Periventricular Heterotopia: New Insights into Ehlers-Danlos Syndrome

Abstract

Nature often employs similar mechanisms to complete similar tasks, thus the evolution of homologous proteins across various organ systems to perform similar but slightly different functions. In this respect, disorders attributed to specific genetic mutations, while initially thought to be restricted in function and purpose, may provide broad insight into general cellular and molecular mechanisms of development and maintenance. One such example can be seen in the brain malformation, periventricular heterotopia (PH), which is characterized by very specific nodules of neurons that line the lateral ventricles beneath the cerebral cortex. PH is seen as a disorder of neuronal migration and can be caused by mutations in filamin A (FLNA), which encodes an actin-binding protein that regulates the cytoskeleton and cell motility. Recent advances in our understanding of the genetic causes of PH suggest that mutations in this gene, however, are also associated with the connective tissue disorder, Ehlers-Danlos syndrome (EDS), in which affected individuals present with joint and skin hyperextensibility and vascular problems including aortic dissection, excessive bleeding and bruisability.While much still remains unknown regarding the mechanistic role of FLNA in giving rise to PH and EDS, a common cellular and molecular basis likely gives rise to these two seemingly unrelated clinical disorders.

Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A

“…It was further proposed that PH may represent a disorder of impaired periventricular intercellular or cell-matrix adhesion and the authors postulated that aortic dilatation and hyperextensible skin observed in EDS-PH may have similar pathological underpinnings. 10 Gó mez-Garre et al 5 reported EDS-PH due to an FLNA mutation (p.Ala128Val), in females in a pedigree presenting with seizures and joint hypermobility, but they reported no cardiovascular involvement except for mitral valve prolapse. Solé et al 7 screened patients presenting with PH for mutations in FLNA and identified 15 carriers out of 32 screened.…”

Ehlers–Danlos syndrome: A cause of epilepsy and periventricular heterotopia

“…[52][53][54][55][56] Otherwise, FLNA mutations could decrease the connection of the cells to the extracellular matrix or compromise regulation to the cytoskeleton through the FLNA binding to integrins proteins. 49,57 Furthermore, a relationship between FLNA and collagen can have a role in the mechanism of platelet aggregation; in fact, mutations in the FLNA and in COL3A1 gene (vascular type of EDS) are both known to determine excessive bleeding, probably due to vascular fragility and platelet dysfunction 49,58 ; mutations in FLNA can cause classic bilateral PNH, [59][60][61][62][63][64]32,65 and the inheritance can be X-linked dominant (mutations in the Filamin A gene) or autosomal recessive (mutations in ARFGEF2 gene). 40 This last mutation has been associated to PNH but in patients without EDS.…”

“…A disruption in the link between the extracellular matrix and cytoskeleton could cause an aberration in cellular migration during development with possible congenital malformations of the vessels and the brain parenchyma, including cortical dysgenesis. 40,48,49 EDS is considered a disorder of the extracellular matrix related with a disruption in glycoproteins, involving collagen or proteoglycans or other extracellular matrix proteins like Tenascin-X. 36,50,51 Cells join to the extracellular matrix by integrins, whose intracellular portion binds to the actin filaments of the cytoskeleton.…”

Peritrigonal and temporo-occipital heterotopia with corpus callosum and cerebellar dysgenesis

“…Our previous experience indicated that mutations of FLNA are found in up to 26% of sporadic patients with classic bilateral PNH 3 and in only 4% of other phenotypic subclasses of PNH, including PNH with Ehlers-Danlos syndrome 24 and unilateral PNH. FLNA cannot be completely ruled out as the causative gene in all patients of this cohort, as mutation in noncoding regions, larger deletions/duplications involving 1 or more exons, and cryptic chromosomal abnormalities involving FLNA might still be present.…”