S626 Achalasia, Recurrent Tuberculosis, Oral Candidiasis, Seizures, and Neurodevelopmental Disorders in Two Brothers: Implications for Common Pathological Basis for Divine Phenome

Introduction: Heterogeneous clinical phenotypes of rare disorders can sometimes provide insight into its occurrences via a genetic defect of a common pathway. We report a case of 2 siblings (brothers, 14 and 11 years old) with a history of mental disability, seizures, in one of them achalasia, tuberculosis and recurrent oral candidiasis. Methods: The patients are from rural Ecuadorean Mountain region. Parents are consanguineous. We performed whole exome sequencing and found a nonsense mutation in NOS1 as follows: (NOS1:NM_001204218:exon12:c.2027delG:p.G676fs). This nNOS mutation may help explain the diverse clinical manifestations. Results: The nNOS mutation determined in our patients may help explain the diverse organ manifestations. The achalasia may have resulted from the nNOS defect. Nitric oxide production in macrophages is a key pathway for cell mediated immunity (CMI) against diseases like tuberculosis and fungal infections. Defects in macrophage function may impact cell-mediated immunity and may be responsible for tuberculosis and recurrent oral candidiasis in our patients. nNOS and macrophage-NOS are much similar in the C terminal, and also functions similar to nNOS in terms of electron transfer, though mac-NOS is ∼255 amino acids shorter than nNOS. 1 Function of nNOS derived NO in macrophages, and its effect on NF-Kb induced transcriptional activity and its impact on cell-mediated immunity have been recently demonstrated.2 There are 3 distinct neuropsychiatric phenotypes linked to nNOS deficiency: autism spectrum disorder, fragile X syndrome and schizophrenia. Conclusion: Fragile x syndrome transcripts control nNOS translation: so can have a significant impact on nNOS expression and function. Interestingly, fragile x syndrome transcripts also regulate expression of Mash1, which is required for cerebral and autonomic nervous system development. Mash1 deficiency can cause achalasia, as well as neurocerebral defects. nNOS are extensively located in the ivy cell, hippocampus and cerebral cortex. It is possible that the genetic defect of nNOS have resulted in the global clinical manifestation. Reference 1. Lowenstein CJ, Glatt CS, Bredt DS, Snyder SH. Cloned and expressed macrophage nitric oxide synthase contrasts with the brain enzyme. Proc Natl Acad Sci USA. 1992;89(15):6711-5.