Dominant transmission of chorea-acanthocytosis with VPS13A mutations remains speculative
Dominant transmission of chorea-acanthocytosis with VPS13A mutations remains speculative
复制标题
伴有 VPS13A 突变的舞蹈病-棘红细胞增多症的主要传播仍是推测
作者：
B. Bader;A. Velayos;R. Walker;A. Danek
石田等[2-4]报道了Saiki等[2-4]早前发表的家族舞蹈病-棘细胞增生症（ChAc）患者的神经病理学研究。通过详细的神经病理学和免疫组织化学研究，石田和他的同事发现ChAc和亨廷顿病之间既有显著的差异，也有显著的相似之处。在将他们的观察结果与其他地方报道的ChAc患者的观察结果进行比较时，作者评论了他们的病例与常染色体显性传播的相似之处，以及典型的常染色体隐性病例。然而，石田等人的观点可能不成立，因为尚不清楚他们的病例是否真正表现为常染色体显性遗传。在两个被感染的兄弟姐妹中，仅在VPS13A的一个等位基因的57外显子的最后一个核苷酸上发现了一个单杂合G > a翻转[2]。他们未被遗弃的母亲，与兄弟姐妹的父亲没有血缘关系，没有这种突变。其他家族成员未采用分子遗传学方法进行研究。父亲和祖父均已去世，据报道为“推定患病”，而父亲的两个姑姑和其中一个姑姑的一个儿子也报告有运动过度、低氧血症和棘细胞增多症。因此，人们认为该突变是从父系引入的，并以常染色体显性方式传播。虽然描述的其他家庭成员的症状与ChAc一致，但没有排除其他情况，也没有提到更强烈提示ChAc的情况，例如，喂养引起的舌肌张力障碍、咬唇或咬舌或其他自残、癫痫发作、精神异常或认知障碍。Ishida等人假设常染色体显性遗传是一种典型的常染色体隐性遗传。然而，不应排除常染色体隐性遗传的可能性。突变，如杂合的全外显子缺失或重排不能检测到使用通常的突变筛选方法[5]。因此，有可能由于技术原因错过了索引兄弟节点的第二个突变，就像在其他案例[6]中报道的那样。先证者的父亲、祖父和其他家庭成员的VPS13A基因缺乏完整的遗传分析，以及日本ChAc的高发病率，削弱了常染色体显性性状的说法。有可能是母亲传递的突变等位基因在她和她的两个孩子身上都没有被发现，而在兄弟姐妹身上发现的突变来自他们的父亲，他的临床状况不允许诊断。ChAc不能明确地排除在父系方面，但这些特征可以用复杂的异族婚姻模式来解释，比如在法裔加拿大人的兄弟姐妹中，在进一步分析后，最初的显性遗传主张被放弃了[6,8]。另一个主要的问题是缺乏关于舞蹈蛋白（VPS13A产品）存在的信息。B. Bader（&）·A. Danek Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität m<s:1> nchen, Munich, Germany, e-mail: benedikt.bader@med.uni-muenchen.de
Ishida et al. [1] report the neuropathological study of a patient with chorea-acanthocytosis (ChAc) from the family published earlier by Saiki et al. [2–4]. Using detailed neuropathological and immunohistochemical studies, Ishida and colleagues found signiWcant diVerences as well as similarities between ChAc and Huntington’s disease. While comparing their observations with those in ChAc patients reported elsewhere, the authors comment on the similarities between their case, with supposedly autosomal dominant transmission, and the typical autosomal recessive cases. However, Ishida et al.’s point may not be valid as it is unclear whether their cases truly show autosomal dominant inheritance. In the two aVected siblings, only a single heterozygous G > A transversion at the last nucleotide of exon 57 on one allele of VPS13A was found [2]. Their unaVected mother, who was not consanguineous with the father of the siblings, did not possess this mutation. No other family members were studied by molecular genetic methods. Father and paternal grandfather were both deceased and were reported as being “presumptively aVected”, while two paternal aunts and a son of one of these were reported to have also had hyperkinetic movements, hyporeXexia, and acanthocytosis. Thus, it was thought that the mutation had been introduced from the paternal side, and was transmitted in an autosomal dominant manner. Although the symptoms described for other family members are consistent with ChAc, other conditions were not excluded, and Wndings more strongly suggestive of ChAc are not mentioned, e.g., feeding-induced tongue dystonia, lipor tongue-biting or other self-mutilation, seizures, psychiatric abnormalities, or cognitive impairment. Ishida et al. postulate autosomal dominant transmission of a condition which is typically autosomal recessive. However, the possibility of autosomal recessive inheritance should not be excluded in their family. Mutations such as heterozygous whole exon deletions or rearrangements cannot be detected using the usual mutation screening methods [5]. Thus, it is possible that the second mutation of the index siblings was missed due to technical reasons, as was reported in other cases [6]. The lack of a complete genetic analysis of the VPS13A gene in the proband’s father, grandfather and other family members as well as the high ChAc incidence in Japan [7] weaken the claim of an autosomal dominant trait. It is possible that a mutated allele transmitted by the mother was missed in both her and her two children, and that the mutation discovered in the siblings came from their father, whose clinical status does not permit a diagnosis. ChAc cannot clearly be excluded on the paternal side, yet such features could be explained by complex patterns of intermarriage such as seen in French-Canadian sibships in whom an initial claim of dominant inheritance was dropped after further analyses [6, 8]. A major additional issue is the absence of information about the presence of chorein, the VPS13A product. Detection of this protein by Western blot (WB) has been proven B. Bader (&) · A. Danek Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität München, Munich, Germany e-mail: benedikt.bader@med.uni-muenchen.de