Deletions in chromosome 6p22.3-p24.3, including ATXN1, are associated with developmental delay and autism spectrum disorders

Interstitial deletions of the short arm of chromosome 6 are rare and have been associated with developmental delay, hypotonia, congenital anomalies, and dysmorphic features. We used array comparative genomic hybridization in a South Carolina Autism Project (SCAP) cohort of 97 subjects with autism spectrum disorders (ASDs) and identified an ~ 5.4 Mb deletion on chromosome 6p22.3-p23 in a 15-year-old patient with intellectual disability and ASDs. Subsequent database queries revealed five additional individuals with overlapping submicroscopic deletions and presenting with developmental and speech delay, seizures, behavioral abnormalities, heart defects, and dysmorphic features. The deletion found in the SCAP patient harbors ATXN1, DTNBP1, JARID2, and NHLRC1 that we propose may be responsible for ASDs and developmental delay

Molecular Genetics and Metabolism 86 (2005) S17-S21 Minireview Response of patients with phenylketonuria in the US to tetrahydrobiopterin

Abstract Tetrahydrobiopterin (BH 4 ) responsive forms of phenylketonuria (PKU) have been recognized since 1999. Subsequent studies have shown that patients with PKU, especially those with mild mutations, respond with lower blood phenylalanine (Phe) concentrations following oral administration of 6-R-L-erythro-5, 6, 7, 8-tetrahydrobiopterin (BH 4 ). To determine the incidence of BH 4 responding PKU patients in the United States and characterize their phenylalanine hydroxylase (PAH) mutations, a study was undertaken at UTMB in Galveston and the Children's Hospital of Los Angeles on 38 patients with PKU. Patients were screened by a single oral dose of BH 4 , 10 mg/kg and blood Phe and tyrosine were determined at 0, 4, 8, and 24 h. Twenty-two individuals (58%) responded with marked decrease in blood Phe (>30%) at 24 h. Some of the patients that responded favourably were clinically described as having Classical PKU. Blood tyrosine concentrations did not change signiWcantly. Twenty subjects with PKU, responsive and nonresponsive to BH 4 , were enrolled in a second study to evaluate blood Phe response to ascending single doses of BH 4 with 10, 20, and 40 mg/kg and to evaluate multiple daily doses, for 7 days each, with 10 and 20 mg/kg BH 4 . The 7-day trial showed a sustained decrease in blood Phe in 14 of 20 patients taking 20 mg/kg BH 4 (70%). Of these 14 patients, 10 (71%) responded with a signiWcant decrease in blood Phe following 10 mg/kg BH 4 daily. To understand the mechanism of response to BH 4 , the kinetics and stability of mutant PAH were studied. We found that mutant PAH responds with increase in the residual enzyme activity following BH 4 administration. The increase in activity is multi-factorial caused by increased stability, chaperone eVect, and correction of the mutant Km. These studies indicate that BH 4 can be of help to patients with PKU, including some considered to have Classical PKU. The PKU population in US is heterogeneous and mutations can be varied so mutations need to be characterized and response to BH 4 tested. It is more likely that mutations with residual activity should respond to BH 4 , therefore the clinical deWnition of "Classical PKU" should be reconciled with the residual activity of PAH mutations