Pediatrics Service, Hospital Moinhos de Vento, Porto Alegre, RS, Brazil.
Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Casa Dos Raros, Porto Alegre, RS, Brazil.
Orphanet J Rare Dis. 2024 Nov 28;19(1):442. doi: 10.1186/s13023-024-03453-x.
Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic neurological disorders frequently associated with iron accumulation in the basal nuclei of the brain characterized by progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. Pantothenate kinase-associated neurodegeneration (PKAN) is one of the most widespread NBIA disorders. The diagnosis of PKAN is established with clinical features and the "eye of the tiger" sign identified on brain MRI and the identification of biallelic pantothenate kinase 2 (PANK2) pathogenic variants on molecular genetic testing. PANK2 catalyzes the first reaction of coenzyme A (CoA) biosynthesis, thus, altered PANK2 activity is expected to induce CoA deficiency as well as low levels of essential metabolic intermediates such as 4'-phosphopantetheine which is a necessary cofactor for critical proteins involved in cytosolic and mitochondrial pathways such as fatty acid biosynthesis, mitochondrial respiratory complex I assembly and lysine and tetrahydrofolate metabolism, among other metabolic processes.
In this manuscript, we examined the effect of a multitarget complex supplements (pantothenate, pantethine, omega-3 and vitamin E) on in vitro patient-derived cellular models and the clinical outcome of the adjuvant supplements in combination with the baseline neurological medication in three PKAN patients.
Multitarget complex supplements significantly reduced iron accumulation and increased PANK2 and ACP expression levels in the cellular models derived from all three PKAN patients. In addition, the adjunct treatment to the standard neurological medication improved or stabilized the clinical symptoms of patients.
Our results suggest that multitarget complex supplements can be clinically useful as augmentation therapy for PKAN patients harboring pathogenic variants with residual enzyme levels.
CAAE: 58219522.6.0000.5330. Registered 25 May 2022-Retrospectively registered, https://plataformabrasil.saude.gov.br/visao/pesquisador/gerirPesquisa/gerirPesquisaAgrupador.jsf .
神经铁沉积伴脑铁沉积（NBIA）是一组遗传性神经退行性疾病，常伴有脑基底核铁沉积，其特征为进行性痉挛、肌张力障碍、肌肉僵硬、神经精神症状和视网膜变性或视神经萎缩。泛酸激酶相关神经变性（PKAN）是最广泛的 NBIA 疾病之一。PKAN 的诊断依据是临床特征和脑 MRI 上的“虎眼”征，以及分子遗传学检测中发现的双等位基因泛酸激酶 2（PANK2）致病性变异。PANK2 催化辅酶 A（CoA）生物合成的第一个反应，因此，改变的 PANK2 活性预计会导致 CoA 缺乏以及必需代谢中间产物水平降低，如 4'-磷酸泛酰巯基乙胺，这是参与细胞质和线粒体途径的关键蛋白的必需辅因子，如脂肪酸生物合成、线粒体呼吸复合物 I 组装以及赖氨酸和四氢叶酸代谢等代谢过程。
在本手稿中，我们研究了多靶点复合物补充剂（泛酸、泛硫乙胺、欧米伽 3 和维生素 E）对来自所有 3 名 PKAN 患者的细胞模型的体外影响，以及在标准神经药物治疗基础上加用补充剂的临床结果。
多靶点复合物补充剂显著降低了来自所有 3 名 PKAN 患者的细胞模型中的铁积累，并增加了 PANK2 和 ACP 的表达水平。此外，辅助治疗对标准神经药物治疗改善或稳定了患者的临床症状。
我们的结果表明，多靶点复合物补充剂可以作为携带残留酶水平致病性变异的 PKAN 患者的增效治疗具有临床应用价值。
CAAE：58219522.6.0000.5330.注册于 2022 年 5 月 25 日-回顾性注册，https://plataformabrasil.saude.gov.br/visao/pesquisador/gerirPesquisa/gerirPesquisaAgrupador.jsf 。
