Ketogenic dietary therapy for Angelman syndrome


Written by: Professor Robin SB Williams PhD FRSB
Matthew’s Friends Medical Advisory Board
Professor of Molecular Cell Biology, Centre for
Biomedical Science, Royal Holloway University of London

Angelman Syndrome (AS) was first identified by Dr Harry Angelman in 1965 providing the syndrome name [1]. AS is a neurodevelopmental disorder, characterised by intellectual disability, slow development, speech impairment, epileptic seizures, sleep disturbances and gait problems [2]. Some individuals also show a happy disposition, with smiling and laughter. Initial diagnosis via assessment of developmental delay often occurs
in the first year of life [3], and is confirmed through a combination of physical characteristics and molecular genetic testing. The syndrome is caused by the loss of function of the maternal copy of the enzyme ubiquitin protein ligase E3A (UBE3A) alternatively called the E3 ligase E6-associated protein (E6AP) [4-6]. The silencing of the maternal copy of UBE3A in the brain can be caused by several mechanisms [7-9]: 70% of cases are caused by a chromosomal deletion; 10% by a single nucleotide change in the gene; 2% from paternal uniparental disomy (UPD). The UBE3A protein functions to attach a small molecule called ‘ubiquitin’ to proteins that are targeted to be recycled. In addition, the UBE3A protein is involved in regulating how neurons in the brain communicate through synapses [10] and this relates to the observed cognitive dysfunction [11]. Since around 85% of individuals with a diagnosis of AS have seizures, epilepsy medicines are commonly used including sodium valproate, lamotrigine, clobazam, and levetiracetam [12] and melatonin treatment may help sleep related issues in AS [1].

Dietary treatments also offer a treatment approach for AS that provide seizure control and often addresses other symptoms. There are several different types of dietary treatments, often called the ‘classical’ or the ‘MCT’ ketogenic diet [13-16] where different ratios of energy provided by ‘fats’ and ‘carbohydrate plus protein’ distinguish the different versions. The 4:1 ratio classical diet provides very high fat levels and very low carbohydrate with adequate protein. Modified Ketogenic Therapies include a very low amount of carbohydrate and promote fat and ‘normal’ protein amounts. Alternatively, the low glycaemic index treatment (LGIT) involves a slightly less strict approach that concentrates on reducing rapid fluctuations in blood glucose levels and has been used, particularly in AS, with good effect [17].

One clinical study of the LGIT identified more than a 90% reduction in seizures in 83% of patients [12]. In another LGIT study, 22% of AS patients became seizure free, 44% were seizure free except during illness or non-convulsive status epilepticus, and 30% showed reduced seizures [18]. Interestingly some of these individuals were able to increase carbohydrate intake without reducing efficacy, and side effects were minimal. In another small LGIT trial, six children with genetically confirmed AS and refractory epilepsy were treated with five exhibiting a >80% reduction in seizures (and >90% seizure reduction after 1 year) [19], and developmental gains. In regard to classical KDs, one case study of a child with a diagnosis of AS including refractory epilepsy was given a 2:1 KD diet after an initial fast, leading to complete resolution of her seizures on the first day and was alert and smiling on day 2 with increasing benefits at 3 months [20]. Another AS case study involving a 5 yr old girl with refractory seizures, with treatment using a 4:1 KD who showed improvements from the first week and was seizure free at two months [21]. Although no clinical studies are available for medium chain triglyceride (MCT) ketogenic diets in AS treatment, the two medium chain fatty acids used in the diet increase UBE3A expression in the brain [22] and improve cognition in animal models [23], but these results need to be validated in patient groups. Exogenous ketone treatment has also been assessed in AS treatment with unclear clinical significance [24], and other types of treatment approaches such as gene therapy remain to be clinically validated [25, 26]. Exogenous ketone treatment is not recommended or available via the NHS in UK at this time as products used have not been adequately tested.  International consensus guidelines suggest a multidisciplinary approach to treatment including pharmacological and dietary approaches to address seizures, but also a range of physical and occupational therapies and behavioural management strategies [27]. Further research is needed to address motor functioning, communication, behaviour and sleep associated aspects of AS [28]. Care costs for AS causes a high impact on caregivers [29], relating to employment impact, household expenses, changes in vehicle and accommodation to meet the complex needs of affected individuals. Suitable neurological and dietary support should be provided to those considering dietary approaches to treatment, it should also include caregiver and family support as a key part of these approaches [13].

References:

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  2. Prasad A, Grocott O, Parkin K, Larson A, Thibert RL. Angelman syndrome in adolescence and adulthood: A retrospective chart review of 53 cases. Am J Med Genet A. 2018;176:1327-34.
  3. Dagli AI, Mathews J, Williams CA. Angelman Syndrome. Seattle: University of Washington; 1998.
  4. Yang L, Shu X, Mao S, Wang Y, Du X, Zou C. Genotype-Phenotype Correlations in Angelman Syndrome. Genes (Basel). 2021;12.
  5. Sutcliffe JS, Jiang YH, Galijaard RJ, Matsuura T, Fang P, Kubota T, et al. The E6-Ap ubiquitin-protein ligase (UBE3A) gene is localized within a narrowed Angelman syndrome critical region. Genome Res. 1997;7:368-77.
  6. Khatri N, Man HY. The Autism and Angelman Syndrome Protein Ube3A/E6AP: The Gene, E3 Ligase Ubiquitination Targets and Neurobiological Functions. Front Mol Neurosci. 2019;12:109.
  7. Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet. 1997;15:70-3.
  8. Matsuura T, Sutcliffe JS, Fang P, Galjaard RJ, Jiang YH, Benton CS, et al. De novo truncating mutations in E6-AP ubiquitinprotein ligase gene (UBE3A) in Angelman syndrome. Nat Genet. 1997;15:74-7.
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  10. Greer PL, Hanayama R, Bloodgood BL, Mardinly AR, Lipton DM, Flavell SW, et al. The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell. 2010;140:704-16.
  11. Wallace ML, Burette AC, Weinberg RJ, Philpot BD. Maternal loss of Ube3a produces an excitatory/inhibitory imbalance through neuron type-specific synaptic defects. Neuron. 2012;74:793-800.
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  13. Kossoff EH, Zupec-Kania BA, Auvin S, Ballaban-Gil KR, Christina Bergqvist AG, Blackford R, et al. Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group. Epilepsia Open. 2018;3:175-92.
  14. Diez-Arroyo C, Garcia-Garcia M, Soto-Mendez MJ, Molina-Montes E, Gil-Campos M, Gil A, et al. Effect of the ketogenic diet as a treatment for refractory epilepsy in children and adolescents: a systematic review of reviews. Nutr Rev. 2024;82:487 502.
  15. van der Louw E, van den Hurk D, Neal E, Leiendecker B, Fitzsimmon G, Dority L, et al. Ketogenic diet guidelines for infants with refractory epilepsy. Eur J Paediatr Neurol. 2016;20:798-809.
  16. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, et al. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia. 2009;50:1109-17.
  17. Muzykewicz DA, Lyczkowski DA, Memon N, Conant KD, Pfeifer HH, Thiele EA. Efficacy, safety, and tolerability of the low glycemic index treatment in pediatric epilepsy. Epilepsia. 2009;50:1118-26.
  18. Grocott OR, Herrington KS, Pfeifer HH, Thiele EA, Thibert RL. Low glycemic index treatment for seizure control in Angelman syndrome: A case series from the Center for Dietary Therapy of Epilepsy at the Massachusetts General Hospital. Epilepsy Behav. 2017;68:45-50.
  19. Thibert RL, Pfeifer HH, Larson AM, Raby AR, Reynolds AA, Morgan AK, et al. Low glycemic index treatment for seizures in Angelman syndrome. Epilepsia. 2012;53:1498-502.
  20. Stein D, Chetty M, Rho JM. A “happy” toddler presenting with sudden, life-threatening seizures. Semin Pediatr Neurol. 2010;17:35-8.
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  22. Wang D, Mitchell ES. Cognition and Synaptic-Plasticity Related Changes in Aged Rats Supplemented with 8- and 10 Carbon Medium Chain Triglycerides. PLoS One. 2016;11:e0160159.
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