Genotype–phenotype correlations in cerebral cavernous malformations patients

Authors

  • Christian Denier MD, PhD,

    1. Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris
    2. Service de Neurologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Paris
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  • Pierre Labauge MD, PhD,

    1. Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris
    2. Service de Neurologie, Centre Hospitalier Universitaire de Nïmes, Nïmes
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  • Françoise Bergametti PhD,

    1. Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris
    2. Université Denis Diderot Paris7
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  • Florence Marchelli MD,

    1. Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris
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  • Florence Riant MD,

    1. Assistance Publique-Hôpitaux de Paris, Laboratoire de Cytogénétique, Hôpital Lariboisière, Paris
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  • Minh Arnoult,

    1. Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris
    2. Université Denis Diderot Paris7
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  • Jacqueline Maciazek,

    1. Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris
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  • Eric Vicaut MD, PhD,

    1. Unité de Recherche Clinique, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris
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  • Laurent Brunereau MD, PhD,

    1. Service de Radiologie, Centre Hospitalier Universitaire de Tours, Paris, France
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  • Elisabeth Tournier-Lasserve MD

    Corresponding author
    1. Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris
    2. Université Denis Diderot Paris7
    3. Assistance Publique-Hôpitaux de Paris, Laboratoire de Cytogénétique, Hôpital Lariboisière, Paris
    • Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, 2, rue A. Paré, 75010 Paris, France
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Abstract

Objective

To compare clinical features of CCM1, CCM2, and CCM3 mutation carriers.

Methods

A detailed clinical and molecular analysis of 163 consecutive cerebral cavernous malformation (CCM) families was performed.

Results

A deleterious mutation was detected in 128 probands. Three hundred thirty-three mutation carriers were identified (238 CCM1, 67 CCM2, and 28 CCM3). Ninety-four percent of the probands with an affected relative had a mutation compared with 57% of the probands with multiple lesions but no affected relative (p < 0.001). The number of affected individuals per family was lower in CCM3 families (p < 0.05). The proportion of patients with onset of symptoms before 15 years of age was higher in the CCM3 group (p < 0.0025). Cerebral hemorrhage was the most common initial presentation in CCM3 patients. The average number of T2-weighted imaging lesions was similar in the three groups, in contrast with a significantly lower number of gradient-echo sequence lesions in CCM2 patients (p < 0.05). The number of gradient-echo sequence lesions increased more rapidly with age in CCM1 than in CCM2 patients (p < 0.05).

Interpretation

Despite similarities among the three groups, there is a significantly lower number of affected individuals in CCM3 pedigrees, CCM3 mutations may confer a higher risk for cerebral hemorrhage, particularly during childhood, and the increment of gradient-echo sequence lesions with age differs between CCM1 and CCM2 patients. Ann Neurol 2006

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