Early Myoclonic Encephalopathy in 9q33‐q34 Deletion Encompassing <i>STXBP1</i> and <i>SPTAN1</i>

Nicita, Francesco; Ulgiati, Fiorenza; Bernardini, Laura; Garone, Giacomo; Papetti, Laura; Novelli, Antonio; Spalice, Alberto

doi:10.1111/ahg.12106

Cited by 14 publications

(29 citation statements)

References 18 publications

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“…7, 8, 30-35 Two of the 4 patients had burst suppression identified at approximately 2 months, resolving by 4 months and 13 months, respectively. Two patients did not have burst suppression after careful review of EEGs.…”

Section: Resultsmentioning

confidence: 99%

Genetics and genotype–phenotype correlations in early onset epileptic encephalopathy with burst suppression

Olson

Kelly

LaCoursiere

et al. 2017

Annals of Neurology

117

111

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Objective We sought to identify genetic causes of early onset epileptic encephalopathies with burst suppression (Ohtahara syndrome and early myoclonic encephalopathy) and evaluate genotype-phenotype correlations. Methods We enrolled 33 patients with a referral diagnosis of Ohtahara syndrome or early myoclonic encephalopathy without malformations of cortical development. We performed detailed phenotypic assessment including seizure presentation, EEG, and MRI. We confirmed burst suppression in 28 out of 33 patients. Research-based exome sequencing was performed for patients without a previously identified molecular diagnosis from clinical evaluation or research-based epilepsy gene panel. Results In 17/28 (61%) patients with confirmed early burst suppression, we identified variants predicted to be pathogenic in KCNQ2 (n=10), STXBP1 (n=2), SCN2A (n=2), PNPO (n=1), PIGA (n=1), and SEPSECS (n=1). In 3/5 (60%) patients without confirmed early burst suppression, we identified variants predicted to be pathogenic in STXBP1 (n=2) and SCN2A (n=1). The patient with the homozygous PNPO variant had a low CSF pyridoxal-5-phosphate level. Otherwise, no early laboratory or clinical features distinguished the cases associated with pathogenic variants in specific genes from each other or from those with no prior genetic cause identified. Interpretation We characterize the genetic landscape of epileptic encephalopathy with burst suppression, without brain malformations, and demonstrate feasibility of genetic diagnosis with clinically available testing in over 60% of our cohort with KCNQ2 implicated in one third. This electroclinical syndrome is associated with pathogenic variation in SEPSECS.

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Section: Resultsmentioning

confidence: 99%

Genetics and genotype–phenotype correlations in early onset epileptic encephalopathy with burst suppression

Olson

Kelly

LaCoursiere

et al. 2017

Annals of Neurology

117

111

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“…The human spectrin family consists of two alpha- and five beta-spectrin subunits, which form heterodimers that assemble into tetramers through head-to-head and lateral associations (Bennett and Lorenzo, 2013). Human dominant in-frame duplications and deletion mutations in SPTAN1 have been found in patients with early-onset epileptic encephalopathies, hypomyelination, intellectual disability and blindness starting in children under age 3 (Saitsu et al, 2010; Nicita et al, 2015). Mutations in βIII-spectrin, which is highly expressed in cerebellar Purkinje neurons, have been associated with spinocerebellar ataxia type 5 (Ikeda et al, 2006).…”

Section: Axonal Domain Proteins In Disease and Injurymentioning

confidence: 99%

Axonal Membranes and Their Domains: Assembly and Function of the Axon Initial Segment and Node of Ranvier

Nelson

Jenkins

2017

Front. Cell. Neurosci.

103

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Neurons are highly specialized cells of the nervous system that receive, process and transmit electrical signals critical for normal brain function. Here, we review the intricate organization of axonal membrane domains that facilitate rapid action potential conduction underlying communication between complex neuronal circuits. Two critical excitable domains of vertebrate axons are the axon initial segment (AIS) and the nodes of Ranvier, which are characterized by the high concentrations of voltage-gated ion channels, cell adhesion molecules and specialized cytoskeletal networks. The AIS is located at the proximal region of the axon and serves as the site of action potential initiation, while nodes of Ranvier, gaps between adjacent myelin sheaths, allow rapid propagation of the action potential through saltatory conduction. The AIS and nodes of Ranvier are assembled by ankyrins, spectrins and their associated binding partners through the clustering of membrane proteins and connection to the underlying cytoskeleton network. Although the AIS and nodes of Ranvier share similar protein composition, their mechanisms of assembly are strikingly different. Here we will cover the mechanisms of formation and maintenance of these axonal excitable membrane domains, specifically highlighting the similarities and differences between them. We will also discuss recent advances in super resolution fluorescence imaging which have elucidated the arrangement of the submembranous axonal cytoskeleton revealing a surprising structural organization necessary to maintain axonal organization and function. Finally, human mutations in axonal domain components have been associated with a growing number of neurological disorders including severe cognitive dysfunction, epilepsy, autism, neurodegenerative diseases and psychiatric disorders. Overall, this review highlights the assembly, maintenance and function of axonal excitable domains, particularly the AIS and nodes of Ranvier, and how abnormalities in these processes may contribute to disease.

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“…The predominant clinical feature seen in patients with 9q33‐9q34 deletion includes EOEE (Nicita et al ., ). Myoclonic seizures were reported in only one patient in association with EME (Nicita et al ., ); our case is the second with myoclonic seizures in the setting of an unclassified EOEE. The majority of patients with deletion involving both STXBP1 and SPTAN1 genes have hypotonia and developmental delay, similar to our patient.…”

Section: Discussionmentioning

confidence: 97%

“…The majority of patients with deletion involving both STXBP1 and SPTAN1 genes have hypotonia and developmental delay, similar to our patient. Thinning of the corpus callosum and microcephaly, observed in our patient, were found in 66% and 67% of patients with deletions involving both genes, respectively (Nicita et al ., ). Facial dysmorphisms present in our patient, including telecanthus and epicanthic folds, as well as other features, such as up‐slanting palpebral fissures, hypertelorism, low‐set ears, clinodactyly, and smooth philtrum, were described in patients with 9q33‐9q34 deletion (Ehret et al ., ; Nicita et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Early‐onset epileptic encephalopathy with myoclonic seizures related to 9q33.3‐q34.11 deletion involving STXBP1 and SPTAN1 genes

Aravindhan

Shah

Pak

et al. 2018

Epileptic Disorders

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We describe a 10‐month‐old boy with early‐onset epileptic encephalopathy who was found to have a hemizygous deletion in 9q33.3‐q34.11 involving STXBP1 and SPTAN1 genes. He presented at the age of 2.5 months with frequent upper extremity myoclonus, hypotonia, and facial dysmorphisms. Interictal EEG showed multifocal polyspike and wave during wakefulness and sleep. Ictal EEG revealed low‐amplitude generalized sharp slow activity, followed by diffuse attenuation. Metabolic testing was unrevealing. Brain MRI showed thinning of the corpus callosum with an absence of rostrum. This patient is the second reported case with 9q33.3‐q34.11 deletion involving STXBP1 and SPTAN1 genes associated with epileptic encephalopathy and myoclonic seizures. Larger case series are needed to better delineate this association.

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Early Myoclonic Encephalopathy in 9q33‐q34 Deletion Encompassing STXBP1 and SPTAN1

Cited by 14 publications

References 18 publications

Genetics and genotype–phenotype correlations in early onset epileptic encephalopathy with burst suppression

Genetics and genotype–phenotype correlations in early onset epileptic encephalopathy with burst suppression

Axonal Membranes and Their Domains: Assembly and Function of the Axon Initial Segment and Node of Ranvier

Early‐onset epileptic encephalopathy with myoclonic seizures related to 9q33.3‐q34.11 deletion involving STXBP1 and SPTAN1 genes

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