Department of Family Relations and Applied Nutrition, University of Guelph, Guelph, Southwestern Ontario, Canada.
Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Southwestern Ontario, Canada.
J Med Genet. 2023 Dec 21;61(1):1-7. doi: 10.1136/jmg-2023-109563.
Mendel's Law of Dominance suggests that recessive disease expression requires the inheritance of two mutated alleles as the dominant, wildtype allele suppresses disease presentation leading to the expression of physiological normal phenotypes. However, there is existing evidence that challenges this school of thought. Here, we summarise existing literature evaluating metabolic and health impacts among carriers of autosomal recessive conditions, focusing on phenylketonuria (PKU), classical homocystinuria, galactosemia and Usher syndrome as examples. Our findings suggest that carriers, often described as 'unaffected', may actually display attenuated symptoms for the recessive disease they are carrying. For instance, PKU is an inborn error of metabolism characterised by the build-up of plasma phenylalanine attributed to the deficiency of the phenylalanine hydroxylase (PAH) enzyme. While less severe, PKU carriers also exhibit this impaired enzymatic activity, leading to elevated plasma phenylalanine levels, especially after phenylalanine consumption. Related to these metabolic alterations in the PAH pathway, there is early evidence to suggest that PKU carriers may have compromised cognitive and mental health outcomes. Overall, research on the health and metabolic impacts of PKU carriers is sparse, with most studies conducted several decades ago. However, early evidence suggests that intermediate phenotypes among carriers of autosomal recessive conditions are plausible. The illustrated possible intermediate phenotypes observed among carriers necessitates future research to determine possible clinical implications among this population.
孟德尔显性法则表明，隐性疾病的表达需要遗传两个突变等位基因作为显性，野生型等位基因抑制疾病表现，导致生理正常表型的表达。然而，现有的证据挑战了这种观点。在这里，我们总结了现有的文献，评估常染色体隐性疾病携带者的代谢和健康影响，重点关注苯丙酮尿症（PKU）、经典同型胱氨酸尿症、半乳糖血症和 Usher 综合征作为例子。我们的研究结果表明，携带者，通常被描述为“未受影响”，实际上可能表现出携带的隐性疾病的症状减轻。例如，PKU 是一种先天性代谢错误，其特征是由于苯丙氨酸羟化酶（PAH）酶的缺乏而导致血浆苯丙氨酸的积累。虽然不那么严重，但 PKU 携带者也表现出这种酶活性受损，导致血浆苯丙氨酸水平升高，尤其是在摄入苯丙氨酸后。与 PAH 途径中的这些代谢改变相关，有早期证据表明 PKU 携带者可能认知和心理健康结果受损。总体而言，PKU 携带者的健康和代谢影响的研究很少，大多数研究是在几十年前进行的。然而，早期证据表明，常染色体隐性疾病携带者的中间表型是合理的。携带者中观察到的可能中间表型需要进一步研究，以确定该人群中的可能临床意义。
