Key result
FLNA loss-of-function variants were associated with cardiovascular anomalies and connective tissue disorder features in 75% of patients, demonstrating a multisystemic syndrome where half of the patients did not present neurological symptoms.
Why the study?
Neurological symptoms in FLNA Loss-of-Function are inconstant, and the study aimed to refine the description of associated cardiovascular and connective tissue disorder features to depict its multisystemic nature.
Observational (n=92)
Yes
Patients with FLNA loss-of-function variants frequently present with cardiovascular and connective tissue anomalies, such as aortic aneurysms, even in the absence of neurological symptoms, warranting systematic cardiovascular assessment.
BACKGROUND: FLNA Loss-of-Function (LoF) causes periventricular nodular heterotopia type 1 (PVNH1), an acknowledged cause of seizures of various types. Neurological symptoms are inconstant, and cardiovascular (CV) defects or connective tissue disorders (CTD) have regularly been associated. We aimed at refining the description of CV and CTD features in patients with FLNA LoF and depicting the multisystemic nature of this condition. METHODS: We retrospectively evaluated FLNA variants and clinical presentations in FLNA LoF patient with at least one CV or CTD feature, from three cohorts: ten patients from the French Reference Center for Rare Vascular Diseases, 23 patients from the national reference diagnostic lab for filaminopathies-A, and 59 patients from literature review. RESULTS: Half of patients did not present neurological symptoms. Most patients presented a syndromic association combining CV and CTD features. CV anomalies, mostly aortic aneurysm and/or dilation were present in 75% of patients. CTD features were present in 75%. Variants analysis demonstrated an enrichment of coding variants in the CH1 domain of FLNA protein. CONCLUSION: In FLNA LoF patients, the absence of seizures should not be overlooked. When considering a diagnosis of PVNH1, the assessment for CV and CTD anomalies is of major interest as they represent interlinked features. We recommend systematic study of FLNA within CTD genes panels, regardless of the presence of neurological symptoms.
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Billon et al. (2021) conducted an observational in FLNA-related periventricular nodular heterotopia type 1 (PVNH1) (n=92). FLNA loss-of-function variants was evaluated on Presence of cardiovascular and connective tissue disorder features. FLNA loss-of-function variants were associated with cardiovascular anomalies and connective tissue disorder features in 75% of patients, demonstrating a multisystemic syndrome where half of the patients did not present neurological symptoms.
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