47例与FLNA相关的脑室周围结节性异位患者。
47 patients with FLNA associated periventricular nodular heterotopia.
作者信息
Lange Max, Kasper Burkhard, Bohring Axel, Rutsch Frank, Kluger Gerhard, Hoffjan Sabine, Spranger Stephanie, Behnecke Anne, Ferbert Andreas, Hahn Andreas, Oehl-Jaschkowitz Barbara, Graul-Neumann Luitgard, Diepold Katharina, Schreyer Isolde, Bernhard Matthias K, Mueller Franziska, Siebers-Renelt Ulrike, Beleza-Meireles Ana, Uyanik Goekhan, Janssens Sandra, Boltshauser Eugen, Winkler Juergen, Schuierer Gerhard, Hehr Ute
机构信息
Department of Neurosurgery, University of Regensburg, Medical Center, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
Department of Neurology, Epilepsy Center, University of Erlangen, Medical Center, Erlangen, Germany.
出版信息
Orphanet J Rare Dis. 2015 Oct 15;10:134. doi: 10.1186/s13023-015-0331-9.
BACKGROUND
Heterozygous loss of function mutations within the Filamin A gene in Xq28 are the most frequent cause of bilateral neuronal periventricular nodular heterotopia (PVNH). Most affected females are reported to initially present with difficult to treat seizures at variable age of onset. Psychomotor development and cognition may be normal or mildly to moderately impaired. Distinct associated extracerebral findings have been observed and may help to establish the diagnosis including patent ductus arteriosus Botalli, progressive dystrophic cardiac valve disease and aortic dissection, chronic obstructive lung disease or chronic constipation. Genotype-phenotype correlations could not yet be established.
METHODS
Sanger sequencing and MLPA was performed for a large cohort of 47 patients with Filamin A associated PVNH (age range 1 to 65 years). For 34 patients more detailed clinical information was available from a structured questionnaire and medical charts on family history, development, epileptologic findings, neurological examination, cognition and associated clinical findings. Available detailed cerebral MR imaging was assessed for 20 patients.
RESULTS
Thirty-nine different FLNA mutations were observed, they are mainly truncating (37/39) and distributed throughout the entire coding region. No obvious correlation between the number and extend of PVNH and the severity of the individual clinical manifestation was observed. 10 of the mutation carriers so far are without seizures at a median age of 19.7 years. 22 of 24 patients with available educational data were able to attend regular school and obtain professional education according to age.
CONCLUSIONS
We report the clinical and mutation spectrum as well as MR imaging for a large cohort of 47 patients with Filamin A associated PVNH including two adult males. Our data are reassuring in regard to psychomotor and cognitive development, which is within normal range for the majority of patients. However, a concerning median diagnostic latency of 17 to 20 years was noted between seizure onset and the genetic diagnosis, intensely delaying appropriate medical surveillance for potentially life threatening cardiovascular complications as well as genetic risk assessment and counseling prior to family planning for this X-linked dominant inherited disorder with high perinatal lethality in hemizygous males.
背景
位于Xq28的细丝蛋白A基因杂合性功能丧失突变是双侧神经元室管膜下结节性异位（PVNH）最常见的病因。据报道，大多数受影响的女性最初在不同发病年龄出现难以治疗的癫痫发作。精神运动发育和认知可能正常或轻度至中度受损。已观察到明显的相关脑外表现，这可能有助于确诊，包括动脉导管未闭、进行性营养不良性心脏瓣膜病和主动脉夹层、慢性阻塞性肺疾病或慢性便秘。尚未建立基因型-表型相关性。
方法
对47例细丝蛋白A相关PVNH患者（年龄范围1至65岁）的大样本队列进行桑格测序和多重连接探针扩增技术（MLPA）检测。对于34例患者，可从结构化问卷和病历中获得关于家族史、发育、癫痫学表现、神经系统检查、认知和相关临床发现的更详细临床信息。对20例患者的可用详细脑磁共振成像进行了评估。
结果
观察到39种不同的FLNA突变，主要为截短突变（37/39），分布在整个编码区域。未观察到PVNH的数量和范围与个体临床表现严重程度之间存在明显相关性。到目前为止，10名突变携带者在中位年龄19.7岁时无癫痫发作。在有教育数据的24例患者中，22例能够根据年龄进入正规学校并接受职业教育。
结论
我们报告了47例细丝蛋白A相关PVNH患者（包括两名成年男性）的临床和突变谱以及磁共振成像。我们的数据对于精神运动和认知发育令人放心，因为大多数患者的这两项发育均在正常范围内。然而，癫痫发作与基因诊断之间的中位诊断延迟令人担忧，为17至20年，这严重延迟了对潜在危及生命的心血管并发症的适当医学监测，以及对这种X连锁显性遗传病进行计划生育前的遗传风险评估和咨询，该疾病在半合子男性中围产期致死率很高。
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