Pathophysiology, prevention, and potential treatment of neural tube defects

Abstract

Neural tube defects (NTD) remain a major cause of morbidity in spite of the reduction in liveborn incidence with periconceptional folic acid. However, the etiology remains unknown. This article reviews studies that address causation and potential treatment of NTD in humans and in animal models that resemble aspects of the common human NTD. Studies of nutritional markers of vitamin B12 and folic acid support a defect in homocysteine metabolism; a thermolabile variant of methylene tetrahydrofolate reductase, an enzyme that remethylates homocysteine to methionine, correlates with a risk of NTD in some human populations. Numerous mouse mutant models of NTD exist, attesting to the ease of disruption of neurulation, and a genetic basis for this malformation. Of these models, the curly tail mouse mutant most closely resembles the common human NTD. Folic acid does not prevent NTD in this model; however inositol supplementation does result in a significant reduction in incidence. Recent advances in fetal surgery, and evidence from mechanically created myelomeningocele in large animals amenable to surgical intervention suggest that the handicaps associated with myelomeningocele and associated Chiari Type II malformation may be prevented by in utero NTD closure. Success will depend on preservation of neurological tissue until such intervention is possible. Further research in animal models at the genetic and cellular levels, together with technological surgical advances, provide hope that prevention of more NTD and the associated handicaps may be possible. MRDD Research Reviews 6:6–14, 2000. © 2000 Wiley‐Liss, Inc.

Developmental control of inositol phosphate biosynthesis is altered in the brain of both curly and phenotypically normal straight tail mutant mice

“…Mouse genetic models provide opportunities to understand mechanisms of abnormal neurulation and to test etiologic hypotheses suggested by human epidemiologic data (Manning et al, 2000; Harris and Juriloff, 2007; Gustavsson et al, 2008). Moreover, the CT mutant mouse exhibits NTDs from the severest forms of exencephaly and spina bifida to milder tail flexion anomalies (Gruneberg, 1954).…”

Nursing Care of the Pediatric Neurosurgery Patient

“…Additionally, it was theorized that the hindbrain herniation may result from leakage of cerebrospinal fl uid through the open neural tube during a critical time of posterior fossa formation (Manning et al 2000 ) . Physicians began to recognize decreased fetal movement in the legs and feet throughout pregnancy, lending to the idea of progressive damage to the open portion of the exposed spinal cord causing increased neurologic damage.…”

Toward understanding the genetic basis of neural tube defects

“…trisomy 13, 18 and 21) or (ii) genetic syndromes (e.g. Meckel syndrome and anal stenosis), (iii) ethnic and racial differences in incidence rates, (iv) increased risk for a second affected child for couples with one affected infant (threefold to fivefold) and for siblings of affected individuals compared to the general population (10-fold) and v) the occurrence of familial settings or distributions that do not follow mendelian inheritance (75,76,77). The inheritance patterns and recurrence risks for such congenital anomalies in families have been suggested to follow a multifactorial threshold model where a continuous variable Ôliability' exists in a population with a Ôdevelopmental' threshold value beyond which the individual becomes affected.…”

“…A recent study suggests that genetic factors pre-disposing to NTDs may be transmitted preferentially from the mother's side of the family (78). Heritability in NTDs is estimated to be 60% with multiple susceptibility genes involved; however, the number, identity and relative contribution of such genes to NTDs remain unknown (76).…”