Greenberg Cheryl R, Dilling Louise A, Thompson G Robert, Seargeant Lorne E, Haworth James C, Phillips Susan, Chan Alicia, Vallance Hilary D, Waters Paula J, Sinclair Graham, Lillquist Yolanda, Wanders Ronald J A, Olpin Simon E
Department of Pediatrics and Child Health, University of Manitoba, Children's Hospital, CE208-820 Sherbrook Street, Winnipeg, MB, Canada R3A 1R9.
Mol Genet Metab. 2009 Apr;96(4):201-7. doi: 10.1016/j.ymgme.2008.12.018. Epub 2009 Feb 13.
Investigation of seven patients from three families suspected of a fatty acid oxidation defect showed mean CPT-I enzyme activity of 5.9+/-4.9 percent of normal controls. The families, two Inuit, one First Nation, live in areas of Canada geographically very distant from each other. The CPT1 and CPT2 genes were fully sequenced in 5 of the patients. All were homozygous for the same P479L mutation in a highly conserved region of the CPT1 gene. Two patients from the first family were also homozygous for the CPT2 F352C polymorphism in the CPT2 gene. Genotyping the patients and their family members confirmed that all seven patients were homozygous for the P479L variant allele in the CPT1 gene, as were 27 of 32 family members. Three of the seven patients and two cousins had hypoketotic hypoglycemia attributable to CPT-Ia deficiency, but adults homozygous for the variant denied hypoglycemia. We screened 422 consecutive newborns from the region of one of the Inuit families for this variant; 294 were homozygous, 103 heterozygous, and only 25 homozygous normal; thus the frequency of this variant allele is 0.81. There was an infant death in one family and at least 10 more deaths in those infants (7 homozygous, 3 heterozygous) consecutively tested for the mutation at birth. Thus there is an astonishingly high frequency of CPT1 P479L variant and, judging from the enzyme analysis in the seven patients, also CPT-I deficiency in the areas of Canada inhabited by these families. Despite the deficiency of CPT-Ia which is the major rate-limiting enzyme for long chain fatty acid oxidation, clinical effects, with few exceptions, were slight or absent. One clue to explaining this paradox is that, judging from the fatty acid oxidation studies in whole blood and fibroblasts, the low residual activity of CPT-Ia is sufficient to allow a reasonable flux through the mitochondrial oxidation system. It is likely that the P479L variant is of ancient origin and presumably its preservation must have conveyed some advantage.
对来自三个家庭的七名疑似脂肪酸氧化缺陷患者的调查显示，肉碱棕榈酰转移酶I（CPT-I）酶活性平均为正常对照的5.9±4.9%。这些家庭，两个是因纽特人家庭，一个是第一民族家庭，居住在加拿大地理上彼此相距甚远的地区。对其中5名患者的CPT1和CPT2基因进行了全序列分析。所有患者在CPT1基因的一个高度保守区域均为相同的P479L突变纯合子。第一个家庭的两名患者在CPT2基因中也为CPT2 F352C多态性纯合子。对患者及其家庭成员进行基因分型证实，所有七名患者在CPT1基因中均为P479L变异等位基因纯合子，32名家庭成员中有27名也是如此。七名患者中的三名以及两名表亲患有因CPT-Ia缺乏导致的低酮性低血糖症，但该变异纯合子的成年人否认有低血糖症状。我们对因纽特人家庭之一所在地区的422名连续新生儿进行了该变异的筛查；294名是纯合子，103名是杂合子，只有25名是纯合正常；因此该变异等位基因的频率为0.81。一个家庭中有一名婴儿死亡，在出生时连续检测该突变的那些婴儿（7名纯合子，3名杂合子）中至少还有10人死亡。因此，在这些家庭居住的加拿大地区，CPT1 P479L变异的频率惊人地高，而且从对七名患者的酶分析来看，CPT-I缺乏的情况也很常见。尽管CPT-Ia是长链脂肪酸氧化的主要限速酶存在缺乏，但除少数例外，临床影响轻微或不存在。解释这一矛盾现象的一条线索是，从全血和成纤维细胞的脂肪酸氧化研究来看，CPT-Ia的低残余活性足以使线粒体氧化系统有合理的通量。P479L变异可能起源古老，推测其得以保留必定带来了某种优势。
