Neurogenetics and Rare Diseases Centre, IRCCS Neuromed, Pozzilli, Italy.
Mov Disord. 2012 Dec;27(14):1714-7. doi: 10.1002/mds.25172. Epub 2012 Sep 24.
Huntington's disease (HD) is a devastating heredoneurodegenerative disorder associated with a wide variety of neurological and psychiatric symptoms caused by an expanded CAG repeat in the HTT gene. The expansion mutation in HTT is dominantly transmitted and codes for a protein named huntingtin (htt).
One hypothesis, according to a multistep mechanism, is that the intergenerational transmission of the normal repeat size causes small, progressive CAG stretch elongations in the general population from one generation to another, until a critical pathological CAG repeat threshold is reached. Mutations may originate in the offspring from paternally transmitted CAG repeats, falling within an intermediate alleles (IA) range of 27 to 35 in repeat length.
There has been emerging evidence that some individuals with IAs might develop an HD phenotype. This presents a challenge for genetic counseling, because these individuals are often reassured that they are "disease free." However, there are many unanswered questions related to the role of IAs in the development of the HD phenotype and in the pathogenesis of HD.
亨廷顿病（HD）是一种遗传性神经退行性疾病，与广泛的神经和精神症状有关，由 HTT 基因中 CAG 重复扩展引起。HTT 的扩展突变呈显性遗传，编码一种名为亨廷顿蛋白（htt）的蛋白质。
根据多步骤机制的一个假说，正常重复大小的代际传递导致一般人群中 CAG 延伸的逐渐扩大，从一代到另一代，直到达到临界病理 CAG 重复阈值。突变可能起源于父系传递的 CAG 重复，落在重复长度为 27 到 35 的中间等位基因（IA）范围内。
有越来越多的证据表明，一些具有 IA 的个体可能会出现 HD 表型。这对遗传咨询提出了挑战，因为这些个体通常会被安慰说他们“没有患病”。然而，关于 IA 在 HD 表型发展和 HD 发病机制中的作用，仍有许多未解决的问题。
