Kuhn Jens, Brümmendorf Tim H, Brassat Ute, Lehnhardt Fritz G, Chung Boi-Dinh, Harnier Simon, Bewermeyer Heiko, Harzheim Andreas, Assheuer Josef, Netzer Christian
Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Strasse 62, Köln, Germany.
Eur Neurol. 2009;61(3):154-8. doi: 10.1159/000186506. Epub 2008 Dec 18.
Cerebral cavernous malformations (CCM) are vascular brain anomalies which can result in a variety of neurological symptoms. Familial CCM is inherited as an autosomal-dominant trait. There is one study in the literature which reports statistical evidence for anticipation in familial CCM.
We reevaluated the clinical course of the disease and performed molecular analyses in a previously described three-generation CCM family with apparent anticipation.
Disease started at a younger age in each generation, strongly suggesting anticipation. The patient in generation I showed no clinical symptoms by the age of 68, whereas his son became wheelchair-bound at the age of 43 due to an intramedullary cavernous malformation at the thoracolumbar transition of the spinal cord. The patient in generation III had a pons hemorrhage at the age of 11 due to a large brainstem cavernoma. The hemorrhage caused facial palsy and hemiparesis, persisting as Millard-Gubler syndrome. Sequencing of KRIT1 identified a novel frameshift mutation in exon 15 (c.1561delC or p.Leu551X) which cosegregated with the phenotype. Flow-FISH analysis of granulocyte and lymphocyte telomere length showed that telomeres were longest in the youngest affected family member.
We could not find any evidence for either of the two currently known molecular mechanisms for genetic anticipation (i.e., expansion of repetitive DNA elements or progressive telomere shortening) in this family. However, the family presented here raises the important question whether surveillance of CCM families with gradient-echo MRI should not only include the cerebrum, but the spinal cord as well.
脑海绵状血管畸形（CCM）是一种脑部血管异常，可导致多种神经症状。家族性CCM以常染色体显性性状遗传。文献中有一项研究报告了家族性CCM存在遗传早现的统计学证据。
我们重新评估了该疾病的临床病程，并对一个先前描述的有明显遗传早现现象的三代CCM家族进行了分子分析。
每一代发病年龄都更小，强烈提示遗传早现。第一代患者68岁时无临床症状，而他的儿子43岁时因胸腰段脊髓髓内海绵状血管畸形而需轮椅代步。第三代患者11岁时因巨大脑干海绵状血管瘤发生脑桥出血。出血导致面瘫和偏瘫，遗留为Millard-Gubler综合征。对KRIT1基因测序发现外显子15有一个新的移码突变（c.1561delC或p.Leu551X），该突变与表型共分离。对粒细胞和淋巴细胞端粒长度进行的流式荧光原位杂交分析显示，端粒在最年轻的受累家族成员中最长。
在这个家族中，我们没有找到目前已知的两种遗传早现分子机制（即重复DNA元件的扩增或端粒逐渐缩短）中的任何一种的证据。然而，本文所报道的这个家族提出了一个重要问题，即对CCM家族进行梯度回波MRI监测时，是否不仅应包括大脑，还应包括脊髓。
