Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder.

PURPOSE: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder. METHODS: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization. RESULTS: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons. CONCLUSION: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.

Ketogenic diet treatment for pediatric super-refractory status epilepticus.

PURPOSE: We aimed to study whether ketogenic diet (KD) therapy leads to resolution of super-refractory status epilepticus in pediatric patients without significant harm. METHOD: A retrospective review was performed at Phoenix Children's Hospital on patients with super-refractory status epilepticus undergoing ketogenic diet therapy from 2011 to 2015. RESULTS: Ten children with super-refractory status epilepticus, ages 2-16 years, were identified. 4/10 patients had immune mediated encephalitis, including Rasmussen encephalitis, anti-N-methyl-d-aspartate receptor encephalitis, and post-infectious mycoplasma encephalitis. Other etiologies included Lennox Gastaut Syndrome, non-ketotic hyperglycinemia, PCDH19 and GABRG2 genetic epilepsy, New Onset Refractory Status Epilepticus, and Febrile Infection-Related Epilepsy Syndrome. 4/10 patients' EEG features suggested focal with status epilepticus, and 6/10 suggested generalized with status epilepticus. Median hospital length was 61days and median ICU length was 27days. The median number of antiepileptic medications prior to diet initiation was 3.0 drugs, and the median after ketogenic diet treatment was 3.5 drugs. Median duration of status epilepticus prior to KD was 18days. 9/10 patients had resolution of super-refractory status epilepticus in a median of 7days after diet initiation. 8/9 patients were weaned off anesthesia within 15days of diet initiation, and within 1day of achieving ketonuria. 1/10 patients experienced side effects on the diet requiring supplementation. CONCLUSION: Most patients achieved resolution of status epilepticus on KD therapy, suggesting it could be an effective therapy that can be utilized early in the treatment of children with super refractory status epilepticus.

Amantadine for patients with severe traumatic brain injury: a critically appraised topic.

BACKGROUND: Research into traumatic brain injury (TBI) has increased significantly. Diagnostic testing and therapeutics for patients with severe TBI are 2 areas on which there is increasing focus. Amantadine hydrochloride is one treatment considered to have potential therapeutic value in this patient population. OBJECTIVE: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario, structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the disciplines of neurocritical care and physical medicine and rehabilitation. RESULTS: A multicenter, placebo-controlled, double-blind, randomized controlled trial was selected for review. The trial compared the rate of recovery, as determined by the overall Disability Rating Scale score, in a total of 184 patients with severe TBI. Patients were randomized to either receive amantadine (87) or visually identical placebo (97) over the 4-week study interval. The rate of recovery, as measured by the Disability Rating Scale, was found to be greater in the treatment arm as compared with the placebo arm (difference in slope -0.24 points/wk, P=0.007) over the 4-week treatment interval. CONCLUSIONS: The results from this study demonstrated that amantadine hydrochloride accelerates recovery in patients with severe TBI.

Successful treatment of recurrent basilar artery occlusion with intra-arterial thrombolysis and vertebral artery coiling in a child.

BACKGROUND: Signs of brainstem ischemia in children may be subtle, and outcome following basilar artery occlusion is often poor. There currently are no guidelines in children regarding the best methods to diagnose and treat basilar artery occlusion. METHODS: Case report and literature review. RESULTS: We describe the presentation and management of recurrent basilar artery occlusion in a previously healthy 5-year-old boy with vertebral artery dissection. Treatment included emergent intra-arterial tPA and mechanical thrombolysis of basilar artery clot, followed by later coiling of the vertebral artery to prevent recurring episodes of basilar artery ischemia. CONCLUSION: Management of brainstem stroke in children requires coordination of neurology, critical care, and interventional radiology services. Delayed intra-arterial thrombolysis and vertebral artery coiling can be successfully used to treat basilar artery occlusion and prevent the recurrence of brainstem ischemia in children.

Acquired microcephaly, regression of milestones, mitochondrial dysfunction, and episodic rigidity in a 46,XY male with a de novo MECP2 gene mutation.

We report a case of acquired microcephaly in a male infant. Testing for mutations in the MECP2 gene identified a de novo hemizygous c.378-3C>G mutation at a highly conserved 3' splice site, consistent with Rett syndrome. Other distinctive features included periodic hypertonicity, decreased mitochondrial complex III activity, and abnormal magnetic resonance imaging (MRI) T2 signal in the pons. Rett syndrome was originally described in females with a clinical phenotype of deceleration of head growth, abnormal hand movements, and developmental regression. The clinical diagnosis can now be supported by genetic testing for MECP2 mutations, and the phenotype of disorder has expanded. Cases of Rett syndrome in males are rare and a total of 17 such cases have been reported. This case extends the clinical phenotype of Rett syndrome in males and associates this mutation with mitochondrial dysfunction.