Novel <i>KRIT1</i> Mutation and No Molecular Evidence of Anticipation in a Family with Cerebral and Spinal Cavernous Malformations

Abstract

Background: Cerebral cavernous malformations (CCM) are vascular brain anomalies which can result in a variety of neurological symptoms. Familial CCM is inherited as an autosomal-dominant trait. There is one study in the literature which reports statistical evidence for anticipation in familial CCM. Methods: We reevaluated the clinical course of the disease and performed molecular analyses in a previously described three-generation CCM family with apparent anticipation. Results: Disease started at a younger age in each generation, strongly suggesting anticipation. The patient in generation I showed no clinical symptoms by the age of 68, whereas his son became wheelchair-bound at the age of 43 due to an intramedullary cavernous malformation at the thoracolumbar transition of the spinal cord. The patient in generation III had a pons hemorrhage at the age of 11 due to a large brainstem cavernoma. The hemorrhage caused facial palsy and hemiparesis, persisting as Millard-Gubler syndrome. Sequencing of KRIT1 identified a novel frameshift mutation in exon 15 (c.1561delC or p.Leu551X) which cosegregated with the phenotype. Flow-FISH analysis of granulocyte and lymphocyte telomere length showed that telomeres were longest in the youngest affected family member. Conclusions: We could not find any evidence for either of the two currently known molecular mechanisms for genetic anticipation (i.e., expansion of repetitive DNA elements or progressive telomere shortening) in this family. However, the family presented here raises the important question whether surveillance of CCM families with gradient-echo MRI should not only include the cerebrum, but the spinal cord as well.

Cerebral Cavernous Malformations: An Update on Prevalence, Molecular Genetic Analyses, and Genetic Counselling

“…2 ). Furthermore, Netzer and colleagues [2009] found no evidence for progressive telomere shortening in CCM1 mutation carriers from a 3-generation family presenting with significantly earlier disease onset in the youngest generation [Kuhn et al, 2009].…”

Adult Intradural Primary Spinal Cord Tumors

“…70 Familial cases have been reported mostly related to KRIT1/CCM1 gene mutations. 71,72 CCM2 and CCM3 mutations have been reported as a cause of multiple cerebral but not spinal cavernous malformations. Spinal cavernous malformations have a slight female preponderance, and the peak of incidence is in the fourth decade.…”

Cerebral cavernous malformations as a disease of vascular permeability: from bench to bedside with caution

“…Germline mutations in CCM1 cause CCMs, and roughly 100 distinct mutations in this gene have been identified to date with familial CCM disease. 11,31,35,37,44,61 Homozygous Ccm1 knockout mice die in midgestation with gross dilations of the major arteries and heart chambers and narrowing of other arteries. 77 CCM lesions are not documented in mice with heterozygous Ccm1 knockout alone but when coupled with Trp53 mutation, vascular anomalies similar to CCMs can develop.…”