Aktuelle Neurologie 2007; 34 - P519
DOI: 10.1055/s-2007-987790

Broad phenotypic spectrum of FLNA-associated disorders resulting in brain malformation, epilepsy, mental retardation and stroke

G Uyanik 1, A Hehr 1, G Schuierer 1, A Bohring 1, S Spranger 1, L Neumann 1, MG Shamdeen 1, B Kasper 1, H Stefan 1, W Reardon 1, U Bogdahn 1, U Hehr 1, J Winkler 1
  • 1Regensburg, Münster, Bremen, Berlin, Saarbrücken, Erlangen; Dublin, IRL

Aims: Mutations of the X-linked Filamin A gene (FLNA) on Xq28 are detected in patients with periventricular nodular heterotopia (PVNH). Due to its X-linked character the most common form of PVNH affects mostly females, while mutations of the FLNA gene in hemizygous males are mostly lethal. Clinically, PVNH is characterized by focal and/or generalized seizures, mild to profound mental retardation and in some cases also with ischemic cerebral lesions due to a profound vasculo-/coagulopathy. Furthermore, gain of function mutations of FLNA result in distinct skeletal phenotypes without any obvious neurological deficits. Recently, we could identify a distinct FLNA mutation in a male patient causing PVNH associated with dysmorphic features and severe constipation.

Methods: Clinical examination, neuroradiological evaluation and sequence analysis of the FLNA gene in patients with PVNH.

Results: We report about 10 PVNH patients with FLNA mutations. Three patients presented a patent ductus arteriosus Botalli. Two patients showed numerous white matter lesions indicative for ischemic damage due to vasculo-/coagulopathy. Following bilateral finger tapping, fMRI revealed a co-activation of periventricular nodules indicating a functional integration of the nodular heterotopia. The presence of exonal deletions, which is frequently missed by sequencing of the gene, could be detected by segregation analysis of SNPs. Interestingly, a male patient with a FLNA mutation showed facial dysmorphism, PVNH and severe constipation.

Conclusions: FLNA mutations result in a broad phenotypic spectrum since Filamin A is crucial for different aspects during cerebral and skeletal development. In particular, loss-of-function mutations affect the forebrain and the vascular system leading to a severe cerebral migration disorder associated with epilepsy, mental retardation and strokes. Gain-of-function mutations are rather associated with skeletal abnormalities.