The incidence of movement disorder increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria
The incidence of movement disorder increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria
复制标题
DOI：
10.1002/jimd.12691
复制
发表时间：
2023-12-04
影响因子：
4.2
通讯作者：
Baruteau，Julien
中科院分区：
文献类型：
--
作者：
Gurung，Sonam;Karamched，Saketh;Baruteau，Julien
精氨琥珀酸裂解酶（ASL）是尿素循环解毒神经毒性氨和一氧化氮（NO）生物合成循环的组成部分。遗传性ASL缺乏症会导致氨基琥珀酸尿症（阿萨），这是一种罕见的高氨血症和NO缺乏症。患者出现发育迟缓、癫痫和运动障碍，与NO介导的中枢儿茶酚胺生物合成下调相关。已提出阿萨的神经退行性表型。为了更好地研究阿萨中的这种神经退行性表型，我们于2022年在英国的六个儿科和成人代谢中心进行了一项回顾性研究。我们确定了60例患者，并专门寻找神经变性相关症状：运动障碍，如共济失调、震颤和肌张力障碍、肌张力减退/疲劳和异常行为。我们分析了一个阿萨患者的神经影像学表现，包括弥散张量成像（DTI）和磁共振成像（MRI）。我们评估了常规和DTI MRI以及多巴胺类似物放射性核素123 I-碘氟烷单光子发射计算机断层扫描（SPECT），在Asl缺陷小鼠中用正常化尿素生成的hASLmRNA治疗。阿萨的运动障碍出现在生命的第二和第三个十年，随着年龄的增长变得更加普遍，并且与高氨血症的发病年龄无关。神经影像学可以显示异常的DTI特征，影响灰质和白色物质，尤其是基底节。具有正常尿素生成的阿萨小鼠模型没有重现这些DTI结果，并且显示正常的123 I-碘氟烷SPECT和脑多巴胺代谢组学。总之，这些发现支持了迟发性运动障碍的病理生理学，伴有细胞自主功能性中枢儿茶酚胺失调，但没有或有限的多巴胺能神经元神经变性，使这些症状适合靶向治疗。
Argininosuccinate lyase (ASL) is integral to the urea cycle detoxifying neurotoxic ammonia and the nitric oxide (NO) biosynthesis cycle. Inherited ASL deficiency causes argininosuccinic aciduria (ASA), a rare disease with hyperammonemia and NO deficiency. Patients present with developmental delay, epilepsy and movement disorder, associated with NO‐mediated downregulation of central catecholamine biosynthesis. A neurodegenerative phenotype has been proposed in ASA. To better characterise this neurodegenerative phenotype in ASA, we conducted a retrospective study in six paediatric and adult metabolic centres in the UK in 2022. We identified 60 patients and specifically looked for neurodegeneration‐related symptoms: movement disorder such as ataxia, tremor and dystonia, hypotonia/fatigue and abnormal behaviour. We analysed neuroimaging with diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) in an individual with ASA with movement disorders. We assessed conventional and DTI MRI alongside single photon emission computer tomography (SPECT) with dopamine analogue radionuclide123I‐ioflupane, inAsl‐deficient mice treated byhASLmRNA with normalised ureagenesis. Movement disorders in ASA appear in the second and third decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonemia. Neuroimaging can show abnormal DTI features affecting both grey and white matter, preferentially basal ganglia. ASA mouse model with normalised ureagenesis did not recapitulate these DTI findings and showed normal123I‐ioflupane SPECT and cerebral dopamine metabolomics. Altogether these findings support the pathophysiology of a late‐onset movement disorder with cell‐autonomous functional central catecholamine dysregulation but without or limited neurodegeneration of dopaminergic neurons, making these symptoms amenable to targeted therapy.