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Discovery of familial cerebral cavernous malformation in a Saudi population.

ABSTRACT: Familial cerebral cavernous malformation is a rare entity. It has been described commonly among the Hispanic population and sparsely among the Italian, French, Swedish and Chinese populations. We discovered two families with this condition among the Saudi population for the first time. Both the index patients had a seizure as a prominent manifestation of their underlying structural lesion. One of them had recurrent attacks of bleeding in the cavernoma leading to a focal neurological deficit. The siblings and the parents of both the patients were screened using CT of the brain imaging. Two members within each family were found to have symptomatic cavernoma. A molecular genetics study revealed heterozygous KRIT1/CCM1 for a frameshift mutation in one of the patients. No detectable mutation was found in the other patient. These cases illustrate the existence of this condition beyond the commonly known geographical area of higher prevalence. Moreover, KRIT1/CCM1 might be the possible target gene that is mutated in this region.

SUBMITTER: Nahrir S

PROVIDER: S-EPMC3841714 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Discovery of familial cerebral cavernous malformation in a Saudi population.

Nahrir Shahpar S Al-Hameed Majed H MH Al-Sinaidi Omar A OA Al Shakweer Wafa W

BMJ case reports 20131121

Familial cerebral cavernous malformation is a rare entity. It has been described commonly among the Hispanic population and sparsely among the Italian, French, Swedish and Chinese populations. We discovered two families with this condition among the Saudi population for the first time. Both the index patients had a seizure as a prominent manifestation of their underlying structural lesion. One of them had recurrent attacks of bleeding in the cavernoma leading to a focal neurological deficit. The ...[more]

PMID: 24265337

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Project description:Background Familial cerebral cavernous alformation (CCM) is an autosomal dominant disease caused by mutations in KRIT1, CCM2, or PDCD10. Cases typically present with multiple lesions, strong family history, and neurological symptoms, including seizures, headaches, or other deficits. Intracranial hemorrhage (ICH) is a severe manifestation of CCM, which can lead to death or long-term neurological deficits. Few studies have reported ICH rates and risk factors in familial CCM. We report ICH rates and assess whether CCM lesion burden, a disease severity marker, is associated with risk of symptomatic ICH during follow-up in a well-characterized cohort of familial CCM cases. Methods and Results We studied 386 patients with familial CCM with follow-up data enrolled in the Brain Vascular Malformation Consortium CCM Project. We estimated symptomatic ICH rates overall and stratified by history of ICH before enrollment. CCM lesion burden (total lesion count and large lesion size) assessed at baseline enrollment was tested for association with increased risk of subsequent ICH during follow-up using Cox regression models adjusted for history of ICH before enrollment, age, sex, and family structure and stratified on recruitment site. The symptomatic ICH rate for familial CCM cases was 2.8 per 100 patient-years (95% CI, 1.9-4.1). Those with ICH before enrollment had a follow-up ICH rate of 4.5 per 100 patient-years (95% CI, 2.6-8.1) compared with 2.0 per 100 patient-years (95% CI, 1.3-3.5) in those without (P=0.042). Total lesion count was associated with increased risk of ICH during follow-up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10-1.71], P=0.006). The symptomatic ICH rate for familial CCM cases was 2.8 per 100 patient-years (95% CI, 1.9-4.1). Those with ICH before enrollment had a follow-up ICH rate of 4.5 per 100 patient-years (95% CI, 2.6-8.1) compared with 2.0 per 100 patient-years (95% CI, 1.3-3.5) in those without (P=0.042). Total lesion count was associated with increased risk of ICH during follow-up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10-1.71], P=0.006). Conclusions Patients with familial CCM with prior history of an ICH event are at higher risk for rehemorrhage during follow-up. In addition, total CCM lesion burden is significantly associated with increased risk of subsequent symptomatic ICH; hence lesion burden may be an important predictor of patient outcome and aid patient risk stratification.

Project description:BackgroundCerebral cavernous malformations (CCMs) are vascular malformations characterized by clusters of enlarged leaky capillaries in the central nervous system. They may result in intracranial haemorrhage, epileptic seizure(s), or focal neurological deficits, and potentially lead to severe disability. Globally, CCMs represent the second most common intracranial vascular malformation in humans, and their familial form (FCCMs) accounts for one-fifth of cases. Neurosurgical excision, and perhaps stereotactic radiosurgery, is the only available therapeutic option. Case reports suggest that propranolol might modify disease progression.MethodsTreat_CCM is a prospective, randomized, open-label, blinded endpoint (PROBE), parallel-group trial involving six Italian clinical centres with central reading of brain magnetic resonance imaging (MRI) and adverse events. Patients with symptomatic FCCMs are randomized (2:1 ratio) either to propranolol (40-80 mg twice daily) in addition to standard care or to standard care alone (i.e. anti-epileptic drugs or headache treatments). The primary outcome is intracranial haemorrhage or focal neurological deficit attributable to CCMs. The secondary outcomes are MRI changes over time (i.e. de novo CCM lesions, CCM size and signal characteristics, iron deposition, and vascular leakage as assessed by quantitative susceptibility mapping and dynamic contrast enhanced permeability), disability, health-related quality of life, depression severity, and anxiety (SF-36, BDI-II, State-Trait Anxiety Inventory).DiscussionTreat_CCM will evaluate the safety and efficacy of propranolol for CCMs following promising case reports in a randomized controlled trial. The direction of effect on the primary outcome and the consistency of effects on the secondary outcomes (even if none of them yield statistically significant differences) of this external pilot study may lead to a larger sample size in a definitive phase 2 trial.Trial registrationClinicalTrails.gov, NCT03589014. Retrospectively registered on 17 July 2018.

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Discovery of familial cerebral cavernous malformation in a Saudi population.

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Discovery of familial cerebral cavernous malformation in a Saudi population.

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