Hindbrain malformation and myoclonic seizures associated with a deleterious mutation in the INPP4A gene.

Hindbrain malformations with predominant cerebellar involvement have many causes including chromosomal disorders, specific genetic syndromes, and prenatal disruptions. The combination of a hindbrain malformation and myoclonic epilepsy is rare. Using exome sequencing in a consanguineous family, we identified a homozygous genomic deletion of 1770 bp within the INPP4A gene in a patient with myoclonic epilepsy, microcephaly, and atrophy of the inferior vermis and cerebellum. INPP4A participates in the excitatory glutamate signaling pathway and is essential for the degradation of phosphatidylinositol (3,4)-bisphosphate. Glutamatergic signaling is important for hindbrain development and is implicated in the pathogenesis of epilepsy, as well as excitotoxic cell death. Indeed, excessive glutamatergic stimulation was previously reported in INPP4A knockout mice. Our data adds a new etiology to the spectrum of hindbrain malformations in human, and when presented with myoclonic epilepsy may lead to the clinical suspicion of INPP4A defect. The present report further underscores the importance of phosphoinositides for the development of the inferior cerebellum and vermis.