In utero seizures revealing dentato‐olivary dysplasia caused by SCN2A mutation

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Most early‐onset epileptic encephalopathies (EOEE) are caused by genetic defects. In the past, mutations, especially in genes encoding sodium channels, have been identified using linkage studies, array‐CGH and more recently next‐generation sequencing (NGS) 1. Mutations in SCN2A gene have been identified in a wide variety of early‐onset epileptic syndromes including benign familial neonatal infantile seizures (BFNIS) 2 and more severe forms leading to encephalopathy such as Ohtahara or West syndromes 3, epilepsy of infancy with migrating focal seizures (EIMFS) 4 and autism spectrum disorders 5. In 2013, mutations in SCN2A gene were reported with dentato‐olivary dysplasia (DOD) in a single family 6 but the link between DOD and severe EOEE needs to be confirmed 6. DOD was first described in 1991 from five unrelated infants with intractable epilepsy 7. Its frequency is underestimated since this structural brain anomaly cannot be detected on brain MRI even with high resolution imaging. This report aims at describing the first foetal case revealed by in utero seizures, including ultrasonography, neuropathological examination and NGS that revealed a novel de novo heterozygous missense mutation in the SCN2A gene.
A gravida 1, para 1, 26‐year‐old woman underwent routine ultrasonography at 20 weeks of gestation (WG) which was considered as normal. The pregnancy was uneventful until routine ultrasonography performed at 30 WG, revealing severe symmetrical bilateral ventriculomegaly, distal arthrogryposis, hydramnios and abnormal movements. During subsequent follow‐up, repetitive tonic–clonic movements were visualized, highly suggestive of in utero seizures (Video S1). There was no personal or family medical history except for the maternal uncle suffering from hypomyelinating leukodystrophy with hypo/oligodontia and hypogonadotropic hypogonadism (4H syndrome‐ MIM#607694), an autosomal recessive disorder which does not classically include epilepsy. Retrospectively, the mother reported occasional shaking movements considered as hiccups. Foetal karyotype was normal (46, XX). A medical termination of the pregnancy was achieved at 32 WG in accordance with French law with the written consent of both parents.
A complete autopsy was performed with the informed consent of both parents according to standardized protocols. The brain was immersed in a 10% formalin‐zinc buffer solution for 1 month. Seven‐micrometre paraffin‐embedded sections were processed from multiple brain areas, and stained with haematoxylin‐eosin.
Molecular analyses were carried out in agreement with our institutional recommendations. Foetal DNA was extracted from thymus and parental DNA from blood samples, according to standardized protocols. Targeted regions were enriched using SureSelect XT Inherited Diseases Panel (Agilent Technologies) and sequencing was performed using an Ion Proton platform (Life Technologies). Sequences were aligned to the hg19 genome reference, and variant calling was performed targeting 64 genes involved in early‐onset epilepsy with the Torrent Suite using low stringency filters for germline disorders (germline_low_stringency_targetseq) (Life Technologies) (Table S1). Candidate variants were confirmed by Sanger sequencing. Grantham score predicted the chemical dissimilarity of codon replacements. Parental DNA analysis was performed to study the mode of inheritance.
External examination confirmed foetal akinesia can be retained akinesia deformation sequence with nonspecific facial dysmorphism. Brain weight and gyration were concordant with term; the brainstem and cerebellum appearing macroscopically normal in size and shape. On coronal sections, the corpus callosum was thin in its posterior part, with mild ventricular dilatation. On infratentorial sections, the dentate and olivary nuclei were poorly convoluted. Histologically, the cytoarchitecture of the cerebellar cortex was normal, but the dentate nuclei were dysmorphic, forming a single C‐shaped mass of neurons (Fig.1A) compared with an age‐matched control (Fig.1B). In the medulla, olivary nuclei were coarse and poorly convoluted (Fig.1C and D for control), but with no fragmentation or associated heterotopias.
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