Limits...
Variable expression of cerebral cavernous malformations in carriers of a premature termination codon in exon 17 of the Krit1 gene.

Lucas M, Costa AF, García-Moreno JM, Solano F, Gamero MA, Izquierdo G - BMC Neurol (2003)

Bottom Line: Patients in this family, harbouring the same mutation, illustrate the very variable clinical and radiological expression of a Krit1 mutation.The early and critical onset in the proband contrasts with minor clinical findings in affected relatives.This consideration is important in genetic counselling.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Biology Services of the Virgen Macarena University Hospital, Avda Dr, Fedriani sn, 41009 Sevilla, Spain. lucas@us.es

ABSTRACT

Background: Cerebral cavernous malformations (CCM) present as either sporadic or autosomal dominant conditions with incomplete penetrance of symptoms. Differences in genetic and environmental factors might be minimized among first-degree relatives. We therefore studied clinical expression in a family with several affected members.

Methods: We studied a three-generation family with the onset of CCM as a cerebral haemorrhage in the younger (four-year-old) sibling. Identification and enumeration of CCMs were performed in T2-weighted or gradient-echo MRIs of the whole brains. Genetic analysis comprised SCCP, sequencing and restriction polymorphism of the Krit1 gene in the proband and at risk relatives.

Results: The phenotypes of cerebral cavernous malformations (CCMs) in carriers of Krit1 mutations were very variable. We identified a novel frameshift mutation caused by a 1902A insertion in exon 17 of the Krit1 gene, which leads to a premature TAA triplet and predicts the truncating phenotype Y634X. A very striking finding was the absence of both clinical symptoms and CCMs in the eldest sibling harbouring the 1902insA.

Conclusions: Patients in this family, harbouring the same mutation, illustrate the very variable clinical and radiological expression of a Krit1 mutation. The early and critical onset in the proband contrasts with minor clinical findings in affected relatives. This consideration is important in genetic counselling.

Show MeSH

Related in: MedlinePlus

MRIs of CCMs. The echo gradient sequences of the proband (left), grandmother (middle) and the older brother (right) harbouring the Y634X mutation (III-2 in figure 3). Note the typical images of cavernous malformation and the absence of lesions in III-2, the asymptomatic carrier of the 1902insA.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC184376&req=5

Figure 1: MRIs of CCMs. The echo gradient sequences of the proband (left), grandmother (middle) and the older brother (right) harbouring the Y634X mutation (III-2 in figure 3). Note the typical images of cavernous malformation and the absence of lesions in III-2, the asymptomatic carrier of the 1902insA.

Mentions: The onset of cerebral hemorrhage in the 4-year-old proband was the main clinical finding in the CVE10 family. The retrospective study of siblings and parents showed minor symptoms though one sibling had epilepsy. The clinical study was completed with MRI scans of consenting symptomatic and asymptomatic at-risk first-degree relatives. Multiple CCMs were observed in the MRIs of the grandmother, mother and two of the siblings and therefore familial characteristic was confirmed (see table 1 and figure 1 for details of number and locations of CCMs). The number of CCMs in patients of this pedigree was related to age with a ratio around 0.9 (range 0.3–2) and no significant differences in location were observed. Comparison of CCM locations is weakened because there were far fewer malformations in the younger patients (table 1).


Variable expression of cerebral cavernous malformations in carriers of a premature termination codon in exon 17 of the Krit1 gene.

Lucas M, Costa AF, García-Moreno JM, Solano F, Gamero MA, Izquierdo G - BMC Neurol (2003)

MRIs of CCMs. The echo gradient sequences of the proband (left), grandmother (middle) and the older brother (right) harbouring the Y634X mutation (III-2 in figure 3). Note the typical images of cavernous malformation and the absence of lesions in III-2, the asymptomatic carrier of the 1902insA.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC184376&req=5

Figure 1: MRIs of CCMs. The echo gradient sequences of the proband (left), grandmother (middle) and the older brother (right) harbouring the Y634X mutation (III-2 in figure 3). Note the typical images of cavernous malformation and the absence of lesions in III-2, the asymptomatic carrier of the 1902insA.
Mentions: The onset of cerebral hemorrhage in the 4-year-old proband was the main clinical finding in the CVE10 family. The retrospective study of siblings and parents showed minor symptoms though one sibling had epilepsy. The clinical study was completed with MRI scans of consenting symptomatic and asymptomatic at-risk first-degree relatives. Multiple CCMs were observed in the MRIs of the grandmother, mother and two of the siblings and therefore familial characteristic was confirmed (see table 1 and figure 1 for details of number and locations of CCMs). The number of CCMs in patients of this pedigree was related to age with a ratio around 0.9 (range 0.3–2) and no significant differences in location were observed. Comparison of CCM locations is weakened because there were far fewer malformations in the younger patients (table 1).

Bottom Line: Patients in this family, harbouring the same mutation, illustrate the very variable clinical and radiological expression of a Krit1 mutation.The early and critical onset in the proband contrasts with minor clinical findings in affected relatives.This consideration is important in genetic counselling.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Biology Services of the Virgen Macarena University Hospital, Avda Dr, Fedriani sn, 41009 Sevilla, Spain. lucas@us.es

ABSTRACT

Background: Cerebral cavernous malformations (CCM) present as either sporadic or autosomal dominant conditions with incomplete penetrance of symptoms. Differences in genetic and environmental factors might be minimized among first-degree relatives. We therefore studied clinical expression in a family with several affected members.

Methods: We studied a three-generation family with the onset of CCM as a cerebral haemorrhage in the younger (four-year-old) sibling. Identification and enumeration of CCMs were performed in T2-weighted or gradient-echo MRIs of the whole brains. Genetic analysis comprised SCCP, sequencing and restriction polymorphism of the Krit1 gene in the proband and at risk relatives.

Results: The phenotypes of cerebral cavernous malformations (CCMs) in carriers of Krit1 mutations were very variable. We identified a novel frameshift mutation caused by a 1902A insertion in exon 17 of the Krit1 gene, which leads to a premature TAA triplet and predicts the truncating phenotype Y634X. A very striking finding was the absence of both clinical symptoms and CCMs in the eldest sibling harbouring the 1902insA.

Conclusions: Patients in this family, harbouring the same mutation, illustrate the very variable clinical and radiological expression of a Krit1 mutation. The early and critical onset in the proband contrasts with minor clinical findings in affected relatives. This consideration is important in genetic counselling.

Show MeSH
Related in: MedlinePlus