Liver transplantation followed by allogeneic hematopoietic stem cell transplantation for atypical mevalonic aciduria.

Mevalonic aciduria because of mutations of the gene for mevalonate kinase causes limited synthesis of isoprenoids, the effects of which are widespread. The outcome for affected children is poor. A child with severe multisystem manifestations underwent orthotopic liver transplantation at age 50 months for the indication of end-stage liver disease. This procedure corrected liver function and eliminated portal hypertension, and the patient showed substantial improvement in neurological function. However, autoinflammatory episodes continued unabated until hematopoietic stem cell transplantation was performed at 80 months. Through this complex therapy, the patient now enjoys a high quality of life without significant disability.

Factors associated with treatment delays in pediatric refractory convulsive status epilepticus.

OBJECTIVE: To identify factors associated with treatment delays in pediatric patients with convulsive refractory status epilepticus (rSE). METHODS: This prospective, observational study was performed from June 2011 to March 2017 on pediatric patients (1 month to 21 years of age) with rSE. We evaluated potential factors associated with increased treatment delays in a Cox proportional hazards model. RESULTS: We studied 219 patients (53% males) with a median (25th-75th percentiles [p25-p75]) age of 3.9 (1.2-9.5) years in whom rSE started out of hospital (141 [64.4%]) or in hospital (78 [35.6%]). The median (p25-p75) time from seizure onset to treatment was 16 (5-45) minutes to first benzodiazepine (BZD), 63 (33-146) minutes to first non-BZD antiepileptic drug (AED), and 170 (107-539) minutes to first continuous infusion. Factors associated with more delays to administration of the first BZD were intermittent rSE (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.14-2.09; p = 0.0467) and out-of-hospital rSE onset (HR 1.5, 95% CI 1.11-2.04; p = 0.0467). Factors associated with more delays to administration of the first non-BZD AED were intermittent rSE (HR 1.78, 95% CI 1.32-2.4; p = 0.001) and out-of-hospital rSE onset (HR 2.25, 95% CI 1.67-3.02; p < 0.0001). None of the studied factors were associated with a delayed administration of continuous infusion. CONCLUSION: Intermittent rSE and out-of-hospital rSE onset are independently associated with longer delays to administration of the first BZD and the first non-BZD AED in pediatric rSE. These factors identify potential targets for intervention to reduce time to treatment.

Platelet 5-HT2 serotonin receptor binding sites in autistic children and their first-degree relatives.

We examined platelet serotonin2 [5-hydroxytryptamine2 (5-HT2)] receptor binding sites, whole blood serotonin (5-HT), and plasma norepinephrine (NE) in male autistic children and their first-degree relatives. Saturation studies utilizing 125I-spiroperidol labeled the 5-HT2 sites with an affinity of 224.6 +/- 84.4 pmol/L (Kd). No group differences, i.e., autistic (n = 12), siblings (n = 6), parents (n = 22), control (adult; n = 7: child; n = 10), were seen for either the Kd or the total number of sites (Bmax: 14.3 +/- 10.9 fmol/mg protein). No correlations were found in any group between binding parameters (Kd or Bmax) and whole blood 5-HT. For the parental group, inverse correlations were found between NE and Bmax (standing NE, rs = -0.67, n = 21, p = 0.001; supine NE, rs = -0.49, n = 22, p = 0.021). In the autistic group, no correlation was seen between plasma NE and Bmax. A correlation between the autistic boys' Bmax and their fathers' Bmax was observed (rs = 0.79, n = 11, p = 0.004). These findings suggest (1) circulating NE may be involved in heterologous regulation of 5-HT2 receptors in the platelet and (2) genetic (paternal-filial) factors may play a role in the expression of 5-HT2 binding sites in the platelet. These preliminary findings are discussed in relation to heterologous receptor regulation. The relationships between these findings and either the pathophysiology of autism or hyperserotonemia in autism are unknown.

Receptor inhibition by immunoglobulins: specific inhibition by autistic children, their relatives, and control subjects.

Forty-two parents of children with autistic disorder, 15 children with autistic disorder, 17 siblings of children with autistic disorder, and 12 unrelated normal adult controls were studied to determine if immunoglobulins isolated from their plasma would inhibit binding of the 5HT1A agonist, [3H]-8-hydroxy-N,N-dipropyl-2-aminotetralin (DPAT) to 5HT1A receptors in human hippocampal membranes. There were no significant differences among the means of percentage inhibition of DPAT binding of parents, children with autistic disorder, siblings, or unrelated controls. In addition, there were no differences in the proportion of subjects with > 15% DPAT inhibition among autistic children, their parents, their siblings, or unrelated controls. Immunoglobulin inhibition was not specific for the 5HT1A receptor binding site, since immunoglobulins inhibited binding to 5HT2, D1, D2, and alpha 2-adrenergic binding sites. The immunoglobulins isolated from normal controls inhibited [3H]-rauwolscine binding at alpha 2-adrenergic sites less than immunoglobulins of children with autistic disorder and their parents and siblings. This study did not support the hypothesis that autoantibodies to 5HT1A or 5HT2 receptors are characteristic of autistic disorder.

Immortalized murine striatal neuronal cell lines expressing dopamine receptors and cholinergic properties.

Immortalized hybrid cells were generated by somatic cell fusion of 18-d-old embryonic corpus striatum of the mouse strain C57BL/6J with the N18TG2 neuroblastoma. One of the cell populations obtained was treated with a combination of 1 mM n-butyric acid and 10 microM SKF 38393 (a specific D1 agonist), and a surviving cell population (E1X) was subcloned. Twenty-seven monoclonal cell lines were obtained and screened for the expression of striatal-specific characteristics including gamma-aminobutyric acid (GABA), choline acetyltransferase (ChAT), acetylcholine (ACh), mRNA for specific dopamine receptors, and dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein, M(r) 32,000 (DARPP-32), and functional D1 and D2 dopamine receptors. Neither the parent hybrid cell population (E1X) nor any of the monoclonal cell lines examined expressed GABA levels significantly different than that of the N18TG2 parent neuroblastoma cells (1.36 +/- 0.07 micrograms/mg protein). The range of ChAT activity in the monoclonal hybrid cell lines was 5.5 +/- 0.3 to 921.3 +/- 97.4 pmol/min/mg protein. Two of the cell lines expressing ChAT activity (X52 and X58) contained ACh (49.64 +/- 4.23 and 1.78 +/- 0.07 ng/mg protein, respectively). The neuronal origin of four of the monoclonal hybrid lines was shown by their immunoreactivity, following differentiation with 10 microM forskolin, to neurofilament protein, a neuron-specific marker. The monoclonal hybrid cell lines, but not the N18TG2 neuroblastoma, were shown to express an array of D1, D2, and D5 receptor mRNA as well as DARPP-32 mRNA. Two monoclonal cell lines expressed D1 receptor binding sites (X57, 29.2 +/- 4.5 fmol/mg protein and X62, 43.8 +/- 6.8 fmol/mg protein) which mediated the stimulation of adenylate cyclase activity. One cell line, X58, expressed only D2 dopamine receptors (80.9 +/- 9.8 fmol/mg protein) which were negatively coupled to adenylate cyclase activity. These findings suggest that the immortalized monoclonal hybrid cell lines are of neuronal origin and have incorporated elements of the medium spiny and cholinergic neurons of the developing striatum.

Human herpesvirus 6 limbic encephalitis after stem cell transplantation.

Central nervous system complications are common in stem cell transplant recipients, but selective involvement of the medial temporal area is unusual. The 5 patients reported here presented after stem cell transplantation with increased hippocampal T2 signal on magnetic resonance imaging and increased hippocampal glucose uptake on [F-18]fluorodeoxyglucose-positron emission tomography (FDG-PET) associated with short-term memory loss, insomnia, and temporal lobe electrographic seizure activity. The initial scalp electroencephalograms (EEGs) failed to detect seizure activity in these patients, although the memory dysfunction along with the magnetic resonance imaging and FDG-PET findings suggested subcortical seizure activity. However, extended EEG monitoring revealed repetitive temporal lobe electrographic seizure activity. Follow-up MRIs in 2 patients and postmortem findings on 1 patient suggested that hippocampal sclerosis had developed following the clinical syndrome. Cerebrospinal fluid studies revealed the presence of human herpesvirus 6, variant B, DNA in all of 3 patients who had lumbar punctures. Immunohistochemical staining for the P41 and P101 human herpesvirus 6 protein antigens showed numerous immunoreactive astrocytes and neurons in the hippocampus of 1 of the patients who died from other causes. Because of its subtle clinical presentation, this syndrome may be underrecognized, but can be diagnosed with appropriate magnetic resonance imaging techniques, EEG monitoring, and cerebrospinal fluid viral studies.