Cask-Related Disorders: Clinical, Electroencephalographic and Neuroradiological Description of Four Genetically Confirmed Cases

Introduction: CASK mutations (Xp11.4) were first identified in female patients with cognitive impairment and microcephaly with pontine and cerebellar hypoplasia (MICPCH). CASK encodes a calcium/calmodulin-dependent serine protein kinase, involved in synaptic interaction, protein trafficking, and regulation of gene expression during neural development. Alterations in this gene are, therefore, associated with many different disorders: X-linked mental retardation, optic atrophy and brainstem and cerebellar hypoplasia, X-linked intellectual disability with/without nystagmus, FG syndrome, epileptic encephalopathy, and, very recently, with autism spectrum disorders. Loss of function CASK mutations causes severe phenotype, while missense mutation seems to produce milder phenotypes. Deletions and intragenic mutations are associated with MICPCH syndrome more commonly than duplications.

A dew studies describe the characteristics of epilepsy in patients with CASK mutations. In this report, we present four genetically confirmed patients with diverse genetic and clinical phenotypes.

Methods: CASK gene screening using array-CGH and sequencing of the coding region showed a de novo mutation in four patients (4 F, age range 17–28 years) presenting different clinical and electroclinical phenotypes. Clinical and neuroradiological data have been collected and electroencephalography (EEG) documentation has been reviewed.

Results: All four patients presented different de novo CASK mutations (two deletions, two puntiform mutations). Neuroradiological pattern was typical for CASK mutations spectrum, but two patients had mild phenotypes with/without epilepsy associated with structured EEG, while the others had a drug-resistant epileptic encephalopathy.

Conclusions: CASK-related disorders compose a complex phenotypical spectrum. Epilepsy and epileptic encephalopathies may be the most important clinical presentations, also with atypical features. Future studies are necessary for a genotype–phenotype correlation.

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