Brunklaus Andreas, Ellis Rachael, Stewart Helen, Aylett Sarah, Reavey Eleanor, Jefferson Ros, Jain Rakesh, Chakraborty Supratik, Jayawant Sandeep, Zuberi Sameer M
The Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK; Developmental Neurosciences Programme at UCL-ICH, Great Ormond Street Hospital for Sick Children, London, UK.
The Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK; Molecular Diagnostics, West of Scotland Genetic Services, Southern General Hospital, Glasgow, UK.
Eur J Paediatr Neurol. 2015 Jul;19(4):484-8. doi: 10.1016/j.ejpn.2015.02.001. Epub 2015 Feb 21.
Mutations in the gene encoding the alpha subunit of the voltage-gated sodium channel SCN1A are associated with several epilepsy syndromes. These range from severe phenotypes including Dravet syndrome to milder phenotypes such as genetic epilepsy with febrile seizures plus (GEFS+). To date the sequence variants identified have been heterozygous in nature as one would expect for a disorder that occurs de novo or is dominantly inherited.
We report the association of two novel homozygous missense mutations of the SCN1A gene in four children with infantile epilepsies from two consanguineous pedigrees. We suggest that the nature and location of the identified amino acid changes allows heterozygous carriers to remain unaffected. However, having such changes on both alleles may have a cumulative and detrimental effect.
The presented cases illustrate how better understanding of the nature and location of SCN1A missense mutations may aid the interpretation of genotype-phenotype associations. SCN1A related epilepsies should be considered in children with infantile onset epilepsies even when an autosomal recessive neurological disorder is suspected.
编码电压门控钠通道SCN1Aα亚基的基因突变与多种癫痫综合征相关。这些综合征范围从严重的表型如Dravet综合征到较轻的表型如伴有热性惊厥附加症的遗传性癫痫（GEFS+）。迄今为止，所鉴定出的序列变异本质上都是杂合的，这与一种新发或显性遗传的疾病预期情况相符。
我们报告了来自两个近亲家系的4名患有婴儿癫痫的儿童中SCN1A基因的两个新的纯合错义突变的关联。我们认为，所鉴定出的氨基酸变化的性质和位置使杂合携带者保持未受影响。然而，两个等位基因上都有这样的变化可能会产生累积和有害的影响。
所呈现的病例说明了对SCN1A错义突变的性质和位置有更好的理解如何有助于解释基因型-表型关联。即使怀疑是常染色体隐性神经系统疾病，婴儿期起病的癫痫儿童也应考虑SCN1A相关的癫痫。
