Date Published: September 26, 2016
Publisher: John Wiley and Sons Inc.
Author(s): S. Tang, E. Hughes, K. Lascelles, M. A. Simpson, D. K. Pal.
We report a de novo SMARCA2 missense mutation discovered on exome sequencing in a patient with myoclonic astatic epilepsy, leading to reassessment and identification of Nicolaides–Baraitser syndrome. This de novo SMARCA2 missense mutation c.3721C>G, p.Gln1241Glu is the only reported mutation on exon 26 outside the ATPase domain of SMARCA2 to be associated with Nicolaides–Baraitser syndrome and adds to chromatin remodeling as a pathway for epileptogenesis. © 2016 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.
Myoclonic astatic epilepsy (MAE), or Doose syndrome, is a genetically heterogenous rare childhood epilepsy syndrome characterized by the onset of myoclonic‐atonic or atonic seizures between the ages of 6 months and 6 years in a previously normally developing child [Doose et al., 1970]. Typical febrile seizures may precede afebrile seizures in two‐thirds of cases. Other generalized seizure types are frequently seen and electroencephalogram (EEG) shows generalized spike wave or polyspike discharges on a normal background. Prognosis is variable from complete seizure remission, with normal or close to normal development, to a drug‐resistant epileptic encephalopathy. Approximately 10% of cases can be attributed to mutations in SCN1A, SCN1B, GABRG2, SLC2A1, CHD2, or SLC6A1, but the majority of cases remain unexplained [Wallace et al., 1998, 2001; Escayg et al., 2001; Mullen et al., 2011; Carvill et al., 2013; Carvill et al., 2015]. We report a patient with MAE who, following exome sequencing, was subsequently diagnosed with Nicolaides–Baraitser syndrome (NCBRS) (OMIM 601358). NCBRS was first described in 1993 and is an intellectual disability and multiple congenital anomalies syndrome associated with seizures [Nicolaides and Baraitser, 1993]. Although much of the phenotype is well delineated and includes sparse hair, microcephaly, typical facial morphology, brachydactyly, prominent interphalangeal joints, and intellectual disability with marked language impairment, the epilepsy features have not been well described before.
A girl of Ghanaian ancestry was born at term with a birth weight of 3.4 kg (50th centile) and a head circumference of 32 cm (0.4th centile). Her mother reported normal early developmental milestones. She sat unsupported at 8 months, walked at 12 months, and was babbling just before her first birthday. However, her mother had concerns that she had reduced visual interest in people and did not smile readily. Her first seizure was at 14 months and was a myoclonic atonic seizure, which continued as her prominent seizure type while she developed generalized tonic‐clonic and absence seizures. Additionally, the patient had feeding problems from 6 months following the introduction of solids. She was hypersensitive to textures and demonstrated food refusal and would hold food in her mouth or vomit during meal times. Developmental assessment showed a delay in language and social communication skills. No dysmorphic features were identified at the time. At 17 months her weight was 10.7 kg (50th–75th centile), height 82.5 cm (75th–91st centile), head circumference 48 cm (98th–99.6th centile). At 2 years 9 months, her weight was 13.9 kg (25th–50th centile), height 94.7 cm (50th–75th centile), and she had developed relative microcephaly with her head circumference at 49 cm (9th–25th centile). Her EEG demonstrated frequent generalized bursts of polyspike and wave activity during wakefulness and sleep against a normal background. An electrographic correlate of negative axial myoclonus was captured (see Supplementary information Figs. S1 and S2). An MRI brain scan was normal. Array CGH analysis with ∼44,000 probes across the genome was normal. Based on these electroclinical features, her epilepsy type was thought compatible with a diagnosis of MAE. She was treated with sodium valproate to which she responded, attaining complete seizure remission at 3 years with normalization of her EEG. Antiepileptic medication was discontinued at 4 years.
We report a patient with MAE and features of NCBRS. Although seizures are reported in two‐thirds of patients with NCBRS, neither seizure semiology nor specific epilepsy syndromes have been well described. The patient described in this study was diagnosed with MAE syndrome and the diagnosis of NCBRS in this patient was only made following identification of the SMARCA2 mutation and clinical re‐examination. This was because the NCBRS phenotype is progressive and in younger ages the features are subtle and difficult to recognize. Moreover, there is no reported association between MAE and NCBRS. A specific role for SMARCA2 mutations has been implicated in NCBRS with at least 80% of patients carrying a mutation in SMARCA2 (OMIM 601358) [Van Houdt et al., 2012], but to our knowledge all causative mutations have been located in exons 15–25, and never before in exon 26. SMARCA2 is a chromatin remodeling gene, and mutations in another gene involved in this pathway CHD2 are known to cause MAE, suggesting this pathway as a potential therapeutic target [Carvill et al., 2013].