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
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.
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
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.
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.
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: firstname.lastname@example.org).
Laberge-Le Couteulx S, Brézin AP, Fontaine B, Tournier-Lasserve E, Labauge P. A Novel KRIT1/CCM1 Truncating Mutation in a Patient With Cerebral and Retinal Cavernous Angiomas. Arch Ophthalmol. 2002;120(2):217-218. doi: