Type 1 diabetes and the OAS gene cluster: association with splicing polymorphism or haplotype?

BACKGROUND: The 2',5'-oligoadenylate synthetase genes (OAS1, OAS2, and OAS3) map to human chromosome 12q24 and encode a family of enzymes pivotal to innate antiviral defence. Recently, the minor allele of an OAS1 single nucleotide polymorphism (SNP) that alters splicing (rs10774671) was found to be associated with increased enzymatic activity and, in a case-sibling control study, with type 1 diabetes (T1D). METHODS: We have confirmed this T1D association in 784 nuclear families (two parents and at least one affected offspring) by the transmission disequilibrium test (TDT; G:A = 386:329, p = 0.033). However, because of linkage disequilibrium within OAS1 and with the other two OAS genes, functional attribution of the association to this SNP cannot be assumed. To help answer this question, we also genotyped two non-synonymous SNPs in OAS1 exons 3 and 7. RESULTS: All three SNPs showed significant transmission distortion. Three of the eight possible haplotypes accounted for 98.4% of parental chromosomes and two of them carried the non-predisposing A allele at rs10774671. Parents heterozygous for these two haplotypes showed significant transmission distortion (p = 0.009) despite being homozygous at rs10774671. CONCLUSIONS: We confirm the T1D association with rs10774671, but we conclude that it cannot be attributed (solely) to the splicing variant rs10774671. A serine/glycine substitution in OAS1 exon 3 is more likely a functional variant.

Reliability of the peabody developmental gross motor scale in children with cerebral palsy.

The test/retest, intrarater, and interrater reliability of the Peabody Development Gross Motor Scale (PDGMS) was assessed in 12 children with mild or moderate cerebral palsy. A baseline test was administered, scored, and videotaped by one rater and rescored from the videotape by a second independent rater. In order to minimize the effect of developmental maturation, test/retest correlation coefficients of the tests were performed two weeks apart. The intraclass correlation coefficients ranged from 0.82 to 0.98. For interrater reliability, testing following the same protocol was repeated at 2 weeks, 3 and 6 months. Interrater correlation coefficients (r) ranged from 0.89 to 0.98. Interrater correlation coefficients (ICC) from scoring and later rescoring ten videotapes with the closest and furthest interrater agreement ranged from 0.88 to 0.99. The balance and locomotor skill categories were most responsive for assessing gross motor function in this population. These data support the use of the PDGMS as an assessment tool for children with cerebral palsy and the reliability of videotaping assessments.

Continence following electrical stimulation and EMG biofeedback in a teenager with imperforate anus.

A teenage boy with repaired high imperforate anus relied on daily enemas for social continence. After treatment with low intensity transcutaneous electrical stimulation and electromyographic biofeedback home programs, he achieved improved fecal continence requiring only one enema per month.

Neuromuscular approach to the motor deficits of cerebral palsy: a pilot study.

Six children with mild cerebral palsy (CP) entered a study of overnight low-intensity transcutaneous electrical stimulation (ES) to the leg muscles. After 6 months, statistically significant improvement was noted on the Peabody Developmental Motor Scales scores in gross motor, locomotor, and receipt/propulsion skills. When ES was withdrawn for 6 months, there was uniform loss in scores. Reinstitution of ES resulted in further significant improvements in total gross motor, balance, locomotor, and receipt/propulsion skills. In selected cases, overnight ES may be a useful addition to standard rehabilitation services.

Gonadotropin-independent precocious puberty ("testotoxicosis"): influence of maturational status on response to ketoconazole.

Three boys, 5.0-7.4 yr of age, with clinical and biochemical features consistent with familial gonadotropin-independent precocious puberty ("testotoxicosis") were treated with the antifungal drug ketoconazole in a dose of 200 mg every 8 h. Serum testosterone levels fell significantly within 24 h in all three patients, with reciprocal changes in serum 17-hydroxyprogesterone, consistent with inhibition of C17-20 lyase activity. However, after 1-3 months of continuing treatment, an "escape" phenomenon occurred, characterized by progressive increases in serum LH, FSH, and testosterone concentrations. Furthermore, for the first time, a marked pubertal-type LH response was found after GnRH administration in contrast to the absent response consistently found in all patients before ketoconazole therapy. Combination treatment with ketoconazole and the GnRH analog buserelin resulted in restoration of pituitary and gonadal hormone concentrations to the upper range of normal for prepubertal children. We hypothesize that the advanced state of maturation of the boys in this study [mean bone age, 13.2 +/- 0.8 (+/- SE) yr] was the major contributing factor to this escape, with the set-point of the GnRH pulse generator (gonadostat) functioning at the adult level of sensitivity. Such escape may limit the successful use of ketoconazole alone. These data together with evidence of normal testosterone responses to hCG during ketoconazole therapy indicate that in testotoxicosis, pituitary and gonadal receptors are functionally intact, with appropriate negative feedback relationships.