Singh Jatinder, Wilkins Georgina, Goodman-Vincent Ella, Chishti Samiya, Bonilla Guerrero Ruben, McFadden Leighton, Zahavi Zvi, Santosh Paramala
Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK.
Brain Sci. 2024 Jun 21;14(7):624. doi: 10.3390/brainsci14070624.
Remethylation disorders such as 5,10-methylenetetrahydrofolate reductase () deficiency reduce the remethylation of homocysteine to methionine. The resulting hyperhomocysteinemia can lead to serious neurological consequences and multisystem toxicity. The role of genotypes has not been investigated in patients with Rett Syndrome (RTT). In this study, we sought to assess the impact of co-occurring genotypes on symptom profiles in RTT.
Using pharmacogenomic (PGx) testing, the genetic polymorphisms rs1801133 (c.665C>T mutation) and rs1801131 (c.1286A>C mutation) were determined in 65 patients (18.7 years ± 12.1 [mean ± standard deviation]) with RTT as part of routine clinical care within the Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, a National and Specialist Child and Adolescent Mental Health Service (CAMHS) in the UK. The clinical severity of patients was assessed using the RTT-anchored Clinical Global Impression Scale (RTT-CGI).
The clinical severity symptom distribution varied between the homozygous and heterozygous rs1801133 and rs1801131 genotypes. Those with the homozygous genotype had a narrower spread of severity scores across several domains (language and communication, ambulation, hand-use and eye contact clinical domains). Patients with the homozygous genotype had statistically significantly greater CGI-Severity scores than individuals with a non-homozygous genotype (Z = -2.44, = 0.015). When comparing the ratings of moderately impaired (4), markedly impaired (5), severely impaired (6) and extremely impaired (7), individuals with the homozygous genotype were more impaired than those with the non-homozygous genotype (Z = -2.06, = 0.039). There was no statistically significant difference in the number of prescribed anti-epileptic drugs between the genotypes.
Our findings show that in those with a pathogenic RTT genetic variant, co-occurring homozygotic rs1801133 and rs1801131 polymorphisms may act as associative genetic modifiers of clinical severity in a subset of patients. Profiling of rs1801133 and rs1801131 in RTT may therefore be useful, especially for high-risk patients who may be at the most risk from symptom deterioration.
5,10-亚甲基四氢叶酸还原酶（MTHFR）缺乏等再甲基化障碍会减少同型半胱氨酸向蛋氨酸的再甲基化。由此产生的高同型半胱氨酸血症可导致严重的神经后果和多系统毒性。MTHFR基因型在雷特综合征（RTT）患者中的作用尚未得到研究。在本研究中，我们试图评估共存的MTHFR基因型对RTT症状谱的影响。
作为英国国家及专科儿童和青少年心理健康服务机构（CAMHS）介入儿科精神药理学中心（CIPP）雷特中心常规临床护理的一部分，对65例RTT患者（平均年龄18.7岁±12.1岁[均值±标准差]）进行药物基因组学（PGx）检测，确定MTHFR基因多态性rs1801133（c.665C>T突变）和rs1801131（c.1286A>C突变）。使用基于RTT的临床总体印象量表（RTT-CGI）评估患者的临床严重程度。
纯合子和杂合子MTHFR rs1801133和rs1801131基因型之间的临床严重程度症状分布有所不同。纯合子基因型患者在几个领域（语言和交流、行走、手部使用和眼神接触临床领域）的严重程度评分分布范围较窄。纯合子基因型患者的CGI-严重程度评分在统计学上显著高于非纯合子MTHFR基因型个体（Z = -2.44，P = 0.015）。在比较中度受损（4分）、明显受损（5分）、重度受损（6分）和极度受损（7分）的评分时，纯合子MTHFR基因型个体比非纯合子MTHFR基因型个体受损更严重（Z = -2.06，P = 0.039）。各基因型之间开具的抗癫痫药物数量在统计学上无显著差异。
我们的研究结果表明，在具有致病性RTT基因变异的患者中，共存的纯合子MTHFR rs1801133和rs1801131多态性可能在一部分患者中作为临床严重程度的关联基因修饰因子。因此，对RTT患者进行rs1801133和rs1801131基因分型可能是有用的，特别是对于那些症状恶化风险最高的高危患者。
