Programme Hospitalier Recherche Clinique, Institut Pasteur, Inserm, French Public Health Agency.

CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of Ca V 2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.

TANGO2 disease is a severe inherited disorder associating multiple symptoms such as metabolic crises, encephalopathy, cardiac arrhythmias, and

There is a duplication of the paternal allele on chromosome 11 in the focal forms of hyperinsulinism lesion. The paternal isodisomy observed rendered the beta-cells homozygous for ABCC8 mutation and harbored a K-channel defect in the lesion similar to that observed in diffuse forms of congenital hyperinsulinism.

The discovery of an isolated SA reveals the difficulties of prenatal diagnosis to correlate the neurological and functional prognosis to morphological findings. The prognosis seemed to be good. It appears necessary to improve the diagnostic performance of fetal brain imaging and to follow-up these children prospectively to assess their long-term cognitive-behavioral outcomes.