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Periventricular nodular heterotopia (PNH)
Gene (#OMIM):FLNA (*300017)
Periventricular nodular heterotopia (PNH), most often bilateral, consists of nodules of grey matter located along the lateral ventricles with a total failure of migration of some neurons. PNH can be highly variable in extent, ranging from isolated single nodules to confluent bilateral lesions. Functional MRI studies suggest that heterotopic nodules can assemble in functionally active aggregates and to participate in integrated networks and depth electrode studies demonstrated that either the heterotopic cortex or the overlying cerebral cortex, or both, can be epileptogenic.
PNH occurs much more frequently in women as an X-linked trait, which is associated with high rates of prenatal lethality in male foetuses and a 50% recurrence risk in the female offspring of affected women. Almost 100% of families with X-linked bilateral periventricular nodular heterotopia and about 26% of sporadic patients harbour mutations of the filamin A gene (FLNA). The low percentage of FLNA mutations in sporadic cases might be explained by somatic mosaicism. Heterozygous females have normal to borderline intelligence and epilepsy. Coagulopathy and cardiovascular abnormalities have been observed in some patients. A few living male patients with bilateral PNH owing to FLNA mutations are on record.
FLNA maps to Xq28 and codes for an actin binding protein that likely influences neuroblast migration during cortical development. FLNA is also important for coagulation and vascular development. These coagulation and vascular-related functions of FLNA might account for the prenatal male lethality observed in most pedigrees. Cardiovascular or gut malformations might also account for prenatal male lethality.
Other genes can cause PNH. A rare recessive form owing to mutations of the ARFGEF2 gene has been reported in consanguineous pedigrees. ARFGEF2 gene encodes for a protein involved in proliferation and migration during cortical development. Affected children have microcephaly, severe delay, and early-onset seizures, including infantile spasms. PNH may also be observed in patients with chromosomal rearrangements, such as duplication of 5p15.1 or 5p15.33.
Our laboratory has contributed to better define the clinical, anatomic and molecular features of Periventricular Heterotopia. We have defined 15 distinct malformation patterns of PH including classical bilateral PNH. We have characterized mutations in the FLNA gene and established phenotype-genotype correlations. In particular, we found FLNA mutations in 100% of familial cases with X-linked PNH and in 26% of sporadic patients with classical bilateral PNH. We are continuing to enrol patients/families with PNH to continue these studies and establish the yield of new diagnostic methods.
If you have a child who you think may have this condition and you would like us to review the diagnosis or provide genetic testing please contact us at email@example.com.