Mutation in Filamin A Causes Periventricular Heterotopia, Developmental Regression, and West Syndrome in Males

Abstract

Summary:Purpose: Familial periventricular heterotopia (PH) represents a disorder of neuronal migration resulting in multiple gray-matter nodules along the lateral ventricular walls. Prior studies have shown that mutations in the filamin A (FLNA) gene can cause PH through an X-linked dominant pattern. Heterozygotic female patients usually remain asymptomatic until the second or third decade of life, when they may have predominantly focal seizures, whereas hemizygotic male fetuses typically die in utero. Recent studies have also reported mutations in FLNA in male patients with PH who are cognitively normal. We describe PH in three male siblings with PH due to FLNA, severe developmental regression, and West syndrome.Methods: The study includes the three affected brothers and their parents. Video-EEG recordings and magnetic resonance image (MRI) scanning were performed on all individuals. Mutations for FLNA were detected by using polymerase chain reaction (PCR) on genomic DNA followed by single-stranded conformational polymorphism (SSCP) analysis or sequencing.Results: Two of the siblings are monozygotic twins, and all had West syndrome with hypsarrthymia on EEG. MRI of the brain revealed periventricular nodules of cerebral gray-matter intensity, typical for PH. Mutational analyses demonstrated a cytosine-to-thymidine missense mutation (c. C1286T), resulting in a threonine-to-methionine amino acid substitution in exon 9 of the FLNA gene.Conclusions: The association between PH and West syndrome, to our knowledge, has not been previously reported. Males with PH have been known to harbor FLNA mutations, although uniformly, they either show early lethality or survive and have a normal intellect. The current studies show that FLNA mutations can cause periventricular heterotopia, developmental regression, and West syndrome in male patients, suggesting that this type of FLNA mutation may contribute to severe neurologic deficits.

Filamin A: Insights into its Exact Role in Cancers

“…Periventricular heterotopia results from neurons' failure to migration, and this disease has been linked to various mutations in FlnA [18][19][20][21]. Heterozygous loss of function of human FlnA causes periventricular nodular heterotopia in females and is generally lethal in hemizygous males [20].…”

The dual role of filamin A in cancer: can't live with (too much of) it, can't live without it

“…Periventricular heterotopia is an X-linked dominant disorder, in which neurons fail to migrate into the cerebral cortex, but remain as nodules lining the ventricular surface. This disease has been linked to various mutations in FlnA , including a frameshift mutation (3045del5) in exon 21 (de Wit et al 2009) and a cytosine-to-thymidine missense mutation (c. C1286T) in exon 9, resulting in a threonine-to-methionine amino acid substitution (Masruha et al 2006). Various other mutations in other parts of the gene, resulting in protein misfolding, has been reported (Sheen et al 2001, 2005, Parrini et al 2006).…”

Genetic and Biologic Classification of Infantile Spasms

“…For example, we found several reports of ISS in patients with Freeman-Sheldon, Schinzel-Giedieon, Smith-Lemli-Opitz, and Sotos syndrome [103–109]. There are also reports of ISS in patients with mutations in FLNA and ARFGEF2 , genetic causes of periventricular nodular heterotopia [110, 111]. However, other seizure types are more common than ISS in most of these disorders, especially patients with heterotopia due to FLNA mutations, making it difficult to argue that these genes are reliably causative.…”