Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder

Fehr, Stephanie; Wong, Kingsley; Chin, Richard; Williams, Simon; Klerk, Nicholas de; Forbes, David; Krishnaraj, R.; Christodoulou, John; Downs, Jenny; Leonard, Helen

doi:10.1212/wnl.0000000000003352

Cited by 87 publications

(156 citation statements)

References 18 publications

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“…13 The most recent Cochrane review reported seizure reduction of up to 50% with KD after approximately 3 months compared to placebo in children and adolescents with refractory epilepsy. 7 Previous studies have reported poor response to the diet in small samples (6 and 17 cases) with the CDKL5 disorder. However, no information was provided on which seizure types responded to the KD, and overall the quality of the evidence was poor.…”

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confidence: 91%

“…It functions to maintain normal synapse activity within the central nervous system (CNS). 7,8 Seizure onset occurs at a median age of 6 weeks, 7,9 and seizure types may include infantile spasms, myoclonic seizures, tonic, and generalized tonic-clonic seizures, often with a complex semiology including multiple seizures types in one epoch. 4 Furthermore, its association with the phosphorylation of MeCP2 and DNA methyl-transferase 1 suggests a role of CDKL5 in the epigenetic regulation of gene expression.…”

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confidence: 99%

“…Mouse model studies have demonstrated neuroprotective effects of the KD through the upregulation of mitochondrial uncoupling proteins leading to a decrease in seizure-related reactive oxygen species. 1,2,7,8 However, the uncertainty regarding long-term efficacy and the significant side effect profile of the KD serve as major barriers against treatment maintenance. 13 The most recent Cochrane review reported seizure reduction of up to 50% with KD after approximately 3 months compared to placebo in children and adolescents with refractory epilepsy.…”

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Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients

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Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients

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“…However, there has been recent evidence demonstrating some differences in clinical features when compared with typical RTT [4–6]. Epilepsy is almost universal and generally occurs in early infancy with a median age of six weeks ranging from one week to 1.5 years [4, 7] and thus symptoms of this disorder appear very early in life. Sleep difficulties appear to be more common in the CDKL5 disorder than in RTT [4, 6].…”

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Impacts of caring for a child with the CDKL5 disorder on parental wellbeing and family quality of life

Mori

Downs

Wong

et al. 2017

Orphanet J Rare Dis

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BackgroundAlthough research in this area remains sparse, raising a child with some genetic disorders has been shown to adversely impact maternal health and family quality of life. The aim of this study was to investigate such impacts in families with a child with the CDKL5 disorder, a newly recognised genetic disorder causing severe neurodevelopmental impairments and refractory epilepsy.MethodsData were sourced from the International CDKL5 Disorder Database to which 192 families with a child with a pathogenic CDKL5 mutation had provided data by January 2016. The Short Form 12 Health Survey Version 2, yielding a Physical Component Summary and a Mental Component Summary score, was used to measure primary caregiver’s wellbeing. The Beach Center Family Quality of Life Scale was used to measure family quality of life. Linear regression analyses were used to investigate relationships between child and family factors and the various subscale scores.ResultsThe median (range) age of the primary caregivers was 37.0 (24.6–63.7) years and of the children was 5.2 (0.2–34.1) years. The mean (SD) physical and mental component scores were 53.7 (8.6) and 41.9 (11.6), respectively. In mothers aged 25–54 years the mean mental but not the physical component score was lower than population norms. After covariate adjustment, caregivers with a tube-fed child had lower mean physical but higher mean mental component scores than those whose child fed orally (coefficient = −4.80 and 6.79; p = 0.009 and 0.012, respectively). Child sleep disturbances and financial hardship were negatively associated with the mental component score. The mean (SD) Beach Center Family Quality of Life score was 4.06 (0.66) and those who had used respite services had lower scores than those who had not across the subscales.ConclusionsEmotional wellbeing was considerably impaired in this caregiver population, and was particularly associated with increased severity of child sleep problems and family financial difficulties. Family quality of life was generally rated lowest in those using respite care extensively, suggesting that these families may be more burdened by daily caregiving.

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“…Cardinal features of epilepsy in the CDKL5 disorder include early onset at a median age of six weeks and poor response to anti-epileptic drugs (AEDs) 2 . The Ketogenic Diet (KD) was first introduced in the 1920s and is as a second- or third-line intervention for paediatric refractory epilepsy 3 .…”

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Ketogenic diet to manage refractory epilepsy in the cdkl5 disorder

Lim

Downs

Wong

et al. 2017

J Neurol Neurosurg Psychiatry

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ObjectivesMutations involving the CDKL5 gene have been identified as a cause of severe epileptic encephalopathy, often later presenting with features similar to Rett syndrome.1 Cardinal features of epilepsy in the CDKL5 disorder include early onset at a median age of six weeks and poor response to anti-epileptic drugs (AEDs).2 The Ketogenic Diet (KD) was first introduced in the 1920s and is as a second- or third-line intervention for paediatric refractory epilepsy.3 This study investigated the use of KD in the CDKL5 disorder and its influences on seizures.MethodsThe International CDKL5 Disorder Database (ICDD), established in 2012, collects information from caregivers and clinicians of individuals with the CDKL5 disorder. Families provided information regarding seizure characteristics, use of and side effects of the KD treatment. Descriptive statistics and time to event analyses were performed.ResultsData regarding KD use was available for 204 individuals with a pathogenic CDKL5 mutation. Median age of ascertainment to the database was 4.8 years (range 0.3–33.9 years) with median age of seizure onset of 6 weeks (range 1 day–65 weeks). History of KD use was reported for 51% (104/204) which was used for a median duration of 17 months (95% CI 9 to 24). Changes in seizure activity after commencing KD were reported for two-thirds of individuals (69/104), with positive effects reported for 88%. Nearly one-third (31.7%) experienced side effects during the diet. At ascertainment, only one-third (32%) remained on the diet with lack of long-term efficacy as the main reason for diet discontinuation (51%, 36/70).ConclusionsBenefits of KD in the CDKL5 disorder coincide with findings of previous trials on refractory epilepsy. However, poor long-term efficacy remains as a significant barrier. In view of its side effects, KD should be commenced under the guidance of a paediatric neurologist and/or specialist dietitian.

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Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder

Abstract: Epilepsy is pervasive but not mandatory for the CDKL5 disorder. Genotype and functional abilities were related to seizure frequency, which appears refractory to antiepileptic drugs.

Cited by 87 publications

References 18 publications

Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients

Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients

Impacts of caring for a child with the CDKL5 disorder on parental wellbeing and family quality of life

Ketogenic diet to manage refractory epilepsy in the cdkl5 disorder

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