Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome.

We identified a novel homozygous 15q13.3 microdeletion in a young boy, with a complex neurodevelopmental disorder characterized by severe cerebral visual impairment with additional signs of congenital stationary night blindness, congenital hypotonia with areflexia, profound intellectual disability, and refractory epilepsy. The mechanisms by which the genes in the deleted region exert their effect are unclear. In this paper, we probed the role of downstream effects of the deletions as a contributing mechanism to the molecular basis of the observed phenotype. We analyzed gene expression of lymphoblastoid cells derived from peripheral blood of the proband and his relatives to ascertain the relative effects of the homozygous and heterozygous deletions. We identified 267 genes with apparent differential expression between the proband with the homozygous deletion and 3 age- and sex-matched typically developing controls. Several of the differentially expressed genes are known to influence neurodevelopment and muscular function, and thus may contribute to the observed cognitive impairment and hypotonia. We further investigated the role of CHRNA7 by measuring TNFα modulation (a potentially important pathway in regulating synaptic plasticity). We found that the cell line with the homozygous deletion lost the ability to inhibit the activation of tumor necrosis factor-α secretion. Our findings suggest downstream genes that may have been altered by the 15q13.3 homozygous deletion, and thus contributed to the severe developmental encephalopathy of the proband. Furthermore, we show that a potentially important pathway in learning and development is affected by the deletion of CHRNA7.

Active comparator-controlled, rater-blinded study of corticotropin-based immunotherapies for opsoclonus-myoclonus syndrome.

To test the efficacy and safety of corticotropin-based immunotherapies in pediatric opsoclonus-myoclonus syndrome, 74 children received corticotropin alone or with intravenous immunoglobulin (groups 1 and 2, active controls); or both with rituximab (group 3) or cyclophosphamide (group 4); or with rituximab plus chemotherapy (group 5) or steroid sparers (group 6). There was 65% improvement in motor severity score across groups (P < .0001), but treatment combinations were more effective than corticotropin alone (P = .0009). Groups 3, 4, and 5 responded better than group 1; groups 3 and 5 responded better than group 2. The response frequency to corticotropin was higher than to prior corticosteroids (P < .0001). Fifty-five percent had adverse events (corticosteroid excess), more so with multiagents (P = .03); and 10% had serious adverse events. This study demonstrates greater efficacy of corticotropin-based multimodal therapy compared with conventional therapy, greater response to corticotropin than corticosteroid-based therapy, and overall tolerability.

BRAF gene deletion broadens the clinical spectrum neuro-cardio-facial-cutaneous syndromes.

Point mutations in the human BRAF gene are associated with a group of heterogeneous autosomal dominant neuro-cardio-facial-cutaneous syndromes. We identified a novel 93 kb intragenic deletion of the BRAF gene in a boy with severe developmental encephalopathy using microarray-based comparative genomic hybridization. The unique genotype and phenotype in this patient expands the spectrum of BRAF-related neurodevelopmental disorders. We propose a BRAF gene loss-of-function mechanism to best explain the biological basis of this severe developmental encephalopathy with postnatal growth deficiency.

B cell depletion therapy for new-onset opsoclonus-myoclonus.

Twelve immunotherapy-naïve children with opsoclonus-myoclonus syndrome and CSF B cell expansion received rituximab, adrenocorticotropic hormone (ACTH), and IVIg. Motor severity lessened 73% by 6 mo and 81% at 1 yr (P < 0.0001). Opsoclonus and action myoclonus disappeared rapidly, whereas gait ataxia and some other motor components improved more slowly. ACTH dose was tapered by 87%. Reduction in total CSF B cells was profound at 6 mo (-93%). By study end, peripheral B cells returned to 53% of baseline and serum IgM levels to 63%. Overall clinical response trailed peripheral B cell and IgM depletion, but improvement continued after their levels recovered. All but one non-ambulatory subject became ambulatory without additional chemotherapy; two relapsed and remitted; four had rituximab-related or possibly related adverse events; and two had low-titer human anti-chimeric antibody. Combination of rituximab with conventional agents as initial therapy was effective and safe. A controlled trial with long-term safety monitoring is indicated.

Stroke associated with central nervous system vasculitis after West Nile virus infection.

We report the association of West Nile virus infection, isolated vasculitis, and stroke in a 9-year-old girl. West Nile virus is of growing epidemiologic importance and should be considered in the differential diagnosis of stroke etiologies, especially during late summer and in patients with a history of exposure in areas where West Nile virus transmission is present.