CDKL5 deficiency disorder: progressive brain atrophy may be part of the syndrome

The clinical phenotype of Cyclin-Dependent Kinase-Like 5 (CDKL5) deficiency disorder (CDD) has been delineated but neuroimaging features have not been systematically analyzed. We studied brain magnetic resonance imaging (MRI) scans in a cohort of CDD patients and reviewed age at seizure onset, seizure semiology, head circumference. Thirty-five brain MRI from 22 unrelated patients were included. The median age at study entry was 13.4 years. In 14/22 patients (85.7%), MRI in the first year of life was unremarkable in all but two. In 11/22, we performed MRI after 24 months of age (range 2.5-23 years). In 8 out of 11 (72.7%), MRI showed supratentorial atrophy and in six cerebellar atrophy. Quantitative analysis detected volumetric reduction of the whole brain (-17.7%, P-value = 0.014), including both white matter (-25.7%, P-value = 0.005) and cortical gray matter (-9.1%, P-value = 0.098), with a reduction of surface area (-18.0%, P-value = 0.032), mainly involving the temporal regions, correlated with the head circumference (& rho; = 0.79, P-value = 0.109). Both the qualitative structural assessment and the quantitative analysis detected brain volume reduction involving the gray and white matter. These neuroimaging findings may be related to either progressive changes due to CDD pathogenesis, or to the extreme severity of epilepsy, or both. Larger prospective studies are needed to clarify the bases for the structural changes we observed

Gabapentin treatment in a patient with KCNQ2 developmental epileptic encephalopathy

De novo variants in KCNQ2 encoding for Kv7.2 voltage-dependent neuronal potassium (K+) channel subunits are associated with developmental epileptic encephalopathy (DEE). We herein describe a the clinical and electroencephalographic (EEG) features of a child with early-onset DEE caused by the novel KCNQ2 p.G310S variant. In vitro experiments demonstrated that the mutation induces loss-of-function effects on the currents produced by channels incorporating mutant subunits; these effects were counteracted by the selective Kv7 opener retigabine and by gabapentin, a recently described Kv7 activator. Given these data, the patient started treatment with gabapentin, showing a rapid and sustained clinical and EEG improvement over the following months. Overall, these results suggest that gabapentin can be regarded as a precision therapy for DEEs due to KCNQ2 loss-of-function mutations

Case report: Marked electroclinical improvement by fluoxetine treatment in a patient with KCNT1-related drug-resistant focal epilepsy

Variants in KCNT1 are associated with a wide spectrum of epileptic phenotypes, including epilepsy of infancy with migrating focal seizures (EIMFS), non-EIMFS developmental and epileptic encephalopathies, autosomal dominant or sporadic sleep-related hypermotor epilepsy, and focal epilepsy. Here, we describe a girl affected by drug-resistant focal seizures, developmental delay and behavior disorders, caused by a novel, de novo heterozygous missense KCNT1 variant (c.2809A > G, p.S937G). Functional characterization in transiently transfected Chinese Hamster Ovary (CHO) cells revealed a strong gain-of-function effect determined by the KCNT1 p.S937G variant compared to wild-type, consisting in an increased maximal current density and a hyperpolarizing shift in current activation threshold. Exposure to the antidepressant drug fluoxetine inhibited currents expressed by both wild-type and mutant KCNT1 channels. Treatment of the proband with fluoxetine led to a prolonged electroclinical amelioration, with disappearance of seizures and better EEG background organization, together with an improvement in behavior and mood. Altogether, these results suggest that, based on the proband’s genetic and functional characteristics, the antidepressant drug fluoxetine may be repurposed for the treatment of focal epilepsy caused by gain-of-function variants in KCNT1. Further studies are needed to verify whether this approach could be also applied to other phenotypes of the KCNT1-related epilepsies spectrum

Diaper changing-induced reflex seizures in CDKL5-related epilepsy

Mutations in the CDKL5 (cyclin-dependent kinase-like-5) gene are known to determine early-onset drug resistant epilepsies and severe cognitive impairment with absent language, hand stereotypies, and deceleration of head growth. Reflex seizures are epileptic events triggered by specific stimuli and diaper changing is a very rare triggering event, previously described in individual cases of both focal and unclassified epilepsy, as well as in Dravet syndrome. Our aim was to describe diaper changing-induced reflex seizures as one of the presenting features in a case of CDKL5-related epilepsy, providing video-EEG documentation and focusing discussion on hyperexcitability determined by the disease. [Published with video sequence on www.epilepticdisorders.com]

Diaper changing-induced reflex seizures in CDKL5-related epilepsy

Mutations in the CDKL5 (cyclin-dependent kinase-like-5) gene are known to determine early-onset drug resistant epilepsies and severe cognitive impairment with absent language, hand stereotypies, and deceleration of head growth. Reflex seizures are epileptic events triggered by specific stimuli and diaper changing is a very rare triggering event, previously described in individual cases of both focal and unclassified epilepsy, as well as in Dravet syndrome. Our aim was to describe diaper changing-induced reflex seizures as one of the presenting features in a case of CDKL5-related epilepsy, providing video-EEG documentation and focusing discussion on hyperexcitability determined by the disease. [Published with video sequence on www.epilepticdisorders.com]

Early-onset bradykinetic rigid syndrome and reflex seizures in a child with PURA syndrome

: PURA syndrome is a distinct form of developmental encephalopathy, characterized by early-onset hypotonia, severe developmental delay, intellectual disability, epilepsy and respiratory and gastrointestinal disorders. We report a child with PURA syndrome, harbouring a previously described mutation, whose phenotype included two peculiar aspects: (1) hypokinetic-rigid syndrome, which was part of the clinical presentation from an early stage of the disease, and (2) reflex seizures, consisting of a series of spasms. We provide detailed clinical description and video recordings demonstrating both these aspects that are newly described in PURA syndrome. The early clinical features described here may therefore be included in the complex phenotype associated with PURA gene mutations and may help in the early diagnosis of patients. Furthermore, PURA syndrome should be considered in the differential diagnosis of early-onset bradykinetic rigid syndromes

Gelastic seizures and “smiling spasms”: A peculiar ictal pattern

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CDKL5 deficiency disorder in males: Five new variants and review of the literature

The X-linked Cyclin-Dependent Kinase-Like 5 (CDKL5) gene encodes a serine-threonine kinase highly expressed in the developing brain. Loss of function of CDKL5 is pointed out to underlie the CDKL5 Deficiency Disorder (CDD), an X-linked dominant disease characterized by early-onset epileptic encephalopathy and developmental delay, usually affecting females more than males. To the best to our knowledge, only 45 males with CDD have been reported so far. Type and position of CDKL5 variants with different impact on the protein are reported to influence the clinical presentation. X-chromosome inactivation occurring in females and post-zygotic mosaicism in males are also believed to contribute to this variability. Based on these issues, genotype-phenotype correlations are still challenging. Here, we describe clinical features of five additional affected males with unreported CDKL5 variants, expanding the molecular spectrum of the disorder. We also reviewed the clinical profile of the previously reported 45 males with molecularly confirmed CDD. Severe developmental delay, cortical visual impairment, and early-onset refractory epilepsy characterize the CDD picture in males. By assessing the molecular spectrum, we confirm that germ-line truncating CDKL5 variants, equally distributed across the coding sequence, are the most recurrent mutations in CDD, and cause the worsen phenotype. While recurrence and relevance of missense substitutions within C-terminal remain still debated, disease-causing missense changes affecting the N-terminal catalytic domain correlate to a severe clinical phenotype. Finally, our data provide evidence that post-zygotic CDKL5 mosaicism may result in milder phenotypes and, at least in a subset of subjects, in variable response to antiepileptic treatments

SYNGAP1-DEE: A visual sensitive epilepsy

International audienceObjective: To further delineate the electroclinical features of individuals with SYNGAP1 pathogenic variants.Methods: Participants with pathogenic SYNGAP1 variants and available video-electroencephalogram (EEG) recordings were recruited within five European epilepsy reference centers. We obtained molecular and clinical data, analyzed EEG recordings and archived video-EEGs of seizures and detailed characteristics of interictal and ictal EEG patterns for every patient.Results: We recruited 15 previously unreported patients and analyzed 72 EEGs. Two distinct EEG patterns emerged, both triggered by eye closure. Pattern 1 (14/15 individuals) consisted of rhythmic posterior/diffuse delta waves appearing with eye-closure and persisting until eye opening (strongly suggestive of fixation-off sensitivity). Pattern 2 (9/15 individuals) consisted of diffuse polyspike-and-wave discharges triggered by eye closure (eye-closure sensitivity). Both patterns presented in 8/15. Including archived video-EEG clips of seizures from 9/15 patients, we analyzed 254 seizures. Of 224 seizures experienced while awake, 161 (72%) occurred at or following eye closure. In 119/161, pattern 1 preceded an atypical absence, myoclonic seizure or myoclonic absence; in 42/161, pattern 2 was associated with eyelid myoclonia, absences and myoclonic or atonic seizures.Conclusions: Fixation-off and eye closure were the main triggers for seizures in this SYNGAP1 cohort.Significance: Combining these clinical and electroencephalographic features could help guide genetic diagnosis