Micalizzi Alessia, Poretti Andrea, Romani Marta, Ginevrino Monia, Mazza Tommaso, Aiello Chiara, Zanni Ginevra, Baumgartner Bastian, Borgatti Renato, Brockmann Knut, Camacho Ana, Cantalupo Gaetano, Haeusler Martin, Hikel Christiane, Klein Andrea, Mandrile Giorgia, Mercuri Eugenio, Rating Dietz, Romaniello Romina, Santorelli Filippo Maria, Schimmel Mareike, Spaccini Luigina, Teber Serap, von Moers Arpad, Wente Sarah, Ziegler Andreas, Zonta Andrea, Bertini Enrico, Boltshauser Eugen, Valente Enza Maria
CSS-Mendel Institute, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Department of Biological and Environmental Sciences, University of Messina, Messina, Italy.
Eur J Hum Genet. 2016 Aug;24(9):1262-7. doi: 10.1038/ejhg.2016.19. Epub 2016 Mar 2.
Cerebellar dysplasia with cysts and abnormal shape of the fourth ventricle, in the absence of significant supratentorial anomalies and of muscular involvement, defines recessively inherited Poretti-Boltshauser syndrome (PBS). Clinical features comprise non-progressive cerebellar ataxia, intellectual disability of variable degree, language impairment, ocular motor apraxia and frequent occurrence of myopia or retinopathy. Recently, loss-of-function variants in the LAMA1 gene were identified in six probands with PBS. Here we report the detailed clinical, neuroimaging and genetic characterization of 18 PBS patients from 15 unrelated families. Biallelic LAMA1 variants were identified in 14 families (93%). The only non-mutated proband presented atypical clinical and neuroimaging features, challenging the diagnosis of PBS. Sixteen distinct variants were identified, which were all novel. In particular, the frameshift variant c.[2935delA] recurred in six unrelated families on a shared haplotype, suggesting a founder effect. No LAMA1 variants could be detected in 27 probands with different cerebellar dysplasias or non-progressive cerebellar ataxia, confirming the strong correlate between LAMA1 variants and PBS.
小脑发育不全伴囊肿及第四脑室形态异常，在无明显幕上异常及肌肉受累的情况下，定义为隐性遗传的波雷蒂 - 博尔茨豪泽综合征（PBS）。临床特征包括非进行性小脑共济失调、程度不一的智力残疾、语言障碍、眼球运动失用症以及近视或视网膜病变的频繁发生。最近，在6例PBS先证者中鉴定出LAMA1基因的功能丧失变异。在此，我们报告了来自15个无关家庭的18例PBS患者的详细临床、神经影像学和遗传学特征。在14个家庭（93%）中鉴定出双等位基因LAMA1变异。唯一未发生突变的先证者表现出非典型的临床和神经影像学特征，对PBS的诊断提出了挑战。鉴定出16种不同的变异，均为新发现。特别是，移码变异c.[第2935位缺失A]在6个无关家庭的共享单倍型上出现，提示存在奠基者效应。在27例患有不同小脑发育不全或非进行性小脑共济失调的先证者中未检测到LAMA1变异，证实了LAMA1变异与PBS之间的强相关性。
