Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient.
Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient.
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DOI：
10.1186/1750-1172-7-18
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发表时间：
2012-03-27
影响因子：
3.7
通讯作者：
Rodriguez D
中科院分区：
文献类型：
--
作者：
Burglen L;Chantot-Bastaraud S;Garel C;Milh M;Touraine R;Zanni G;Petit F;Afenjar A;Goizet C;Barresi S;Coussement A;Ioos C;Lazaro L;Joriot S;Desguerre I;Lacombe D;des Portes V;Bertini E;Siffroi JP;de Villemeur TB;Rodriguez D
脑桥小脑发育不全（PCH）是一组异质性疾病，其特征是小脑和脑干的发育缺乏和/或早期神经退行性变。根据临床特征，PCH有7种亚型，其中与TSEN 54突变相关的PCH 2型最常见。PCH最常见的是常染色体隐性遗传，尽管最近在患者（主要是女性）中发现了X连锁基因CASK的新生异常，表现为智力残疾、小头畸形和PCH（MICPCH）。纳入了14例在神经影像学检查时表现为PCH且临床特征未提示PCH 1或PCH 2的患者（12例女性和2例男性;年龄16个月-14岁）。使用Array-CGH和测序进行CASK基因筛选。收集临床和神经放射学特征。我们观察到CASK突变患者的高频率（13/14）。10名患者（8名女孩和2名男孩）有基因内突变，3名女性患者有Xp11.4亚显微缺失，包括CASK基因。所有突变均为新生突变。表型的严重程度不同，但在11名女孩中高度相似，其特征为精神发育迟滞、严重智力残疾、进行性小头畸形、肌张力障碍、轻度畸形和脊柱侧凸。其他体征也经常相关，如生长迟缓、眼科异常（青光眼、巨角膜和视神经萎缩）、耳聋和癫痫。正如预期的X-连锁疾病，主要表现在女性，男孩半合子的剪接突变有一个非常严重的表型，几乎没有发展和难治性癫痫。我们描述了一个轻微的表型在一个男孩与镶嵌截断突变。我们发现了一定程度的相关性之间的严重程度，蚓部发育不全和临床表型。本研究描述了一系列新的PCH女性患者CASK失活突变，并证实这些患者有一个可识别的，但可变的表型组成的特定形式的脑桥小脑发育不全。此外，我们报告了第二例男性患者，目前与一个严重的MICPCH表型和从头CASK突变，并首次描述了一个轻度影响的男性患者窝藏镶嵌突变。在我们的参考中心，CASK相关PCH是PCH的第二大常见原因。在这些患者中鉴定出一种新生突变，可以提供准确和可靠的遗传咨询。
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of diseases characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. According to clinical features, seven subtypes of PCH have been described, PCH type 2 related to TSEN54 mutations being the most frequent. PCH is most often autosomal recessive though de novo anomalies in the X-linked gene CASK have recently been identified in patients, mostly females, presenting with intellectual disability, microcephaly and PCH (MICPCH). Fourteen patients (12 females and two males; aged 16 months-14 years) presenting with PCH at neuroimaging and with clinical characteristics unsuggestive of PCH1 or PCH2 were included. The CASK gene screening was performed using Array-CGH and sequencing. Clinical and neuroradiological features were collected. We observed a high frequency of patients with a CASK mutation (13/14). Ten patients (8 girls and 2 boys) had intragenic mutations and three female patients had a Xp11.4 submicroscopic deletion including the CASK gene. All were de novo mutations. Phenotype was variable in severity but highly similar among the 11 girls and was characterized by psychomotor retardation, severe intellectual disability, progressive microcephaly, dystonia, mild dysmorphism, and scoliosis. Other signs were frequently associated, such as growth retardation, ophthalmologic anomalies (glaucoma, megalocornea and optic atrophy), deafness and epilepsy. As expected in an X-linked disease manifesting mainly in females, the boy hemizygous for a splice mutation had a very severe phenotype with nearly no development and refractory epilepsy. We described a mild phenotype in a boy with a mosaic truncating mutation. We found some degree of correlation between severity of the vermis hypoplasia and clinical phenotype. This study describes a new series of PCH female patients with CASK inactivating mutations and confirms that these patients have a recognizable although variable phenotype consisting of a specific form of pontocerebellar hypoplasia. In addition, we report the second male patient to present with a severe MICPCH phenotype and a de novo CASK mutation and describe for the first time a mildly affected male patient harboring a mosaic mutation. In our reference centre, CASK related PCH is the second most frequent cause of PCH. The identification of a de novo mutation in these patients enables accurate and reassuring genetic counselling.
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DOI：
10.1053/ejpn.2000.0295
发表时间：
2000-01-01
期刊：
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society
影响因子：
--
作者：
Chaves-Vischer, V;Pizzolato, G P;Haenggeli, C A
通讯作者：
Haenggeli, C A
影响因子：
4
作者：
Moog, Ute;Kutsche, Kerstin;Uyanik, Goekhan
通讯作者：
Uyanik, Goekhan
影响因子：
2
作者：
Rankin, Julia;Brown, Ruth;Brown, Garry
通讯作者：
Brown, Garry
影响因子：
9.8
作者：
Edvardson, Simon;Shaag, Avraham;Elpeleg, Orly
通讯作者：
Elpeleg, Orly
影响因子：
6
作者：
Durmaz, Burak;Wollnik, Bernd;Ozkinay, Ferda
通讯作者：
Ozkinay, Ferda