Towards a neurocognitive profile in familial cerebral cavernous malformations

TL;DR

This paper explores cognitive and neurological effects in a family with a rare brain condition called familial cerebral cavernous malformations.

Contribution

The study identifies a genetic variant in the CCM2 gene and highlights previously underrecognized cognitive impairments in FCCM.

Findings

Memory complaints and cognitive dysfunction are common in FCCM patients despite normal neurological exams.

A nonsense variant in the CCM2 gene was found in all affected family members.

Recurrent microhemorrhages may contribute to cognitive impairment in FCCM.

Abstract

Familial cerebral cavernous malformations (FCCM) is a rare autosomal dominant disease, characterized by vascular malformations that can lead to macro and microhemorrhages. The neurocognitive impact of FCCM is still underrecognized.

We report the clinical, neurocognitive, imaging and genetic data of a three generation family with FCCM.

A 63-year-old man (proband) had progressive memory impairment since the last year. Neurologic exam was unremarkable. Brain MRI showed multiple large cavernomas (mainly in the pons, left temporal, and right temporo-parietal) and scattered microhemorrhages. Neuropsychological assessment mainly revealed left frontal and right temporo-parietal dysfunction. A 41-year-old daughter, presented with headache, vertigo and memory complaints in the last 2 years. Neurological examination revealed left central facial paralysis. Brain MRI showed two small right parietal and internal capsule cavernomas, as well as microhemorrhages. Neuropsychological assessment showed moderate temporal neocortical left dysfunction. A 34-year-old daughter had recurrent headache and memory complaints, with unremarkable neurological exam. Brain MRI revealed two large cavernomas (left fronto-orbitary and inferior temporal), with few microhemorrhages. Neuropsychological assessment was normal. A granddaughter had mild headaches and a small right cerebellar cavernoma, without microhemorrhages. Neuropsychological assessment showed mild temporal neocortical left dysfunction. A nonsense variant, c.55C > T; p.R19* generating a premature stop codon in CCM2 gene shared by all affected family members was identified.

Neuropsychological evaluation showed that memory complaints and cognitive impairment could be an important unrecognized finding in FCCM. Its pathophysiological mechanisms are still unknown but the role of recurrent microhemorrhages could provide an interesting hypothesis.

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