Combinations Of Genetic And Nutritional Factors

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Neural tube defects (NTD), including spina bifida, anencephaly, and meningomyelocele, result from failure of neural tube closure during the third to eighth week of gestation. The cause of a majority of cases of NTD is related to a nutritional deficit of folate and a small proportion of cases is related to a genetic problem (Czeizel, 1995; MRC Vitamin Study Group, 1991; Wild et al., 1986). The incidence of all levels of NTDs in the United States is 1-3 per 1000 births and 2-5% in children with a previous affected sibling (Cohen, 2000). NTDs are associated with a wide range of intellectual function and only a small proportion of MR is attributable to NTDs. Hydrocephalus occurs in 95% of high lumbar and thoracic lesions and 60-85% of low lumbar and sacral defects. Since shunting of cerebral spinal fluid is now a well-established surgical intervention, only a small proportion of these children has MR. The use of preconception and early conceptual folate supplementation through diet or vitamin pills can prevent a substantial proportion of occurrence and reoccurrence of NTDs.

Phenyketonuria (PKU) deficiency is a rare defect of amino acid metabolism with a frequency of about 1 per 15,000 in White populations. Because it is a single gene defect and PKU deficiency is identified during newborn screening in all states in the United States, the sequella of MR can be prevented with adherence to a strict diet during infancy and early childhood. The realization that the sequella of PKU can be prevented by strict diet during childhood unfortunately overlooked the fact that the female survivors who then became pregnant needed to go onto the diet perinatally, so the intrauterine environment of the fetus Is not toxic with phenyke-tones (Baumeister & Woodley-Zanthos, 1996; Hanley et al., 1999; Lenke & Levy, 1980; Levy & Ghavami, 1996; Levy & Waisbren, 1983; Rouse et al., 1997; Waisbren, Chang, et al., 1988; Waisbren, Doherty, Bailey, Rohr, & Levy, 1998). Severe MR and microcephaly are observed in 75-90% of children of mothers with classic PKU (defined as blood phenylalanine level > 1200 mol/l). Less severe cognitive deficit may affect children of mothers with atypical PKU (elevations of blood phenylalanine levels to between 594 and 1194 mol/l, Levy & Ghavami, 1996). Dietary restrictions during pregnancy to reduce maternal blood phenylalanine levels and prevent phenylalanine metabolite accumulation can improve the outcome in offspring if the diet is started prior to conception and maintained throughout pregnancy.

A third nutritionally related cause of MR is hypothyroidism during pregnancy. A genetic form of hypothyroidism (which, when untreated is referred to as cretinism), unrelated to iodine deficiency, can result in progressive neurological deficits after 3 months of age. In the United States, screening of all newborns is mandatory in all states and thus the occurrence of cretinism is rare. Cretinism can also result when there is maternal, fetal, or neonatal nutritional thyroid hormone deficiency; the supplementation of iodine in the mother needs to occur prior to conception. Cretinism can result in neurodevelopmental deficits in the newborn, including MR and a number of other sensory and motor impairments. When both fetal and maternal hypothyroxinemia are present, such as in iodine-deficient regions of China, it has been shown that iodine replacement in the first trimester of pregnancy was necessary to prevent neurological deficits (Cao et al., 1994; Liu, Momotani, & Yoshimura, 1994; O'Donnell et al., 2002; Wasserstrum & Anania, 1995). Iodine deficiency can range from mild to severe, and the associated outcomes range from mild cognitive impairments and cerebral palsy to death. Worldwide iodine deficiency is estimated to affect over 20 million people and it has been reported as a leading cause of MR (Hetzel, 1989).

Children with PKU and hypothyroidism can be identified at birth, so their parents can receive instruction about the appropriate diet or medication needed to prevent the onset of MR. The effectiveness of newborn screening strategies to identify and treat infants with PKU and hypothy-roidism has resulted in a significant decline in children with MR from these causes in the United States during the past 25 years.

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