[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.158.98.119. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Clinicopathologic Reports, Case Reports, and Small Case Series
February 2002

A Novel KRIT1/CCM1 Truncating Mutation in a Patient With Cerebral and Retinal Cavernous Angiomas

Arch Ophthalmol. 2002;120(2):217-218. doi:

Cerebral cavernous malformations (CCM) are defined by abnormally enlarged capillary cavities without intervening brain parenchyma. Clinical symptoms include seizures, hemorrhage, and focal neurological deficits. Their prevalence is close to 0.5% in the general population. Familial forms are increasingly recognized. Three CCM loci were mapped to chromosomes 7q (CCM1), 7p (CCM2), and 3q (CCM3). KRIT1, a protein of unknown function, was recently identified as the mutated protein in families with the CCM1 gene.1

Cavernomas have been observed in other organs such as the retina. We report what is to our knowledge the first observation of a KRIT1 mutation in a patient with retinal and cerebral cavernous angiomas.

Report of a Case

A 34-year-old woman was followed up for recurrent herpetic keratitis of the left eye. A fundus examination and retinal angiograms of the same eye showed a peripheral retinal vascular lesion, characteristic of a cavernous angioma (Figure 1A and B). The lesion had first been observed when the patient was 11 years old. The right fundus was normal. Her visual acuity between episodes of keratitis was 20/20 OU. There was no other eye abnormality. From 1995 to 1999, we did not observe any change of the retinal cavernoma. Results of dermatological and neurological examinations were normal. Brain magnetic resonance imaging showed 4 cavernomas (Figure 1C). Five relatives of the patient were also known to have cerebral cavernomas. We could not perform ophthalmological examinations on these subjects because they live in another country.

Figure 1.
A, Fundus examination of the left
eye showing a localized peripheral cluster of saccular whitish to dark red
aneurysms of various sizes. B, The same lesion was observed using fluorescein
angiography. The adjacent vessels were normal, and there was no sign of leakage.
C, Magnetic resonance imaging (1.5 T; T2-weighted imaging axial sequences)
showing a cerebral cavernoma close to the right ventricle (white arrow), seen
as a mixed hypointense and hyperintense signal.

A, Fundus examination of the left eye showing a localized peripheral cluster of saccular whitish to dark red aneurysms of various sizes. B, The same lesion was observed using fluorescein angiography. The adjacent vessels were normal, and there was no sign of leakage. C, Magnetic resonance imaging (1.5 T; T2-weighted imaging axial sequences) showing a cerebral cavernoma close to the right ventricle (white arrow), seen as a mixed hypointense and hyperintense signal.

Sequencing of exon 10 of the KRIT1 gene in our patient revealed a heterozygous insertion of cytosine after nucleotide 1374 that caused a frameshift leading to a premature stop codon (Figure 2), and therefore a truncated protein. This mutation was not detected in a panel of 50 healthy controls. The DNA sequence of the complete gene was determined, and no other mutation was found.

Figure 2.
Chromatograms of mutated (MT)
DNA of the patient and wild-type (WT) DNA of a healthy control. The arrow
indicates the site of the mutation.

Chromatograms of mutated (MT) DNA of the patient and wild-type (WT) DNA of a healthy control. The arrow indicates the site of the mutation.

Comment

Retinal cavernomas are rare and usually asymptomatic. The largest series reported so far consists of 9 cases.2 Most reports are of sporadic retinal cavernomas with no associated neurological disease. The occurrence of retinal and familial brain cavernomas has seldom been described.3,4 In the absence of a systematic fundus examination, retinal cavernomas could be undiagnosed in patients with brain cavernomas. In rare cases such as that described in this report, the diagnosis of retinal cavernomas can lead to the detection of asymptomatic cerebral cavernomas.

The vascular nature of the lesions observed in the retina and brain as well as the cosegregation of both types of lesions strongly suggest that the occurrence of these 2 conditions is not coincidental. Interestingly, the mutation observed in our patient is similar in nature to those observed in families with CCM; namely, mutations leading to a truncation of the C-terminal part of KRIT1.1 Because the insertion of a cytosine at nucleotide 1374 has not previously been reported, we can not exclude the possibility that this mutation is associated specifically with the occurrence of both retinal and cerebral lesions. In this article, we show for the first time that a mutation in KRIT1, a gene known to exist in most families who have CCM with isolated brain cavernomas, is present in a patient with both retinal and brain cavernomas. Another mutation in the KRIT1 gene was recently found in one family characterized by the cosegregation of cutaneous and brain cavernomas.5 These results strongly suggest that these lesions are underlaid by a common mechanism and that KRIT1 plays an important role in cutaneous, retinal, and cerebral vascular development.

Dr Laberge-Le Couteulx received a fellowship from the Fondation pour la Recherche Médicale. Dr Labauge benefited from a poste d'accueil INSERM and was supported by the Collège des Enseignants de Neurologie. This work was supported by INSERM and the Ministère de l'Enseignement Supérieur et de la Recherche.

Corresponding author: Pierre Labauge, MD, Faculté de Médecine Lariboisière, Laboratoire de Génétique des Maladies Vasculaires, 10 Avenue de Verdun, EPI 99-21, 75010 Paris, Cedex, France (e-mail: labauge@hotmail.com).

References
1.
Laberge-Le Couteulx  SJung  HHLabauge  P  et al.  Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet. 1999;23189- 193Article
2.
Messmer  ELaqua  HWessing  ASpitznas  MWeidle  E Nine cases of cavernous hemangioma of the retina. Am J Ophthalmol. 1983;95383- 390
3.
Dobyns  WBMichels  VVGoover  RV  et al.  Familial cavernous malformations of the central nervous system and retina. Ann Neurol. 1987;21578- 583Article
4.
Sarraf  DPayne  AMKitchen  NDSehmi  KSDownes  SMBird  AC Familial cavernous hemangioma: an expanding ocular spectrum. Arch Ophthalmol. 2000;118969- 973Article
5.
Eerola  IPlate  KHSpiegel  RBoon  LMMulliken  JBVikkula  M KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation. Hum Mol Genet. 2000;91351- 1355Article
×