Holoprosencephaly: molecular study of a California population

Holoprosencephaly (HPE) is a common developmental anomaly of the forebrain and midface in which the cerebral hemispheres fail to separate into distinct left and right halves. HPE is extremely heterogeneous. In addition to teratogenic agents, several genes are implicated in the cause of HPE. Using samples from a population-based birth defects registry in California, we performed a mutational analysis of the known HPE genes Sonic Hedgehog (SHH), ZIC2, and SIX3, in addition to two HPE candidate genes, TG-interacting factor (TGIF), and Patched (PTC), on a group of sporadic HPE patients. This is the first molecular study of HPE in a population-based sample of patients. Among these patients, a deletion in the homeodomain of SIX3 and several polymorphisms in SIX3 and TGIF were identified. No sequence changes were detected in SHH, ZIC2, and PTC. Our results suggest that mutations in the currently recognized HPE genes may explain <5% of all sporadic HPE cases.     

Sleep problems in children with autism spectrum disorders, developmental delays, and typical development: a population-based study

This study compared parent-reported sleep characteristics in 2- to 5-year-old children with autism spectrum disorders (ASD) to children with other developmental delays (DD) and typical development (TD). We included 529 children (303 ASD [167 males], 63 DD [46 males], and 163 TD [134 males]) enrolled in the CHARGE study, an ongoing population-based case-control study. The mean age of participants was 3.6 years (standard deviation, 0.8 years). ASD diagnosis was confirmed with Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedules (ADOS). Cognitive and adaptive functioning was assessed using Mullen Scales of Early Learning (MSEL) and Vineland Adaptive Behavior Scales (VABS), respectively. Demographic, medical and sleep history information were ascertained from California birth records, telephone interview, medical assessments at clinic visit, and parent-administered questionnaires. Fifty-three percent of children with ASD had at least one frequent sleep problem, followed by 46% of children with DD, and 32% of the TD group (P < 0.0001). Exploratory factor analyses of sleep history data yielded two factors: sleep onset problems and night waking. Children with ASD had marginally higher sleep onset factor scores and significantly higher night waking factor scores compared with the TD group. Factor scores for children with DD were intermediate between the ASD and TD groups. Cognitive or adaptive development did not predict severity of sleep problems in the ASD group.     

Psychotropic Medication Use among Insured Children with Autism Spectrum Disorder

This study examined psychotropic medication use among 7901 children aged 1–17 with autism spectrum disorder (ASD) in five health systems, comparing to matched cohorts with no ASD. Nearly half (48.5?%) of children with ASD received psychotropics in the year observed; the most common classes were stimulants, alpha-agonists, or atomoxetine (30.2?%), antipsychotics (20.5?%), and antidepressants (17.8?%). Psychotropic treatment was far more prevalent among children with ASD, as compared to children with no ASD (7.7?% overall), even within strata defined by the presence or absence of other psychiatric diagnoses. The widespread use of psychotropics we observed, particularly given weak evidence supporting the effectiveness of these medications for most children with ASD, highlights challenges in ASD treatment and the need for greater investment in its evaluation.     

Maternal Dietary Patterns during Pregnancy and Child Autism-Related Traits: Results from Two US Cohorts

We examined the relationship between maternal intake of established dietary patterns and child autism-related outcomes in two prospective cohorts in the United States. Participants were drawn from the Early Autism Risk Longitudinal Investigation (EARLI, n = 154) and the Nurses’ Health Study II (NHSII, n = 727). Dietary information was collected via food frequency questionnaires (FFQs) and used to calculate the empirical dietary inflammatory pattern (EDIP), Alternative Healthy Eating Index (AHEI), Western and Prudent dietary patterns, and the alternative Mediterranean Diet (aMED) score. Primary analyses examined associations with continuous autism-related traits as measured by the Social Responsiveness Scale (SRS), and secondary analyses with autism spectrum disorder (ASD) diagnosis. We used crude and multivariable quantile regression fixed at the 50th percentile to examine associations between quartiles of dietary patterns and SRS scores, and logistic regression to examine associations with ASD diagnosis. There was suggestion of a positive association with the Western diet (Q4 vs. Q1, ß = 11.19, 95% CI: 3.30, 19.90) in EARLI, though the association was attenuated with adjustment for total energy intake, and no clear associations were observed with other dietary patterns and ASD diagnosis or SRS scores. Further work is needed to better understand the role of maternal dietary patterns in ASD and related outcomes.     

Neuroimaging abnormalities in infants with congenital hemiparesis

Clinical and neuroimaging characteristics of congenital hemiparesis were examined in a retrospective cohort study nested within 199,176 births within the Kaiser Permanente Medical Care Program, 1997-2002. Infants with a physician diagnosis of paresis or cerebral palsy were electronically identified, and charts were reviewed to confirm congenital hemiparesis. A neuroradiologist reviewed available head MRI and CT scans. Of 96 infants with congenital hemiparesis (population prevalence 4.8 per 10,000), 81% received either a head magnetic resonance imaging (n = 55) or head computed tomography only (n = 23). Perinatal arterial infarction was the most common (30%) neuroimaging finding in term infants. Infants with right-sided hemiparesis (relative risk 4.6, 95% confidence interval 1.4-14.4) or moderate to severe weakness (relative risk 4.4, 95% confidence interval 1.1-17.7) were more likely to have had a perinatal arterial infarction. Periventricular white matter lesions predominated in preterm infants (71%). Brain malformations observed in 14 (18%) patients included polymicrogyria, heterotopia, and schizencephaly. The 14 infants (18%) with a normal head imaging study were more likely to outgrow all signs of hemiparesis by age 3 than were infants with an abnormal brain image (29% vs 0%, P < 0.001). Neuroimaging studies provide useful diagnostic and prognostic information in infants with congenital hemiparesis.     

Congenital anomalies associated with autism spectrum disorders

This study examined whether major congenital structural anomalies identified in infancy occurred more frequently in children later diagnosed with autism spectrum disorders (ASD; n=417; 341 males, 76 females) than in comparison children (n=2,067; 1,681 males, 386 females). Participants were sampled from infants born at Kaiser Permanente Northern California facilities between 1995 and 1999 who remained health plan members for at least 2 years (n=88,163). Comparison children were frequency-matched to children with ASD according to sex, birth year, and birth hospital. Congenital anomalies were diagnosed in 10.8% of children with ASD and 6.2% of comparison children (crude odds ratio [ORc] 1.8, 95% confidence interval [CI] 1.3-2.6). This association remained significant after adjustment for key maternal and infant covariates (adjusted OR [ORa] 1.7, 95% CI 1.1-2.4). Almost all organ-system anomaly categories were more prevalent in children with ASD, however only gastrointestinal anomalies were significantly associated with ASD in adjusted analyses (1.9 vs 0.4%, ORa 5.1, 95% CI 1.8-14.1).     

Congenital abnormalities among children with cerebral palsy: More evidence for prenatal antecedents

OBJECTIVES: To investigate the association between cerebral palsy (CP) and congenital abnormalities among children with very low, low, and normal birth weight.Study design: A population-based, case-control study among the cohort of 155,636 live births delivered between 1983 and 1985 in 4 California counties. Children with moderate or severe congenital CP (n = 192) diagnosed by age 3 were identified from 2 California State service agencies, and 551 control children were randomly sampled from birth certificate files. Information on congenital abnormalities diagnosed by the age of 1 year was obtained from the California Birth Defects Monitoring Program registry. Odds ratios (OR) and 95% CIs were calculated to estimate risk for CP associated with congenital abnormalities. RESULTS: Among singletons, congenital abnormalities were present in 33 (19.2%) children with CP and 21 (4.3%) control children (OR = 5.2, 95% CI 2.8-9.7). For each birth weight group, the percent of children with congenital abnormalities among children with CP exceeded that among control children. Structural abnormalities of the central nervous system were more common among children with CP (OR = 16.2, 95% CI 5.8-49.3) than control children. In contrast, the percent of children with non-central nervous system abnormalities only was similar between case patients and control subjects. CONCLUSION: These findings provide further evidence that factors operating in the prenatal period contribute significantly to the etiology of CP.     

Aortenisthmusstenose bei Erwachsenen: operative Korrektur – mittel- und langfristige Ergebnisse

Zusammenfassung Fragestellung Ziel dieser retrospektiven Untersuchung war es, die Mittel- und Langzeitergebnisse der operativen Korrektur von Aortenisthmusstenosen (ISTHA) bei Erwachsenen zu erfassen. Patienten und Methodik Zwischen August 1985 und Januar 1999 wurden 20 Patienten (8 Frauen, 12 M?nner) wegen ISTHA im Alter 19–60 Jahren (im Mittel 33 Jahre) operiert. Alle Patienten fielen klinisch durch Bluthochdruck der oberen Extremit?ten auf (im Mittel 177/92 mmHg). Bei 9 Patienten von 16 (56%) handelte es sich um einen Zufallsbefund (bei 4 konnte dies nicht eruiert werden). Eine eingeschr?nkte pr?operative Belastbarkeit wiesen 13 Patienten (65%) auf. Herzrhythmusst?rungen zeigten sich bei 3 Patienten (15%). 14 Patienten (70%) zeigten im R?ntgenbild Rippenusuren. Als operative Therapie erfolgte bei 5 Patienten (25%) eine End-zu-End Anastomose, bei 7 (35%) eine Erweiterungsplastik, bei weiteren 3 (15%) eine Rohrprothesenimplantation und bei 5 Patienten (25%) ein extraanatomischer Bypass. Die Operationsdauer betrug zwischen 105 und 240 Minuten, im Durchschnitt 159 Minuten. Ergebnisse Perioperativ trat bei einem Patienten eine Nachblutung wegen Nahtdehiszenz auf, die eine Not-Rethoracotomie erforderlich machte. Die Folgen des h?morrhagischen Schocks führten am n?chsten Morgen zum Tod. Die Frühmortalit?t betrug somit 5% (1/20). Bei 10 Patienten normalisierte sich der Blutdruck direkt postoperativ, bei 5 Patienten blieb er leicht erh?ht (RR zwischen 140 und 160 mmHg systolisch). Bei den übrigen 4 Patienten konnte dies nicht mehr eruiert werden. In 14 F?llen (73,7%) war ein postoperatives Follow-up nach durchschnittlich 9,4 Jahren (Minimum 1,2; Maximum 13,8 Jahre) durchführbar. Ein Patient war 12,4 Jahre nach der Operation an Herzversagen verstorben. Somit betrug die Sp?tmortalit?t 7,1% (1/14). Im Durchschnitt verbesserten sich die Patienten um 0,85 NYHA-Klassen in ihrer Belastbarkeit. Zum Zeitpunkt des Follow-up hatte nur einer von 13 Patienten einen fortbestehenden Hypertonus. Schlussfolgerung Die chirurgische Behandlung von Aortenisthmusstenosen bei Erwachsenen reduziert die arterielle Hypertonie und verbessert die Belastbarkeit von Patienten. Im dem von uns beobachteten Kollektiv zeigte sich eine geringe Früh- sowie Sp?tmortalit?t und Morbidit?t. Zeitlebens sollten Verlaufsbeobachtungen in spezialisierten Zentren durchgeführt werden. Eingegangen: 17. Dezember 2001 Akzeptiert: 7. Mai 2002     

Peri-Pregnancy Cannabis Use and Autism Spectrum Disorder in the Offspring: Findings from the Study to Explore Early Development

Journal of Autism and Developmental Disorders - The association of autism spectrum disorder (ASD) with self-reported maternal cannabis use from 3&nbsp;months pre-conception to delivery...