Spastic paraplegia as the only symptom in two adult‐onset patients carrying a novel pathogenic variant in <i>PYCR2</i>

Xie, Juan‐Juan; Wang, Ni; Wei, Qiao; Wu, Zhi‐Ying

doi:10.1111/ene.14530

Cited by 5 publications

(2 citation statements)

References 7 publications

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“…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). Previously reported patients with this rare disease had common features as microcephaly, developmental delay with no ambulation and no speech, progressive, and poor growth (Meng et al, 2017;Nakayama et al, 2015;Zaki et al, 2016).…”

Section: Introductionmentioning

confidence: 96%

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

Gürbüz,

Gülbakan,

Özgül

et al. 2024

American J of Med Genetics Pt A

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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.

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Section: Introductionmentioning

confidence: 96%

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

Gürbüz,

Gülbakan,

Özgül

et al. 2024

American J of Med Genetics Pt A

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“…PYCR2 remains the least investigated enzyme for its role in cancer, though recent studies have demonstrated its prognostic significance in cervical; hepatocellular; and, recently, colon carcinoma [15,16]. A non-cancer role for PYCR2 in brain abnormalities and neuronal dysfunctions such as hypomyelination, microcephaly, leukodystrophy, and spastic paraplegia has also been reported [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Pyrroline-5-Carboxylate Reductase-2 Promotes Colorectal Carcinogenesis by Modulating Microtubule-Associated Serine/Threonine Kinase-like/Wnt/β-Catenin Signaling

Tamang

Kumar

Patel

et al. 2023

Cells

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Background: Despite significant progress in clinical management, colorectal cancer (CRC) remains the third most common cause of cancer-related deaths. A positive association between PYCR2 (pyrroline-5-carboxylate reductase-2), a terminal enzyme of proline metabolism, and CRC aggressiveness was recently reported. However, how PYCR2 promotes colon carcinogenesis remains ill understood. Methods: A comprehensive analysis was performed using publicly available cancer databases and CRC patient cohorts. Proteomics and biochemical evaluations were performed along with genetic manipulations and in vivo tumor growth assays to gain a mechanistic understanding. Results: PYCR2 expression was significantly upregulated in CRC and associated with poor patient survival, specifically among PYCR isoforms (PYCR1, 2, and 3). The genetic inhibition of PYCR2 inhibited the tumorigenic abilities of CRC cells and in vivo tumor growth. Coinciding with these observations was a significant decrease in cellular proline content. PYCR2 overexpression promoted the tumorigenic abilities of CRC cells. Proteomics (LC-MS/MS) analysis further demonstrated that PYCR2 loss of expression in CRC cells inhibits survival and cell cycle pathways. A subsequent biochemical analysis supported the causal role of PYCR2 in regulating CRC cell survival and the cell cycle, potentially by regulating the expression of MASTL, a cell-cycle-regulating protein upregulated in CRC. Further studies revealed that PYCR2 regulates Wnt/β-catenin-signaling in manners dependent on the expression of MASTL and the cancer stem cell niche. Conclusions: PYCR2 promotes MASTL/Wnt/β-catenin signaling that, in turn, promotes cancer stem cell populations and, thus, colon carcinogenesis. Taken together, our data highlight the significance of PYCR2 as a novel therapeutic target for effectively treating aggressive colon cancer.

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Rare forms of hypomyelination and delayed myelination

Mura,

Parazzini,

Tonduti

2024

Handbook of Clinical Neurology

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Spastic paraplegia as the only symptom in two adult‐onset patients carrying a novel pathogenic variant in PYCR2

Cited by 5 publications

References 7 publications

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

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

Pyrroline-5-Carboxylate Reductase-2 Promotes Colorectal Carcinogenesis by Modulating Microtubule-Associated Serine/Threonine Kinase-like/Wnt/β-Catenin Signaling

Rare forms of hypomyelination and delayed myelination

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