bims-meglyc 2023-12-10 papers

J Neuroimmunol. 2023 Nov 24. pii: S0165-5728(23)00237-0. [Epub ahead of print]386 578251

Adult-onset neurodegeneration in XMEN disease.

Daniel Benavides, Anusha Ebrahim, Juan C Ravell, Michael Lenardo, William A Gahl, Camilo Toro.

BACKGROUND: XMEN (X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV), and N-linked glycosylation defect) disease results from loss-of-function mutations in MAGT1, a protein that serves as a magnesium transporter and a subunit of the oligosaccharyltransferase (OST) complex. MAGT1 deficiency disrupts N-linked glycosylation, a critical regulator of immune function. XMEN results in recurrent EBV infections and a propensity for EBV-driven malignancies. Although XMEN is recognized as a systemic congenital disorder of glycosylation (CDG), its neurological involvement is rare and poorly characterized.
CASES: Two young men, ages 32 and 33, are described here with truncating mutations in MAGT1, progressive behavioral changes, and neurodegenerative symptoms. These features manifested well into adulthood. Both patients still presented with many of the molecular and clinical hallmarks of the typical XMEN patient, including chronic EBV viremia and decreased expression of NKG2D.
CONCLUSION: While previously unrecognized, XMEN may include prominent and disabling CNS manifestations. How MAGT1 deficiency directly or indirectly contributes to neurodegeneration remains unclear. Elucidating this mechanism may contribute to the understanding of neurodegeneration more broadly.

Keywords: Genetics; Neurodegeneration; Neuroimmunology; Primary immunodeficiency; XMEN disease

DOI: https://doi.org/10.1016/j.jneuroim.2023.578251

Eur J Paediatr Neurol. 2023 Dec 04. pii: S1090-3798(23)00183-6. [Epub ahead of print]48 69-77

Neurological presentations of inborn errors of purine and pyrimidine metabolism.

Marie-Cécile Nassogne, Sandrine Marie, Joseph P Dewulf.

Purines and pyrimidines are essential components as they are the building blocks of vital molecules, such as nucleic acids, coenzymes, signalling molecules, as well as energy transfer molecules. Purine and pyrimidine metabolism defects are characterised by abnormal concentrations of purines, pyrimidines and/or their metabolites in cells or body fluids. This phenomenon is due to a decreased or an increased activity of enzymes involved in this metabolism and has been reported in humans for over 60 years. This review provides an overview of neurological presentations of inborn errors of purine and pyrimidine metabolism. These conditions can lead to psychomotor retardation, epilepsy, hypotonia, or microcephaly; sensory involvement, such as deafness and visual disturbances; multiple malformations, as well as muscular symptoms. Clinical signs are often nonspecific and thus overlooked, but some diseases are treatable and early diagnosis may improve the child's future. Although these metabolic hereditary diseases are rare, they are most probably under-diagnosed. When confronted with suggestive clinical or laboratory signs, clinicians should prescribe genetic testing in association with a biochemical screening including thorough purine and pyrimidine metabolites analysis and/or specific enzyme evaluation. This is most likely going to increase the number of confirmed patients.

Keywords: Metabolism defects; Neurological presentations; Purine; Pyrimidine

DOI: https://doi.org/10.1016/j.ejpn.2023.11.013

Neurol Sci. 2023 Dec 06.

Zhixu Fang, Chaoping Hu, Shuizhen Zhou, Lifei Yu.

INTRODUCTION: PIGW-related glycosylphosphatidylinositol deficiency is a rare disease that manifests heterogeneous clinical phenotypes.
METHODS: We describe a patient with PIGW deficiency and summarize the clinical characteristics of the case. In addition, we conducted a literature review of previously reported patients with pathogenic variants of PIGW.
RESULTS: A Chinese girl presented with refractory epilepsy, severe intellectual disability, recurrent respiratory infections, and hyperphosphatasia. Seizures worsened during fever and infections, making her more susceptible to epileptic status. She was found to carry a heterozygous variant of PIGW and a deletion of chromosome 17q12 containing PIGW. Only six patients with homozygous or compound heterozygous pathogenic variants of PIGW have been identified in the literature thus far. Epileptic seizures were reported in all patients, and the most common types of seizures were epileptic spasms. Distinctive facial and physical features and recurrent respiratory infections are common in these patients with developmental delays. Serum alkaline phosphatase (ALP) levels were elevated in four of the six patients.
CONCLUSIONS: PIGW-related glycosylphosphatidylinositol deficiency is characterized by developmental delay, epilepsy, distinctive facial features, and multiple organ anomalies. Genetic testing is an important method for diagnosing this disease, and flow cytometry and serum ALP level detection are crucial complements for genetic testing.

Keywords: Alkaline phosphatase; Epilepsy; Glycosylphosphatidylinositol deficiency; PIGW

DOI: https://doi.org/10.1007/s10072-023-07225-6

Free Radic Biol Med. 2023 Dec 04. pii: S0891-5849(23)01126-7. [Epub ahead of print]

Drug screening identifies aldose reductase as a novel target for treating cisplatin-induced hearing loss.

Yaqi Liao, Huanyu Mao, Xian Gao, Hailiang Lin, Wenyan Li, Yan Chen, Huawei Li.

Cisplatin is a frequently used chemotherapeutic medicine for cancer treatment. Permanent hearing loss is one of the most serious side effects of cisplatin, but there are few FDA-approved medicines to prevent it. We applied high-through screening and target fishing and identified aldose reductase, a key enzyme of the polyol pathway, as a novel target for treating cisplatin ototoxicity. Cisplatin treatment significantly increased the expression level and enzyme activity of aldose reductase in the cochlear sensory epithelium. Genetic knockdown or pharmacological inhibition of aldose reductase showed a significant protective effect on cochlear hair cells. Cisplatin-induced overactivation of aldose reductase led to the decrease of NADPH/NADP+ and GSH/GSSG ratios, as well as the increase of oxidative stress, and contributed to hair cell death. Results of target prediction, molecular docking, and enzyme activity detection further identified that Tiliroside was an effective inhibitor of aldose reductase. Tiliroside was proven to inhibit the enzymatic activity of aldose reductase via competitively interfering with the substrate-binding region. Both Tiliroside and another clinically approved aldose reductase inhibitor, Epalrestat, inhibited cisplatin-induced oxidative stress and subsequent cell death and thus protected hearing function. These findings discovered the role of aldose reductase in the pathogenesis of cisplatin-induced deafness and identified aldose reductase as a new target for the prevention and treatment of hearing loss.

Keywords: Aldose reductase; Flavonoids; Hearing loss; High-throughput screening; Ototoxic drugs; Oxidative stress

DOI: https://doi.org/10.1016/j.freeradbiomed.2023.11.025

Sci Adv. 2023 Dec 08. 9(49): eadg2615

Human-specific features and developmental dynamics of the brain N-glycome.

Comparative "omics" studies have revealed unique aspects of human neurobiology, yet an evolutionary perspective of the brain N-glycome is lacking. We performed multiregional characterization of rat, macaque, chimpanzee, and human brain N-glycomes using chromatography and mass spectrometry and then integrated these data with complementary glycotranscriptomic data. We found that, in primates, the brain N-glycome has diverged more rapidly than the underlying transcriptomic framework, providing a means for rapidly generating additional interspecies diversity. Our data suggest that brain N-glycome evolution in hominids has been characterized by an overall increase in complexity coupled with a shift toward increased usage of α(2-6)-linked N-acetylneuraminic acid. Moreover, interspecies differences in the cell type expression pattern of key glycogenes were identified, including some human-specific differences, which may underpin this evolutionary divergence. Last, by comparing the prenatal and adult human brain N-glycomes, we uncovered region-specific neurodevelopmental pathways that lead to distinct spatial N-glycosylation profiles in the mature brain.

DOI: https://doi.org/10.1126/sciadv.adg2615