Abstracts

Rationale: Periventricular nodular heterotopia (PNH) are a well recognized malformation of cortical development. Bilateral symmetrical frontally-predominant PNH form the largest group of PNH and are associated with mutations of FLNA in 50% of cases. However, PNH are not always anteriorly predominant and may be associated with an array of abnormalities involving posterior fossa structures. We examined the spectrum of radiological features associated with posterior predominant PNH and the clinical genetics of this malformation. Methods: We classified the MRI scans of 45 patients with bilateral posterior PNH based on a detailed analysis of imaging findings. We defined posterior PNH as restricted to the region around the posterior horns, atria or temporal horns of the lateral ventricles. The shape, location and symmetry of PNH were analysed and the presence of all associated abnormalities was documented. FLNA was examined by either denaturing high performance liquid chromatography or sequencing in each patient. Results: The cohort comprised 29 females (64%) and 16 males and included 2 sister pairs, one monozygotic twin brother pair and one mother-son pair. Ages ranged from a fetus (in-utero scan) to 67 years. 23/45 (51%) patients had posterior fossa abnormalities: 16 had dysplastic cerebella with or without cyst and 5 had morphologically normal but small cerebella. 21/45 patients (47%) had posterior fossa cysts. 35/45 (78%) had corpus callosum abnormalities: 5 agenesis and 20 with thin posterior body and splenium. 19/45 patients had decreased posterior white matter volume and 23/45 had colpocephaly. 35/45 (78%) had associated posterior / Sylvian cortical malformations or abnormalities of sulcation, including 18/45 (40%) with abnormal Sylvian fissures. No patient had a mutation of FLNA. Conclusions: Posterior PNH are the second largest group of PNH and are radiologically and genetically distinct from suprasylvian/frontal PNH due to FLNA mutations. 98% of patients have associated brain malformations largely confined to the infrasylvian region. We therefore propose that these forms of PNH be termed infrasylvian PNH . The malformations associated with infrasylvian PNH have a characteristic spectrum of radiological features. Evidence for a genetic basis can be drawn from the monozygotic twins, sibling pairs and mother-son pair with infrasylvian PNH who show a range of abnormalities within the infrasylvian PNH spectrum. Our observations suggest that currently unidentified genetic determinants are likely to cause the infrasylvian PNH spectrum of abnormalities.