Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation

Pilar Gomez-Garre ¹, Manuel Seijo ², Eva Gutierrez-Delicado ¹, María Castro del Rio ², Carlos de la Torre ², Cristina Gomez-Abad ¹, Jose Morales-Corraliza ¹, Miguel Puig ² and Jose María Serratosa ^1*

¹ Fundación Jiménez Díaz, Spain
² Complexo Hospitalario de Pontevedra, Spain

^* To whom correspondence should be addressed. E-mail: serratosa{at}telefonica.net.

Accepted 27 June 2005

Abstract

Background: The Ehlers-Danlos syndrome (EDS) comprises a group of hereditary connective tissue disorders associated with high clinical and genetic variability. At least six types of EDS, with various subtypes are recognized. Still, many patients remain unclassified as some subtypes are not totally defined and overlapping among phenotypes is common. Periventricular nodular heterotopia (PNH) is a human neuronal migration disorder characterized by seizures and conglomerates of neural cells along or protruding into the lateral ventricules of the brain and caused by FLNA mutations. FLNA encodes Filamin A, an ubiquitous actin-binding protein involved in cytoskeletal organization. Structurally, filamins are large dimeric phosphoproteins presenting an amino-terminal actin binding domain (ABD) and 24 repeats. ABD contains two tandem calponin homology domains depicted as CHD1 and CHD2.

Methods: We performed a clinical and molecular study of three females from a Spanish family manifesting the EDS in combination with PNH. Clinical histories, physical and neurological examinations, brain magnetic resonance imaging studies and skin biopsies were performed. Genetic analysis of the FLNA gene was performed by direct sequencing and restriction fragment length polymorphism analysis.

Findings: Mutation analysis of the FLNA gene resulted in the identification of a novel mutation in exon 3 (c.383CT) segregating with the combination of both syndromes. This mutation results in a substitution of an Alanine residue (A128V) in CHD1.

Interpretation: Our findings suggest that the Ala128Val mutation causes the dual EDS-PNH phenotype and that this association constitutes a new variant within the EDS spectrum. This is the first description of a familial EDS-PNH association with a mutation in FLNA.

Keywords: Ehlers-Danlos syndrome, FLNA, Filamin A, Mutation, Periventricular Nodular Heterotopia

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