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

• Published in: American journal of medical genetics. Part A Vol. 194; no. 9; pp. e63645 - n/a
• Main Authors: Gürbüz, Berrak Bilginer, Gülbakan, Basri, Özgül, Rıza Köksal, Yalnızoğlu, Dilek, Yılmaz, Didem Yücel, Göçmen, Rahşan, Koşukcu, Can, Kandemir, Nurgün, Acar, Neşe Vardar, Salih, Bekir, Dursun, Ali
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.09.2024; Wiley Subscription Services, Inc
• Subjects: Amino acids; Auxotrophy; Carboxylate reductase; Cerebrospinal fluid; Child; delta-1-Pyrroline-5-Carboxylate Reductase; Female; Glutamic Acid - metabolism; Hereditary Central Nervous System Demyelinating Diseases - diagnosis; Hereditary Central Nervous System Demyelinating Diseases - genetics; Hereditary Central Nervous System Demyelinating Diseases - pathology; Humans; hypomyelinating leukodystrophy 10; Infant; Ketoglutaric Acids - blood; Ketoglutaric Acids - metabolism; Leukodystrophy; Magnetic Resonance Imaging; Male; Metabolic Networks and Pathways - genetics; Metabolome - genetics; Metabolomics; Metabolomics - methods; Mutation - genetics; Pedigree; Proline; Proline - cerebrospinal fluid; Purines - metabolism; PYCR2 deficiency; Pyrimidines; Pyrroline Carboxylate Reductases - deficiency; Pyrroline Carboxylate Reductases - genetics; untargeted metabolomics; Xanthine - blood; PYCR2 deficiency; hypomyelinating leukodystrophy 10; untargeted metabolomics
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.63645

Proline‐5‐carboxylate reductase 2, encoded by PYCR2 gene, is an enzyme that catalyzes the last step of proline synthesis from pyrroline‐5‐carboxylate synthetase to proline. PYCR2 gene defect causes hypomyelinating leukodystrophy 10. Up until now, to our knowledge around 38 patients with PYCR2 defect have been reported. Herein, we describe clinical, neuroradiological, biochemical findings, and metabolomic profiling of three new genetically related cases of PYCR2 defects from a large family. Cerebrospinal fluid (CSF) amino acid levels were measured and untargeted metabolomic profiling of plasma and CSF were conducted and evaluated together with the clinical findings in the patients. While plasma and CSF proline levels were found to be totally normal, untargeted metabolomic profiling revealed mild increases of glutamate, alpha‐ketoglutarate, and l‐glutamate semialdehyde and marked increases of inosine and xanthine. Our findings and all the previous reports suggest that proline auxotrophy is not the central disease mechanism. Untargeted metabolomics point to mild changes in proline pathway and also in purine/pyrimidine pathway.