Medicine (Austin & Northern Health) - Research Publications
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ItemSevere infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45(WILEY, 2018-01)Heterozygous de novo variants in the autophagy gene, WDR45, are found in beta-propeller protein-associated neurodegeneration (BPAN). BPAN is characterized by adolescent onset dementia and dystonia; 66% patients have seizures. We asked whether WDR45 was associated with developmental and epileptic encephalopathy (DEE). We performed next generation sequencing of WDR45 in 655 patients with developmental and epileptic encephalopathies. We identified 3/655 patients with DEE plus 4 additional patients with de novo WDR45 pathogenic variants (6 truncations, 1 missense); all were female. Six presented with DEE and 1 with early onset focal seizures and profound regression. Median seizure onset was 12 months, 6 had multiple seizure types, and 5/7 had focal seizures. Three patients had magnetic resonance susceptibility-weighted imaging; blooming was noted in the globus pallidi and substantia nigra in the 2 older children aged 4 and 9 years, consistent with iron accumulation. We show that de novo pathogenic variants are associated with a range of developmental and epileptic encephalopathies with profound developmental consequences.
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ItemSleep problems in Dravet syndrome: a modifiable comorbidity(WILEY, 2018-02)AIM: Many children with severe developmental and epileptic encephalopathies experience significant sleep disturbance, causing major disruption to the family's quality of life. We aimed to determine the frequency and nature of sleep problems in individuals with Dravet syndrome. METHODS: The Sleep Disturbance Scale for Children and a seizure questionnaire were distributed to the parents/guardians of 96 patients with Dravet syndrome. Sixteen patients had two nights of home oximetry. RESULTS: Fifty-seven out of 96 questionnaires were completed. Forty-three out of 57 (75%) individuals had sleep problems. Twenty-five out of 57 (44%) individuals had an abnormal total sleep score, with difficulty initiating and maintaining sleep (22 out of 57, 39%), sleep-wake transition disorders (20 out of 57, 35%), and sleep breathing disorders (19 out of 57, 33%). Twenty-two out of 57 (39%) individuals took medication to assist sleep, predominantly melatonin (n=14). Thirty out of 57 (53%) recently had nocturnal seizures. Overnight oximetry showed 14 out of 16 (88%) had a higher oxygen desaturation index (>3%), and six out of 16 (38%) had higher mean pulse rates than normative values. Home oximetry was normal or inconclusive in all patients. INTERPRETATION: Seventy-five per cent of individuals with Dravet syndrome had sleep problems, highlighting the importance of routinely assessing sleep and initiating appropriate behavioural and pharmacological interventions to improve the patient and family's quality of life. A high oxygen desaturation index and mean pulse rates on pulse oximetry may reflect unrecognized nocturnal seizures. WHAT THIS PAPER ADDS: More than 70% of patients with Dravet syndrome have sleep problems. Difficulty initiating and maintaining sleep was most common, particularly in those older than 20 years. Second most common were sleep-wake transition disorders, affecting more than 50% of those younger than 5 years. Sleep breathing disorders were a frequent problem across all age groups. Oximetry was not diagnostic of sleep-disordered breathing or obvious seizures.
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ItemEpileptic spasms are a feature of DEPDC5 mTORopathy(LIPPINCOTT WILLIAMS & WILKINS, 2015-08)OBJECTIVE: To assess the presence of DEPDC5 mutations in a cohort of patients with epileptic spasms. METHODS: We performed DEPDC5 resequencing in 130 patients with spasms, segregation analysis of variants of interest, and detailed clinical assessment of patients with possibly and likely pathogenic variants. RESULTS: We identified 3 patients with variants in DEPDC5 in the cohort of 130 patients with spasms. We also describe 3 additional patients with DEPDC5 alterations and epileptic spasms: 2 from a previously described family and a third ascertained by clinical testing. Overall, we describe 6 patients from 5 families with spasms and DEPDC5 variants; 2 arose de novo and 3 were familial. Two individuals had focal cortical dysplasia. Clinical outcome was highly variable. CONCLUSIONS: While recent molecular findings in epileptic spasms emphasize the contribution of de novo mutations, we highlight the relevance of inherited mutations in the setting of a family history of focal epilepsies. We also illustrate the utility of clinical diagnostic testing and detailed phenotypic evaluation in characterizing the constellation of phenotypes associated with DEPDC5 alterations. We expand this phenotypic spectrum to include epileptic spasms, aligning DEPDC5 epilepsies more with the recognized features of other mTORopathies.