Verbeek Marcel M, Willemsen Michel A A P, Wevers Ron A, Lagerwerf Aart J, Abeling Nico G G M, Blau Nenad, Thöny Beat, Vargiami Euthymia, Zafeiriou Dimitrios I
Department of Neurology, Laboratory of Pediatrics and Neurology, 830 LKN, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Donders Centre for Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Department of Pediatric Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Donders Centre for Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Mol Genet Metab. 2008 Aug;94(4):403-409. doi: 10.1016/j.ymgme.2008.04.003. Epub 2008 May 27.
Sepiapterin reductase (SR) deficiency is a rare inherited disorder of neurotransmitter metabolism; less than 25 cases have been described in the literature so far.
We describe the clinical history and extensive cerebrospinal fluid (CSF) and urine examination of two Greek siblings with the diagnosis of SR deficiency. The diagnosis was confirmed by enzyme activity measurement in cultured fibroblasts and by mutation analysis.
Both patients suffered from a progressive and complex L-dopa responsive movement disorder. Very low concentrations of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) were observed in CSF. CSF neopterin and biopterin concentrations were abnormal in one case only, whereas in both cases sepiapterin concentrations were abnormally high and 5-hydroxytryptophan was undetectable. Urine concentrations of HVA, 5-HIAA and vanillyl mandelic acid (VMA) were decreased in both cases. Both patients had no detectable SR enzyme activity in primary dermal fibroblasts, and upon analysis of genomic DNA revealed the same homozygous point mutation introducing a premature stop codon into the reading frame of the SPR gene (mutant allele K251X).
Our cases illustrate that, apart from HVA and 5-HIAA analysis, the specific quantification of sepiapterin in CSF, rather than neopterin and biopterin alone, is crucial to the final diagnosis of SR deficiency. In addition, urinary concentrations of neurotransmitter metabolites may be abnormal in SR deficiency and may provide an initial indication of SR deficiency before CSF analysis is performed. The known, impressive beneficial response of SR deficient patients to treatment with L-dopa, is illustrated again in our cases.
蝶呤还原酶（SR）缺乏症是一种罕见的神经递质代谢遗传性疾病；迄今为止，文献中报道的病例不足25例。
我们描述了两名被诊断为SR缺乏症的希腊同胞的临床病史以及全面的脑脊液（CSF）和尿液检查情况。通过培养的成纤维细胞中的酶活性测定和突变分析确诊。
两名患者均患有进行性且复杂的左旋多巴反应性运动障碍。脑脊液中神经递质代谢物高香草酸（HVA）、5-羟吲哚乙酸（5-HIAA）和3-甲氧基-4-羟基苯乙二醇（MHPG）的浓度极低。仅1例脑脊液新蝶呤和生物蝶呤浓度异常，而2例患者的蝶呤浓度均异常升高且未检测到5-羟色氨酸。2例患者尿液中HVA、5-HIAA和香草扁桃酸（VMA）的浓度均降低。两名患者的原代表皮成纤维细胞均未检测到SR酶活性，对基因组DNA分析显示相同的纯合点突变，该突变在SPR基因的阅读框中引入了一个过早的终止密码子（突变等位基因K251X）。
我们的病例表明，除了HVA和5-HIAA分析外，脑脊液中蝶呤的特异性定量，而非仅新蝶呤和生物蝶呤，对于SR缺乏症的最终诊断至关重要。此外，SR缺乏症患者尿液中神经递质代谢物的浓度可能异常，并且在进行脑脊液分析之前可能提供SR缺乏症的初步迹象。我们的病例再次说明了SR缺乏症患者对左旋多巴治疗有显著的有益反应。
