GSTM1-null and GSTT1-active genotypes as risk determinants of primary open angle glaucoma among smokers.

AIM: To evaluate glutathione transferase theta 1 and mu 1 (GSTT1 and GSTM1) polymorphisms as determinants of primary open angle glaucoma (POAG) risk, independently or in combination with cigarette smoking, hypertension and diabetes mellitus. METHODS: A case-control study with 102 POAG patients and 202 age and gender-matched controls was carried out. Multiplex-polymerase chain reaction method was used for the analysis of GSTM1 and GSTT1 polymorphisms. The differences between two groups were tested by the t-test or χ2 test. Logistic regression analysis was used for assessing the risk for disease development. RESULTS: The presence of GSTM1-null genotype did not contribute independently towards the risk of POAG. However, individuals with GSTT1-active genotype were at almost two-fold increased risk to develop glaucoma (P=0.044) which increased up to 4.36 when combined with GSTM1-null carriers (P=0.024). When glutathione transferase (GST) genotypes were analyzed in association with cigarette smoking, hypertension and diabetes, only carriers of GSTT1-active genotype had significantly increased risk of POAG development in comparison with GSTT1-null genotype individuals with no history of smoking, hypertension and diabetes, respectively (OR=3.52, P=0.003; OR=10.02, P<0.001; OR=4.53, P=0.002). CONCLUSION: The results obtained indicate that both GSTM1-null and GSTT1-active genotypes are associated with increased POAG risk among smokers, suggesting potential gene-environment interaction in glaucoma development.

Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance.

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss.

OBJECTIVE: To determine the molecular basis of a severe neurologic disorder in a large consanguineous family with complete agenesis of the corpus callosum (ACC), pontocerebellar hypoplasia (PCH), and peripheral axonal neuropathy. METHODS: Assessment included clinical evaluation, neuroimaging, and nerve conduction studies (NCSs). Linkage analysis used genotypes from 7 family members, and the exome of 3 affected siblings was sequenced. Molecular analyses used Sanger sequencing to perform segregation studies and cohort analysis and Western blot of patient-derived cells. RESULTS: Affected family members presented with postnatal microcephaly and profound developmental delay, with early death in 3. Neuroimaging, including a fetal MRI at 30 weeks, showed complete ACC and PCH. Clinical evaluation showed areflexia, and NCSs revealed a severe axonal neuropathy in the 2 individuals available for electrophysiologic study. A novel homozygous stopgain mutation in adenosine monophosphate deaminase 2 (AMPD2) was identified within the linkage region on chromosome 1. Molecular analyses confirmed that the mutation segregated with disease and resulted in the loss of AMPD2. Subsequent screening of a cohort of 42 unrelated individuals with related imaging phenotypes did not reveal additional AMPD2 mutations. CONCLUSIONS: We describe a family with a novel stopgain mutation in AMPD2. We expand the phenotype recently described as PCH type 9 to include progressive postnatal microcephaly, complete ACC, and peripheral axonal neuropathy. Screening of additional individuals with related imaging phenotypes failed to identify mutations in AMPD2, suggesting that AMPD2 mutations are not a common cause of combined callosal and pontocerebellar defects.