SUMMARYMutations in the KCNQ2 gene encoding for voltage-gated potassium channel subunits have been found in patients affected with early onset epilepsies with wide phenotypic heterogeneity, ranging from benign familial neonatal seizures (BFNS) to epileptic encephalopathy with cognitive impairment, drug resistance, and characteristic electroencephalography (EEG) and neuroradiologic features. By contrast, only few KCNQ3 mutations have been rarely described, mostly in patients with typical BFNS. We report clinical, genetic, and functional data from a family in which early onset epilepsy and neurocognitive deficits segregated with a novel mutation in KCNQ3 (c.989G>T; p.R330L). Electrophysiological studies in mammalian cells revealed that incorporation of KCNQ3 R330L mutant subunits impaired channel function, suggesting a pathogenetic role for such mutation. The degree of functional impairment of channels incorporating KCNQ3 R330L subunits was larger than that of channels carrying another KCNQ3 mutation affecting the same codon but leading to a different amino acid substitution (p.R330C), previously identified in two families with typical BFNS. These data suggest that mutations in KCNQ3, similarly to KCNQ2, can be found in patients with more severe phenotypes including intellectual disability, and that the degree of the functional impairment caused by mutations at position 330 in KCNQ3 may contribute to clinical disease severity.

Microdeletions of 17q12 including the hepatocyte nuclear factor 1 beta (HNF1B) gene, as well as point mutations of this gene, are associated with the Renal Cysts and Diabetes syndrome (RCAD, OMIM 137920) and genitourinary alterations. Also, microdeletions encompassing HNF1B were identified as a cause of Mayer-RokitanskyKüster-Hauser Syndrome (MRKH, OMIM 277000) in females and, recently, were associated with intellectual disability, autistic features, cerebral anomaly and facial dysmorphisms. In this report, we describe a boy with a deletion in 17q12 region detected by SNP array, encompassing the HNF1B gene, that showed dysmorphic features, intellectual disability (ID), serious speech delay and autistic features. In addition, obesity was observed. In order to study the parental origin of the rearrangement, we analyzed selected SNPs in the deleted area in the patient and his parents, showing Mendelian incompatibilities suggesting a de novo deletion on the chromosome of maternal origin. Our case confirms the incomplete penetrance and variable expressivity of this deletion, its complex clinical variability, and strengthens the evidence that ID and stereotyped behaviors may be part of the phenotypic spectrum characterizing the affected patients. Also, it is useful to further delineate the phenotypes associated to the deletion being the first case in which obesity has been documented. We present a genotype-phenotype correlation discussing the possible role of some genes, encompassed by the deletion, in the etiology of the observed phenotypes.

Benign myoclonic epilepsy in infancy (BMEI) is a rare syndrome of idiopathic generalized epilepsies with onset below 3 years of age. It has been reported that BMEI is associated with a good prognosis, however, recently some studies suggest less favourable neuropsychological outcome. We report a long-term follow-up of seven patients with BMEI. Seizure outcome and neuropsychological, cognitive, and behavioural evolution were discussed for each of them. At the end of follow-up, 86% of children showed neuropsychological and intellectual disorders: two children had mental retardation, three patients achieved a borderline IQ and one normal but low IQ. All but one displayed neuropsychological disabilities including fine motor skill deficits, attention deficits, and language impairment and learning disorders. Our clinical data and the previous reports suggest that the early onset of the seizures may be one of the main factors of the illness giving rise to a less favourable outcome. Additional interacting factors such as delayed start of treatment, and efficacy of the drugs may play an important role, too. We believe that BMEI does not exert, different from some epileptic encephalopathies, a quick destroying effect but may interfere with the growth of developing functions, which results in long-term neuropsychological disabilities. q

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