Bozaci Ayse Ergul, Er Esra, Yazici Havva, Canda Ebru, Kalkan Uçar Sema, Güvenc Saka Merve, Eraslan Cenk, Onay Hüseyin, Habif Sara, Thöny Beat, Coker Mahmut
Department of Pediatrics, Division of Pediatric Metabolism Ege University Faculty of Medicine Izmir Turkey.
Tepecik Research and Training Hospital, Department of Genetics Izmir Turkey.
JIMD Rep. 2021 Feb 1;59(1):42-51. doi: 10.1002/jmd2.12199. eCollection 2021 May.
The present study describes clinical, biochemical, molecular genetic data, current treatment strategies and follow-up in nine patients with tetrahydrobiopterin (BH4) deficiency due to various inherited genetic defects.
We analyzed clinical, biochemical, and molecular data of nine patients with suspected BH4 deficiency. All patients were diagnosed at Ege University Faculty of Medicine in Izmir, Turkey and comprised data collected from 2006 to 2019. The diagnostic laboratory examinations included blood phenylalanine and urinary or plasma pterins, dihydropteridine reductase (DHPR) enzyme activity measurement in dried blood spots, folic acid and monoamine neurotransmitter metabolites in cerebrospinal fluid, as well as DNA sequencing.
Among the nine patients, we identified one with autosomal recessive GTP cyclohydrolase I (ar GTPCH) deficiency, two with 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, three with sepiapterin reductase (SR) deficiency, and three with DHPR deficiency. Similar to previous observations, the most common clinical symptoms are developmental delay, intellectual disability, and movement disorders. All patients received treatment with l-dopa and 5-hydroxytryptophan, while only the ar GTPCH, the PTPS, and one DHPR deficient patients were supplemented in addition with BH4. The recommended dose range varies among patients and depends on the type of disease. The consequences of BH4 deficiencies are quite variable; however, early diagnosis and treatment will improve outcomes.
As BH4 deficiencies are rare group of treatable neurometabolic disorders, it is essential to diagnose the underlying (genetic) defect in newborns with hyperphenylalaninemia. Irreversible brain damage and progressive neurological deterioration may occur in untreated or late diagnosed patients. Prognosis could be satisfying in the cases with early diagnose and treatment.
本研究描述了9例因各种遗传性基因缺陷导致四氢生物蝶呤（BH4）缺乏患者的临床、生化、分子遗传学数据、当前治疗策略及随访情况。
我们分析了9例疑似BH4缺乏患者的临床、生化和分子数据。所有患者均在土耳其伊兹密尔的埃杰大学医学院确诊，数据收集时间为2006年至2019年。诊断性实验室检查包括血液苯丙氨酸、尿液或血浆蝶呤、干血斑中二氢蝶啶还原酶（DHPR）酶活性测定、脑脊液中的叶酸和单胺神经递质代谢物，以及DNA测序。
在这9例患者中，我们鉴定出1例常染色体隐性GTP环化水解酶I（ar GTPCH）缺乏症患者、2例6-丙酮酰四氢蝶呤合酶（PTPS）缺乏症患者、3例蝶啶还原酶（SR）缺乏症患者和3例DHPR缺乏症患者。与先前观察结果相似，最常见的临床症状是发育迟缓、智力残疾和运动障碍。所有患者均接受左旋多巴和5-羟色氨酸治疗，而只有ar GTPCH、PTPS和1例DHPR缺乏症患者额外补充了BH4。推荐剂量范围因患者而异，取决于疾病类型。BH4缺乏的后果差异很大；然而，早期诊断和治疗将改善预后。
由于BH4缺乏是一组罕见的可治疗的神经代谢疾病，对于高苯丙氨酸血症的新生儿，诊断其潜在（基因）缺陷至关重要。未经治疗或诊断较晚的患者可能会发生不可逆的脑损伤和进行性神经功能恶化。早期诊断和治疗的病例预后可能令人满意。
