NIH Research Festival
Introduction: Cerebral cavernous malformations (CCM) are structurally abnormal, irregularly clustered, and dilated capillaries found in the brain and spinal cord. While isolated CCMs are common and often discovered incidentally, familial cerebral cavernous malformation (FCCM), an autosomal dominant disease in which innumerable CCMs could form, results in a variety of neurological symptoms. The three genes associated with FCCM are KRIT1, CCM2, and PDCD10, but mutations in KRIT1 are the most frequent cause of FCCM. While many patients might remain asymptomatic, others experience seizures, focal neurological deficits, headaches, vision changes, strokes, and intracerebral hemorrhages. Multiple focal lesions with hemosiderin deposits are prototypical in FCCM. Here we describe a patient with a novel VUS in KRIT1 (c.1942 G>A, p.A648T) identified on clinical WES and WGS, with leptomeningeal cavernomas, diffuse superficial siderosis, and numerous brainstem lacunar strokes including several without hemosiderin deposits.
Case Presentation: The proband, a now 29-year-old African American male, presented to the NIH Undiagnosed Diseases Program (UDP) with progressive stepwise cognitive decline, balance issues, dysarthria, and spasticity. His MRI was atypical in that multiple non-hemorrhagic brainstem lacunae coexisted with more typical CCM features.
Conclusions: This is the first association of this specific variant of KRIT1 (c.1942 G>A, p.A648T) with FCCM. The presentation of ischemic non-hemorrhagic lacunar strokes restricted to the brainstem as well as a single leptomeningeal cavernoma with subarachnoid hemorrhage would be unusual for FCCM. Other monogenic vasculopathies associated with mutations in NOTCH3, COL4A1, NEU1, HRTA, and GLA were excluded.
Scientific Focus Area: Genetics and Genomics
This page was last updated on Monday, September 25, 2023