A study on Presymptomatic recognition and prevention of late-onset ornithine transcarbamylase deficiency in male

1)对来自10个独立家系的14例晚发型男性患者进行了OTC基因突变分析，发现7个家系的10例患者携带R40H突变，2个家系的2例患者携带Y55D突变，1个家系的2例患者携带R277W突变。这些观察结果的独特之处在于，这些患者具有常见的突变，而新生儿发病的患者总是具有私人突变。2）Y55D和R277W突变仅从母体侧传递给其后代。估计从头产生的R40H突变的发生率不超过12%。在10对中观察到R40H基因的母婴传播，而仅在3对中发现父女传播。半合子男性患者比杂合子女性患者更高的生殖损失可能导致了这种差异。2例杂合子女性患者出现症状性疾病，提示携带该突变的杂合子女性患者的预后并不总是公平的。3）建立了检测这3种突变的简便方法。首次尝试通过PCR产物Tm值的差异来检测突变，但重复性差。4）对3例新生儿发病的男性患者进行的突变分析显示，每个家庭都存在离散的新突变。5）对生命预后因素的分析显示，血浆中赖氨酸和其他8种氨基酸的浓度是重要的决定因素。干预可以改善晚发男性患者高氨血症危象的结局。

1)Mutational analysis of ornithine transcarbamylase(OTC)gene in 14 male patients with late-onset presentation from 10 discrete families revealed 10 patients from 7 families carried the R40H mutation, 2 patients from 2 families harbored the Y55D mutation and 2 patients from one family had the R277W mutation. These observations were unique in that these patients had the common mutations, in contrast to patients with neonatal onset, who invariably have private mutations.2)The Y55D and R277W mutations were transmitted exclusively from maternal side to their offspring. The incidence of the R40H mutation generated de novo was estimated to be not more than 12%. Mother-to-child transmission of the R40H gene was observed in 10 pairs, while father-to daughter transmission was found only in 3 pairs. A higher reproductive loss in hemizygous male patients than in heterozygous females may have contributed to this difference. Two heterozygous female developed symptomatic diseases, indicating that prognosis of heterozygous females carrying this mutation is not always fair.3)Development of simple method to detect the 3 mutations was studied. Detection of the mutation by means of difference in Tm values of PCR products was first tried but reproducibility was poor. In stead, a multiplex PCR method is now being developed.4)Mutational analysis in 3 male patients with neonatal onset revealed discrete, novel mutations in each family.5)Analysis of prognostic factor of life revealed that concentration of lysine and the other 8 amino acids in plasma were found to be significant determinants.6)It was proved that an early diagnosis and conventional, though appropriate, intervention could improve outcome of a hyperammonemic crisis in the late-onset male patients.