American Journal of Medical Genetics 35:394-396 (1990)

Neural Tube Defects: Are Neurulation and Canalization Forms Causally Distinct?

Mary J. Seller Division of Medical and Molecular Genetics. United Medical and Dental Schools of Guy’s and S t Thomas’s Hospitals, London, England.

Neural tube defects (NTD) may be separated according to the overall location and proba- ble embryological origin into 2 groups: upper or neurulation defects, and lower or canaliza- tion defects. Evidence as to whether these 2 forms are causally related or distinct was sought from 2 sources. Families with more than one NTD individual were studied to ex- amine whether there was concordance within sibships for these 2 types of lesion. Seven of the 38 sibships were discordant (18%). Eight of the 10 cases of NTD that had arisen despite maternal periconceptional vitamin supple- mentation were neurulation defects and 2 were canalization defects. Both observations suggest that upper and lower types of NTD are causally related, and offer no support for the suggestion that they are distinct.

KEY WORDS: neural tube defect, anen- cephaly, spina bifida, site of lesion, causal heterogeneity, vitamin therapy

INTRODUCTION Neural tube defects (NTD) exhibit wide phenotypic

variation from total craniorachischisis through anen- cephaly and spina bifida cystica to spina bifida occulta. The differing forms of the abnormality have always been regarded as causally related because they are observed to occur within sibships [Carter, 19741. More recently, another classification for NTD has been used, according to the presumed pathogenesis: neurulation defects or upper NTD and canalization defects, or lower NTD [Toriello and Higgins, 1985; Seller, 19871, the demarka- tion line between the 2 being taken as T11!12. While Seller [1987] found a significant difference in the sex preponderance between the 2 groups, with a marked male excess in the canalization group, Toriello and Hig-

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Received for publication March 30, 1989; revision received Au- gust 22, 1989.

Address reprint requests to M. J. Seller, Division of Medical and Molecular Genetics, Guy’s Hospital, London SE1 9RT, England.

0 1990 Wiley-Liss, Inc.

gins [1985] and subsequently Hall and Keena [19861 observed another phenomcnon: that within sibships, although the type and precise site of the lesion may differ, there was complete concordance as to the group, upper or lower. This finding has implications, for it sug- gests that the 2 groups may be genetically distinct. Frecker et al. [19881 have been unable to confirm this finding in a Newfoundland population. This paper pre- sents further evidence to the contrary from 2 sources.

METHOD The families studied are patients of the South East

Thames Regional Genetics Centre which has a catch- ment area of South East London and the suburbs, Kent, East Surrey and East Sussex: a predominantly Cauca- sian population. All families with more than 1 NTD sib, in which at least 1 of the sibs was personally examined, were entered into the study. In all cases, the examined sib was a fetus that was photographed and fully dis- sected. Details of the extent and precise site of the le- sions of the other sib or sibs were obtained from the referring letters or hospital notes. A total of 57 sibships was known, but 19 had to be excluded from the study: 17 because there were no definite data on the exact level of the lesion in the unexamined sib, and 2 because the first sib had hydrocephalus without spina bifida.

Each affected sib was assigned to its category of NTD according to the site of the lesion. Lesions of the neural tube down to and including T11 were classified as neu- rulation defects; those from T12 downward were desig- nated canalization defects. The former group included craniorachischisis, anencephalus, encephalocele, and cervical and thoracic spina bifida; in the latter group, lumbar and sacral spina bifida. A spinal lesion com- mencing in the midthorax and extending into the lum- bosacral region was classified as an upper defect.

Included in the study population were individuals with NTD that had occurred despite the fact that the mother had received full periconceptional multivitamin supplementation (Pregnavite Forte F, Bencard) [Smithells et al., 1980; Seller, 19851. These individuals were also classified with respect to the category of lesion to examine whether only one, or both types were escap- ing the presumably preventive effect of the vitamin therapy.

Neurulation and Canalization NTD 395

TABLE I. Concordance for Upper and Lower Neural Tube Defects in Sibships

Concordant Discordant Uooer (%) Lower (%i Total

2 Sibs 26 1 6 33

3 Sibs 4 0 1 5

Overall 31 (82) 7 (18) 38

Total (%) 27 (82) 6 (18)

Total (%) 4 (80) 1 (20)

RESULTS Of the 38 sibships for which adequate details are

known, 33 involved 2 sibs and 5 involved 3 sibs (Tables I, 11). Total concordance was not observed. There was con- cordance for the defects in 82% of the 2 sib families and in 80% of the 3 sib series. Therefore, overall 18% of families were discordant. In this study, neurulation de- fects were far more common than were canalization de- fects. The study population is biased because details of the precise location of the lesion are more often missing from cases of spina bifida than anencephaly, which will

always be neurulation defects. All the 17 sibships that were excluded for insufficient information related to a spina bifida patient. Of these, i t is probable that at least 5 (29%) were actually discordant, suggesting that the discordance rate in Table I is an underestimate.

There were 10 patients with NTD in 9 sibships in which there was a recurrence of NTD, while the mother received full periconceptional vitamin supplementa- tion. Both categories of NTD were observed; 8 were neu- rulation defects and 2 were canalization defects.

DISCUSSION In this population of NTD individuals from Southeast

England, discordance within sibships for location of the lesion is observed. It is less common than concordance, but there is no doubt that i t exists. It is accepted that there are shortcomings in this series-that hospital re- cords can be inaccurate, and that every NTD individual should have a radiological examination-but i t is known that these have not unduly influenced the results; in- deed, the acknowledged bias has probably underesti- mated the extent of the discordance. It is postulated that

TABLE 11. Level of Defect in Families of Affected Sibs Two-sib Families

Defect in Defect in Number of first sib second sib sibships

1. Concordant “upper” ASB lesions A

ASB A ASB ASB SB mid T-L S B C + L A A A ENC SB “low” living:

SB “low” living:

SB: L1-5 A A SB: T10-S5 SB: Tl-S2

2. Concordant “lower” lesions no paralysis

3. Discordant lesions minimal effects

ASB ASB A A (I*) SB: T10-S5 SB: T2-S5 ASB* ASB SB: T-L SB: C-L1 SB: C-S5 ASB SB: L2-S5

A

A* SB: L4-S3* SB: L4-S5

SB: Ll-S2 SB: S3-S5*

3 5

1 1 1 1 1 1 1

Total = 27 1

1 Total = 6

Three-sib Families Defect in Defect in Defect in first sib second sib third sib

1. Concordant “upper” A A ASB* lesions A A SB: TlO-Sl*

A A SB: T10-L5 SB: C-L ASB* A*

Total = 4 2. Discordant lesions A SB “low” living SB: L3-S2

and well Total = 1

ASB, craniorachischisis; A, anencephaly; SB, spina bifida; ENC, encephalocele; C , cervical; T, thoracic; L, lumbar; S, sacral. *Vitamin supplemented (sib data complete on 8 of the 9 families).

396 Seller

the findings support the idea that upper and lower NTD are related.

The findings agree with those of Frecker et al. [1988] but differ from those of Toriello and Higgins r19851 and Hall and Keena 119861, who consider the 2 groups dis- tinct. Toriello and Higgins [19851 also cite as evidence of a difference that upper lesions far more often than lower lesions have associated major congenital 2bnormalities. However, these associated anomalies do not have a ran- dom distribution, but follow a specific pattern, which suggests that they arise simply by mechanical induction from the specific disturbance of the neural tube and its surrounding tissue [Seller and Kalousek, 19861.

The 2 groups of NTD appear to be related. Further evidence for this may be found in the present study in that both neurulation and canalization defects are ob- served in the group of NTD that have occurred despite maternal periconceptional vitamin supplementation, which is thought to prevent a large number of NTD. The fact that both types have “escaped prevention suggests a common underlying factor. If they were different, a differential response to the vitamin therapy might be expected.

Crucial to the whole topic, however, is the precise level of final closure of the posterior neuropore, for it is this which is regarded as the junction between neumlation and canalization. The 3 studies that prompted the pres- ent paper [Toriello and Higgins, 1985; Hall and Keena, 1986; Frecker et al., 19881 took T11/12 as the demarca- tion line between upper and lower lesions, which was based on the work of LeMire et al. 119751. However, the more recent study of Muller and O’Rahilly [19871 sug- gests that the final site of closure is at the level of the future somite 31, which corresponds to the second sacral vertebra. According to this hypothesis, defects as low as

S2 would represent neurulation defects, and would cast a different complexion on the present work and its prede- cessors. Indeed, Copp and Brook (19891 based their re- cent paper on this.

ACKNOWLEDGMENTS I acknowledge financial support from the Spastics

Society.

REFERENCES Carter CO (1974): Clues to the aetiology ofneural tube malformations.

Dev Med Child Neurol 16:3-15. Copp AJ, Brook FA (1989): Does lumbosacral spina bifida arise by

failure of neural folding or by defective canalisation? J Med Genet 26:160-166.

Frecker MF, Fraser FC, Heneghan WD (1988?: Are “upper” and ”lower” neural tube defects aetiologically different? J Med Genet 25:503-504.

Hall JG, Keena BA (1986): Adjusting recurrence risks for neural tube defects based on B.C. data. Am J Hum Genet (suppl) 39:A64.

LeMire FLJ, Loeser JD, Leech RW; Alvord EC (1975): “Normal and Abnormal Development of the Human Nervous System.” New York: Harper & Row, pp 54-83.

Muller F, O’Rahilly R (1987): The development of the human brain, the closure of the caudal neuropore, and the beginning of secondary neurulation a t stage 12. Anat Embryo1 176:413-430.

Seller MJ (1985): Periconceptional vitamin supplementation to prevent recurrence of neural tube defects. Lancet 1:1392-1393.

Seller MJ 11987): Neural tube defects and sex ratios. Am J Med Genet 26:699-707.

Seller MJ, Kalousek DK (1986): Neural tube defects: Heterogeneity and homogeneity. Am J Med Genet (suppl) 277-87.

Smithells RW, Sheppard S, Schorah CJ, Seller W , Nevin NC, Harris R, Read AP (1980): Possible prevention of neural tube defects by peri- conceptional vitamin supplementation. Lancet 1:339-340.

Toriello HV, Higgins JV (1985): Possible causal heterogeneity in spina bifida cystica. 4 m J Med Genet 21:13-20.