Neural Tube Defects, Susceptibility to

Alternative Names

  • NTD
  • Spina Bifida
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WHO-ICD-10 version:2010

Congenital malformations, deformations and chromosomal abnormalities

Congenital malformations of the nervous system

OMIM Number

182940

Mode of Inheritance

Autosomal dominant form

Gene Map Locus

1p13.1, 1q23.2,6q27,17q12,19q13.33

Description

Neural tube defects (NTD) are congenital defects of the brain and spinal cord, caused by incomplete closure of the embryonic neural tube during the first few weeks of development. Different forms of NTDs depend on the portion of the neural tube left open. Spina bifida results from the spinal cord remaining incomplete, in addition to the vertebra overlying the open portion of the cord also remaining unfused. As a result, the incomplete spinal cord pushes out through the opening in the bones. In anencephaly, it is the cerebral part of the neural tube that does not close. Different forms of spina bifida can also be seen. In its mildest form, known as spina bifida occulta, only the bone of the vertebra do not close. However, the meninges and spinal cord are normal. Such cases may actually go undetected, with affected people leading a normal, asymptomatic life, apart from back pain and a predisposition to herniation in some. Myelomeningocele and meningocele are more serious forms, in which the meninges and other tissue protrude out through the opening. Typical symptoms of spina bifida include paralysis of the nerves below the affected area, causing ambulatory difficulties, lack of bladder and bowel control, loss of sensation to some areas of the body, deformities of the hips, knees, and feet, loss of muscle tone, mental retardation, and seizures. In severe cases, the disease is fatal immediately after birth.

Racial, geographic and seasonal variations seem to affect the incidence of NTDs. The greatest risk factor for development of spina bifida is recognized as low blood folate level in the mother during the first four weeks of embryonal development. All women of child-bearing age are therefore, recommended to intake at least 400 micrograms of folic acid each day. On the other hand, case reports and epidemiologic studies have implicated a number of chemicals, widely differing therapeutic drugs, environmental contaminants, pollutants, infectious agents, and solvents. Maternal hyperthermia, use of valproate by epileptic women during pregnancy, deficiency and excess of certain nutrients and chronic maternal diseases (e.g. diabetes mellitus) are reported to cause a manifold increase in the incidence of NTD.

Prenatal diagnosis of the condition is possible by way of an ultrasound scan of the fetus late in the pregnancy. However, in early stages, a high level of alpha fetoprotein in the amniotic fluid can also be used as an indication for the condition. Milder versions of the disease do not require any treatment. However, more serious conditions may require surgery to prevent further complications.

The genetic nature of NTD is exemplified by an increased risk of developing the condition in families with a history of the disease. However, no Mendelian pattern of inheritance has been reported. It has been observed that a genetic component most notably increases the rate of recurrence of the condition in siblings and in the offspring of an affected person. Several genes have been identified to be associated with spina bifida. These include VANGL1, VANGL2, CELSR1, FUZ  and the C677T polymorphism of the MTHFR gene. NTDs are also known to be a feature of chromosomal conditions like trilogy 13, trisomy 18, and certain chromosomal rearrangements.

Molecular Genetics

Etiology of NTD is unknown. Most of the non-syndromic NTD are of multifactorial origin. Recent in vitro and in vivo studies have highlighted the molecular mechanisms of neurulation in vertebrates but the morphologic development of human neural tube is poorly understood.

Encouraged by the results of clinical studies, numerous laboratory investigations focused on the genes involved in the folic acid, vitamin B12 and homocysteine metabolism during neural tube development.

Epidemiology in the Arab World

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Other Reports

Egypt

Assaad et al. (1989) operated 250 children with spina bifida during a period of 4 years (December 1983-December 1987) at the outpatient clinic of the New Children's Hospital. Among these 250 children there were 200 cases of spinal bifida aperta (SBA) and 50 of spina bifida occulta (SBO). All of the patients came from poor families. SBA cases were operated upon as soon as possible from the time of their presentation; their preliminary assessment included an exhaustive general, neurological, urological, and orthopedic examination; and investigations such as plain X-rays to the back and skull, CT scanning of the cranium, spinal myelogram, and metrizamide CT scanning to the back. The surgical outcome is far from being satisfactory in the sense of producing an ambulatory, intelligent, healthy individual, especially in a meningomyelocele patient having a high-level lesion. Assaad et al. (1989) indicated that malnutrition, many siblings per family, poor maternal care, and repeated pregnancies and abortions have added to the large incidence of such a handicap in Egypt.

Jordan

Abu-Heija and El-Sunna (1998) studied the incidence of NTD in Jordan by reviewing the obstetric data of all deliveries in a North Jordanian hospital in 1995 and 1996. Of the total of 19,050 births that took place in these two years, 55 cases of NTD were seen. This gave the condition an incidence of 2.9 in every 1,000 births, an incidence higher than previous reports in the same region. Of these 55, 26 (1.36/1,000 births) were cases of spina bifida cystica. These included 24 cases of myelomeningocele and two of meningocele. The spina bifida lesions were dorsolumbar in 50% of the cases. Other lesion sites included lumbosacral (19%), cervical (15%), lumbar (12%), and sacral (4%). Encephalocele was seen in 10 cases (0.52/1,000 births). In nine of these, the encephalocele was occipital, while it was frontal in one. Almost 54% of cases of spina bifida and encephalocele were associated with other congenital anomalies. In the case of spina bifida, these included hydrocephaly (7), anencephaly (3), hydrocephalus with club foot (2), hypospadias (2), club foot (1), scoliosis (1), and chondroplasia (1). Encephalocele was found to be associated with rocker bottom foot with low-set ears in two patients, and short trunk, chondroplasia, or ambiguous genitalia in one patient each. The high incidence of these defects prompted Abu-Heija and El-Sunna (1998) to recommend the increase in awareness of daily consumption of folic acid among women in the child bearing age.

[Abu-Heija A, El-Sunna E. Neural tube defects in patients delivered at the Princess Badeea Teaching Hospital in North Jordan. J Bahrain Med Soc. 1998; 10(2):83-7.]

Kuwait

Naguib (1997) presented an overview of neural tube defects in Kuwait covering 177 patients. Of these, 48 were delivered at a maternal hospital at a rate of 4.3 per 1000 live birth which is relatively high. This study reported a male to female ratio of 1:1.46, a mean maternal age of 27.44 and a mean paternal age of 32.54. Genetic investigations revealed chromosomal abnormalities in 0.6%, autosomal recessive inheritance in 7.9%, and multifactorial inheritance in 88% of the cases. Clinical manifestations included meningocele / myelomeningocele at different sites (62%), anencephaly (25%), inencephaly (5%), Meckel Gruber (7%) and myelomeningocele with VATER association (0.5%). In conclusion, young maternal age, parity, polyhydramnios, abnormal presentation, and abnormal mode of delivery were risk factors for neural tube defects.

[Naguib KK. Neural tube defects in Kuwait: an overview study. Bull High Inst Pub Health. 1997; 27(Supp. 1):100-5.]

 

Oman

Rajab et al. (1998) conducted a retrospective study to determine the population-based incidence of neural tube defects and congenital hydrocephalus in Oman. Data was obtained from the hospital records of patients with neural tube defects and congenital hydrocephalus, who were treated in the hospital from year 1992 to 1995 as well as delivery records of those with these anomalies from year 1989 to 1995. Data was also obtained by interviewing parents of cases with neural tube defects and congenital hydrocephalus as regarding full family pedigree, parental ages, birth order, family history of similar condition, maternal history of illness during pregnancy and occupational exposures. The total incidence of neural tube defects was calculated to be 1.25 per 1000 births which was comparable with those from other Gulf countries. Neural tube defects included anencephaly (0.69 per 1000), myelomeningocele (0.45 per 1000), and encephalocele (0.107 per 1000), while the incidence of congenital hydrocephalus was 0.53 per 1000 births with male to female ratio of 1.5 to 1 (suggesting X-linked hydrocephalus), and the incidence of congenital hydrocephalus with associated spina bifida was 0.44 per 1000 (higher than that of Iran 0.38 per 1000). Positive family history was found in 16% of those with congenital hydrocephalus and it was found that 57% of the children with congenital hydrocephalus who were treated in hospital had associated congenital anomalies including agenesis of corpus callosum, congenital heart lesions, exomphalos, and renal agenesis which had caused death in 30%, while seven with encephalocele had cystic renal lesions and polydactyly which were then diagnosed as Meckel-Gruber syndrome (incidence of 0.027 per 1000 births). Other types of neural tube defects had lower frequency of abnormalities, presence of which were associated with higher mortality as evident by the higher mortality among those with congenital hydrocephalus (51% died shortly after birth or were stillborn) when compared to only seven per cent of cases with myelomeningocele. The effect of seasonal variation and maternal exposure to chemical agents and drugs were not found to be significantly associated with the development of neural tube defects or congenital hydrocephalus. The effect of birth order (as determined by the mean and the variance in each sibship) and paternal age were not found to be significantly associated with myelomeningocele, but Student's-t test had shown its significant association with the maternal age as the mean age of mothers of patients with myelomeningocele (28.95 SD6.9 years) was higher than in the general population (23.23 SD 5.6 years). Consanguinity was higher (56%) among those with neural tube defects as when compared to that in the general population. About 75% of those with myelomeningocele and all six patients with encephalocele had consanguineous parents, while all 11 children with congenital hydrocephalus had consanguineous parents. This study did not show any tribal aggregation or geographical variation in the incidence of myelomeningocele which varied among tribes from 1 in 2000 to 1 in 7500 deliveries. Rajab et al. (1998) suggested promoting a healthy and well balanced peri-conceptional diet for women in order to reduce the incidence of neural tube defects.

Sharma et al. (1999) reported the development of calcified subdural hematoma in a nine year old boy who was operated upon at the age of one-day for lumbar meningomyelocele and had ventriculoperitoneal medium-pressure shunt insertion at the age of six months for progressive hydrocephalus. Following the surgery, the patient was asymptomatic until the age of nine-years, when he presented with two days history of repeated vomiting and altered sensorium. Clinically, he was drowsy, had papilledema on fundi examination and had left spastic hemiparesis. CT scan of the brain revealed a large right-sided chronic subdural hematoma with calcification in the inner and outer membranes with areas of calcifications in the content. There was significant compression of the right lateral ventricle, while the left lateral ventricle was dilated with mild shift of the midline to the left. An emergency large right-sided osteoplastic craniotomy was performed with evacuation of the contents and complete removal of the membrane. Intra-operatively, the brain appeared normal with good brain pulsation and expansion. Repeat CT scan before discharge revealed good expansion of the brain with no shift of the midline. But, the ventricles were moderately enlarged with outward bulging of the bone flap. However, since the patient was asymptomatic, the shunt was not revised, and he was discharged after 10 days. The diagnosis of calcified subdural hematoma was confirmed as the histological examination of the tissue revealed fibrous tissue with focal calcification. He continued to be followed up and was asymptomatic and no hydrocephalous was detected on repeat CT done six months later. Sharma et al. (1999) recommended the follow up of such patients with interval CT scans and to always bear in mind the occurrence of calcified subdural hematoma.

Sawardekar (2005) conducted a study to establish the prevalence of major congenital malformations in children born during a 10-year period in Nizwa Hospital. Of the 21,988 total births in the hospital, 46 children were born with Neural tube defects. Sawardekar (2005) hinted for a possible genetic contribution in these children and indicated that 10 children were born with meningomyelocele and spina bifida.

Palestine

Zlotogora (1997) studied all the 2000 Palestinian Arab families that attended the only genetics clinic in Jerusalem. Of these, individuals from 47 families were found to present with open NTD. This condition was non-syndromal in 42 of these families. The defect was myelomeningocele in 26 families, and related to anencephaly in 14. The two remaining families had occipital encephalocele. More than one affected member was seen in nine of the families. Five of the families had the condition as part of a syndrome; Meckel Syndrome in four, and Carpenter Syndrome in one. In addition, 9 more families were seen to have one member affected with NTD, while another member was affected with isolated hydrocephalus.

Qatar

Nogueira (1992) studied all cases of hydrocephalus diagnosed between 1986 and 1989 in Qatar. These included 34 cases diagnosed antenatally, and 31 diagnosed within the first 10-days of life. Meningomyelocele was present in 17 of the cases, giving an incidence of 41 in every 100,000 live births for the condition.

Saudi Arabia

Murshid (2000) undertook a study to calculate the incidence of spina bifida in Al-Madinah over a period of one year (1996-1997) in the two public health centers in the city. During this period, there were 18 cases of spina bifida (12 males, 6 females) among the Saudi population of the city. This worked out to an incidence of 1.09 per 1,000 live births. This incidence was comparable to that reported earlier by Magbool et al. (1989) and Al Awary et al. (1997) from the Eastern region of Saudi Arabia. Data from these 18 births were compared to 72 controls. The only statistically significant difference between the cases and the control group was the level of consanguinity. As much as 89% of the cases were products of consanguineous unions, compared to 67% of the controls. None of the mothers in either group had had any folic acid supplementation in the periconceptional period.

Alshehri (2005) studied the pattern and classification of all major congenital anomalies in Asir region between the years 1997 and 2002. Of the total of 691 neonates born with anomalies, 81 were diagnosed with spina bifida and encephaloceles. This constituted 45% of neonates with central nervous system anomalies. In fact, spina bifida and encephalocele put together ranked first among all congenital anomalies. [Alshehri MA. Pattern of major congenital anomalies in southwestern Saudi Arabia. Bahrain Med Bull. 2005; 27(1).]

Kari et al. (2009) investigated the urological complications in children with spina bifida in Saudi Arabia. All 33 babies born with spina bifida at KAU Hospital between 1997 and 2006 were enrolled in the study, and their data was reviewed. The myleomeningocele site was thoracolumbar in 26 patients and lumbosacral in seven. Of these 33 babies, 16 were Saudis. The children in this study developed a considerable renal damage at an early age, as shown by evidence of renal scars in 12 children (36%) by the age of 5-years. According to Kari et al. (2009), this high incidence of renal damage was due to the delay in proper management, lack of good medical follow up, and the absence of specialized spina bifida clinics. Close to 90% of the patients were diagnosed as neurogenic bladder, and 78% had vesico-uretral reflex (16 children having bilateral VUR). Only eight patients received clean intermittent catheterization (CIC). The children who did not receive CIC were found to have a higher incidence of VUR, UTI, and renal scars, with one patient even progressing to renal failure at an early age.

United Arab Emirates

Hosani and Czeizel (2000) evaluated the pilot dataset [March-May 1998] of the UAE National Congenital Abnormality Registry (NCAR). vA total of 4,861 births were recorded in this study period, with a birth prevalence of total congenital anomalies being 30.3/1,000 births. Neural Tube defects were identified in three neonates, resulting in an incidence rate of 0.62/1,000 births.

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