Mitochondrial enzyme dysfunction in autism spectrum disorders; a novel biomarker revealed from buccal swab analysis.

AIM: Mitochondrial function studies in autism spectrum disorders (ASD) have detected skeletal muscle mitochondrial enzyme deficiencies in respiratory complex (RC) activities. As a muscle biopsy is expensive and invasive, we assessed RC-I and RC-IV activities in buccal swabs. METHODS: 92 children with ASD and 68 controls were studied with immunocapture for RC-I and microspectrophotometry for RC-IV. RESULTS: Significant RC activity deficiencies were found in 39 (42%) ASD patients (p < 0.01) and more prevalent in more severe cases. Aberrant RC overactivity was seen in 9 children. RC-I/RC-IV activity ratio was significantly increased in 64% of the entire ASD cohort including 76% of those more severely affected (p < 0.05). CONCLUSION: Buccal swab analysis revealed extensive RC abnormalities in ASD providing a noninvasive biomarker to assess mitochondrial function in ASD patients.

The genetics of reading disability in an often excluded sample: novel loci suggested for reading disability in Rolandic epilepsy.

BACKGROUND: Reading disability (RD) is a common neurodevelopmental disorder with genetic basis established in families segregating "pure" dyslexia. RD commonly occurs in neurodevelopmental disorders including Rolandic Epilepsy (RE), a complex genetic disorder. We performed genomewide linkage analysis of RD in RE families, testing the hypotheses that RD in RE families is genetically heterogenenous to pure dyslexia, and shares genetic influences with other sub-phenotypes of RE. METHODS: We initially performed genome-wide linkage analysis using 1000 STR markers in 38 US families ascertained through a RE proband; most of these families were multiplex for RD. We analyzed the data by two-point and multipoint parametric LOD score methods. We then confirmed the linkage evidence in a second US dataset of 20 RE families. We also resequenced the SEMA3C gene at the 7q21 linkage locus in members of one multiplex RE/RD pedigree and the DISC1 gene in affected pedigrees at the 1q42 locus. RESULTS: In the discovery dataset there was suggestive evidence of linkage for RD to chromosome 7q21 (two-point LOD score 3.05, multipoint LOD 3.08) and at 1q42 (two-point LOD 2.87, multipoint LOD 3.03). Much of the linkage evidence at 7q21 derived from families of French-Canadian origin, whereas the linkage evidence at 1q42 was well distributed across all the families. There was little evidence for linkage at known dyslexia loci. Combining the discovery and confirmation datasets increased the evidence at 1q42 (two-point LOD = 3.49, multipoint HLOD = 4.70), but decreased evidence at 7q21 (two-point LOD = 2.28, multipoint HLOD  = 1.81), possibly because the replication sample did not have French Canadian representation. DISCUSSION: Reading disability in rolandic epilepsy has a genetic basis and may be influenced by loci at 1q42 and, in some populations, at 7q21; there is little evidence of a role for known DYX loci discovered in "pure" dyslexia pedigrees. 1q42 and 7q21 are candidate novel dyslexia loci.

Efficacy and tolerability of topiramate in pediatric migraine.

About 5-10% of school-age children manifest migraine headaches. Treatment options for pediatric migraine are limited. Topiramate is approved for migraine prophylaxis in adults, but its use in children is limited. We retrospectively reviewed the records of 37 patients, i.e., 22 (60%) girls and 15 (40%) boys (mean age, 14 years; range, 7.3-20.5 years), diagnosed with migraine without aura in 30 (81%), with aura in four (11%), and abdominal, ophthalmoplegic, and catamenial in one each. The mean follow-up was 12 +/- 5 months standard deviation (S.D.). Clinical response was qualified as excellent, good, no change, or worse. Numbers of headaches per month were 15 +/- 7 S.D. prior to treatment and 3 +/- 3.4 S.D. (P < 0.001) after treatment. An excellent or good response (>50% migraine reduction) was attained in 28 patients (76%). Ten (27%) patients exhibited adverse effects. Patients taking >2 mg/kg/day were more likely to demonstrate side effects. The mean dose for patients without adverse effects was 1.27 +/- 0.7 mg/kg/day S.D. Those who reported adverse effects were taking a mean dose of 2.8 +/- 1.5 mg/kg/day S.D. This study demonstrated that topiramate is an effective, safe alternative for the prophylaxis of pediatric migraine. An acceptable risk/benefit maintenance dose was < or =2 mg/kg/day.

Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4).

Rolandic epilepsy (RE) is the most common human epilepsy, affecting children between 3 and 12 years of age, boys more often than girls (3:2). Focal sharp waves in the centrotemporal area define the electroencephalographic (EEG) trait for the syndrome, are a feature of several related childhood epilepsies and are frequently observed in common developmental disorders (eg, speech dyspraxia, attention deficit hyperactivity disorder and developmental coordination disorder). Here we report the first genome-wide linkage scan in RE for the EEG trait, centrotemporal sharp waves (CTS), with genome-wide linkage of CTS to 11p13 (HLOD 4.30). Pure likelihood statistical analysis refined our linkage peak by fine mapping CTS to variants in Elongator Protein Complex 4 (ELP4) in two independent data sets; the strongest evidence was with rs986527 in intron 9 of ELP4, providing a likelihood ratio of 629:1 (P=0.0002) in favor of an association. Resequencing of ELP4 coding, flanking and promoter regions revealed no significant exonic polymorphisms. This is the first report of a gene implicated in a common focal epilepsy and the first human disease association of ELP4. ELP4 is a component of the Elongator complex, involved in transcription and tRNA modification. Elongator depletion results in the brain-specific downregulation of genes implicated in cell motility and migration. We hypothesize that a non-coding mutation in ELP4 impairs brain-specific Elongator-mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders.

Sleep study abnormalities in children with attention deficit hyperactivity disorder.

The study objective was to describe polysomnographic findings in children with attention deficit hyperactivity disorder (ADHD) with diverse sleep problems. Polysomnographic data were retrospectively analyzed for 33 children (age 3-16 years) with ADHD who had sleep studies performed for diverse sleep complaints. Eight patients (24%) had obstructive sleep apnea, 10 (30%) had periodic limb movements of sleep, 8 (24%) had upper airway resistance syndrome, and 5 (15%) had obstructive hypoventilation. The ADHD group showed decreased sleep efficiency, increased arousal index, increased wake after sleep onset, decreased oxygen saturation nadir, and increased snoring, compared with control subjects. Compared with ADHD children without sleep disordered breathing, those who had sleep disordered breathing were significantly more obese and had more sleep architectural abnormalities (including increased sleep latency, increased rapid eye movement latency, increased wake after sleep onset, and increased arousal index with more oxygen desaturations), although total sleep time and sleep efficiency were not significantly different. Sleep disordered breathing and periodic limb movements of sleep appear to be common among children with ADHD who have symptoms of disturbed sleep.

Efficacy and safety of lamotrigine monotherapy in children and adolescents with epilepsy.

Lamotrigine (LTG) has shown to confer broad-spectrum, well-tolerated control of epilepsy. Monotherapy is preferable over polytherapy because of better compliance, fewer adverse events, less interactions, lower teratogenicity and lower cost. The aim of this study is to evaluate the efficacy and safety of LTG monotherapy on seizure control in a cohort of children and adolescents with epilepsy. We retrospectively reviewed the records of children and adolescents treated with LTG monotherapy at our institution between 2001 and 2006. Data collected included demographics, seizure type, etiology of seizures, age at onset of seizures and at initiation of LTG treatment, number of antiepileptic drugs (AEDs) prior to LTG, dose of LTG, length of follow-up, treatment response, and adverse events. Seventy-two children and adolescents were identified (mean age 12.1 years); 37.5% had mental retardation. Age at onset of epilepsy was 5.7 years (0-16). Twenty three percent had symptomatic focal epilepsy, 15.5% idiopathic focal epilepsy, 19.4% symptomatic generalized epilepsy and 41.6% idiopathic generalized epilepsy. LTG was used as first-line monotherapy in 26.4% of patients and as a second-line monotherapy in 73.6%. Age at initiation of LTG therapy was 10 years (2.8-19). Mean number of AEDs tried prior to LTG was 1.3 (0-6). Mean dose of LTG was 5.5mg/kg/day (1.1-13.7). Mean follow-up period was 33 months (3 weeks to 11.5 years). The degree of seizure reduction was as follows: seizure free in 42%, 75-90% reduction in 17.4%, 50-74% in 11.6%, 25-49% in 10%. Sixteen percent had no change in seizure control and 3% became worse. The most common adverse event was rash (6.9%). Six (8.3%) patients discontinued LTG because of the adverse events. No patient had Stevens-Johnson syndrome. In conclusion, LTG was effective and well-tolerated as monotherapy in children and adolescents for both focal and generalized epilepsies.

Oxcarbazepine therapy in very young children: a single-center clinical experience.

Oxcarbazepine is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and children >or=4 years of age. The purpose of this retrospective chart review was to assess efficacy and tolerability of oxcarbazepine in children

Efficacy and tolerability of zonisamide in juvenile myoclonic epilepsy.

The recommended treatment for juvenile myoclonic epilepsy (JME) is valproate (VPA). Recently, topiramate and lamotrigine have also been shown to be effective. The objective of this study was to evaluate the efficacy and tolerability of zonisamide (ZNS) in the treatment of JME. We retrospectively analyzed the records of 15 patients (three M, 12 F, ages 11-20 years) diagnosed with JME at our institution during 2001-2003, and treated with ZNS. Generalized tonic-clonic (GTC), myoclonic and absence seizure response was assessed. The ZNS dose range was 200-500 mg/day (2.0-8.5 mg/kg/day). ZNS was started as the first drug, and as monotherapy, in 13 and was added to VPA in two patients. Follow-up range was 2-24 months (mean 12 months). Overall, 80% of patients on ZNS monotherapy showed good control (> or = 50% seizure reduction). Sixty-nine, 62 and 38% of patients were free of GTC, myoclonic, and absence seizures, respectively. Seizure control was achieved within four to eight weeks of attaining the maintenance dose. One patient on polytherapy had a 75% reduction in seizure frequency, whereas the other patient showed no response. There were no ZNS-VPA interactions. One patient stopped ZNS and was switched to VPA because of poor seizure control. Three patients (20%) experienced side effects (weight loss, headache, dizziness) during escalation, which resolved during maintenance. In this open-label, retrospective study, ZNS was shown to be an effective and well-tolerated drug in the treatment of patients with JME. The ease of titration, good safety profile, once-a-day dosing, lack of significant drug interaction, and short latency for onset of efficacy make ZNS an attractive therapeutic alternative for the treatment of JME.