Chromosome 9q33q34 microdeletion with early infantile epileptic encephalopathy, severe dystonia, abnormal eye movements, and nephroureteral malformations.

Microdeletion of chromosome 9q33q34 is an emerging disease disorder associated with early infantile epileptic encephalopathy, intellectual disability, and a variety of movement disorders. We describe a male infant with early infantile epileptic encephalopathy with suppression-burst (Ohtahara syndrome) who carried a de novo 2.0-Mb microdeletion in chromosome 9q33q34, including STXBP1. The previously reported examples of 9q33q34 microdeletion including STXBP1 are reviewed. The patient developed infantile spasms at 4 months of age, and these were refractory to multiple antiepileptic drugs. He also developed severe dystonia during infancy, rotatory nystagmus, and nephroureteral malformations. Immunoglobulin and clobazam administered at 11 months were effective for the spasms, but profound psychomotor retardation remained. A comparative genomic hybridization array analysis and the fluorescence in situ hybridization analysis revealed a de novo 2.0-Mb microdeletion in chromosome 9q33q34, which encompasses STXBP1, ENG, SPTAN1, and 52 other genes. A total of 14 patients (13 from the literature) with a 9q33q24 microdeletion including STXBP1 were reviewed, five of them displayed early infantile epileptic encephalopathy with suppression-burst, and six of them had early-onset epilepsy but not early infantile epileptic encephalopathy. Dystonia has been previously described in 9q33q34 deletions involving TOR1A but not STXBP1. Neither abnormal eye movements nor nephroureteral malformations has been previously described. This patient adds unique clinical presentations of neurological and nephroureteral abnormalities to the features of 9q33q34 microdeletion.

Matsumoto H ，Zaha K ，Nakamura Y ，Hayashi S ，Inazawa J ，Nonoyama S ... -  《-》

Early myoclonic encephalopathy in 9q33-q34 deletion encompassing STXBP1 and SPTAN1.

Deletions in the 9q33-q34 region have been reported in patients with early onset epileptic encephalopathy, but a consistent phenotype has yet to emerge. We report on the diagnosis of a de novo 9q33-q34.12 microdeletion of 4 Mb in a 15-month-old girl presenting with severe psychomotor delay, facial dysmorphisms, thin corpus callosum and early myoclonic encephalopathy. This deletion encompasses 101 RefSeq genes, including the four autosomal dominant genes STXBP1, SPTAN1, ENG and TOR1A. We discuss genetic, clinical and epileptic features comparing our patient with those previously reported in the literature.

Nicita F ，Ulgiati F ，Bernardini L ，Garone G ，Papetti L ，Novelli A ，Spalice A ... -  《-》

Epileptic patients with de novo STXBP1 mutations: Key clinical features based on 24 cases.

Mutations in the syntaxin binding protein 1 gene (STXBP1) have been associated mostly with early onset epileptic encephalopathies (EOEEs) and Ohtahara syndrome, with a mutation detection rate of approximately 10%, depending on the criteria of selection of patients. The aim of this study was to retrospectively describe clinical and electroencephalography (EEG) features associated with STXBP1-related epilepsies to orient molecular screening. We screened STXBP1 in a cohort of 284 patients with epilepsy associated with a developmental delay/intellectual disability and brain magnetic resonance imaging (MRI) without any obvious structural abnormality. We reported on patients with a mutation and a microdeletion involving STXBP1 found using array comparative genomic hybridization (CGH). We found a mutation of STXBP1 in 22 patients and included 2 additional patients with a deletion including STXBP1. In 22 of them, epilepsy onset was before 3 months of age. EEG at onset was abnormal in all patients, suppression-burst and multifocal abnormalities being the most common patterns. The rate of patients carrying a mutation ranged from 25% in Ohtahara syndrome to <5% in patients with an epilepsy beginning after 3 months of age. Epilepsy improved over time for most patients, with an evolution to West syndrome in half. Patients had moderate to severe developmental delay with normal head growth. Cerebellar syndrome with ataxic gait and/or tremor was present in 60%. Our data confirm that STXBP1 mutations are associated with neonatal-infantile epileptic encephalopathies. The initial key features highlighted in the cohort of early epileptic patients are motor seizures either focal or generalized, abnormal initial interictal EEG, and normal head growth. In addition, we constantly found an ongoing moderate to severe developmental delay with normal head growth. Patients often had ongoing ataxic gait with trembling gestures. Altogether these features should help the clinician to consider STXBP1 molecular screening.

Di Meglio C ，Lesca G ，Villeneuve N ，Lacoste C ，Abidi A ，Cacciagli P ，Altuzarra C ，Roubertie A ，Afenjar A ，Renaldo-Robin F ，Isidor B ，Gautier A ，Husson M ，Cances C ，Metreau J ，Laroche C ，Chouchane M ，Ville D ，Marignier S ，Rougeot C ，Lebrun M ，de Saint Martin A ，Perez A ，Riquet A ，Badens C ，Missirian C ，Philip N ，Chabrol B ，Villard L ，Milh M ... -  《-》

STXBP1-related encephalopathy presenting as infantile spasms and generalized tremor in three patients.

Dominant mutations in the STXBP1 gene are a recently identified cause of infantile epileptic encephalopathy without metabolic and structural brain anomalies. To date, 25 patients with heterozygous mutation or deletion of STXBP1 have been reported. A diagnosis of early infantile epileptic encephalopathy with suppression-burst (Ohtahara syndrome) was made in most of them, with infantile spasms and nonsyndromic infantile epileptic encephalopathy being the diagnosis in other patients. Although the phenotypic spectrum of STXBP1-related encephalopathy is emerging with evidence suggesting the relatively frequent involvement of this gene in infantile epileptic encephalopathies, accurate clinical descriptions of patients are still necessary to delineate this entity. The sequence of the STXPB1 gene was analyzed in 29 patients with early onset syndromic or nonsyndromic infantile epileptic encephalopathy without brain magnetic resonance imaging (MRI) anomalies and with normal chromosomal and metabolic checkup. Another patient with a complex phenotype was analyzed by comparative genomic hybridization (CGH) array. From the studied series, 2 of 29 patients were found to carry a de novo heterozygous mutation in STXBP1. One patient carried the recurrent p.Arg406His mutation and the other an insertion of 10 bases leading to a premature termination codon. CGH array experiment detected a deletion of 3-3.5 Mbp in the third patient with infantile epileptic encephalopathy and nail malformations. All three had infantile spasms associated with partial seizures that responded to antiepileptic drug therapy. Intellectual abilities were severely impaired in all of them. Generalized tremor was the main neurologic striking feature in the three patients, with one of them further displaying unilateral akinetic-hypertonic syndrome. Mutations in STXBP1 are relatively frequent in patients with infantile epileptic encephalopathies. STXBP1-related encephalopathy may present as drug-responsive infantile spasms with focal/lateralized discharges. Generalized tremor appearing after the first year of life may be a clue to the diagnosis in some patients.

Mignot C ，Moutard ML ，Trouillard O ，Gourfinkel-An I ，Jacquette A ，Arveiler B ，Morice-Picard F ，Lacombe D ，Chiron C ，Ville D ，Charles P ，LeGuern E ，Depienne C ，Héron D ... -  《-》

Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1, SPTAN1, ENG, and TOR1A.

Campbell IM ，Yatsenko SA ，Hixson P ，Reimschisel T ，Thomas M ，Wilson W ，Dayal U ，Wheless JW ，Crunk A ，Curry C ，Parkinson N ，Fishman L ，Riviello JJ ，Nowaczyk MJ ，Zeesman S ，Rosenfeld JA ，Bejjani BA ，Shaffer LG ，Cheung SW ，Lupski JR ，Stankiewicz P ，Scaglia F ... -  《-》