Objective: To describe two cases affected by childhood onset ataxia and seizures carrying de novo variants in the gene FRMD5

Background: FRMD5 belongs to the family of FERM domain-containing proteins (FDCP) that localize to the adherens junctions. Recently, Lu et al. (PMID:36206744) identified rare heterozygous FRMD5 de novo variants in eight patients with developmental delay, intellectual disability, ataxia, and eye movement abnormalities

Method: Informed consent was obtained from the subjects’ parents. Medical records and MRIs were reviewed. Trio-based whole-exome sequencing was performed

Results: Patient 1 is a 6-year-old female presenting with developmental delay, nystagmus, bilateral foot dystonia, diffuse choreiform movements, gait ataxia, and epilepsy. Video-EEG showed pleomorphic polyspike and wave discharges in the right central regions. She carries a novel, likely pathogenic variant in FRMD5 (c.1064T>C; p.Ile355Thr).

Patient 2 is a 10-year-old male with developmental delay, nystagmus, ataxic gait, and tonic seizures. Additional features are abnormal palmar creases, prominent ears, and a café au lait macule on his abdomen. EEG showed bitemporal sharp waves. Multiple nonspecific T2\FLAIR hyperintensities in the bilateral periventricular white matter were seen on brain MRI. He carries a de novo pathogenic variant in FRMD5 (c.1054T>C; p.Cys352Arg), which was previously described by Lu et al. in an unrelated case with ataxia

Conclusion: Our report described two patients affected by developmental delay, childhood-onset ataxia and seizures, carrying very rare missense de novo variants in FRMD5.

Lu et al. identified seven FRMD5 variants in eight patients with similar phenotype, five of them clustering in the FERM-adjacent (FA) domain within a very small hotspot region. Interestingly, both variants we identified fall within this protein domain as well.

Our report confirms that FRMD5 variants are a cause of childhood-onset cerebellar ataxia with prominent oculomotor abnormalities and expands the phenotype associated with FRMD5 variants to include chorea, dystonia and diffuse hyperintense MRI white matter (WM) lesions.

We are currently performing network analysis to investigate the mechanisms of FRMD5 in disease pathogenesis and its potential interactions with other genes known to cause cerebellar disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/frmd5-de-novo-variants-in-two-cases-with-childhood-onset-ataxia-and-seizures/