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From the Neurogenetics Laboratory (Drs. Moro and Volzone), Division of Child Neurology and Psychiatry, University of Pisa and IRCCS "Fondazione Stella Maris", Pisa; Medical Genetics (Dr. Carrozzo), IRCCS San Raffaele Hospital, Milan; Department of Child Neuropsychiatry (Dr. Veggiotti), IRCCS ‘Fondazione Istituto Neurologico Casimiro Mondino‘, Pavia; Department of Medical Paediatric and Surgical Sciences (Dr. Tortorella), University of Messina; and National Research Council (Dr. Toniolo), Institute of Genetics, Biochemistry and Evolution (IGBE-CNR), Pavia, Italy; and Neurosciences Unit (Dr. Guerrini), Institute of Child Health and Great Ormond Street Hospital for Children, University College London, UK.
Address correspondence and reprint requests to Dr. Renzo Guerrini, Neurosciences Unit, Institute of Child Health and Great Ormond Street Hospital for Children, University College London, The Wolfson Centre, Mecklenburgh Square, London WC1N 2AP, UK; e-mail: R.Guerrini{at}ich.ucl.ac.uk
Objective: To examine the clinical and MRI associations in bilateral periventricular nodular heterotopia (BPNH) (MIM # 300049) in two families segregating a missense mutation and a C-terminal deletion of the filamin 1(FLN1) gene.
Background: Classical familial BPNH, an X-linked dominant disorder, has been associated with protein truncations or splicing mutations, which tend to cluster at the N-terminal of the FLN1 protein, causing severe predicted loss of the protein function. The clinical syndrome includes symmetrical contiguous nodular heterotopia lining the lateral ventricles, epilepsy, mild retardation to normal cognitive level in affected females, and prenatal lethality in hemizygous boys.
Methods: Clinical examination, cognitive testing, MRI, mutation analysis (direct sequencing, single-strand conformation polymorphism) in seven patients from two families with BPNH.
Results: In Family 1, harboring an A > T change in exon 2 (E82V), heterotopic nodules were few, asymmetric, and noncontiguous. Five boys born from affected females had died unexpectedly early in life. In Family 2, harboring an 8 base pair deletion in exon 47 (7627_7634del TGTGCCCC), heterotopic nodules were thick and contiguous. Affected females in both families showed normal to borderline IQ and epilepsy.
Conclusion: Missense mutations and distal truncations consistent with partial loss of FLN1 function cause familial BPNH with the classical clinical phenotype including epilepsy and mild mental retardation, if any. However, missense mutations have milder anatomic consequences in affected females and are possibly compatible with live birth but short survival of boys.
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