Search

Abstract Neuronal ceroid lipofuscinoses (NCLs) are genetically heterogeneous neurodegenerative disorders, characterized by progressive cognitive and motor decline, epilepsy, visual impairment, and shortened life‐expectancy. CLN6‐related NCLs include both late‐infantile and adult myoclonic form. We report a 21‐year‐old patient, with mild developmental delay, who developed occipital seizures at 14 years, and subsequently cognitive decline, cortical myoclonus, and photosensitivity at low and higher frequencies. Overall, the picture suited progressive myoclonus epilepsy. Electroretinogram was normal. A skin biopsy revealed a mixed storage of curvilinear and fingerprint profiles. A brain MRI showed severe cortical atrophy. Performing genetic analyses, two biallelic variants were identified in the CLN6 gene, each inherited from one of the healthy parents, one c.722T>C, p.(Met241Thr) already described in the late‐infantile form and the other one c.486+28T>C, intronic and novel, causing aberrant splicing. In the patient, the expression of the allele containing c.722T>C variant was increased, in comparison with the carrier parent. The peculiar genetic pattern observed in the patient could explain a milder clinical picture when compared with late‐infantile form, since CLN6 expression was partially preserved. However, the presence of a delay, and the early cognitive decline suggested a continuum phenotype connecting late‐infantile and adult CLN6‐related forms. Plain Language Summary We report a patient with CLN6 disease who developed symptoms at an intermediate age: 9 years for mild intellectual disability and 14 years for occipital seizures and progressive myoclonus epilepsy, without visual impairment. The patient is compound heterozygous for a CLN6 missense variant c.722T>C, p.(Met241Thr) already described in the late‐infantile form and for a novel intronic variant c.486+28T>C, causing aberrant splicing. In the patient, the expression of the allele containing c.722T>C variant was increased, compared with the carrier parent. The splice site variant had a milder effect. The peculiar genetic pattern may explain the continuum phenotype between late‐infantile and adult forms.

Variants in genes encoding for voltage-gated K+ (Kv) channels are frequent cause of drug-resistant pediatric epilepsies. Obtaining a molecular diagnosis gives the opportunity to assess the efficacy of pharmacological strategies based on in vitro features of mutant channels. In this retrospective observational study, we selected patients with drug-resistant pediatric epilepsies caused by variants in potassium channel encoding genes, followed at the Fondazione IRCCS Istituto Neurologico Carlo Besta of Milan, Italy. After the experimental characterization of variants’ functional properties in transiently transfected Chinese Hamster Ovary (CHO) cells, we identified drugs to be used as pharmacological approaches. We recruited six patients carrying different missense variants in four Kv channels (Kv7.2, Kv7.3, Kv3.1, and KNa1.1). In vitro experiments demonstrated that variants in Kv7 channels induced loss-of-function (LoF) effects, while those affecting Kv3.1 or KNa1.1 led to gain-of-function (GoF). Moreover, we found that the Kv7 channels activator gabapentin was able to revert the LoF effects caused by Kv7.2/Kv7.3 variants, and the potassium channel-blocker fluoxetine counteracted the GoF effects in Kv3.1 or KNa1.1 variants. According to experimental data, patients carrying Kv7 variants were treated with gabapentin. While this treatment resulted successful in two patients (#1, Kv7.2 G310S variant; #3, Kv7.3 V359L + Kv7.3 D542N), it resulted detrimental in the remaining case (#2, Kv7.2 D535E), requiring drug withdrawal. The application in vivo of fluoxetine to counteract GoF effects induced by Kv3.1 or KNa1.1 variants determined a significant reduction of both seizure frequency and behavior disturbances in patient #4 (Kv3.1 V425M), and in both subjects carrying KNa1.1 variants (#5, S937G and #6, R262Q). However, for the latter case, this drug was halted due to severe behavioral side effects. For most of the patients herein reported, pharmacological strategies, selected according to the in vitro functional properties of Kv-channels pathogenic variants, resulted in a significant improvement of both epileptic and cognitive features.