Respiratory Disturbances in Rett Syndrome: Don't Forget to Evaluate Upper Airway Obstruction

Rett syndrome is characterized by loss of motor and social functions, development of stereotypic hand movements, seizures, and breathing disturbances. This study evaluates the presence of overnight respiratory disturbances. Polysomnography in combination with a questionnaire (the Sleep Disturbance Scale for Children) was performed in 12 Dutch patients with Rett. Respiratory disturbances were present in all, clinically relevant in 10 (apnea hypopnea per hour 1.0-14.5). In 8 children, central apneas were present during the day often with obstructive apneas at night. In 6, obstructive sleep apnea syndrome was diagnosed, in 3 severe, with frequent oxygen desaturations. Significant respiratory complaints were present in 3 patients, all had obstructive sleep apnea syndrome. Of the 12 patients with Rett, 8 (67%) snored, and in 5 obstructive sleep apnea syndrome was present. In children, hypertrophied tonsils and adenoids are a common cause of obstructive sleep apnea syndrome, which may benefit from therapeutic intervention. We recommend performing polysomnography in patients with Rett syndrome and respiratory complaint

Magnetic resonance imaging of the lumbosacral spine in children with chronic constipation or non-retentive fecal incontinence: a prospective study

OBJECTIVE: To determine the prevalence of lumbosacral spine (LSS) abnormalities in children with defecation disorders, intractable constipation, or non-retentive fecal incontinence (NRFI) and evaluate whether LSS abnormalities on magnetic resonance imaging (MRI) are clinically detected by neurologic examination. STUDY DESIGN: MRI of the LSS and complete neurologic examination by a pediatric neurologist blinded to the MRI results were performed in patients with intractable defecation disorders. RESULTS: Patients with intractable constipation (n = 130; 76 males; median age, 11 years; range, 6-18 years), and patients with NRFI (n = 28; 18 males; median age, 10 years; range, 7-15 years) participated. One occult spina bifida (OSB) and 3 terminal filum lipomas were found in patients with a normal neurologic examination. One patient had a terminal filum lipoma and neurologic complaints. Gluteal cleft deviation was found in 3 of 4 patients with LSS abnormalities. Neurosurgical treatment was not required in any patient during the 12-week follow-up. CONCLUSIONS: MRI showed LSS abnormalities in 3% of patients with defecation disorders and normal neurologic examination, all of whom reported symptom relief at the 12-week follow-up without neurosurgical intervention. Thus, whether or not LSS abnormalities play a role in defecation disorders remains unclear

Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy : A Molecular Neuropharmacological Approach

Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation

SLC6A1 variant pathogenicity, molecular function, and phenotype: a genetic and clinical analysis

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function, and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6, and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease vs. non-severe disease (P = 2.9e-3, 95% CI: 1.5 - 15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function, and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 Portal (https://slc6a1-portal.broadinstitute.org/)