Phenotypic and imaging features of FLNA-negative patients with bilateral periventricular nodular heterotopia and epilepsy
Introduction
Periventricular nodular heterotopia (PVNH) is a malformation of cortical development due to impaired neuronal migration, resulting in the formation of nodular masses of neurons and glial cells in close proximity to the ventricular walls and through the white matter [1]. Several large case series of patients have described nodular heterotopia that include the periventricular, subcortical, and leptomeningeal varieties [2]. Most of these studies have included a variety of patients with different imaging abnormalities (unilateral or bilateral) and associated neurologic phenotypes. The most common presenting findings of patients with PVNH are central nervous system (CNS) malformations, other congenital malformations, seizures, and developmental delay [3]. Central nervous system malformations typically include ventriculomegaly, cortical and cerebellar abnormalities, and abnormalities of the corpus callosum [3]. Cardiac malformations are the most common non-CNS abnormality associated with FLNA-related PVNH [3]. The majority of the seizures in this population are focal onset and frequently difficult to treat [3], [4], [5]. Periventricular nodular heterotopia has been described in association with Filamin 1 (FLNA) mutations, particularly in females and in families [8]. However, the vast majority of sporadic cases have no known mutations.
We report the imaging and clinical characteristics of a large case series of FLNA mutation-negative patients with bilateral periventricular heterotopia and epilepsy ascertained by the Epilepsy Phenome/Genome Project (EPGP). The aim of this study was to determine how MRI-based imaging measures, utilizing qualitative and quantitative MRI assessments, relate to clinical features of individuals with PVNH. Specifically, we investigated the relationship between clinical characteristics of FLNA mutation-negative patients with bilateral periventricular heterotopia and qualitative assessment of (i) lesion location and (ii) number of nodules, and (iii) quantitative assessment of heterotopic gray matter (GM) volume.
Section snippets
Ascertainment
The present series includes 77 patients enrolled from 19 sites located within and outside of the United States recruited through the Epilepsy Phenome/Genome Project (EPGP), a multicenter collaborative effort to collect detailed phenotypic data and DNA on a large number of individuals with epilepsy, including a cohort with symptomatic epilepsy related to PVNH, with the ultimate goal of establishing genotype–phenotype correlations in epilepsy [6]. Each site's local institutional review board
Descriptive results
Six patients were excluded after exome analysis revealed a FLNA mutation that had not been identified prior to enrollment in the EPGP cohort. Thus, 71 FLNA-negative cases were included with bilateral PVNH. Of these, 56 cases had MRI data that were suitable for visual assessment and 43 cases (28 female, mean age: 22.81 ± 10.7 years) had MRI scans that were adequate for processing using the quantitative methods described above. For each category described below, n denotes the total number of
Discussion
This is the largest reported cohort of FLNA-negative bilateral PVNH patients with epilepsy. Filamin 1 mutations are frequently found in females as an X-linked trait [15]. The mutation is also associated with a high rate of prenatal lethality in males [12]. Although not statistically significant, there was a trend towards a female predominance in our cohort of FLNA-negative patients. Interestingly, when controlling for gender, this analysis of FLNA-negative patients showed a marginally
Acknowledgments
This study was supported by NINDS U01 NS 053998, as well as planning grants from the Finding a Cure for Epilepsy and Seizures (FACES) Foundation, the Andrew's Foundation and the Richard Thalheimer Philanthropic Fund. A.P. was supported by the NINDS (K23 NS069784).
We would like to acknowledge the recruitment contributions of the EPGP Community Referral Network (CRN). The CRN consists of health-care professionals not paid by the EPGP grant who refer eligible families to EPGP. A list of individual
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The clinical and imaging features of FLNA positive and negative periventricular nodular heterotopia
2022, Biomedical JournalCitation Excerpt :Previous studies also reported that 51–74% of anterior predominant PVNH were negative for FLNA variants [2,17,22]. As for other associated features, we found that FLNA positive cases are likely to have more systemic manifestations (∼78%) while none of the FLNA negative patients had associated internal organ abnormality or cardiovascular abnormality [23–25]. The most common extracerebral features are cardiac abnormalities followed by gut dysfunction and joint hypermobility.
X-linked hereditary periventricular nodular heterotopia
2022, NeurologiaSporadic periventricular nodular heterotopia: Classification, phenotype and correlation with Filamin A mutations
2017, Epilepsy ResearchCitation Excerpt :Periventricular nodular heterotopia (PNH) is the most common and widely studied form of neuronal heterotopia. PNH is defined by groups of normal neurons that line the ventricular walls and is characterized by seizures, normal intelligence, and dyslexia (Fallil et al., 2015). PNH consists of clusters of neurons that fail to migrate away from the embryonic ventricular zone to the developing cerebral cortex (Battaglia et al., 2006; Dubeau et al., 1995).
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