Everolimus precision therapy for the GATOR1-related epilepsies: A case series.

BACKGROUND: Pathogenic variants in the GAP activity towards RAGs 1 (GATOR1) complex genes (DEPDC5, NPRL2, NPRL3) cause focal epilepsy through hyperactivation of the mechanistic target of rapamycin pathway. We report our experience using everolimus in patients with refractory GATOR1-related epilepsy. METHODS: We performed an open-label observational study of everolimus for drug-resistant epilepsy caused by variants in DEPDC5, NPRL2 and NPRL3. Everolimus was titrated to a target serum concentration (5-15 ng/mL). The primary outcome measure was change in mean monthly seizure frequency compared with baseline. RESULTS: Five patients were treated with everolimus. All had highly active (median baseline seizure frequency, 18/month) and refractory focal epilepsy (failed 5-16 prior anti-seizure medications). Four had DEPDC5 variants (three loss-of-function, one missense) and one had a NPRL3 splice-site variant. All patients with DEPDC5 loss-of-function variants had significantly reduced seizures (74.3%-86.1%), although one stopped everolimus after 12 months due to psychiatric symptoms. Everolimus was less effective in the patient with a DEPDC5 missense variant (43.9% seizure frequency reduction). The patient with NPRL3-related epilepsy had seizure worsening. The most common adverse event was stomatitis. CONCLUSIONS: Our study provides the first human data on the potential benefit of everolimus precision therapy for epilepsy caused by DEPDC5 loss-of-function variants. Further studies are needed to support our findings.

Neurological involvement in children with hemolytic uremic syndrome.

Our objective was to establish the rate of neurological involvement in Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome (STEC-HUS) and describe the clinical presentation, management and outcome. A retrospective chart review of children aged ≤ 16 years with STEC-HUS in Children's Health Ireland from 2005 to 2018 was conducted. Laboratory confirmation of STEC infection was required for inclusion. Neurological involvement was defined as encephalopathy, focal neurological deficit, and/or seizure activity. Data on clinical presentation, management, and outcome were collected. We identified 240 children with HUS; 202 had confirmed STEC infection. Neurological involvement occurred in 22 (11%). The most common presentation was seizures (73%). In the neurological group, 19 (86%) were treated with plasma exchange and/or eculizumab. Of the 21 surviving children with neurological involvement, 19 (91%) achieved a complete neurological recovery. A higher proportion of children in the neurological group had renal sequelae (27% vs. 12%, P = .031). One patient died from multi-organ failure.Conclusion: We have identified the rate of neurological involvement in a large cohort of children with STEC-HUS as 11%. Neurological involvement in STEC-HUS is associated with good long-term outcome (complete neurological recovery in 91%) and a low case-fatality rate (4.5%) in our cohort. What is Known: • HUS is associated with neurological involvement in up to 30% of cases. • Neurological involvement has been reported as predictor of poor outcome, with associated increased morbidity and mortality. What is New: • The incidence of neurological involvement in STEC-HUS is 11%. • Neurological involvement is associated with predominantly good long-term outcome (90%) and a reduced case-fatality rate (4.5%) compared to older reports.

RHOBTB2 Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood.

OBJECTIVE: To explore the phenotypic spectrum of RHOBTB2-related disorders and specifically to determine whether patients fulfill criteria for alternating hemiplegia of childhood (AHC), we report the clinical features of 11 affected individuals. METHODS: Individuals with RHOBTB2-related disorders were identified through a movement disorder clinic at a specialist pediatric center, with additional cases identified through collaboration with other centers internationally. Clinical data were acquired through retrospective case-note review. RESULTS: Eleven affected patients were identified. All had heterozygous missense variants involving exon 9 of RHOBTB2, confirmed as de novo in 9 cases. All had a complex motor phenotype, including at least 2 different kinds of movement disorder, e.g., ataxia and dystonia. Many patients demonstrated several features fulfilling the criteria for AHC: 10 patients had a movement disorder including paroxysmal elements, and 8 experienced hemiplegic episodes. In contrast to classic AHC, commonly caused by mutations in ATP1A3, these events were reported later only in RHOBTB2 mutation-positive patients from 20 months of age. Seven patients had epilepsy, but of these, 4 patients achieved seizure freedom. All patients had intellectual disability, usually moderate to severe. Other features include episodes of marked skin color change and gastrointestinal symptoms, each in 4 patients. CONCLUSION: Although heterozygous RHOBTB2 mutations were originally described in early infantile epileptic encephalopathy type 64, our study confirms that they account for a more expansive clinical phenotype, including a complex polymorphic movement disorder with paroxysmal elements resembling AHC. RHOBTB2 testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for ATPA1A3 mutations.

Status dystonicus due to missense variant in ARX: Diagnosis and management.

Movement disorders are increasingly identified in infantile encephalopathies due to single gene disorders (e.g. SCN2A, CDKL5, ARX). The associated movement disorder can be challenging to recognise and treat. We report a 2 year-old boy with a background history of Ohtahara syndrome due to a missense variant in ARX (the aristaless-related homeobox gene) who subsequently developed status dystonicus. ARX is a transcription factor that plays a critical role in cortical neuronal development and is associated with a range of important neurodevelopmental disorders depending on the site of the pathogenic variant. Cases of status dystonicus are described with variants affecting the polyalanine expansion region of ARX but have not been reported previously with variants affecting the aristaless domain of ARX as in this case. Dystonic episodes posed a challenge in recognition and treatment, including confusion with status epilepticus. We discuss the difficulties in diagnosis and management of status dystonicus, an underreported life-threatening emergency in children.

Pseudoexon activation increases phenotype severity in a Becker muscular dystrophy patient.

We report a dystrophinopathy patient with an in-frame deletion of DMD exons 45-47, and therefore a genetic diagnosis of Becker muscular dystrophy, who presented with a more severe than expected phenotype. Analysis of the patient DMD mRNA revealed an 82 bp pseudoexon, derived from intron 44, that disrupts the reading frame and is expected to yield a nonfunctional dystrophin. Since the sequence of the pseudoexon and canonical splice sites does not differ from the reference sequence, we concluded that the genomic rearrangement promoted recognition of the pseudoexon, causing a severe dystrophic phenotype. We characterized the deletion breakpoints and identified motifs that might influence selection of the pseudoexon. We concluded that the donor splice site was strengthened by juxtaposition of intron 47, and loss of intron 44 silencer elements, normally located downstream of the pseudoexon donor splice site, further enhanced pseudoexon selection and inclusion in the DMD transcript in this patient.

De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.

Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.

Partial status epilepticus - rapid genetic diagnosis of Alpers' disease.

We describe four children with a devastating encephalopathy characterised by refractory focal seizures and variable liver dysfunction. We describe their electroencephalographic, radiologic, genetic and pathologic findings. The correct diagnosis was established by rapid gene sequencing. POLG1 based Alpers' disease should be considered in any child presenting with partial status epilepticus.

Dancing Eye Syndrome associated with spontaneous recovery and normal neurodevelopment.

Five patients with spontaneously recovering Dancing Eye Syndrome/Opsoclonus Myoclonus Syndrome are described. Age at presentation ranged from 4 to 19 months. Four had symptoms of fever and a coryzal illness within days to a few weeks prior to the onset. One of the 4 also had varicella zoster 4 weeks before presentation. All had opsoclonus, myoclonus/ataxia and irritability. Associated infective agents identified were Coxsackie virus and rotavirus. Spontaneous improvement of symptoms started within 9 days of presentation and total duration of illness ranged from 10 to 24 days. Developmental progress at follow-up was normal in all cases. A range of immunomodulatory therapies have been advocated for the treatment of Dancing Eye Syndrome/Opsoclonus Myoclonus Syndrome. However, in some children, early spontaneous recovery may occur, an observation which should be borne in mind when designing therapeutic trials in this condition.