year-old founder effect in Thai families (PMID:34037307).

Clinically, core features across cohorts include progressive microcephaly, global developmental delay, hypotonia with peripheral spasticity, facial dysmorphism, movement disorders, seizures, failure to thrive, and hypomyelination or delayed myelination on brain MRI (PMID:27860360; PMID:34037307). A single case report noted additional systemic features of diarrhea and febrile convulsions (PMID:37228935).

Cellular and biochemical assays demonstrate that PYCR2 variant proteins are unstable, with reduced steady-state levels in patient lymphoblasts and HEK293FT cells and normal mitochondrial targeting but increased apoptosis under oxidative stress (PMID:25865492). Morpholino knockdown of the zebrafish PYCR2 ortholog recapitulates microcephaly and white-matter defects, which are rescued by wild-type but not mutant human PYCR2 mRNAs (PMID:25865492).

Enzyme kinetics of missense variants Arg119Cys and Arg251Cys reveal 40–366× and 7–26× reductions in catalytic efficiency, respectively, confirming loss-of-function (PMID:33771508). Untargeted metabolomics shows normal proline levels but perturbations in purine/pyrimidine pathways (PMID:38709052). In FBD-102b oligodendroglial cultures, mutant R119C and R251C proteins induce enlarged mitochondria, decreased fission, and impaired morphological differentiation (PMID:36548190). Pycr2 knockout mice mirror human pathology with neurodegeneration, excess cerebral glycine via SHMT2 upregulation, and partial rescue upon SHMT2 knockdown (PMID:32330411).

Overall, the convergence of robust segregation in multiple families, a spectrum of recessive PYCR2 variants, consistent biochemical impairment, and animal and cellular models supports a Strong gene–disease association. PYCR2 sequencing should be included in leukodystrophy diagnostic panels, and metabolic modulation of glycine offers a promising therapeutic avenue.

References

• Annals of Medicine and Surgery • 2023 • Mutation in PYCR2 gene and hypomyelinating leukodystrophy in children: a case report study. PMID:37228935
• American Journal of Medical Genetics Part A • 2021 • Expanding the genotypic spectrum of PYCR2 and a common ancestry in Thai patients with hypomyelinating leukodystrophy 10. PMID:34037307
• American Journal of Medical Genetics Part A • 2017 • Homozygous variants in pyrroline-5-carboxylate reductase 2 (PYCR2) in patients with progressive microcephaly and hypomyelinating leukodystrophy. PMID:27860360
• American Journal of Human Genetics • 2015 • Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination. PMID:25865492
• Archives of Biochemistry and Biophysics • 2021 • Disease variants of human Î1-pyrroline-5-carboxylate reductase 2 (PYCR2). PMID:33771508
• Neurology International • 2022 • Hypomyelinating Leukodystrophy 10 (HLD10)-Associated Mutations of PYCR2 Form Large Size Mitochondria, Inhibiting Oligodendroglial Cell Morphological Differentiation. PMID:36548190
• Neuron • 2020 • Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2. PMID:32330411
• American Journal of Medical Genetics Part A • 2024 • Exploring metabolic alterations in PYCR2 deficiency: Unveiling pathways and clinical presentations of hypomyelinating leukodystrophy 10. PMID:38709052

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