The spectrum of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency -: Clinical experience based on 22 patients front 18 Spanish families
The spectrum of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency -: Clinical experience based on 22 patients front 18 Spanish families
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DOI：
10.1097/00005792-200103000-00003
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发表时间：
2001-03-01
期刊：
影响因子：
1.6
通讯作者：
O'Neill, P
中科院分区：
文献类型：
--
作者：
Puig, JG;Torres, RJ;O'Neill, P
酶次黄嘌呤-鸟嘌呤磷酸核糖基转移酶（EC 2.4. 2.8., HPRT）在尿酸合成和嘌呤代谢中起着至关重要的作用。该酶催化次黄嘌呤和鸟嘌呤分别转化为肌苷一磷酸（IMP）和鸟苷一磷酸（GMP），并使用磷酸核糖焦磷酸（PRPP）作为辅助底物和能量来源（35）。由HPRT催化的嘌呤核苷酸合成的补救途径每摩尔产物仅利用1摩尔ATP（三磷酸腺苷），而“从头”嘌呤核苷酸合成利用6摩尔，因此节省了大量能量。1964年，Lesch和Nyhan（19）描述了2名兄弟患有临床综合征，其特征为高尿酸血症、高尿酸尿和严重神经功能障碍，包括舞蹈手足徐动症、精神发育迟滞和自伤行为。1967年，Seegmiller等人（34）报道了HPRT酶活性的完全缺乏是临床综合征的原因。幸运的是，并非所有HPRT缺乏的患者都表现出Lesch-Nyhan综合征的显著临床特征。有些患者没有神经系统症状，仅显示尿酸过度生成、痛风和肾结石（17）。在其他情况下，HPRT缺乏症与较低程度的神经功能缺损相关，最终可能会阻止独立生活，但没有Lesch和Nyhan描述的神经症状的严重性（26）。HPRT缺乏症在人群中的患病率尚不准确，尽管加拿大这种疾病的最低频率估计为1/380，000出生（5）。HPRT基因位于X染色体q26-q27区域（11）。HPRT基因中自然发生的突变是异质的，大多数是点突变或小的缺失或插入，分散在所有基因中（33）。大约30%的患者有非遗传性突变（从头突变）。大多数HPRT缺陷的女性携带者是健康的，但由于X染色体的随机失活，他们的体细胞在HPRT活性方面是镶嵌的（23）。HPRT缺乏症的一系列临床后果已在小系列患者和广泛的综述中得到认可（8，10，17，18，26，29），但在同一观察者检查的单一系列患者中尚未描述神经系统疾病的完整谱。自1984年以来，我们已经诊断出22名患者属于18个不同的西班牙家庭与HPRT缺乏症。我们在这里报告这些患者的临床，生化，酶学和分子遗传学研究。
The enzyme hypoxanthine-guanine phosphoribosyltransferase (EC 2.4. 2.8., HPRT) plays a crucial role in uric acid synthesis and purine metabolism. This enzyme catalyzes the conversion of hypoxanthine and guanine to inosine monophosphate (IMP) and guanosine monophosphate (GMP), respectively, and uses phosphoribosylpyrophosphate (PRPP) as a cosubstrate and as a source of energy (35). The salvage pathway for purine nucleotide synthesis, catalyzed by HPRT, utilizes only 1 mole of ATP (adenosine triphosphate) per mole of product, as compared to 6 moles utilized by “de novo” purine nucleotide synthesis, and thus saves much energy. In 1964, Lesch and Nyhan (19) described 2 brothers with a clinical syndrome characterized by hyperuricemia, hyperuricosuria, and severe neurologic dysfunction including choreoathetosis, mental retardation, and self-injurious behavior. In 1967, Seegmiller et al (34) reported a complete deficiency of the activity of the enzyme HPRT as the cause of the clinical syndrome. Fortunately, not all patients with HPRT deficiency exhibit the dramatic clinical characteristics of Lesch-Nyhan syndrome. Some patients do not suffer neurologic symptoms and show only uric acid overproduction, gout, and nephrolithiasis (17). In other cases, HPRT deficiency is associated with a lesser degree of neurologic impairment that may eventually prevent an independent life but is without the severity of the neurologic symptoms described by Lesch and Nyhan (26). The prevalence of HPRT deficiency in the population is not accurately known, although an estimate of the minimum frequency of the disorder in Canada is 1 in 380,000 births (5). The HPRT gene is located on the X chromosome in the region q26-q27 (11). Naturally occurring mutations in the HPRT gene are heterogeneous, with most being point mutations or small deletions or insertions, dispersed through all the gene (33). About 30% of the patients have a noninherited mutation (de novo mutation). Most female carriers of HPRT deficiency are healthy, but their somatic cells are mosaics in term of HPRT activity because of random inactivation of the X chromosome (23). A spectrum of clinical consequences of HPRT deficiency has been recognized in small series of patients and in extensive reviews (8, 10, 17, 18, 26, 29), but the complete spectrum of the neurologic disorder has not been described in a single series of patients examined by the same observers. Since 1984, we have diagnosed 22 patients belonging to 18 different Spanish families with HPRT deficiency. We report here clinical, biochemical, enzymatic, and molecular genetic studies on these patients.