Parfrey P S, Bear J C, Morgan J, Cramer B C, McManamon P J, Gault M H, Churchill D N, Singh M, Hewitt R, Somlo S
Department of Medicine, Memorial University of Newfoundland, St. John's, Canada.
N Engl J Med. 1990 Oct 18;323(16):1085-90. doi: 10.1056/NEJM199010183231601.
Autosomal dominant polycystic kidney disease is usually caused by a mutant gene at the PKD1 locus on the short arm of chromosome 16, but in about 4 percent of families with the disorder it is caused by unknown mutations elsewhere in the genome. The natural course of the disease in both genetic forms is not well characterized.
We studied 17 families with autosomal dominant polycystic kidney disease to compare presymptomatic diagnosis by ultrasonography with diagnosis by genetic-linkage studies and to relate clinical variation of the disease to whether the PKD1 mutation was implicated.
In 10 families the disorder was found to cosegregate with polymorphic DNA markers flanking the PKD1 locus, in 2 families it did not, and in 5 families linkage could not be determined. In the 10 families with the PKD1 mutation, 46 percent of the members less than 30 years old who had a 50 percent risk of inheriting a mutation had renal cysts, as compared with 11 percent of the members of the two families without linkage (P less than 0.001). In the PKD1 families, all 67 diagnoses made by ultrasonography were confirmed by determination of the genotype as inferred from linkage. Forty of 48 members (83 percent) less than 30 years old who inherited the PKD1 mutation had renal cysts. All 27 members 30 years old or older who inherited the mutation had renal cysts, suggesting that the probability of a false negative diagnosis did not exceed 0.13 in this age group (P less than 0.05). The mean (+/- SE) age at the onset of end-stage renal disease among members of the PKD1 families was 56.7 +/- 1.9 years, as compared with 69.4 +/- 1.7 years among members with cysts in the families without linkage (P = 0.0025). Hypertension and renal impairment were less frequent and occurred later in the families without the PKD1 mutation.
At present, in most persons with a 50 percent risk of autosomal dominant polycystic kidney disease, imaging techniques are the only mode of reaching a diagnosis before symptoms appear. In such persons a negative ultrasonographic study during early adult life indicates that the likelihood of inheriting a PKD1 mutation is small. In the few who inherit a non-PKD1 mutation for polycystic kidney disease, renal failure is likely to occur relatively late in life.
常染色体显性遗传性多囊肾病通常由位于16号染色体短臂PKD1位点的突变基因引起，但在约4%的患该疾病的家族中，其病因是基因组其他位置的未知突变。两种遗传形式的疾病自然病程尚未得到充分描述。
我们研究了17个常染色体显性遗传性多囊肾病家族，比较超声检查的症状前诊断与基因连锁研究的诊断，并将疾病的临床变异与PKD1突变是否相关联。
在10个家族中，发现该疾病与PKD1位点侧翼的多态性DNA标记共分离，在2个家族中未发现共分离，在5个家族中无法确定连锁关系。在10个有PKD1突变的家族中，有50%遗传突变风险的30岁以下成员中有46%有肾囊肿，相比之下，在两个无连锁关系的家族中，该比例为11%（P<0.001）。在有PKD1突变的家族中，超声检查做出的所有67例诊断均通过连锁分析推断的基因型测定得到证实。48名30岁以下遗传了PKD1突变的成员中有40名（83%）有肾囊肿。所有27名30岁及以上遗传了该突变的成员都有肾囊肿，这表明该年龄组假阴性诊断的概率不超过0.13（P<0.05）。PKD1突变家族成员中终末期肾病开始的平均（±SE）年龄为56.7±1.9岁，相比之下，无连锁关系家族中有囊肿的成员中该年龄为69.4±1.7岁（P = 0.0025）。无PKD1突变的家族中高血压和肾功能损害较少见且出现较晚。
目前，对于大多数有50%常染色体显性遗传性多囊肾病风险的人来说，成像技术是症状出现前进行诊断的唯一方式。在这类人中，成年早期超声检查结果为阴性表明遗传PKD1突变的可能性较小。在少数遗传了非PKD1突变的多囊肾病患者中，肾衰竭可能在生命后期发生。
