A novel CCM1 gene mutation causes cerebral cavernous malformation in a Chinese family

Familial cerebral cavernous malformations (CCMs) are characterized by an autosomal dominant transmission with incomplete penetrance. We have previously reported a 1292delAT mutation in the CCM1 gene in a Chinese family with CCM. Here we report a novel deletion of CCM1 that correlates strongly with CCM formation in another family. Ten affected family members were observed among the 25 participants, and multiple CCM lesions were detected in seven individuals. Nucleotide sequencing analysis in the index patient and other affected members showed a CAAA deletion in exon 12 at nucleotide (NT) 1197. We predict this deletion produces a premature stop code (TGA) at NT 1228, resulting in a truncated protein of 409 amino acids.     

Exome capture sequencing identifies a novel CCM1 mutation in a Chinese family with multiple cerebral cavernous malformations

Purpose: Cerebral cavernous malformations (CCMs) are vascular anomalies predominantly in the central nervous system but may include lesions in other tissues, such as the retina, skin and liver. The main clinical manifestations include seizures, hemorrhage, recurrent headaches and focal neurological deficits. Previous studies of familial CCMs (FCCMs) have mainly reported in Hispanic and Caucasian cases. Here, we report on FCCMs in a Chinese family further characterized by a novel CCM1 gene mutation. Materials and methods: We investigated clinical and neuroradiological features of a Chinese family of 30 members. Furthermore, we used exome capture sequencing to identify the causing gene. The CCM1 mRNA expression level in three patients of the family and 10 wild-type healthy individuals were detected by real-time quantitative polymerase chain reaction (real-time RT-PCR). Results: Brain magnetic resonance imaging demonstrated multiple intracranial lesions in seven members. The clinical manifestation of CCM was found in five of these cases, including recurrent headaches, weakness, hemorrhage and seizures. Moreover, we identified a novel nonsense mutation c.1159G>T (p. E387*) in the CCM1 gene in the pedigree. Based on real-time RT-PCR results, we have found that the CCM1 mRNA expression level in three patients was reduced by 35% than that in wild-type healthy individuals. Conclusions: Our finding suggests that the novel nonsense mutation c.1159G>T in CCM1 gene is associated with FCCM, and that CCM1 haploinsufficiency may be the underlying mechanism of CCMs. Furthermore, it also demonstrates that exome capture sequencing is an efficient and direct diagnostic tool to identify causes of genetically heterogeneous diseases.     

中国汉族家族性脑海绵状血管瘤：1家系谱回顾分析

目的　探讨汉族人家族性脑海绵状血管瘤的临床、影像学及病理特点。方法 对1家族性脑海绵状血管瘤家系进行临床、影像学和病理分析,并绘制家系遗传图谱。结果 该家系16人共4人发病,符合常染色体显性不完全外显遗传,临床以头痛、出血、局灶性神经功能障碍为主要表现,头颅MRITlWI多呈混杂信号,T2WI多为不均匀高信号为主的混杂信号,内部可见夹杂低信号,边缘为低信号环。镜下脑海绵状血管瘤由缺乏肌层和弹力纤维的大小不等的海绵状血管窦组成,病灶内可见玻璃样变、钙化或不同阶段的出血,病灶周围可有胶质增生带,病灶内部或周围含有含铁血黄素。结论 家族性脑海绵状血管瘤是常染色体不完全显性遗传病。头颅MRIT2加权像病灶周围含铁血黄素沉积的“铁环征”,是脑海绵状血管瘤的特征性MRI表现。其病理结构是其易反复少量出血及MRI影像表现复杂多样的主要原因。     

Large germline deletions and duplication in isolated cerebral cavernous malformation patients

Cerebral cavernous malformations (CCM) are vascular lesions that predispose to headaches, seizures, and hemorrhagic stroke. Hereditary CCMs are usually associated with the occurrence of multiple CCMs and occur with a frequency of 1:2,000 to 1:10,000. In this study, eight isolated cases with multiple CCMs but no CCM1-3 point mutation were analyzed using the multiplex ligation-dependent probe amplification assay. Four genomic rearrangements were identified including a previously unreported large duplication within the CCM1 gene and a novel deletion involving the entire coding region of the CCM2 gene. Consequently, systematic screening for CCM deletions/duplications is recommended.     

Familial occurrence of cerebral arteriovenous malformation in sisters: case report * and review of the literature

Cerebral arteriovenous malformations (AVMs) are considered to be congenital disorders. However, their familial occurrence has so far been described in only 19 families in the literature. The authors report on two cases in one family and review the literature. A 45-year-old female subject with sudden onset of headache and vomiting due to a subarachnoid haemorrhage from a small AVM in the posterior part of the corpus callosum near the midline on the left side was studied. Irradiation of the AVM using Leksell’s gamma knife led to its complete obliteration. Her older sister presented with temporal seizures at the age of 49 and later also with left hemiparesis, left hemihypaesthesia and dizziness – caused by a large AVM in the right temporal lobe. This AVM was treated by a combination of embolization and irradiation by the Leksell’s gamma knife.     

Familial Chiari type I malformation with syringomyelia in two siblings: case report and review of the literature

Objective Familial cases of Chiari malformation with syringomyelia are rare. The majority of the reported series and case reports detail sporadic cases. The authors report two siblings who presented with Chiari type I malformation and syringomyelia (CMI+S).Clinical presentation We report two sisters who each presented with scoliosis on routine school physicals. Their clinical examination was unremarkable; however, imaging studies demonstrated a Chiari malformation with syringomyelia. Both underwent cervicomedullary decompression, and follow-up imaging studies revealed resolution of the syringomyelia.Conclusion A review of the literature reveals fewer than ten previous reports of familial CMI+S in the past 30 years. Although rare, the existence of familial cases of CMI+S suggests a genetic component to the pathogenesis of this condition in at least a proportion of patients. Neurosurgeons should be aware of the familial aggregation of CMI+S.     

Familial intracranial ependymoma mimicking an extra-lesion: A case report and review of the literature

Familial occurrence of intracranial ependymoma, in the absence of neurofibromatosis type 2 (NF2), is very rare with only a few cases reported in the literature. We report a 62-year-old man, who presented with a posterior fossa ependymoma with the majority of the lesion in the cerebellopontine angle, mimicking an extra-axial tumour. His two brothers also had 4th ventricular ependymomas requiring surgical resection. Such cases add weight to the suggestion of a genetically predisposing mutation in familial cases of intracranial ependymomas. Further genetic testing may help to elucidate the location of the genetic abnormality in patients with non-NF2 familial intracranial ependymomas and promote a better understanding of this rare pathological entity.     

Familial intracranial hypertension: a case report

We report the cases of a father and his daughter developing idiopathic intracranial hypertension within a few months' of each other.A second daughter is affected by uveitis, while a third daughter presented an episode of visual loss of unknown nature.

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Sommario Viene descritto il caso di padre e figlia con ipertensione intracranica idiopatica. Una seconda figlia è affetta da uveite, ed una terza ha presentato un episodio di calo visivo di causa non nota.

     

Intramedullary spinal arteriovenous malformation in a boy of familial cerebral cavernous hemangioma

Object The coexistence of spinal arteriovenous malformation (AVM) and a familial cerebral cavernous hemangioma (CCH) is extremely rare. Methods A 9-year-old boy suddenly developed severe paraplegia and urinary dysfunction. Spinal magnetic resonance imaging (MRI) scan revealed a cervical and upper thoracic intramedullary lesion. Due to acute neurological dysfunction, the patient underwent emergency surgical exploration. An intramedullary vascular lesion was found and excised. Pathologically, AVM was noted. After the surgery, the boy was ambulatory with left lower limb stiffness. MRI scan of the brain revealed multiple cerebral cavernous hemangioma. Symptomatic multiple CCH in his mother and grandmother were also noted. Conclusions We concluded that the presence of spinal AVM should be suspected if the patient with familial CCH develops the signs of space-occupying lesion of the spinal cord, facilitating early diagnosis of the spinal AVM.     

脑动静脉畸形的血管构筑特征与使用Onyx栓塞治疗的体会

目的 探讨脑动静脉畸形的血管构筑特征与使用Onyx进行血管内栓塞治疗的技巧. 方法 选择自2005年3月至2006年12月广州医学院附属第二医院神经外科收治的26例脑动静脉畸形患者,根据脑血管造影和超选择造影后脑动静脉畸形的血管构筑特征,使用Onyx进行血管内栓塞治疗. 结果 脑动静脉畸形栓塞治疗前需分析房隔结构.引流静脉数量,引流是否通畅,供血方式及混合伴有动脉瘤或静脉结构等.粗大、危险性小的供血动脉及伴发动脉瘤的脑动静脉畸形应优先栓塞,对于多支供血的脑动静脉畸形需保护引流静脉.本组栓塞治疗后畸形血管团完全消失7例,消失90%以上10例,消失70%～90%的7例.消失70%以下2例. 结论 全面的脑血管造影可正确指导使用Onyx栓塞治疗脑动静脉畸形,掌握一定的推注技巧可以显著提高脑动静脉畸形血管内治疗的效果.     

家族性髓母细胞瘤一例报告并文献复习

目的 报告家族性髓母细胞瘤1例并对文献进行回顾,探讨其可能病因.方法 该家族中共有4名患者,其中少年儿童3例,成人1例;男3例,女1例,有2名患者为同胞姐弟,表现为颅高压症状,均接受手术治疗.结果 4名患者病理证实髓母细胞瘤,其中1例于术后次日死亡,2例因肿瘤复发已死亡,1例现存活良好.结论 家族性髓母细胞瘤罕见,家族性髓母细胞瘤的发病可能与家族遗传易感性有关,但确切的发病机制及遗传学仍不明了,需进一步深入研究.     

Intracerebral vascular occlusion in familial erythrophagocytic lymphohistiocytosis: a case report of two siblings

Neuropathological findings in two siblings with familial erythrophagocytic lymphohistiocytosis (FEL) are reported. Case 1 showed the typical neuropathological findings of FEL with lymphohistiocytic infiltration of the leptomeninges and perivascular spaces. A characteristic erythrophagocytosis was detected in inguinal lymph nodes, lung and bone marrow. Case 2 revealed calcification and necrotic lesions in the brain. In the necrotic areas, parenchymal calcification, vascular medial calcification, and occlusion of many vessels due to subendothelial fibrosis were detected. The areas of necrosis correlated with the distribution of occluded vessels. These changes were most prominent in putamen, internal capsule, thalamus and dentate nucleus. Hypercytokinemia is suspected to be the underlying mechanism for the clinical and laboratory findings in patients with FEL, although the relationship to the vascular pathology is unclear.     

散发性颅内海绵状血管畸形CCM1基因新突变位点

BACKGROUND： A cerebral cavernous malformation-1 （CCM1） gene mutation might result in functional loss of KREV interaction trapped-1 （KRIT1）, which is related to onset of cavernous malformations （CM）. However, data addressing sporadic CM in Chinese patients remains limited to date. OBJECTIVE： To analyze CCM1 mutation of Chinese patients with sporadic intracranial CM. DESIGN, TIME AND SETTING： Genetics experiment was performed in the Department of Neurosurgery, Huashan Hospital Affiliated to Fudan University between January 2004 and December 2005. PARTICIPANTS： Ninety patients with sporadic CM served as the CM group, and 30 healthy subjects were considered to be the control group. METHODS： Peripheral blood was collected from patients with CM and from control group subjects Genomic DNA was extracted, and exons 8, 9, 11, 12, 13, 15, 16, 17, and 18, as well as the related introns, were amplified using polymerase chain reaction. DNA sequences were compared with GeneBank. MAIN OUTCOME MEASURES： Abnormal mutable site of CCM1 gene in the two groups. RESULTS： Four exclusive mutations of CCM1 were detected in the CM group, with a sporadic CM mutational rate of 32% （6/19）. Of the four exclusive mutations, there was one missense mutation [exon 12, 1172C→T （S391 F）], one insertion mutation [exon 8, 704insT （K246stop）], one intervening sequence mutation （IVS12-4C→T）, and one synonymous mutation （exon 17, 1875C→T）. With the exception of 1875C→T, all mutations detected in the CM group led to functional changes of the KRIT1 protein, which was encoded by the CCM1 gene. Gene mutations were not detected in the control group. CONCLUSION： Four exclusive mutations of the CCM1 gene were determined in Chinese patients with sporadic CM, which led to functional changes or loss of the encoding KRIT1 protein. KRIT1 protein is considered to be the genetic basis of CM occurrence.     

Familial monomelic amyotrophy: a case report from India

Monomelic amyotrophy (MMA) is a benign lower motor neuron disorder in the young with male preponderance. It is characterized by insidious onset and progressive weakness and wasting of a distal extremity over a few years followed by spontaneous arrest. The exact pathogenesis is unknown. It is predominantly a sporadic disorder but rarely familial forms have been documented. In this report, we describe the phenotype of a 21-year-old man and his mother who were diagnosed to have MMA. The index case presented with left upper limb weakness and wasting of 3 years duration while his mother had right upper limb amyotrophy and weakness of 34 years. A total of 190 patients were diagnosed to have MMA in our institute over the last 27 years and this is the first case of familial MMA.     

Identification of a novel KRIT1 mutation in an Italian family with cerebral cavernous malformation by the protein truncation test

Familial cerebral cavernous malformation (CCM) exhibits autosomal dominant inheritance and is characterized by vascular disorders of the brain, which can lead to seizures, focal neurological deficits, hemorrhagic stroke, and migraine. Three CCM loci have been mapped, but the gene for only one locus--KRIT1 coding for Krev-1/rap1 interaction trapped 1 (KRIT1) protein, which is responsible for more than 40% of familial cases--has been identified. To date, a total of 72 mutations have been described, with one founder effect in the Mexican/Hispanic community. We report the case of an Italian family with CCM that has a novel KRIT1 gene mutation leading to a truncated KRIT1 protein. The protein truncation test (PTT) has been used as a rapid method of identifying germline mutations in the KRIT1 gene.     

Familial hemiplegic migraine: clinical features and probable linkage to chromosome 1 in an Italian family

We describe an Italian family with familial hemiplegic migraine (FHM), subtle cerebellar signs and probable linkage to chromosome 1. FHM is genetically heterogeneous; in about 50% of families it is caused by mutations within the CACNA1A gene on chromosome 19. Linkage to 1q31 and 1g21–23 has also been established. Other families do not link either to chromosome 19 or 1. Chromosome 19-linked FHM may display nystagmus and cerebellar ataxia. Affected family members were neurologically examined; linkage analysis was performed with markers for chromosomes 19p13, 1q21–23, and 1q32. Five family members had hemiplegic migraine, and 3 displayed additional cerebellar signs (scanning speech and nystagmus). In 1 patient, episodes of hemiplegic migraine triggered by mild head trauma. Epilepsy and mental retardation were also found in 1 affected relative each. Lod scores for linkage to 19p13 were negative, while the maximum two-point lod score was 1.81 to 1q21–23. This family with FHM and associated subtle cerebellar signs, epilepsy and mental retardation showed probable linkage to 1q21–23. Received: 27 December 2001 / Accepted in revised form: 27 February 2002     

Clinical features and microsurgical treatment of pediatric patients with cerebral cavernous malformation

The aim of the present study was to describe the clinical features and to evaluate the surgical treatment outcomes of pediatric patients with cerebral cavernous malformations (CCM). We investigated 85 children (53 boys and 32 girls), aged from 6 months to 17.9 years with CCM. Seizures and symptomatic hemorrhages, which were the most frequent symptoms, occurred in 81 patients. Nine patients had a positive family history of CCM. Eighty patients underwent microsurgical treatment after strict operative indications were met. Neuronavigation, combined with intraoperative ultrasonography or functional MRI, was used for precise localization of the lesions. The principles of minimally invasive techniques were followed during surgery. A total of 89 lesions were removed in 80 patients, and there were no deaths. During their hospital stay, only nine patients suffered from postoperative seizures, which were controlled with medication. Postoperative neurological deficits improved in 27 patients, were unchanged in nine, and worsened in two. With the help of advanced neuroimaging, a satisfactory surgical outcome was achieved for 10 lesions located in eloquent brain areas and four lesions in the brain stem. A follow-up study of 66 patients showed that all of these patients remained seizure-free, and nine patients with postoperative neurological deficits gradually recovered. Microsurgical treatment should be performed early for pediatric patients with CCM. Accurate localization of the lesions and the use of minimally invasive techniques and functional MRI monitoring were the key features of the surgical procedures.     

磁共振梯度回波T2*加权成像诊断家族性多发性脑海绵状血管畸形的价值

目的 探讨磁共振梯度回波T2*加权成像(GRE T2*-WI)诊断家族性多发性脑海绵状血管畸形(FCCM)的价值.方法 对FCCM患者的2个家系26名成员进行颅脑CT、常规MRI(T1WI、T2WI、T2FLAIR、DWI及SE)及GRE T2*-WI检查.结果 GRE T2*-WI检查发现FCCM患者12例,均为多发病灶,平均检出病灶23个,病灶主要位于基底节区,其次为皮质-皮质下、丘脑、小脑和脑干.病灶呈特异的高低混杂信号,周边围有一圈黑色低信号环,极具特征性.常规MRI检出脑内病灶数目(平均病灶数5～17个)、疑诊或确诊为FCCM患者的例数(平均例数3～9例),由多至少依次为SE、DWI、T2FLAIR、T1WI和T2WI,均较GRE T2*-WI少.而颅脑CT仅对病灶较大、合并有钙化或出血的3例患者疑诊为脑海绵状血管畸形.结论与CT和常规MRI相比,GRE T2*-WI可以更清楚地显示脑海绵状血管畸形病灶,为诊断提供更可靠的依据.     

Clinical impact of CCM mutation detection in familial cavernous angioma

Introduction and background A 3-year-old Bosnian girl with a large symptomatic brainstem and multiple supratentorial cavernous angiomas, who underwent neurosurgical treatment, is presented. As multiple cavernomas are more common in familial cases, genetic analyses and neuroradiological imaging were performed in the patient and her parents to see whether there was any evidence for inheritance. This information is important for genetic counseling and provision of medical care for at-risk relatives. Currently, no recommendation is available on how to manage these cases.Results Genetic analyses demonstrated a novel CCM1 frameshift mutation (c.1683_1684insA; p.V562SfsX6) in the child and the asymptomatic 27-year-old mother. Sensitive gradient-echo magnetic resonance imaging of the mother revealed multiple supratentorial lesions, whereas analogous imaging of the father showed no pathological findings.Conclusion This case exemplifies that seemingly sporadic cases with multiple lesions might well be hereditary and that presymptomatic genetic testing of family members may identify relatives for whom clinical and neuroradiological monitoring is indicated.