Periventricular nodular heterotopia (FLNA)
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A young woman with normal intelligence presents with adult-onset focal seizures. Brain MRI shows multiple smooth nodules of gray matter lining both lateral ventricles. Family history reveals a sister with epilepsy and a brother who died in utero with cardiac and skeletal malformations.
- Most common form: X-linked dominant, FLNA (filamin A, Xq28); typically male-lethal in utero, so cases are almost exclusively female
- Surviving males are rare and usually carry hypomorphic variants
- Allelic with the otopalatodigital spectrum and several connective-tissue/skeletal phenotypes (FLNA has wide pleiotropy)
- Rare AR forms: ARFGEF2 (with microcephaly and developmental delay)
- Bilateral, smooth, ovoid gray-matter nodules along the walls of the lateral ventricles (failure of late neuroblast migration from the ventricular zone to the cortex)
- Heterozygous females: epilepsy (often adolescent/adult onset), usually normal-to-near-normal cognition
- Frequent extracerebral findings in FLNA: patent ductus arteriosus, valvular dysplasia, aortic dilation, joint hypermobility, easy bruising
- Hemizygous males: severe (cardiac, skeletal, often lethal prenatally)
- MRI is the diagnostic imaging study; the bilateral periventricular nodules are characteristic
- FLNA sequencing in affected females; consider a broader brain-malformation panel if FLNA is negative
- Echocardiogram and aortic imaging at diagnosis given the cardiovascular risk
- Antiseizure medication; epilepsy is often pharmacoresponsive, occasionally surgical for intractable focal seizures arising from a nodule
- Cardiovascular surveillance (echo, aortic imaging) per the connective-tissue features
- Reproductive counseling: an affected woman has 50% transmission risk; expect male pregnancy losses and affected daughters
- Bilateral smooth periventricular nodules on MRI in a young woman with focal seizures should put FLNA at the top of the differential.
- The same gene that causes a brain-migration defect also causes connective-tissue and cardiac disease, a useful illustration of pleiotropy and a reminder to image the heart and aorta.
- Contrast with subcortical band heterotopia (DCX): SBH bands sit beneath the cortex (a "double cortex"), while PNH nodules sit against the ventricles.
"FLNA: Females Live, Nodules Abound": X-linked, male-lethal, female phenotype dominated by periventricular nodules.
"Filamin lines the wall": Filamin-A is needed for neuroblasts to leave the ventricular wall; without it, neurons stall and form nodules right where they started.