Donald L. Gilbert

The ecoresponsive genome of Daphnia pulex

The Daphnia genome reveals a multitude of genes and shows adaptation through gene family expansions. We describe the draft genome of the microcrustacean Daphnia pulex, which is only 200 megabases and contains at least 30,907 genes. The high gene count is a consequence of an elevated rate of gene duplication resulting in tandem gene clusters. More than a third of Daphnia’s genes have no detectable homologs in any other available proteome, and the most amplified gene families are specific to the Daphnia lineage. The coexpansion of gene families interacting within metabolic pathways suggests that the maintenance of duplicated genes is not random, and the analysis of gene expression under different environmental conditions reveals that numerous paralogs acquire divergent expression patterns soon after duplication. Daphnia-specific genes, including many additional loci within sequenced regions that are otherwise devoid of annotations, are the most responsive genes to ecological challenges.

L-Histidine Decarboxylase and Tourette's Syndrome

Tourettes syndrome is a common developmental neuropsychiatric disorder characterized by chronic motor and vocal tics. Despite a strong genetic contribution, inheritance is complex, and risk alleles have proven difficult to identify. Here, we describe an analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding L-histidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. Our findings, together with previously published data from model systems, point to a role for histaminergic neurotransmission in the mechanism and modulation of Tourettes syndrome and tics.

Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.

Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. They are responsible for a heterogeneous group of at least 6 major phenotypes of neurodegenerative disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders (MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant Progressive External Ophthalmoplegia (adPEO). Due to the clinical heterogeneity, time‐dependent evolution of symptoms, overlapping phenotypes, and inconsistencies in muscle pathology findings, definitive diagnosis relies on the molecular finding of deleterious mutations. We sequenced the exons and flanking intron region from approximately 350 patients displaying a phenotype consistent with POLG related mitochondrial disease and found informative mutations in 61 (17%). Two mutant alleles were identified in 31 unrelated index patients with autosomal recessive POLG‐related disorders. Among them, 20 (67%) had Alpers syndrome, 4 (13%) had arPEO, and 3 (10%) had ANS. In addition, 30 patients carrying one altered POLG allele were found. A total of 25 novel alterations were identified, including 6 null mutations. We describe the predicted structural/functional and clinical importance of the previously unreported missense variants and discuss their likelihood of being pathogenic. In conclusion, sequence analysis allows the identification of mutations responsible for POLG‐related disorders and, in most of the autosomal recessive cases where two mutant alleles are found in trans, finding deleterious mutations can provide an unequivocal diagnosis of the disease. Published 2008 Wiley‐Liss, Inc.

DEFINITION AND CLASSIFICATION OF HYPERKINETIC MOVEMENTS IN CHILDHOOD

Hyperkinetic movements are unwanted or excess movements that are frequently seen in children with neurologic disorders. They are an important clinical finding with significant implications for diagnosis and treatment. However, the lack of agreement on standard terminology and definitions interferes with clinical treatment and research. We describe definitions of dystonia, chorea, athetosis, myoclonus, tremor, tics, and stereotypies that arose from a consensus meeting in June 2008 of specialists from different clinical and basic science fields. Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Chorea is an ongoing random‐appearing sequence of one or more discrete involuntary movements or movement fragments. Athetosis is a slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Myoclonus is a sequence of repeated, often nonrhythmic, brief shock‐like jerks due to sudden involuntary contraction or relaxation of one or more muscles. Tremor is a rhythmic back‐and‐forth or oscillating involuntary movement about a joint axis. Tics are repeated, individually recognizable, intermittent movements or movement fragments that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement. Stereotypies are repetitive, simple movements that can be voluntarily suppressed. We provide recommended techniques for clinical examination and suggestions for differentiating between the different types of hyperkinetic movements, noting that there may be overlap between conditions. These definitions and the diagnostic recommendations are intended to be reliable and useful for clinical practice, communication between clinicians and researchers, and for the design of quantitative tests that will guide and assess the outcome of future clinical trials.

Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders

Objective: To test the hypothesis that atomoxetine does not significantly worsen tic severity relative to placebo in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid tic disorders. Methods: Study subjects were 7 to 17 years old, met Diagnostic and Statistical Manual of Mental Disorders–IV criteria for ADHD, and had concurrent Tourette syndrome or chronic motor tic disorder. Patients were randomly assigned to double-blind treatment with placebo (n = 72) or atomoxetine (0.5 to 1.5 mg/kg/day, n = 76) for up to 18 weeks. Results: Atomoxetine treatment was associated with greater reduction of tic severity at endpoint relative to placebo, approaching significance on the Yale Global Tic Severity Scale total score (–5.5 ± 6.9 vs –3.0 ± 8.7, p = 0.063) and Tic Symptom Self-Report total score (–4.7 ± 6.5 vs –2.9 ± 5.2, p = 0.095) and achieving significance on the Clinical Global Impressions (CGI) tic/neurologic severity scale score (–0.7 ± 1.2 vs –0.1 ± 1.0, p = 0.002). Atomoxetine patients also showed greater improvement on the ADHD Rating Scale total score (–10.9 ± 10.9 vs –4.9 ± 10.3, p < 0.001) and CGI severity of ADHD/psychiatric symptoms scale score (–0.8 ± 1.1 vs –0.3 ± 1.0, p = 0.015). Discontinuation rates were not significantly different between treatment groups. Atomoxetine patients had greater increases in heart rate and decreases of body weight, and rates of treatment-emergent decreased appetite and nausea were higher. No other clinically relevant treatment differences were seen in any other vital sign, adverse event, or electrocardiographic or laboratory measures. Conclusions: Atomoxetine did not exacerbate tic symptoms. Rather, there was some evidence of reduction in tic severity with a significant reduction of attention deficit/hyperactivity disorder symptoms. Atomoxetine treatment appeared safe and well tolerated.

Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism.

BACKGROUND Studies of copy number variation (CNV) have characterized loci and molecular pathways in a range of neuropsychiatric conditions. We analyzed rare CNVs in Tourette syndrome (TS) to identify novel risk regions and relevant pathways, to evaluate burden of structural variation in cases versus controls, and to assess overlap of identified variations with those in other neuropsychiatric syndromes. METHODS We conducted a case-control study of 460 individuals with TS, including 148 parent-child trios and 1131 controls. CNV analysis was undertaken using 370 K to 1 M probe arrays, and genotyping data were used to match cases and controls for ancestry. CNVs present in < 1% of the population were evaluated. RESULTS While there was no significant increase in the number of de novo or transmitted rare CNVs in cases versus controls, pathway analysis using multiple algorithms showed enrichment of genes within histamine receptor (subtypes 1 and 2) signaling pathways (p = 5.8 × 10(-4) - 1.6 × 10(-2)), as well as axon guidance, cell adhesion, nervous system development, and synaptic structure and function processes. Genes mapping within rare CNVs in TS showed significant overlap with those previously identified in autism spectrum disorders but not intellectual disability or schizophrenia. Three large, likely pathogenic, de novo events were identified, including one disrupting multiple gamma-aminobutyric acid receptor genes. CONCLUSIONS We identify further evidence supporting recent findings regarding the involvement of histaminergic and gamma-aminobutyric acidergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and autism spectrum disorders.

Association of cortical disinhibition with tic, ADHD, and OCD severity in Tourette syndrome.

Hyperkinetic disorders may involve excess excitatory output from thalamus to cerebral cortex. Case–control, neurophysiological studies in persons with Tourette Syndrome (TS), Attention Deficit Hyperactivity Disorder (ADHD), and Obsessive‐Compulsive Disorder (OCD) support this model. To compare the strength of association between motor cortex inhibition and tic, ADHD, and OCD severity in TS, we used transcranial magnetic stimulation to measure motor cortex inhibition in 36 children and adults with TS. Current symptom severity was assessed with standard clinical rating scales and compared with neurophysiological measures using correlational and multivariate regression analyses. Severity of ADHD symptoms and motor tics were associated significantly and independently with short interval intracortical inhibition (SICI) (r2 = 0.50; F[2,27] = 13.7; P < 0.001), particularly in subjects not taking neuroleptics (r2 = 0.68; F[2,17] = 17.8; P < 0.0001). The correlation of cortical disinhibition was greater with ADHD symptoms severity (r = 0.53; P = 0.003) than with tic severity (r = 0.42; P = 0.02), suggesting that in TS, the association between SICI and ADHD symptoms may be more consistent or direct than the association between SICI and tics.

The ketogenic diet: Seizure control correlates better with serum β-hydroxybutyrate than with urine ketones

The objective of this study was to determine the relationship between β-hydroxybutyrate levels and seizure control in children on the ketogenic diet. Seventy-four children on the ketogenic diet presenting for routine follow-up visits had blood levels of β-hydroxybutyrate correlated with their seizure control. Forty-two children admitted for initiation of the ketogenic diet had urine ketones measured by dipstick and correlated with simultaneous blood levels of β-hydroxybutyrate. Blood β-hydroxybutyrate levels statistically correlated with seizure control (P = .003). Children with blood β-hydroxybutyrate levels greater than 4 mmol/L were significantly more likely to have a decrease in seizure frequency than those with levels less than 4 mmol/L. Urine ketones of 4+ (160 mmol/L) were found on dipstick when blood β-hydroxybutyrate levels exceeded 2 mmol/L. Seizure control correlates with blood β-hydroxybutyrate levels and is more likely when blood β-hydroxybutyrate levels are greater than 4 mmol/L. The traditional measurement of urine ketones by dipsticks in children on the ketogenic diet provides a less than optimal assessment of the degree of blood ketosis. Three to four plus (80-160 mmol/L) urine ketones are necessary, but not necessarily sufficient, to achieve optimal seizure control in children on the ketogenic diet. At present, however, urine ketones are the only readily available inexpensive approach to ketone assessment. (J Child Neurol 2000; 15:787-790).

Tic Reduction With Risperidone Versus Pimozide in a Randomized, Double-Blind, Crossover Trial

OBJECTIVE To compare the tic suppression, electrocardiogram (ECG) changes, weight gain, and side effect profiles of pimozide versus risperidone in children and adolescents with tic disorders. METHOD This was a randomized, double-blind, crossover (evaluable patient analysis) study. Nineteen children aged 7 to 17 years with Tourettes or chronic motor tic disorder were randomized to 4 weeks of treatment with pimozide or risperidone, followed by the alternate treatment after a 2-week placebo washout. The primary efficacy outcome measure was change in tic severity assessed by the Yale Global Tic Severity Scale (YGTSS). ECG results, weight gain, and side effects were also compared. RESULTS Compared to pimozide treatment, risperidone treatment was associated with significantly lower tic severity scores (YGTSS: baseline 43.3 +/- 17.5, pimozide 34.2 +/- 14.2, risperidone 25.2 +/- 13.6; p =.05). Weight gain during the 4-week treatment periods was greater for risperidone (mean 1.9 kg) than pimozide (1.0 kg). No patient suffered a serious adverse event, but 6 of 19 subjects failed to complete the protocol. Neither medication was associated with ECG changes. CONCLUSIONS In this study, risperidone appeared superior to pimozide for tic suppression but was associated with greater weight gain.

Efficacy and Mortality in Treatment of Refractory Generalized Convulsive Status Epilepticus in Children: A Meta-Analysis

There is no consensus on the choice of drug treatment for refractory generalized convulsive status epilepticus in children. The objective of this meta-analysis of the published literature was to determine the effects of drug treatments on efficacy (seizure cessation) and mortality in children with this condition, controlling for potential confounding factors. One hundred eleven children, treated with diazepam, midazolam, thiopental, pentobarbital, or isoflurane, met strict inclusion criteria. Diazepam was significantly less efficacious than other treatments (P = .006) stratifying for etiology. Overall mortality was 20% in symptomatic cases and 4% in idiopathic cases (P = .038). Mortality was less frequent in midazolam-treated patients (P = .021) stratifying for etiology. Midazolam appears to be a good choice for initial treatment of refractory generalized convulsive status epilepticus in children, but the attribution of differences in efficacy and mortality solely to drug effect is not possible based on the published literature. (J Child Neurol 1999;14:602-609).