Pulmonary outcome measures in long-term survivors of infantile Pompe disease on enzyme replacement therapy: A case series.

OBJECTIVES: To report the respiratory function of school-aged children with infantile Pompe disease (IPD) who started enzyme replacement therapy (ERT) in infancy and early childhood. STUDY DESIGN: This is a retrospective chart review of pulmonary function tests of: (a) patients with IPD 5 to 18 years of age, (b) who were not ventilator dependent, and (c) were able to perform upright and supine spirometry. Subjects were divided into a younger (5-9 years) and older cohort (10-18 years) for the analysis. Upright and supine forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) were analyzed. RESULTS: Fourteen patients, all cross-reactive immunologic material (CRIM)-positive, met the inclusion criteria and were included in this study. Mean upright and supine FVC were 70.3% and 64.9% predicted, respectively, in the 5- to 9-year-old cohort; and 61.5% and 52.5% predicted, respectively, in the 10- to 18-year-old group. Individual patient trends showed stability in FVC overtime in six of the 14 patients. MIPs and MEPs were consistent with inspiratory and expiratory muscle weakness in the younger and older age group but did not decline with age. CONCLUSION: Data from this cohort of CRIM-positive patients with IPD showed that ERT is able to maintain respiratory function in a subgroup of patients whereas others had a steady decline. There was a statistically significant decline in FVC from the upright to a supine position in both the younger and older age groups of CRIM-positive ERT-treated patients. Before ERT, patients with IPD were unable to maintain independent ventilation beyond the first few years of life.

Sequencing analysis of the ATOH7 gene in individuals with optic nerve hypoplasia.

BACKGROUND: The Atonal Homolog 7 (ATOH7) gene has been implicated in association studies with optic nerve head diameter size. Hence, we screened optic nerve hypoplasia (ONH) patient DNA samples from Australia, France, and the United States for sequence variants in theATOH7 gene using Sanger sequencing. METHODS: Sanger sequencing of theATOH7 gene was performed on 34 affected individual DNA samples. Sequencing was also carried out in three unaffected family members to confirm segregation of identified single nucleotide variations. RESULTS: Seven sequence variations were identified in ATOH7. No disease-causing sequence changes in the ATOH7 gene was discovered in the ONH patient samples. CONCLUSIONS: Mutations within the ATOH7 gene are not implicated in the pathogenesis of optic nerve hypoplasia in our patient cohort.

CYP1B1, MYOC, and LTBP2 mutations in primary congenital glaucoma patients in the United States.

PURPOSE: To screen primary congenital glaucoma patients in the United States for sequence variants within the CYP1B1, LTBP2, and MYOC genes using Sanger and whole exome sequencing. DESIGN: Retrospective case-control study. METHODS: Fifty-seven primary congenital glaucoma patients (47 families), 71 unaffected family members of the primary congenital glaucoma probands, and 101 healthy unrelated individuals were recruited from a single institution. Sanger sequencing of the primary congenital glaucoma gene, CYP1B1, was performed on 47 proband deoxyribonucleic acid samples. Simultaneously, whole exome sequencing was conducted on 3 families, each including more than 1 affected individual. Concurrently, 33 of 47 primary congenital glaucoma probands with extended family deoxyribonucleic acid samples were screened for LTBP2 and MYOC gene mutations. Exome-sequenced variations were validated by additional Sanger sequencing to confirm segregation of filtered disease-causing single nucleotide variations. RESULTS: Seven primary congenital glaucoma families (14.9%) manifested disease phenotypes attributable to CYP1B1 mutations. One primary congenital glaucoma family possessed homozygous mutant alleles, whereas 6 families carried compound heterozygous mutations. Five novel combinations of compound heterozygous mutations were identified, of which 2 combinations were found with whole exome sequencing. No disease-causing mutations within the LTBP2 and MYOC genes were discovered. CONCLUSIONS: This study analyzed CYP1B1, LTBP2, and MYOC mutations in a cohort of primary congenital glaucoma patients from the United States, applying whole exome sequencing as a complementary tool to Sanger sequencing. Whole exome sequencing, coupled with Sanger sequencing, may identify novel genes in primary congenital glaucoma patients who have no mutations in known primary congenital glaucoma genes.