Anticipation and phenotype in familial intracranial aneurysms

BACKGROUND: In familial intracranial aneurysms there is evidence for genetic heterogeneity, probably from mutations at separate loci. OBJECTIVES: To compare demographic and clinical features in patients of families with familial intracranial aneurysm and different patterns of inheritance; and to compare the ages of patients with subarachnoid haemorrhage (SAH) in affected parent-child pairs to determine whether there is anticipation. METHODS: Pedigrees for 53 families with familial intracranial aneurysms were constructed, divided into patterns of inheritance suggestive or not suggestive of autosomal dominant transmission. Demographic and clinical features were compared. The age at time of SAH in affected parent-child pairs was compared using the Wilcoxon test. RESULTS: No differences in demographic or clinical features were found between families compatible with an autosomal dominant pattern of inheritance and those with a non-dominant pattern. In families with affected members in two successive generations the age at time of SAH in parents was 55.2 years and in children 35.4 years (mean difference, 19.8 years, p<0.001). CONCLUSIONS: Phenotypes are similar in families with and without a probable autosomal dominant pattern of inheritance. Thus in future genetic studies on familial intracranial aneurysms, stratification according to phenotype is not likely to be useful. Anticipation probably occurs, as affected parents are significantly older at the time of SAH than their affected children.     

Familial Intracranial Aneurysms

Objective

Numerous studies have compared the characteristics of familial intracranial aneurysms with those of non-familial aneurysms. To better understand familial subarachnoid hemorrhage (SAH), we studied a series of patients with SAH who had at least one first-degree relative with SAH, and compared our results with those of previous studies.

Methods

We identified patients treated for SAH at our hospital between January 1993 and October 2006 and analyzed those patients with one or more first-degree relatives with SAH. We retrospectively collected data from patients with a family history and searched for patients who had relatives with aneurysms or who had been treated at other hospitals for SAH.

Results

We identified 12 patients from six families with at least two first-degree relatives with SAH. All patients had affected first-degree relatives; in five families, they were siblings. The mean age at the time of rupture was 49.75 years; in four families, the age difference was within 5 years. In five patients (42%), the aneurysm was located in the middle cerebral artery. Only one patient had an aneurysm in the anterior communicating artery.

Conclusion

In agreement with previous studies, our results showed that familial aneurysms, in comparison with non-familiar aneurysms, ruptured at a younger age and smaller size, had a high incidence in the middle cerebral artery, and were underrepresented in the anterior communicating artery. Interestingly, the age at the time of rupture was similar between relatives. Screening should be considered in the fifth or sixth decade for those who have a sibling with SAH.     

Cerebral aneurysms and polycystic kidney disease: a critical review.

The pathogenic basis of the association between adult polycystic kidney disease (APKD) and cerebral aneurysms is unknown. We have compared cerebral aneurysms in 79 patients with APKD gleaned from the literature to the sporadic aneurysm cases reported by the Cooperative Study to determine if there are significant biological differences between these two groups. Sixty-eight patients had a single aneurysm and 11 (14%) had multiple aneurysms. In APKD patients with subarachnoid hemorrhage from a single aneurysm there was a significant over-representation of males (72%, p less than 0.01); and the APKD group had more aneurysms of the middle cerebral artery (37%, p less than 0.05). The peak decennial incidence and mean age of rupture of APKD-associated aneurysms was younger (mean age 39.7 years, p less than 0.01) and over 77% of APKD-associated aneurysms had ruptured by age 50 versus 42% for sporadic aneurysms (p less than 0.001). Cerebral aneurysms co-existed with APKD in the absence of hypertension in 25% of 45 cases where the presence or absence of hypertension was recorded. These biological differences and the occurrence of aneurysms in normotensive APKD patients suggests an etiology which may be independent of hypertension and that APKD-associated aneurysms may be genetically determined. It is hypothesized that cases of inherited, familial cerebral aneurysms could be linked to a genetic defect resembling that which occurs on chromosome 16 in APKD.     

Characteristics of intracranial aneurysms and subarachnoid haemorrhage in patients with polycystic kidney disease

Background and Purpose: Subarachnoid haemorrhage is a common cause of death in patients with autosomal dominant polycystic kidney disease (ADPKD), but little is known about specific characteristics of subarachnoid haemorrhage and intracranial aneurysms in this group of patients. We performed a systematic review on site, size and number of aneurysms, age at time of rupture, gender, and family history in patients with ADPKD and intracranial aneurysms. We also studied the frequency of ADPKD in patients with subarachnoid haemorrhage treated in our hospital. Methods: We performed a MEDLINE search and checked the reference lists of all relevant publications to identify all articles published from 1980 to 2000 on intracranial aneurysms or subarachnoid haemorrhage in ADPKD. We studied our database of patients with subarachnoid haemorrhage treated between 1978 and 1999 for the presence of ADPKD. Results: We included 53 articles on 369 ADPKD patients (139 [54 %] women) with 462 intracranial aneurysms. Of the 273 aneurysms with specified locations 105 (38 %) were located on the middle cerebral artery in and on the anterior communicating artery in 83 patients (30 %). In 253 patients with data about relatives, the family history was positive for intracranial aneurysms or subarachnoid haemorrhage in 102 (40 %). The average age at which subarachnoid haemorrhage had occurred in 258 was 41 years; of 158 in whom the gender was given; 96 (52 %) were women. Of the 160 patients with data on outcome, 69 (43 %) had died as the result of the subarachnoid haemorrhage. Of the 1147 patients treated for aneurysmal subarachnoid haemorrhage in our institution (mean age 53 years; 65.5 % women), 5 (0.44 %) had ADPKD. Conclusions: Compared with data on patients without ADPKD, subarachnoid haemorrhage in patients with ADPKD occurs not only often in a familial setting of subarachnoid haemorrhage, but also at an earlier age and more often in men. In patients with ADPKD, the most frequent site of aneurysms is the middle cerebral artery. The proportion of patients with ADPKD among all patients with subarachnoid haemorrhage is very small. Received: 17 April 2002, Received in revised form: 11 October 2002, Accepted: 16 October 2002 Correspondence to Professor Gabriel J. E. Rinkel     

Anticipation of age at onset in familial multiple sclerosis

Background and objective: Anticipation of age at onset in the younger generations is a widely known characteristic of many diseases with genetic inheritance. This study was performed to assess whether there is anticipation of age at onset in younger generations of familial multiple sclerosis (MS) in a Spanish population and to compare clinical characteristics of familial and sporadic MS. Methods: We studied a cohort of 1110 patients diagnosed with MS and followed‐up in our MS Unit. Patients were considered as familial MS if they had in their family at least one relative of first or second degree diagnosed with MS. Otherwise, patients were considered to have sporadic MS. We compared the age at onset between relatives from different generations, and we also compared the age at onset of familial and sporadic MS. Results: A lower age at onset in the younger generations was found (median 22 years vs. 30 years, P < 0.001) and a significant lower age at onset of the disease in familial MS comparing to sporadic MS (median 25 years vs. 29 years, P = 0.042). Conclusions: There is an anticipation of the age at onset of MS in the younger generations of patients with familial MS. There is also a lower age at onset in familial versus sporadic MS.     

Familial motor neuron disease: differing penetrance in large pedigrees

It is likely that adult-onset motor neuron disease is inherited more frequently than has previously been believed. We have studied 9 families with familial motor neuron disease and have found apparently wide variation in penetrance. Only one has autosomal dominant inheritance with high penetrance and in this family the average age of onset is similar to that reported in reviews of familial motor neuron disease. The remaining families have a pattern consistent with autosomal dominant inheritance with diminished penetrance. The average ages of onset in these families are comparable with those in sporadic motor neuron disease. Low penetrance appears to be related to higher average age of disease onset because gene carriers have an increased likelihood of dying from other causes before developing motor neuron disease. When penetrance is low the family history may be unknown, causing affected individuals to be mistakenly regarded as having sporadic disease. We conclude that the incidence of familial motor neuron disease is likely to have been underestimated by the exclusion of apparently sporadic cases in which the familial disease has low penetrance. These results and conclusions imply that the lower average age of disease onset reported in familial motor neuron disease may be due to selective recognition of high penetrance families with lower average ages of onset.     

Autosomal dominant essential tremor: a novel family with anticipation

Essential tremor (ET) is a common progressive movement disorder characterized by a clear genetic predisposition. In the last years, many efforts have been done to map susceptibility loci for ET. Here, we report a clinical and genetic study of a family with ET showing autosomal dominant inheritance and anticipation over three generations. The family has five affected members and exhibits a remarkable anticipation of age at onset of the disease along the generations. We excluded linkage to any of the three loci previously mapped in autosomal dominant ET families. Our data suggest the existence of an additional locus in which a repeat expansion is the possible genetic defect underlying ET.     

Intracranial aneurysms and autosomal dominant polycystic kidney disease

The implementation of a screening program for first degree relatives of patients with sporadic subarachnoid hemorrhage by means of magnetic resonance angiography does not seem to be warranted, since the resulting increase in life expectancy does not offset the risk of postoperative sequelae. Some exceptions, however, should be considered. We present a family suffering from autosomal dominant polycystic kidney disease. Two of the four siblings had a subarachnoid hemorrhage from an aneurysm of a cerebral artery. Although intracranial aneurysms are accepted as extrarenal manifestations of autosomal dominant polycystic kidney disease, the exact frequency of the association is unknown. Nevertheless, the maximum rate of coincidence dealt with in the literature is 41 percent. Because of this high association every patient suffering from a subarachnoid hemorrhage due to an intracranial aneurysm should be screened by an abdominal ultrasound. In case of an association first degree relatives should be examined for a polycystic kidney disease and in the case of a positive result a magnetic resonance angiography of the intracranial vessels should be performed.     

Congenital oculo-facial paralysis (Moebius syndrome): evidence of dominant inheritance in two families

Moebius syndrome is usually sporadic. The few familial cases reported in the literature have autosomal dominant inheritance, with absence of the associated congenital malformations often described in the sporadic form. Here we report two families with more than one member affected by congenital, unilateral paresis of cranial nerves, transmitted with autosomal dominant inheritance.     

Familiäre mitochondriale chronisch progressive externe Ophthalmoplegie Fünf Familien mit unterschiedlicher Genetik

Chronic progressive external ophthalmoplegia (CPEO) is considered the most frequent form of mitochondrial encephalomyopathies. Most cases occur sporadically. We investigated 18 consecutive patients with CPEO. Thirteen cases were sporadic and five cases were familial. In one family with maternal inheritance the mitochondrial point mutation A3243G was identified. In index patients of three other families multiple deletions of mitochondrial DNA were found. One of these families showed autosomal recessive inheritance. In the two other pedigrees a definitive determination of the mode of inheritance was impossible. The fifth family revealed autosomal dominant or maternal inheritance. In their index patient no alteration of mitochondrial DNA could be identified (including sequencing of hot spots for mitochondrial mutations). CONCLUSIONS: CPEO was familial in 28% of our patients. There are three different modes of inheritance: (i) maternal transmission associated with mitochondrial point mutations as it is known for other mitochondrial disorders, (ii) autosomal recessive, and (iii) autosomal dominant inheritance. In contrast to sporadic cases with single mitochondrial deletions autosomal inheritance can be associated with multiple deletions of mitochondrial DNA. They are due to so far unknown nuclear mutations.     

动脉瘤性蛛网膜下腔出血形态分析

目的 探讨动脉瘤性蛛网膜下腔出血计算机断层扫描（computed tomography,CT）形态特征,根据CT出血形态预判颅内动脉瘤的部位。方法 回顾性分析82例动脉瘤性蛛网膜下腔出血患者CT出血形态及全脑血管造影结果,总结不同部位动脉瘤破裂出血CT形态特征。结果 大脑前动脉、前交通动脉、大脑中动脉动脉瘤出血CT形态特异,为单纯前纵裂、外侧裂出血,蛛网膜下腔出血伴前纵裂、额叶、外侧裂血肿;颈内动脉、后交通动脉瘤出血CT形态多样,特异性较差,但常见形态为一侧鞍上池、外侧裂出血,波及其他脑池,前纵裂出血少或无出血;大脑后动脉、椎动脉、基底动脉、小脑后下动脉等后循环动脉瘤出血CT形态较典型,为脚间池、桥前池、环池、四叠体池、小脑延髓外侧池、小脑幕上下出血,但与脑干周围非动脉瘤性蛛网膜下腔出血鉴别困难。结论 根据特异性CT出血形态能够预判部分大脑前动脉、前交通动脉、大脑中动脉动脉瘤,预判颅内后循环动脉瘤时与脑干周围非动脉瘤性蛛网膜下腔出血鉴别困难,预判颈内动脉、后交通动脉瘤特异性差。     

Intracranial aneurysms and subarachnoid hemorrhage in children and adolescents

Thirty-eight cases of symptomatic cerebral aneurysms or spontaneous subarachnoid hemorrhage in children and adolescents were observed from 1965 to 1984; 33 cases were treated from 1970 to date. This group represents 2.6% of the total number of patients with subarachnoid hemorrhage treated at our institute in the same period. The cause of subarachnoid hemorrhage was unknown in 7 cases; an intracranial aneurysm had ruptured in 29 cases, and was unruptured but symptomatic in 2 remaining cases. Three aneurysms were mycotic. The most frequent aneurysmal locations were the internal carotid bifurcation and the anterior communicating artery; peripheral branches of the middle cerebral artery were also a relatively common location. Four patients were 3 years of age or younger: each presented peculiar clinical features, and 3 of the 4 had middle cerebral artery aneurysms. The remaining 34 patients were all above 9 years of age. Two groups were identified: (a) in 14 patients between 10 and 15 years of age, the aneurysm was most commonly at the internal carotid bifurcation (37%), and an intracerebral hematoma was observed in 50% of these cases; (b) in 20 patients between 16 and 20 years of age, the most common aneurysmal location was the anterior communicating artery (35%), and intracerebral hematomas were rare (10% of cases). Among patients with aneurysms, 19 underwent surgical exclusion by clip, with 10% morbidity and 5% mortality; 5 patients in moribund conditions were not operated on; 5 patients were conservatively treated; in 2 patients the aneurysm had disappeared at a second angiography. Ischemic deterioration from vasospasm was observed only in 3 patients, all above 17 years of age, and with a consistent or thick subarachnoid blood deposition on early CT scan. Hydrocephalus was also rarely observed (13% of cases), requiring a shunt in only 3 patients. Overall management results were significantly better than in adult patients, with 73% good results and 21% deaths. The better prognosis in the group under 20 years of age is probably accounted for (a) by the frequently observed reversibility of neural injury in young patients and (b) the very low incidence of ischemic disturbances in this age group.     

Patterns of inheritance in familial ALS

We investigated 185 families with ALS for evidence of anticipation and mitochondrial inheritance. Although initial analysis demonstrated significant anticipation of age at death between generations in patients with familial ALS, further analysis demonstrated features of regression to the mean, suggesting that the perceived differences are the result of bias. In addition, there was no evidence of an effect of preferential maternal inheritance, which would have supported transmission of mitochondrial DNA mutations.     

Identical cerebral aneurysms in siblings: report of two families.

Two pairs of sisters with identical cerebral aneurysms are reported. In the first family, a sibship of three, the two female members presented with subarachnoid haemorrhages from identical, left internal carotid artery bifurcation aneurysms. The subarachnoid haemorrhage occurred in one of the sisters at the age of 20 and at the age of 50 in the other. The remaining healthy sibling, a 40-year-old male, underwent elective cerebral angiography, which was normal. The other sibship, two 48-year-old female identical twins, had identical right middle cerebral artery aneurysms. The first twin became symptomatic after subarachnoid haemorrhage. The aneurysm in her identical twin was identified by screening angiography. There were no verified subarachnoid haemorrhages among the parents and grandparents in either family. No systemic anomalies were identified and collagen type 3 deficiencies were excluded. The identical location of these familial aneurysms, particularly in view of the relatively rare location in the first family, suggests that local factors in the developing vascular tree may play a role in the pathogenesis of saccular aneurysms in addition to systemic anomalies affecting the general structure of cerebral vascular walls.     

3D-CTA对破裂大脑中动脉瘤诊断及手术指导意义

目的探讨3D-CTA对破裂大脑中动脉瘤诊断和手术指导作用。方法我院神经外科从2010年1月-2011年12月经3D-CTA对收住自发性蛛网膜下腔出血病人检查证实的122例颅内动脉瘤,其中18例为大脑中动脉动脉瘤,进行了术前CTA手术模拟。17例行翼点入路开颅显微外科手术,动脉瘤夹闭手术,与术前CTA影像学资料进行了对比。结果术前经3D-CTA诊断不同部位大脑中动脉瘤术中所见完全一致。术中除1例大脑中动脉瘤M2段梭形动脉瘤行包裹术外,其余17例动脉瘤均成功行夹闭手术。术后16例病人恢复良好痊愈出院。1例术前破裂大脑中动脉瘤病人,Hunt-Hess分级V级,术后双侧脑疝死亡。1例病人入院做术前准备时,动脉瘤二次破裂出血,急诊手术,术后病人偏瘫生活不能自理。结论术前单独依靠CTA对不同部位大脑中动脉瘤进行诊断及模拟手术,对破裂大脑中动脉瘤成功手术夹闭具有较好应用价值。     

The inheritance of Alzheimer's disease: a new interpretation

Ninety-one families of Alzheimer patients were studied to determine the proportion of familial cases, to obtain pedigrees for the analysis of the mode of inheritance, and to look for clinical differences between the familial and the nonfamilial cases. The diagnosis was confirmed by autopsy in 26 cases. Thirty-nine cases (43%) were familial, which is defined as more than one case in the family. Our interpretation of the pedigree data is that Alzheimer's disease is etiologically heterogeneous: it may be genetic or sporadic. In the familial type we think that the disease is inherited as an autosomal dominant, with a wide range of age of onset within a family. In one-third of these families the gene is not expressed until over age 70. No clinical differences were found between the familial and the sporadic groups.     

Familial intracranial aneurysms. A review.

BACKGROUND: A familial occurrence of intracranial aneurysms is defined by the presence of such aneurysms in two or more first to third-degree family members. Families with two affected members may represent accidental aggregation. Other families show a frequency compatible with an autosomal dominant mode of inheritance. A genetic basis is also suggested by the younger average age of familial cases with a ruptured intracranial aneurysm (42.3 years versus an age range of 50-54 years for nonfamilial cases), occurrence at the same site or a mirror site in sibling pairs, occurrence in identical twins, and the association of intracranial aneurysms with genetically transmitted disorders. SUMMARY OF REVIEW: No reliable data are available about the occurrence of familial intracranial aneurysms among all patients with ruptured aneurysms; a frequency of 6.7% has been reported from a retrospective study, but a large part of the "familial" occurrence can be explained by fortuitous aggregation. The pathogenesis of familial intracranial aneurysms is not fully explained; a (partial) deficiency of type III collagen has been reported in sporadic, but not in familial, cases. Clinical decision analysis shows how the risk of harboring an intracranial aneurysm and the age of the patient are the main determinants for elective screening; lifetime risk of rupture (and therefore age) and surgical risks are the determinants for neurosurgical treatment. CONCLUSIONS: Surgical treatment is recommended for patients aged less than 70 years with a moderate or low surgical risk, and screening (preferably by intra-arterial digital subtraction angiography) is recommended only for relatives aged 35-65 years. Magnetic resonance angiography may develop into a useful alternative for screening, but the risks of diagnostic procedures play only a minor role in the decision analysis.     

Comparison of sporadic and familial disease amongst 580 cases of motor neuron disease.

A review of 580 hospital case notes of patients with motor neuron disease (MND) revealed 20 families in which more than one case had been reported. For 27 of the cases in these families full medical records were available, and a history of a further 37 affected family members were obtained. The cases in these 20 families are termed familial and the remainder sporadic. Parent to child transmission occurred in 16 of the 20 families of the familial cases, suggesting autosomal dominant inheritance. In three families there was involvement of siblings only, and in one family two cousins were affected. The sex ratio for the documented familial case records seen was 0.8:1 (M/F = 12:15), for the total (documented and historical) it was 1.06:1 (33:31), but in sporadic cases it was 1.6:1 (341:212) and more frequent occurrence of sensory features at presentation was reported in the familial cases (15% in the familial cases and 5% in the sporadic cases). However, none of these differences reached statistical significance. Familial cases also differed from sporadic cases in having a younger age of onset (a mean of 52 years in the familial cases compared with 56 years in the sporadic) and in the shorter median reported duration of illness (1.1 year in the familial cases; 2.6 years in the sporadic). However, in only one fifth of sporadic cases was the age at onset and death known, although this was known for 22 of the 27 familial cases, so that the data on survival and age of onset are too incomplete to test formally.     

The endovascular management of superior cerebellar artery aneurysms

BACKGROUND: Superior cerebellar artery aneurysms are rare. We present a clinical series of twelve of these aneurysms that were treated exclusively with endovascular coils. METHOD: A retrospective analysis of a prospectively collected database of cerebral aneurysms treated with coil embolization was performed. Clinical notes and radiological images were reviewed. RESULTS: Twelve superior cerebellar artery aneurysms were treated in eleven patients between 1992 and 2001. Seven patients presented with subarachnoid hemorrhage, two with neurologic deficit, and two had asymptomatic aneurysms. Coiling resulted in complete aneurysm obliteration in six patients and incomplete obliteration in the other six. No subsequent hemorrhage occurred with follow-up between 6 and 119 months (mean follow-up 50 months). Procedural morbidity was one superior cerebellar artery infarct with good recovery. Management morbidity was one middle cerebral artery embolus during a follow-up angiogram that required thrombolysis with a good clinical result. Nine out of 11 patients on follow-up were performing at Glasgow Outcome Scale (GOS) 5. One patient with GOS 3 presented with a poor grade subarachnoid hemorrhage and the other patient with GOS 4 presented with a parenchymal hemorrhage due to an arteriovenous malformation. CONCLUSION: Endovascular treatment of superior cerebellar artery aneurysms is an effective treatment strategy with low morbidity.