Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations

Abstract

Purpose The phenotypic manifestations of cerebral cavernous malformation (CCM) disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase (ROCK) mediated hyperpermeability, a potential therapeutic target, has not been established. Methods We analyze PDCD10-siRNA treated endothelial cells for stress fibers, ROCK activity and permeability. ROCK activity is assessed in CCM lesions. Brain permeability and CCM lesion burden is quantified, and clinical manifestations are assessed in prospectively enrolled subjects with PDCD10 mutations. Results We determine that PDCD10 protein suppresses endothelial stress fibers, ROCK activity and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrate robust ROCK activity in murine and human CCM vasculature, and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared to the more common KRIT1 and CCM2 familial and sporadic CCM, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features including scoliosis, cognitive disability and skin lesions, unrelated to lesion burden or bleeding. Conclusion These findings define a unique CCM disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling and the design of trials.

Vascular Permeability in Cerebral Cavernous Malformations

“…This hyperpermeability is associated with RhoA kinase (ROCK) activation, and can be rescued by ROCK inhibition. 3,6,7 We also showed hyperpermeability to Evans blue dye in vivo in the brain and lungs of Ccm1 haploinsufficient mice, also rescued by ROCK inhibition. 3 The ROCK activity has been linked to increased CCM lesion burden in mice, and ROCK inhibition is being tested as a potential therapy to prevent CCM lesion development.…”

Peripheral Plasma Vitamin D and Non-HDL Cholesterol Reflect the Severity of Cerebral Cavernous Malformation Disease

“…Features of acute clinical aggressiveness included a demonstrated lesional growth or a symptomatic hemorrhage in the preceding year, or new lesion formation on comparable MRI image sequences in the preceding year in familial cases. Given the small numbers of cases with each disease aggressiveness feature, and the known correlation among the different features (i.e., patients with earlier symptom onset are more likely to experience greater lesion burden and multiple hemorrhages, patients with recent hemorrhage are more likely to experience recent lesional growth) [3], we subsequently considered the respective features of disease aggressiveness in chronic or acute domains for our primary hypothesis testing. Since CCM disease beginning in pediatric patients has been shown to be more severe than when disease onset is in adults [3,[5][6][7], we used symptoms beginning at or before 18 years of age as a feature of chronic disease aggressiveness.…”

“…A relevant disease biomarker might reflect chronic disease aggressiveness over the patient's lifetime, or more acute clinical activity [3,9,14]. We considered validated features of chronic disease aggressiveness including a history of multiple adjudicated clinically overt hemorrhages, early age of clinical onset or high lesion burden in familial cases.…”

“…Patients may harbor solitary lesions occurring sporadically and often associated with a developmental venous anomaly [2], or multifocal lesions, typically inherited as autosomal dominant traits at three known gene loci (CCM 1, 2 & 3). While the CCM3 genotype portends more aggressive disease, the clinical behavior of CCM cases, regardless of genotype, remains widely unpredictable [3]. Some patients remain asymptomatic, while others are disabled from recurrent bleeds and/or high lesion burden [4].…”

Neurocysticercosis, familial cerebral cavernomas and intracranial calcifications: differential diagnosis for adequate management

“…In another multicenter study it was reported a very aggressive profile of FCCM cases due to mutations of the gene CCM3 22 , with a mean age at presentation of 12 years and an excessive lesion burden, meaning 33% of the patients having more than 100 lesions and 78% with more than 20 lesions. Epilepsy was also the most common symptom of this aggressive form of the disease.…”