ORIGINAL RESEARCH article
Front. Neurol.
Sec. Pediatric Neurology
Volume 16 - 2025 | doi: 10.3389/fneur.2025.1588273
Characteristics of clinical manifestations and molecular genetics of inherited hyperhomocysteinemia in children and adolescents: A single centre experience from China
Provisionally accepted
- 1The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- 2Xuzhou Cancer Hospital, Xuzhou, Jiangsu Province, China
- 3Xuzhou University of Technology, Xuzhou, Jiangsu, China
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Introduction: Accurate identification of the genetic cause of inherited hyperhomocysteinemia (HHcy) is essential for targeted therapies and individualized treatment. However, reported cases in China remain limited. In this study, we investigated the clinical and molecular genetic characteristics of HHcy in Chinese children/adolescents. Methods: Between 2021 and 2024, eight children/adolescents with inherited HHcy were identified at a tertiary hospital. The patients' clinical presentations, biochemical findings, and genetic profiles were analyzed. Results: Eight Chinese patients exhibited elevated plasma total homocysteine (tHcy) levels (85.7–227.2 μmol/L). These patients revealed 11 variants across 3 genes, including 2 novel variants and 9 previously reported pathogenic variants. All patients were compound heterozygotes. Six patients (P1–6) were diagnosed with cystathionine β-synthase (CBS) deficiency, with seven CBS variants identified. Among these, one novel frameshift variant (c.860del) was detected. Major clinical manifestations included marfanoid features, lens dislocation, myopia, mild developmental delay, osteoporosis, epilepsy, and cerebral venous sinus thrombosis, with ectopia lentis or myopia as common early signs (ages 4–6 years). One child had methylenetetrahydrofolate reductase deficiency, with two variants (c.1632+2T>G, c.1552C>T) and the variant c.1552C>T was novel. The patient displayed developmental delays, microcephaly, and status epilepticus. One child (P8) showed elevated tHHcy and urine methylmalonic acid levels, attributed to cobalamin C deficiency caused by MMACHC variants (c.482G>A, c.609G>A). He presented with epilepsy, weakness in both lower limbs, cognitive dysfunction, and urinary incontinence. Comprehensive interventions including dietary and pharmacological therapies, significantly reduced tHHcy levels in most cases. Discussion: Elevated tHcy is an important biomarker for inherited HHcy. Genetic testing is crucial for precise diagnosis, therapy initiation, and genetic counselling. Two novel pathogenic variants were identified, enriching the variant spectrum for inherited HHcy.
Keywords: Hyperhomocysteinemia, cystathionine β-synthase, cerebral venous sinus thrombosis, Methylenetetrahydrofolate reductase, Cobalamin C
Received: 05 Mar 2025; Accepted: 25 Aug 2025.
Copyright: © 2025 Qu, Han, Zhao, Qu and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yang Zhao, Xuzhou Cancer Hospital, Xuzhou, Jiangsu Province, China
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