Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.

Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations-identified by whole-genome and targeted "HAR-ome" sequencing-showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases. Using chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice, we identified disease-linked, biallelic HAR mutations in active enhancers for CUX1, PTBP2, GPC4, CDKL5, and other genes implicated in neural function, ASD, or both. Our data provide genetic evidence that specific HARs are essential for normal development, consistent with suggestions that their evolutionary changes may have altered social and/or cognitive behavior. PAPERCLIP.

Using whole-exome sequencing to identify inherited causes of autism.

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.

Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected].

Genes disrupted in human microcephaly (meaning "small brain") define key regulators of neural progenitor proliferation and cell-fate specification. In comparison, genes mutated in human lissencephaly (lissos means smooth and cephalos means brain) highlight critical regulators of neuronal migration. Here, we report two families with extreme microcephaly and grossly simplified cortical gyral structure, a condition referred to as microlissencephaly, and show that they carry homozygous frameshift mutations in NDE1, which encodes a multidomain protein that localizes to the centrosome and mitotic spindle poles. Both human mutations in NDE1 truncate the C-terminal NDE1domains, which are essential for interactions with cytoplasmic dynein and thus for regulation of cytoskeletal dynamics in mitosis and for cell-cycle-dependent phosphorylation of NDE1 by Cdk1. We show that the patient NDE1 proteins are unstable, cannot bind cytoplasmic dynein, and do not localize properly to the centrosome. Additionally, we show that CDK1 phosphorylation at T246, which is within the C-terminal region disrupted by the mutations, is required for cell-cycle progression from the G2 to the M phase. The role of NDE1 in cell-cycle progression probably contributes to the profound neuronal proliferation defects evident in Nde1-null mice and patients with NDE1 mutations, demonstrating the essential role of NDE1 in human cerebral cortical neurogenesis.

Identifying autism loci and genes by tracing recent shared ancestry.

To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of "homozygosity mapping" in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.

Transient nonketotic hyperglycinemia and defective serotonin metabolism in a child with neonatal seizures.

Neonatal nonketotic hyperglycinemia is usually fatal or, less commonly, severely developmentally disabling, whereas transient nonketotic hyperglycinemia has usually been followed by normal development. We report a boy who had transient neonatal nonketotic hyperglycinemia but a coexistent disorder of serotonin metabolism manifested by initially low cerebrospinal fluid 5-hydroxyindoleacetic acid (which later normalized), low whole blood serotonin, and decreased platelet serotonin uptake. He survived the neonatal period but was neurodevelopmentally delayed and developed an autistic-like disorder. Later, his positron emission tomographic (PET) scans with alpha[(11)C] methyl-l-tryptophan revealed a pattern characteristic of autistic children. Although we know of no link between glycine and serotonin metabolism, and our patient had low, rather than high, central and peripheral serotonin, this case might represent a novel infantile disorder that affects both the glycine and serotonin neurotransmitter systems.

Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.

Joubert syndrome is a congenital brain malformation of the cerebellar vermis and brainstem with abnormalities of axonal decussation (crossing in the brain) affecting the corticospinal tract and superior cerebellar peduncles. Individuals with Joubert syndrome have motor and behavioral abnormalities, including an inability to walk due to severe clumsiness and 'mirror' movements, and cognitive and behavioral disturbances. Here we identified a locus associated with Joubert syndrome, JBTS3, on chromosome 6q23.2-q23.3 and found three deleterious mutations in AHI1, the first gene to be associated with Joubert syndrome. AHI1 is most highly expressed in brain, particularly in neurons that give rise to the crossing axons of the corticospinal tract and superior cerebellar peduncles. Comparative genetic analysis of AHI1 indicates that it has undergone positive evolutionary selection along the human lineage. Therefore, changes in AHI1 may have been important in the evolution of human-specific motor behaviors.

Randomized treatment study of inosiplex versus combined inosiplex and intraventricular interferon-alpha in subacute sclerosing panencephalitis (SSPE): international multicenter study.

The efficacy of oral inosiplex alone (group A) versus combined treatment of inosiplex (Isoprinosine) and intraventricular interferon-alpha2b (Intron A) (group B) in patients with subacute sclerosing panencephalitis (SSPE) was compared. One hundred and twenty-one patients who met the diagnostic criteria for subacute sclerosing panencephalitis and presented at stage 2 or less were randomized into group A or B. Data were analyzable on 67 patients who met the inclusion criteria and adhered to the protocol. The inosiplex dosage was 100 mg/kg/day to a maximum of 3 g/day, taken orally in three divided doses for 6 months. Interferon-alpha2b started with 100,000 U/m2 and escalated to 1,000,000 U/m2 over 5 inpatient days and then 1,000,000 U/m2 twice a week for 6 months. Neurologic status was rated by the Neurological Disability Index, Brief Assessment Examination, and stages. Kaplan-Meier survival rates were not statistically significant between group A and group B (log-rank test chi2 = .1374, P = .7109). In longitudinal morbidity analyses, regression results were fitted to three outcome measures: the Neurological Disability Index, the Brief Assessment Examination, and stage. Group medians of the estimated regression slopes were then compared using the Wilcoxon rank-sum test. There was no statistically significant difference between the two groups on any of these three measures. Morbidity comparisons of clinical classification of outcomes (improvement, stabilization, worsening after treatment stopped, deterioration) also showed no statistically significant difference between groups. There were no statistically significant differences between the two treatment groups on any efficacy measure. However, the observed rates of satisfactory outcome (stabilization, improvement) of 34% in group A and 35% in group B were higher than the spontaneous remission rates of 5 to 10% reported in the literature, suggesting that treatment was superior to no treatment.

Supplementation with omega-3 polyunsaturated fatty acids in the management of recurrent migraines in adolescents.

PURPOSE: To examine whether dietary supplementation with fish oil rich in very long-chain n-3 polyunsaturated fatty acids might reduce frequency and severity of migraines in adolescents. METHODS: Twenty-seven adolescents suffering from frequent migraines for at least 1 year (mean 4 +/- 1 years since migraine onset) participated in a randomized, double-blind, cross-over study consisting of 2 months of fish oil, 1-month washout period, and 2 months of placebo (olive oil). Participants self-assessed severity and duration of headache episodes (7-point faces and 10-point visual analog pain scales, 5-point frequency and severity rating scale) throughout the study. At the end of every 2-month treatment period, participants rated the effectiveness of treatment on a 7-point Likert scale (1,"not effective, not worthwhile"; 4,"moderately effective, moderately worthwhile"; 7, "totally effective, totally worthwhile"). A score of > or = 4 on the Likert scale was considered as improvement. RESULTS: Twenty-three adolescents (16 girls, 7 boys, 18 Whites, 3 Hispanics, 1 African-American, 1 Cape Verdean, mean age 15 +/- 1 years) completed the study. Compared with frequency of headaches before the study (31 +/- 4 episodes/2 months), there was a significant (p <.0001) reduction in headache frequency during fish oil treatment (4 +/- 1 episodes/2 months) and during placebo (olive oil) treatment (4 +/- 1 episodes/2 months) but no significant (NS) difference between treatments. Likewise, self-assessment on a 7-point faces pain scale revealed a significant reduction in headache severity during fish oil treatment (2.9 +/- 0.5, p =.01) and during placebo (olive oil) treatment (3.5 +/- 0.4,