Association of a Functional Inducible Nitric Oxide Synthase Promoter Variant with Susceptibility to Infantile Cerebral Palsy

Abstract

IntroductionThe hypoxic ischemic encephalopathy (HIE) secondary to perinatal asphyxia, affects a 1.5 to 5% of newborns; unfortunately 10% to 20% of infants with moderate HIE die and 30% to 40% develop neurological abnormalities, whilst 50% of infants with severe HIE, die and the remainder develop neurological conditions [1]. To our knowledge, the reason why some children that suffered perinatal asphysxia develop infant cerebral palsy while other children with similar clinical histories develop memory and learning difficulties but no motor disabilities remains unknown. Infantile cerebral palsy (ICP) is a neurological disease resulting from damage of the immature brain in newborn children, clinically it is a non-progressive brain insult that produces permanent and progressive secondary postural and movement disorders [2] and induces long-term complications such as muscle hypotrophy, deformities in the skull and spine [3]. In Mexico there are approximately 500,000 diagnosed cases of CP, be the leading cause of death in children from 5 to 14 years old [4] and it is the most common cause of physical disability in children throughout the world [5]. The main clinical spectrum of ICP includes quadriparesis, hemiparesis, and diparesis that affect upper and lower limbs to varying degrees. The therapeutic management of ICP is targeted at the lesions caused on the central nervous system, bone deformations and muscle hypotrophy [6]. The initial inflammatory response in the immature brain as a result of a traumatic birth can be mapped from proteins and metabolites that participate in inflammation and oxidative stress [7,8]. The main oxidative metabolite which is produced in the inflammatory response is the Nitric oxide (NO), it is a multifunctional molecule that has been Abstract Background: Recently it has been shown an increase in the interleukin 1 beta and nitrite levels in cerebrospinal fluid as a primary response of the immature brain to oxygen deprivation in newborns that suffered perinatal asphyxia, 30% to 40% of these patients later develop neurological abnormalities incluiding cerebral palsy. Formerly was shown that an increased enzyme activity of NOS2 is responsible for the increase in nitrite levels in cerebrospinal fluid. The NOS2A gene has a polymorphic microsatellite (CCTTT) n located at -2.6 Kb from the gene promoter. The expansion of this microsatellite to 13 or 14 repeats increases transcription of the NOS2A gene and triples the nitric oxide level under hypoglycemia and hypoxia conditions. The study aim was shown that the expansion of -2.6 Kb CCTTT microsatellite in the NOS2 gene promoter, constitutes a risk factor for developing cerebral palsy in newborns that suffered perinatal asphyxia