Magrinelli Francesca, Bhatia Kailash P, Beiraghi Toosi Mehran, Arab Fatemeh, Karimiani Ehsan Ghayoor, Sedighzadeh Sahar, Ansari Behnaz, Neshatdoust Maedeh, Rocca Clarissa, Houlden Henry, Maroofian Reza
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology University College London London United Kingdom.
Department of Pediatrics, School of Medicine Mashhad University of Medical Sciences Mashhad Iran.
Mov Disord Clin Pract. 2022 Aug 23;10(1):101-108. doi: 10.1002/mdc3.13529. eCollection 2023 Jan.
Biallelic variants in were linked to isolated dystonia (formerly DYT2) in 2015. Since then, the clinical spectrum of -related disorder has expanded up to including a complex syndrome encompassing neurodevelopmental delay, generalized dystonia with bulbar involvement, and infantile seizures.
We report four individuals with a new phenotype of childhood-onset choreo-dystonia belonging to two unrelated Iranian pedigrees and harboring a novel homozygous nonsense pathogenic variant NM_002143.3:c.49C>T p.(Arg17*) in . Although the families are both Iranian, haplotype analysis of the exome data did not reveal a founder effect of the variant.
A systematic review of articles on and dystonia published since the disease gene discovery (PubMed; search on July 09, 2022; search strategy "HPCA AND dystonia", "HPCA AND movement disorder", "hippocalcin AND dystonia", and "hippocalcin AND movement disorder"; no language restriction) resulted in 18 references reporting 10 cases from six families. -related dystonia was isolated or in various combinations with neurodevelopmental delay, intellectual disability, seizures, cognitive decline, and psychiatric comorbidity. Onset of dystonia ranged from infancy to early adulthood. Dystonia started in the limbs or neck and became generalized in most cases. Brain MRI was unremarkable in nearly all cases where performed. There was poor or no response to common antidystonic medications in most cases.
Our case series expands the pheno-genotypic spectrum of -related disorder by describing childhood-onset choreo-dystonia as a new phenotype, reporting on a recurrent novel pathogenic nonsense variant in , and suggesting that exon 2 of might be a mutational hotspot.
2015年，双等位基因变异与孤立性肌张力障碍（原DYT2）相关联。从那时起，与该基因相关疾病的临床谱已扩展至包括一种复杂综合征，涵盖神经发育迟缓、伴有延髓受累的全身性肌张力障碍以及婴儿期癫痫发作。
我们报告了4名患有儿童期起病的舞蹈样肌张力障碍新表型的个体，他们来自两个不相关的伊朗家系，且携带一种新的纯合无义致病性变异NM_002143.3:c.49C>T p.(Arg17*)。尽管这两个家族均为伊朗家族，但外显子数据的单倍型分析未发现该变异存在奠基者效应。
对自疾病基因发现以来发表的关于该基因与肌张力障碍的文章进行系统综述（PubMed；2022年7月9日搜索；搜索策略为“HPCA AND dystonia”“HPCA AND movement disorder”“hippocalcin AND dystonia”以及“hippocalcin AND movement disorder”；无语言限制），得到18篇参考文献，报告了来自6个家族的10个病例。与该基因相关的肌张力障碍可为孤立性，或与神经发育迟缓、智力残疾、癫痫发作、认知衰退及精神共病等多种情况合并出现。肌张力障碍的起病年龄从婴儿期到成年早期不等。肌张力障碍起始于四肢或颈部，多数情况下会发展为全身性。几乎所有进行脑部MRI检查的病例结果均无明显异常。多数情况下，对常用的抗肌张力障碍药物反应不佳或无反应。
我们的病例系列通过将儿童期起病的舞蹈样肌张力障碍描述为一种新表型、报告该基因中一个反复出现的新致病性无义变异以及提示该基因的第2外显子可能是一个突变热点，扩展了与该基因相关疾病的表型-基因型谱。
