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  • 8/12/2019 Curr Prob Ped Northrup 2000

    1/16

    I I

    S p i n a i fi d a a n d O t h e r N e u r a l T u b e D e f e c t sHope Northrup M D and Ke l ly A . Vo lc ik

    ~ e u r a l t u b e d e f e ct s ( N T D s ) a re t h e m o s t c o m m o ns e v e r e ly d i s a b l i n g b i r t h d e f e c t s i n t h e U n i t e dS ta t e s , w i th a f r e q u e n c y o f a p p r o x ima te ly 1 o f

    e v e r y 2 0 0 0 b i r t h s. N T D s i n c lu d e a ll c o n g e n i t a l a n o m-a l i e s t h a t i n v o lv e f a i l u r e o f t h e n e u r a l t u b e t o c lo s ed u r i n g t h e f o u rt h w e e k o f e m b r y o g e n e s i s . N T D s c a no c c u r a n y w h e r e a l o n g t h e f o r m a t i o n o f t h e s p i n a lc o r d , f r o m th e b r a in t o t h e s a c r u m. T h e t e r m neuraltube defects i s mo s t o f t e n u s e d t o r e f e r t o c o n g e n i t a ld e f e c t s o f t h e c e n t r a l n e r v o u s s y s t e m, w h ic h i n v o lv ee x p o s e d n e r v o u s t i s s u e s u c h a s c r a n io r a c h i s c h i s i s( e x p o s u r e o f t h e e n t i r e c e n t r a l n e r v o u s s y s t e m ) , a n e n -c e p h a l y ( e x p o s e d o r a b s e n t b ra i n) , m e n i n g o m y e l o c e l e( a n e x p o s e d a r e a o f s p in a l c o r d ), o r e n c e p h a lo c e l e ( ap r o t r u s io n o f me n in g e a l o r s k in c o v e r e d b ra in ).1 T h ema jo r i t y o f N T D s r e s u l t i n e i t h e r a n e n c e p h a ly o rm e n i n g o m y e l o c e l e , w i t h e a c h d e f e c t s e en i n a l m o s te q u a l p r o p o r t i o n s a t b i r t h . A n e n c e p h a ly i s a l e t h a ld e f e c t , c h a r a c t e r i z e d b y a c r a n i a a n d r u d ime n ta r y o ra b s e n t c e r e b r a l h e m i s p h e r e s a n d c e r e b e l l u m . 2,3M e n i n g o m y e l o c e l e , a l so c a l le d sp ina b i f ida o r spinabifida cystica i s c o mp a t ib l e w i th l i f e b u t r e s u l t s i nh a n d i c a p a p p r o x i m a t e l y 9 9 % o f t he t i m e . Inm e n i n g o m y e l o c e l e , p r o t r u s io n o f t h e s p i n a l c o r d a n dme n in g e s t h r o u g h a d e f e c t i n t h e v e r t e b r a l a r c h c a no c c u r a n y w h e r e a l o n g t h e s p i n a l c o l u m n b u t i s m o s tc o m m o n i n t h e lu m b a r r e g i o n .

    S k i n c o v er s 1 5 % t o 2 0 % o f N T D s ; w h e n t h e s acc o n t a in s me n in g e s a n d c e r e b r o s p in a l f l u id , b u t t h es p in a l c o r d a n d s p in a l r o o t a r e i n t h e i r n o r ma l p o s i -t i o n , t h e d e f e c t is r e f e r r e d t o a s a m e n in g o c e l e . S p in a lc o r d a n d r o o t a b n o r ma l i t i e s c a n b e s e e n d e s p i t e t h e i rn o r m a l l o ca t io n . M e n i n g o m y e l o c e l e i s m o r e c o m m o nt h a n m e n i n g o c e l e a n d r es u l ts i n a m a r k e d n e u r o l o g i cd e f i c i t i n f e r i o r t o t h e l e v e l o f t h e p r o t r u d in g s a c .

    From the Depar tment of P ediatr ics , D iv is ion of Medical Genet ics ,Universi ty of Texas Medical S chool, Houston , Texas.Curt Probl Pediatr 2000;30 317-32.Copyr ight 200 0 by Mosby, Inc.0 0 4 5 - 9 3 8 0 / 2 0 0 0 / $ 1 2 . 0 0 + . 15 5 3 / 1 / 1 1 2 0 5 2d o i :l O . 1 0 6 7 / m p p. 2 0 0 0 . 1 1 2 0 5 2

    A l t h o u g h s p i n a b i f id a o c c u rs m o s t c o m m o n l y i n t h elu m b a r r e g io n s o f t h e s p in e , i t c a n o c c u r a t a n y l e v e l . 4

    S p in a b i f i d a r a n g e s f r o m min o r t y p e s ( s p in a b i f i d aoccul ta ) to seve re , c l in ica l ly s ign i f ican t types ( sp inab i f i d a c y s t ic a ) . P e o p l e w i th s p in a b i f i d a c y s t i c a h a v eme d ic a l p r o b l e ms a n d p h y s i c a l h a n d i c a p s t h a t d r a ma t -ica l ly im pac t the i r l ives and the l ives o f the i r fami l ie s .D e p e n d in g o n t h e l e v e l o f t h e l e s i o n , i n t e r r u p t i o n o ft h e s p in a l c o r d a t t h e s i t e o f t h e d e f e c t c a u s e s p a r a ly -s i s o f t h e l e g s , i n c o n t i n e n c e o f u r i n e a n d f e c e s, a n e s -t h e s i a o f t h e s k in , a n d a b n o r ma l i t i e s o f t h e h ip s , k n e e s ,and fee t .

    Spina BifldaS p i n a i f i d a O c c u l t a

    S p in a b i f i d a o c c u l t a ( h id d e n ) i s t h e mi ld e s t f o r mo f s p in a b i f i d a , r e s u l t i n g f r o m a g a p i n o n e o r mo r ev e r t e b r a l a r c h e s , b u t t h e s p in a l c o r d a n d me n in g e sr e m a in e n t i r e ly w i th in t h e v e r t e b r a l c a n a l. S p in a b i f i-d a o c c u l t a ma y ma n i f e s t a s a s ma l l c a v i t y ( d e r ma ls in u s ) b e tw e e n 2 a d j a c e n t v e r t e b r a e , i n d i c a t i n g t h a tt h e v e r t e b r a e d id n o t f u s e p r o p e r ly ; e v id e n c e o f t h i sd e f e c t ma y b e a s ma l l d imp le w i th a h a i r y p a t c h o rb i r t h ma r k a b o v e i t. 4,5 W h e n t h i s a b n o r m a l i t y i n v o lv e sf a i lu r e o f o n ly a s i n g l e v e r t e b r a t o f u s e a n d t h e s p in a lc o r d a n d s p in a l n e r v e s a r e n o r ma l , n e u r o lo g i c s y mp -t o m s a r e c o m m o n l y a b s en t , p r o d u c i n g n o c l i n i ca ls y m p to m s . I n f a c t, s p in a b i f i d a o c c u l t a o c c u r s i n l o w e rlu mb a r o r s a c r a l v e r t e b r a e i n a p p r o x ima te ly 1 0 % o fo th e r w i s e h e a l t h y p e o p l e , t h u s b e in g r e g a r d e d a s an o r m a l v a r i a ti o n i n t h e p o p u l a t i o n .4,5 Ho we ver , i f sev-e r al v e r t e b r a e a r e i n v o lv e d in t h i s mi ld e r t y p e o f N T D ,b o w e l , b l a d d e r , o r mo to r p r o b l e ms ma y e v e n tu a l l yd e v e lo p .6S p i n a i f i d a C y s t i c a

    Severe types of sp ina b i f ida involve pro t rus ion of thesp ina l cord and/or menin ges through a d e fec t in the ve r -tebra l a rch and a re r e fe r red to a s sp ina b i f ida cys t icabecause of the cys t - l ike sac tha t i s a ssoc ia ted wi th these

    Cur r P robl Ped ia t r, Novem ber /December 2000 317

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    ma l f o r ma t io n s . W h e n th e s a c c o n t a in s me n in g e s a n dce rebrospina l flu id , bu t the sp ina l cord an d sp ina l roo ta re in the i r no rma l pos i t ion , the de fec t i s r e fe r red tO as amen ingoce le . Despi te the i r norm al loca tion , sp ina l cordabnormal i t ie s can be seen wi th the meningoce le . Inme n in g o m y e lo c e l e , t h e sp in al c o r d a n d /o r n e r v e r o o t spro t rude throug h the de fec t in the ve r tebra l a rch and a rein c lu d e d i n t h e s a c. M e n in g o m y e lo c e l e i s a mo r e c o m -m o n a n d mo r e s e v e re ma l f o r ma t io n th a n me n in g o c e l e .

    D e p e n d in g o n t h e l e v e l o f t h e l e s io n , i n t e rr u p t io n o fth e sp in a l c o r d a t t h e s i t e o f t h e me n in g o my e lo c e l ed e f e c t c a u se s p a r a ly s i s o f t h e l e g s , i n c o n t in e n c e o fu r in e a n d f e c e s , a n e s th e s i a o f t h e sk in , a n d a b n o r ma l -i t ie s of the h ips , knees , and fee t . In f ac t , on ly 1% ofc h i ld r e n b o r n w i th a n o p e n N T D a r e f r e e o f h a n d ic a p .C h i l d r en b o r n w i t h a m e n i n g o m y e l o c e l e n e e d m u l t i-p l e su r g e r i e s a n d i n v a s iv e p r o c e d u r e s . F o r e x a mp le ,su r g e r y i s n e e d e d w i th in 2 4 t o 4 8 h o u r s a f t e r b i r t h t or e p a i r a n o p e n d e f e c t i n o r d e r t o r e d u c e t h e r i sk o fin f e c t i o n . W i th o u t t h i s su r g e r y , o n ly 2 0 % o f t h e sein f a n t s su r v iv e t o a g e 2 y e a r s . 4 Mo s t a f f e c te d i n d iv id -u a l s h a v e a n a s so c i a t e d d e f o r mi ty a t t h e b a se o f t h eb r a in , t h e A r n o ld - C h ia r i t y p e I I ma l f o r m a t io n , w h ic hp r o b a b ly a c c o u n t s f o r t h e w e l l - e s t a b l i sh e d h y d r o -c e p h a lu s p r e se n t a t b i r t h i n a b o u t 8 0 % o f c a se s ]A l th o u g h me n ta l d e f i c i e n c y o c c u r s i n f r e q u e n t ly i nc h i l d re n w i t h m e n i n g o m y e l o c e l e , t h e b r a in a n d s p i na lc o r d a b n o r ma l i t i e s a s so c i a t e d w i th sp in a b i f i d a a l soa f f e c t l e a r n in g . Mo s t c h i l d r e n h a v e n o r ma l i n t e l l i -g e n c e b u t sh o w p r o b l e m s w i th p e r c e p tu a l mo to r sk il l s,a t ten t ion , m em ory , and organiza t ion . 8,9

    Neura l Tube eve lopm entN e u r u l a t i o n

    N e u r a l t u b e f o r ma t io n a n d c lo su r e i n v o lv e c o mp le xce l lu la r , ex t race l lu la r , and in te rce l lu la r processes .F o r m a t io n b e g in s w i th p r ima r y n e u r u l a t i o n a n d i s c o m-p le t e d b y t h e p r o c e s s o f c a n a l i z a t i o n , w h ic h o c c u r sd u r in g s e c o n d a r y n e u r u l a t i o n . P r ima r y n e u r u l a t i o nb e g in s w h e n th e n o to c h o r d i n d u c e s t h e o v e r ly in ge mb r y o n ic e c to d e r m to f o r m a c e l l u la r pl a t e. T h e n o to -c h o r d d e f in e s t h e p r imi t i v e ax i s o f t h e e m b r y o , w h e r e -a s t h e c e l l u l a r n e u r a l p l a te w i l l f o r m th e n e u r a l t u b ea n d i s t h e p r e c u r so r o f t h e c e n t r a l n e r v o u s sy s t e m( b r ain a n d sp in a l c or d ) . A s t h e n o to c h o r d f o rms a n de lo n g a te s , t h e n e u r a l p l at e b r o a d e n s a n d e x t e n d s b e y o n dth e e d g e s o f t h e n o to c h o r d . O n a p p r o x im a te ly d a y 1 8in h u m a n f e t a l d e v e lo p me n t , t h e n e u r a l p l a t e b e g in s t o

    invagina te a long i t s cen t ra l ax is , formin g a longi tud ina lm e d ia n g r o o v e w i th n e u r a l f o ld s o n e a c h o f 'i ts s id e s .he mid l in e o f t h e n e u r a l p l a t e b e c o me s a n c h o r e d t o

    th e u n d e r ly in g a x i a l me so d e r m, e s t a b l i sh in g a h in g ea r o u n d w h ic h t h e l a te r a l f o ld s e i e v at e . O n e o f t h e f i r s ts t e p s i n e l e v a ti o n o f t h e n e u r a l f o ld s i s t h e d e v e lo p me n to f h in g e p o in t s , w h ic h a r e f o r me d th r o u g h a l t e r at i o n sin n e u r o e p i th e l i a l c e l l sh a p e c a l l e d wedging T h ef o r c e s o f c e l l w e d g in g , mig r a t i o n , a n d e x p a n s io n o f t h esu r fa c e e c to d e r m, a s w e l l a s g r o w th a n d e x p a n s io n o fth e u n d e r ly in g me so d e r m, a r e a l l fa c to rs t h a t p r o v id eth e m e c h a n ic a l imp e tu s t o b r in g t h e l a t e r a l h a lv e s o fth e n e u r a l p l a t e t o t h e m id l in e . 1 B y d a y s 2 2 t o 2 4 o fd e v e lo p m e n t , t h e p r o c e s s o f e l e v a t io n i s f o l l o w e d b yf u s io n o f t h e n e u r a l f o ld s , c o n v e r t i n g t h e n e u r a l p l a t ein to t h e n e u r a l t u b e . U p o n in i ti a l c l o su r e , t h e n e u r a lt u b e h a s o p e n in g s a t e it h e r e n d - - th e a n t e r io r a n d p o s -t e r i o r n e u r o p o r e s - - w h ic h a l l o w , f o r t h e f l u id o f t h ea m n i o t ic c a v i ty t o c o m m u n i c a t e w i t h t h e l u m e n o f t h en e u r a l t u b e . T h e a n t e r io r n e u r o p o r e c lo se s o n d a y s 2 4to 2 6 , f o l l o w e d b y p o s t e r i o r n e u r o p o r e c lo su r e o n d a y s2 5 t o 2 8 o f d e v e lo p m e n t .1

    P r ima r y n e u r u l a t i o n r e su l t s i n a c lo se d n e u r a l t u b ew i th i t s c a u d a l l imi t i n t h e u p p e r l u m b a r sp in a l c o r d .T h e c a u d a l p o r t i o n o f t h e n e u r a l t u b e d o e s n o t a r is e b yf u s io n o f t h e n e u r a l f o ld s b u t d e v e lo p s f r o m a c e l l u l arm a s s k n o w n a s t h e c a u d a l e m i n e n c e . O n c e t h e p o s t e -r i o r n e u r o p o r e i s c lo se d , n e u r a l t i s su e i s l a id d o w n a sa n e u r a l c o r d i n to w h ic h t h e c a v i ty o f t h e m o r e r o s t ra l ,n e w ly d e v e lo p e d n e u r a l t u b e e x t e n d s . T h e p r o c e s s b yw h i c h t h e r e m a i n i n g m o s t c a u d a l e l e m e n t s o f t h esp in a l c o r d a r e f o r me d i s k n o w n a s c a n a l i z a t i o n , o rs e c o n d a r y n e u r u l a t i o n , a n d c o r r e sp o n d s t o t h e f u tu r eve r tebra l leve l 8 2 . 5 1 1 ~l o s u r e T h e o r ie sT w o p r ima r y t h e o r i e s e x i s t r e g a r d in g t h e f u s io n s i te s

    a n d t h e t im in g o f n e u r a l t u b e f o r m a t io n . F ir s t, t h e t r a -d i t i o n a l z ip p e r mo d e l s t a te s t h a t t h e n e u r a l tu b ec l o s e s i n a c o n t i n u o u s , b i d i r e c t i o n a l p r o c e s s .A c c o r d in g t o t h i s mo d e l , t h e n e u r a l f o ld s f i r s t me e ta n d c lo se i n t h e c e r v i c a l r e g io n , a n d f u s io n t h e n p r o -ceeds b id i rec t io na l ly unt i l a tube i s form ed. 11a

    I n 1 9 93 , V a n A l l e n e t a l l 2 p r o p o se d t h e s e c o n d th e o r yo f n e u r a l t u b e c lo su r e , s t a t i n g t h a t t h e h u ma n n e u -ra l tube c loses a t mu l t ip le loca t ions . The mu l t i - s i te c lo-su r e mo d e l s t at e s t h at t h e p r o c es s o f n e u r a l fo ld f u s io nis in i t ia ted at 5 s i te s a long the fu ture neura l tube . VanAllen e t a112 prop ose tha t mul t i - s i ( e neura l tube c losurep r o v id e s th e b e s t e x p l a n a t io n f o r N T D s in h u m a n s , a n d

    31 8 Cur r P rob l P ed ia t r Nov em ber /D ecem ber .20 00

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    severa l r ecent s tudies have provided addi t iona l ev i -denc e supp or t ing th is mod e l of neura l tube c los ureJ 2-15According to the mul t i - s i te c losure mode l , the in i t ia ls i te of c losure (c losure 1) i s in the midcervica l r eg ionand proceeds c rania l ly and cauda l ly , c los ing over thea rea of the fu ture sp ine a t the leve l of L2. C losure 2be g ins a t t he p r ose nc e pha lon /m e se nc e pha lon b o u n d a r yand proceeds b id i rec t iona l ly , whereas c losure 3 pro-c e e ds r o s tr a l ly f r om the s tom ode u m a nd m e e t s t he c r a -n ia l end of c losure s i te 2 . C losure 4 takes p lace in ther e g ion o f t he r hom be nc e p ha lon a nd p r oc e e ds r o s tr a ll y .F ina l ly , c losure 5 unid i rec t ion a l ly c loses the cauda l en do f t he ne u r a l t ube f r om the l e ve l o f f u tu r e $2 t h r oughL2. Fa i lure of the neura l tube to c lose wi th in these 5s i te s can expla in a l l types of NTDs, wi th sp ina b i f idar e su l ti ng f r om inc om p le t e f u s ion o f c lo su r e 5 o r o f r o s -tra l or caudal c losure 1.12

    bnorm a l Neuru la tionA s s t a t ed e a rl ie r , in no r m a l ne u r a l t ube de ve lop m e n t

    the e dge s o f t he ne u r a l p la t e f o ld t ow a r d e a c h o the r a ndf use t o f o r m the ne u r a l t ube . A s t he ne u r a l p l a t e de ve l -ops i n to t he sp ina l c o rd , bone a nd m u sc l e f o r m a p r o -tec t ive ba r r ie r a round i t . Spina b i f ida resul t s f roma bnor m a l ne u r u l a t i on in w h ic h a po r t i on o f t he ne u r a lp l a t e f ai l s t o j o in t oge ther , a nd the r e f o r e bone a n d m us -c l e a r e una b le t o g r ow ove r t h i s ope n se c t i on o f t hede ve lop in g sp ina l c o lum n .6 Th e resul t i s a hole in theb a c k t h r o u g h w h i c h t h e s p in a l c o r d a n d / o r m e n i n g e s( ne r ve ti s sue s) p r o t r ude . The s e ve r it y o f sy m p tom s i sde t e r m ine d by the pa r t i c u l a r ne r ves i nv o lve d ( t he l e velo f t he de f e c t ) a nd the i r de g r e e o f da m a ge a nd /o rm a l d e v e l o p m e n t . C h i l d r e n w i t h m e n i n g o m y e l o c e l eha ve n e u r o log i c de f i c it s a t t he l e ve l o f t he de f e c t a ndbe low , r e su l t ing i n va r y ing de g r e e s o f m usc l e pa r a ly s is ,b l a dde r a nd bow e l p r ob l e m s , l o s s o f sk in s e nsa t i on ,a nd s p in e a nd l im b de f o r m i t i e s .8

    Management and areP r e n a t a l e t e c t io n

    A lp ha f e top r o t e in ( A F P ) i s a p r o t e in p r e se n t i n f e ta lt i s sue s du r ing de v e lopm e n t a nd i s u t i li z e d f o r p r e na t a ld i a gnos i s o f N TD s . A S the e m br yo de ve lops , c lo su r eo f t he a bdom ina l w a l l a nd ne u r a l t ube p r e ve n t s r el e a seo f A F P in to t he a m n io t i c f l u id . I f a n N TD i s p r e se n t ,A F P p r oduc e d by the f e tu s l e a ks i n to t he a m n io t i cf lu id t h r ough the de f e c t a nd d i f f u se s i n to m a te r na l c i r -c u l a t i on a nd c a n be de t e c t e d i n m a te r na l s e r um , t hus

    a l l o w i n g f o r p r e n a t a l d i a g n o s i s o f N T D s . s '1 6M e a s u r e m e n t o f m a t e r n a l A F P i s a s t a n d a rd p a r t o f t h e

    t r i p le sc r e e n t e s ts pe r f o r m e d on p r e gna n t w om e ndur ing the i r f i r s t t r imeste r . The t r ip le sc reen te s t cani d e n t if y a p p ro x i m a t e l y 7 5 % t o 8 0 % o f m e n i n g o m y -e loc e l e - c om pl i c a t e d p r e gna nc i e s a t 16 w e e ks ' ge s t a -t i on . I f a n e l e va t e d m a te r na l A F P l e ve l i s de t e c t e d ,a m n ioc e n te s i s i s pe r f o r m e d to c he c k the a m n io t i cf lu id f o r A F P ; u l t r a sonogr a phy o f t he f e tu s i s t he nuse d to c on f i r m the d i a gnos i s a nd e va lua t e t he f e tu sfor anom al ies . 17Del ivery nd Neurosurgery

    A l though som e w ha t c on t r ove r s i a l , t he m a jo r i t y o fs tud i e s suppo r t t he de l i ve r y o f ba b i e s w i th sp ina b i f i daby p l a nne d c e sa r e a n s e c t i on , thus a l l ow ing m or e c a re -f u l de l i ve ry o f t he ba by to p r o t e c t t he sp ina l c o r d f r omin ju r y a nd to p r e ve n t pos s ib l e r up tu r e o f t he m e n inge a ls a c . 8 1 7 1 8 O n c e a c h i l d w i t h a m e n i n g o m y e l o c e l e i sde l ive red , i t i s necessa ry to rep a i r the de fec t wi th in 24to 48 h ours to redu ce the r i sk of infec t ion . In i t ia l eva l -ua t i ons o f t he ne w bor n a r e im por t a n t t o a s se s s t hepo te n t i a l c om pl i c a t i ons ( i nc lud ing the p r e se nc e o fh y d r o c e p h a l u s , d e f o r m i t i e s o f t h e l e g s , a n d l e g -m o ve m e n t p r ob l e m s) a nd inc lude a s e nso r y e xa m ina -t i on t o de t e r m in e t he l e vel o f t he l e s ion a nd p r ognos i sfor motor abi l i ty and a uro logic eva lua t ion to de te r -m ine c on t ine nc e . 1

    C h i l d r e n b o r n w i t h a m e n i n g o m y e l o c e l e h a v e a b n o r -m a l i t i e s t ha t a r e no t l im i t e d t o t he sp ina l c o r d , i nc lud -i n g t h e d e v e l o p m e n t o f h y d r o c e p h a l u s a n d t h e d e v e l -o p m e n t o f s y m p t o m s r e l a t e d t o t h e a r e a w h e r e t h eb r a in a nd sp ina l c o r d j o in ( A r no ld - C h ia r i m a l f o r m a -t i o n ) J 9 A p p r o x i m a t e l y 8 5 % t o 9 0 % o f b a b i e s w i t hsp ina b i f i da e i t he r ha ve hyd r oc e pha lus a t b i r t h o rde ve lop i t soon a ft er . H y dr oc e pha lu s i s a c ond i t i on i nw h ic h a n e n l a r ge m e n t o f the ve n t r i c u l a r sy s t e m o f t heb r a in oc c u r s be c a use o f a n im ba la nc e be tw e e n the p r o -duc t ion a nd a bso r p t ion o f c e r e b r osp ina l f l u id . Theh ighe r t he l e ve l o f l e s ion , t he g r e a t e r t he i nc ide nc e o fhyd r oc e ph a lus . H ydr oc e pha lus i s a l l e v i a t e d by u t i l iz a -t i on o f a shun t to p r ov id e d r a ina ge t o t he b loc ke d ve n -t r icle s . A shun t i s a smal l f lex ib le tube inse r ted throu gha sm a l l ope n ing in t he sku l l , l e a d ing f r om the b r a inve n t r i c l e unde r ne a th t he sk in o f t he he a d a nd ne c k , t od r a in e xc e s s c e r e b r osp ina l f l u id f rom the b r a in i n to t hea b d o m e n w h e r e i t is a b s o rb e d . T w o c o m m o n p ro b l e m sw i th shun t s a r e m a l f unc t ion a nd in f e c t i on , bo th o fw h ic h c a n be t r e a t e d by shun t r e v i s ion . The r e a r e c on -f l i c ti ng v i e w s c onc e r n in g w he the r a c h i ld w i th hyd r o -

    Cur r P rob l P ed ia t r Nove mb er /Dec emb er 20 00 31 9

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    4/16

    c e p h a lu s s h o u ld h a v e a s h u n t p r o c e d u r e p e r f o r me d .S tu d i e s o f i n t e l l e c tu a l f u n c t i o n in g o f c h i l d r e n w i thm e n i n g o m y e l o c e l e h a v e s h o w n t h a t c h i ld r e n w h oh a v e n e v e r h a d a s h u n t p r o c e d u r e g e n e r a l l y d o b e t te ri n t e l l e c tu a l l y t h a n c h i l d r e n w h o h a v e h a d a s h u n t p r o -cedure . How ever , in te rpre ta t ion of these s tud ies i s d i f -f i c u l t b e c a u s e t h e c h i l d r e n w i th s h u n t s h a d mo r es e v e r e h y d r o c e p h a lu s i n i t i a l l y , w h ic h c o u ld b e t h ed e t e r m in a n t o f t h e i r l im i t e d i n t e l l e c tu a l f u n c t i o n in g ,zA n a d d i t i o n a l s t u d y c o n c lu d e d th a t i t i s t h e r e v i s io n o fshunts , pa r t icu la r ly a f te r age 2 yea r s , tha t i s a ssoc ia t -e d w i t h p o o r l o n g - t e r m a c h i e v e m e n t i n a d u l t s w i t hspin a bif ida . 21

    T h e A r n o ld - C h ia r i t y p e I I ma l f o r ma t io n a f f e c t s t h eh in d b r a in a n d u p p e r c e r v i c a l s p in e a n d i s c h a r a c t e r -i z e d b y a d o w n w a r d h e r n i a ti o n o f t h e c e r e b e l lu m a n dpor t io n o f the bra in s tem in to th e c e rv ica l sp ine . 5,11,19T h e v a s t ma jo r i t y o f p a t ie n t s w i th s p in a b i f i d a e x h ib i ts o m e d e g r e e o f t h i s ma l f o r ma t io n , w i th a p p r o x im a te -l y o n e t h i rd o f c h i l d r e n w h o a r e b o r n w i t h a m e n i n g -o m y e l o c e l e d e v e l o p i n g s y m p t o m a t i c A r n o l d - C h i a r im a l f o r m a t i o n ; a l t h o u g h t h e s y m p t o m s r e s o l v e f o rmo s t p a t i e n t s , a t h i r d o f t h o s e w h o r e ma in s y mp to -ma t i c w i l l d i e ( a p p r o x ima te ly 1 2 % o f t h e t o t a l ). 22 T h ed e v e l o p m e n t o f s y m p t o m s r e l a te d t o t h e A r n o l d -C h ia r i ma l f o r ma t io n a p p e a rs t o b e r e l a t e d to t h e s e v e r -i t y o f t h e m a l f o rm a t i o n , w h i c h i s p r i m a r i l y d e t e r m i n e db y t h e d e g r e e o f d e s c e n t o f t h e b r a in i n to t h e c e r v i c a ls p in e . S y m p t o m s t y p i c al l y c o m e f r o m 1 o f 3 a r ea s o ft h e c e n t r a l n e r v o u s s y s t e m , i n c lu d in g t h e c e r e b e l l u m,th e l o w e r b r a in s t e m, a n d /o r t h e s p in a l c o r d . L o w e rb r a i n -s t e m s y m p t o m s m o s t o f t e n p r e s en t i n n e w b o r n sa n d y o u n g i n f a n t s i n c l u d e d i f f i c u l t y s w a l l o w i n g ,insp i ra tory s t r idor , weak or poor c ry , and sus ta ineda r c h i n g o f t h e h e a d . W h e n s e v e r e , t h e s e s y m p t o m sm a y r e s u l t i n i n s u f f i c ie n t b r e a th in g t o ma in t a in l i fe ,m a k i n g s y m p t o m a t i c A r n o l d - C h i a ri m a l f o r m a t i o n th el e a d in g c a u s e o f d e a th i n c h i l d r e n w i th s p in a b if i d a . A sa c h i l d w i th A r n o ld - C h ia r i ma l f o r ma t io n p r o g r e s s e sin to a d o l e s c e n c e , h e o r s h e ma y d e v e lo p s t i f f n e s s o rs p a s t ic i t y o f th e a r ms a n d h a n d s a lo n g w i th a l o s s o ff e e l i n g o r s e n s a t io n , o f t e n d u e t o a n a b n o r m a l i t y o f t h es p i n a l c o r d . S y m p t o m s a r i s i n g f r o m t h e c e r e b e l l u ma r e l e a s t l i k e ly t o o c c u r a n d p r o d u c e p r o b l e ms w i thba lanc e and coord ina t ion . 19

    C o n t r o v e r sy e x i s ts r e g a rd i n g p r o p e r m a n a g e m e n t o ft h e A r n o ld - C h ia r i m a l f o r ma t io n ; h o w e v e r , i t is g e n e r -a l l y a c c e p t e d t h a t t h e i n i t i a l s t e p b e d i r e c t e d t o w a r dr e l i e v in g in t r a c ra n i a l p r e s s u r e b y u s e o f a s h u n t . M o s tp a t ie n t s w i t h A r n o l d - C h i a ri m a l f o r m a t i o n d o n o t n e e d

    s u r g e r y u n l e s s s e ri o u s s y m p to m s a re p r e s e n t , i n w h ic hc a s e s u r g i c a l i n t e r v e n t i o n s h o u ld b e c o n s id e r e d . T h es u r g i c a l a p p r o a c h c o n s i s t s o f p o s t e r i o r f o s s a d e c o m-p r e s s io n a n d l a m i n e c t o m y a n d t h e e s t a b l i sh m e n t a n dm a i n t e n a n c e o f n o r m a l m o v e m e n t o f t h e c e re b r o s p in a lf lu id . 19,22 Gr iebe l e t a122 s ta te tha t beca use of t her e v e r s ib i l i t y o f p o t e n t i a l l y l e t h a l s y mp to ms i n s o mep a t i e n t s [ w i th A r n o ld - C h ia r i ] a n d b e c a u s e o f t h e l o wr i s k s i n v o lv e d i n s u r g er y , w e f e e l t h a t p o s t e r i o r f o s s ad e c o mp r e s s io n a n d l a min e c to my i s j u s t i f i e d i n c h i l -d r e n w i th s e ri o u s b ra in s t e m s y m p to m s .O r t h o p e d i c s

    T h e q u e s t i o n o f w h e t h e r a c h i l d w i t h s p i n a b i f id aw i l l b e a b l e t o w a l k i s m o s t d e p e n d e n t u p o n t h e l e s i o nl e v el o f t h e m e n i n g o m y e l o c e l e . C h i l d r e n w i t h l o w -leve l le s ions ( low lumbar and sac ra l leve ls ) a re usua l -l y a b l e t o w a lk , a l t h o u g h t h e y ma y n e e d t h e h e lp o fb r a c e s a n d /o r c r u t c h e s . P a t i e n t s w i th mid l e v e l l e s i o n s( mid lu m b a r l ev e l ) t y p i c a l ly r e q u i r e s i g n i f i c a n t s u p p o r ti n t h e f o r m o f b r a c e s , tw i s t e r c a b l e s , c r u t c h e s , o rw a lk e r s t o w a lk f o r e v e n b r i e f p e r i o d s . Mo s t p a t i e n t sw i th l e s i o n s a t t h e u p p e r l u mb a r l e v e l a n d a b o v er e q u i r e w h e e l c h a i r s f o r mo b i l it y .8 T h e p e r c e n t a g e o fc h i l d r e n w h o c a n w a lk w i th in e a c h l e s io n - l e v e l g r o u pi s e s t ima t e d t o b e : s a c ra l , 1 0 0 % ; l o w lu m b a r , 9 5 % ;hig h lumb ar , 30% ; an d thorac ic , 33% . 23

    T h e t y p e s o f o r t h o p e d i c p r o b l e ms a p e r s o n w i th s p in abi f ida i s f aced wi th inc lude c lubfoot , h ip dysplas ia , andspina l de formi t ie s such as sco l ios is and kyphos is .Deve lopmenta l o r pa ra ly t ic sp ina l de formi t ie s such asscol ios is ( lateral bend of the sp ine ) and kyp hos is ( for-ward bending of the lower sp ine ) r equi re or tho t ic sup-p o r t i n y o u n g e r p a t ie n t s i n t h e f o r m o f b r a c in g , w i th aposs ib i l i ty of surg ica l t r ea tment dur ing the pre teeny e a r s . T h e p r ima r y c a u s e o f h ip a b n o r ma l i t i e s i nme n in g o m y e lo c e l e p a t i en t s i s mu s c l e imb a l a n c e , w h ic hp r o d u c e s a b n o r ma l f o r c e s a c r o s s t h e h ip j o in t .P ro lon ged s i t ting , because of lack o f mobi l i ty , can leadto f l e x io n d e fo r mi t i es o f t h e k n e e o b s e r v e d i n 5 0 % o fpa t ien ts wi th uppe r leve l le s ions , 20% of lum bar le s ions ,and 15% o f sac ra l le s ions . The f r equency of va r ious footd e f o r mi t i e s , i n c lu d in g c lu b f o o t ( mi s a l i g n me n t o f t h ebones in the f ron t pa r t o f the foo t r e su l ting in an abnor -ma l s h a p e) , th a t o c c u r s w i th me n in g o m y e lo c e l e s q u i t eh ig h a n d p r ima r i ly c a u s e d b y mu s c l e imb a l a n c e.23

    e u r o p s y c h o l o g yT h e b r a in a n d s p in a l c o r d a b n o r ma l i t i e s a s s o c i a t e d

    wi th sp ina b i f ida a l so a f fec t lea rn ing , typ ica l ly d is -

    320 Cu r r P robl Ped ia t r Novem ber /Decembe r 2000

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    p la y e d t h r o u g h p r o b l e m s w i th p e r c e p tu a l - m o to r sk i l ls ,n u me r i c a l r e a so n in g , a t t e n t i o n , me mo r y , a n d o r g a n i -z a t io n . 8,9 A l th o u g h m o s t c h i l d r e n w i th sp in a b i f i d ah a v e n o r ma l i n t e l li g e n c e , t h e y d o h a v e p a r t i c u l a r le a r n -in g d i s a b i l i t ie s o r w e a k n e s se s t h a t o f t e n m a k e i t d i ff i -c u l t f o r t h e m to o b t a in su b s t a n t i v e e d u c a t i o n , g a in f u le m p l o y m e n t , a n d a u t o n o m y i n d a i l y l i v i n g . T h e s ew e a k n e s s i n c lu d e t h e f o l l o w in g : p o o r e y e - h a n d c o o r -d in a t i o n ( p e r c e p tu a l - mo to r ) , ma y sp e a k w e l l b u t n o tb e a b l e t o e x p l a in w e l l o r f u l l y u n d e r s t a n d ( c o mp r e -h e n s io n ) , e a s i l y d i s t r a c t e d ( a t t e n t i o n ) , r e s t l e s sn e s s( h y p e r a c t i v i t y ) , t r o u b l e r e me mb e r in g w h a t i s s a id o rs e e n ( me m o r y ) , d i so r g a n i z e d ( o r g a n i z at i o n ) , u n a b l e t ok e e p t h in g s i n o r d e r ( s e q u e n c in g ) , a n d d i f f i c u l t y i nma k in g d e c i s io n s a n d so lv in g p r o b l e m s ( r e a so n in g ) . 9

    T h e r o l e o f e d u c a t i o n a l e n v i r o n me n t s i n a s s i s t i n gc h i ld r e n w i th sp in a b i f i d a t o d e v e lo p sk i l l s n e c e s sa r yf o r a u to n o my in a d u l th o o d i s e sp e c i a l l y imp o r t a n t .E v id e n c e su g g e s t s t h a t c h i l d r e n w i th sp in a b i f i d a w h oa r e e n r o l l e d i n r e g u la r , i n t e g r a t e d s c h o o l e n v i r o n m e n t sc o m p o s e d o f b o t h p h y s i c a l l y h a n d i c a p p e d a n d n o n -h a n d ic a p p e d s tu d e n t s f u n c t i o n b e t t e r a c a d e mic a l l y ,p sy c h o lo g i c a l l y , a n d so c i a l ly t h a n t h e i r c o u n te r p a r t s i nsp e c i a l i z e d s c h o o l s . 24 I f c h i l d r e n a n d a d o l e sc e n t s w i thsp in a b i f i d a p a r t i c ip a t e i n i n d iv id u a l i z e d e d u c a t i o n a lp r o g r a ms d e s ig n e d t o r e in f o r c e a c a d e mic s t r e n g th s ,i n c r e a se so c i a l c o n f id e n c e a n d i n d e p e n d e n t l i v in gsk i ll s , a n d p r o v id e o p t io n s f o r f u tu r e w o r k , t h e y w i l lb e m o r e p r e p a re d t o c o p e w i t h a n d h a n d l e t h e m a n yc h a l l e n g e s o f a d u l th o o d .24

    S p i n a i f i d a a s a M u l t i f a c t o r i a l D i s e a s eGe n e t i c ac f o r s

    G e n e t i c o r i n h e r i t e d f a c to r s a r e imp o r t a n t to u n c o v -e r t h e e t i o lo g y o f N T D s ( T a b le 1 ). T h e c a se f o r t he x i s t e n c e o f a g e n e t i c p r e d i sp o s i t i o n f o r N T D s i s su p -p o r t e d b y s e v e r al l i n e s o f e v id e n c e i n c lu d in g t h a t ( 1 )t h e i n c i d e n c e o f N T D s v a ri e s g r ea t l y a m o n g p o p u l a -t i o n s a n d e th n i c g r o u p s , ( 2 ) t h e r isk o f o c c u r r e n c e o fN T D s in o f f sp r in g o f p a r e n t s w i th p r io r a f fe c t e d p re g -n a n c i e s i s S u b s t a n ti a ll y h ig h e r n o t o n ly f o r t h o se p a r -en ts bu t a lso for the i r f i r s t- and secon d-deg ree re la -t ives , and (3) a l te ra t ions in genes involved in fo la teme ta b o l i sm a r e a s so c i a t e d w i th i n c r e a se d r i sk f o rNT Ds. 10

    T h e i n c i d e n c e o f N T D s v a r i e s w o r l d w i d e , f r o mabout 1 to abou t 9 pe r 100 0 to ta l b i r ths in d i f fe ren t e th-n i c g r o u p s a n d i n d i f f e r e n t p a r t s o f t h e w o r ld . F o r

    e x a mp le , so me o f t h e g r o u p s w i th t h e h ig h e s t i n c i -d e n c e o f N T D s a re p o p u l a t i o n s f r o m s o u t h e rn W a l es(7 .6 pe r 1000) an d No r the rn I r e land (8 .6 pe r 1000) . 7 ,25T h e g e n e r al p o p u l a t i o n ri s k f o r N T D s i n t h e U n i t e dS ta t es i s a p p r o x im a te ly 1 p e r 2 0 0 0 , w i th sp in a b i f id ar e p r e se n t in g r o u g h ly h a l f o f t h e se d e f e c t s . 26 I n -t e r e s t i n g ly , t h e i n c id e n c e o f N T D s v a r i e s w i th g e o -g r a p h i c a l l o c a t i o n w i th in t h e U n i t e d S t a t e s . G r e e n b e r ge t a l e 7 f o u n d th a t t h e r i sk f o r sp in a b i f i d a g e n e r a l l yd e c r e a se s f r o m e a s t t o w e s t , w i th t h e h ig h e s t r a t e o fsp in a b i f i d a s e e n i n so u th e r n A p p a l a c h i a ( 0 . 8 p e r1 0 0 0 ) a n d t h e lo w e s t r a te s e e n i n t h e R o c k y M o u n ta ins ta te s and th e Pac i f ic Nor thw est (0 .1 pe r 1000) . 27

    T h e i n c i d e n c e o f N T D s v a r i e s w i t h e t h n i c i t y a n dg e o g r a p h ic a l l o c a t i o n w i th in t h e U n i t e d S t a t e s. A f r i c a nA me r i c a n s h a v e a l o w e r r a t e o f N T D s th a n w h i t e s ,w h e r e a s A s i a n A m e r i c a n s h a v e b e e n s h o w n t o h a v e alo w e r i n c id e n c e t h a n e i t h e r A f r i c a n A me r i c a n s o rwhi te s . 28-3 Hisp anic pe r so ns in the Un i ted S ta te s ,p a r t i c u l ar l y i n T e x a s , h a v e a h ig h e r r i sk f o r h a v in g ac h i ld w i th a n N T D th a n o th e r e th n i c g r o u p s i n t h eU n i t e d S t a te s .

    A g e n e t i c c o n t r i b u t i o n t o ma l f o r m a t io n s o f t h e n e u -r a l t u b e i s su g g e s t e d b y f a m i l i a l r e c u r r e n c e r i sk s a n dan a l te red sex ra t io . The h e r i tab i l i ty for sp in a b i f ida i se s t im a ted to be 60 . 31 Her i tab i l i ty i s de f in ed as thep r o p o r t i o n o f p h e n o t y p i c v a r ia t io n i n a p o p u l a t i o n d u eto gene t ic va r iat ion . In o the r wo rds , he r i tab l i l i ty i s t hp r o p o r t i o n o f a p e r so n ' s o u tw a r d , v i s i b l e e x p r e s s io n o fth e i r g e n e s t h a t is d u e so l e ly to t h e i r g e n e t i c ma k e u pa n d e x c lu d e s e n v i r o n m e n ta l o r o th e r f a cto r s.

    N T D s c lu s t e r i n f a mi l i e s . T h e r e c u r r e n c e r i sk i sr e f l e c t e d b y t h e l o c a l p o p u la t i o n p r e v a l e n c e a n d i n f lu -e n c e d b y t h e n u m b e r o f f a m i l y m e m b e r s a f f ec t ed , w i t hth e r e c u r r e n c e r i sk r i s i n g a s t h e n u mb e r o f a f f e c t e dperso ns in a f am i ly inc reases . 32-34 In the g ene ra l p op-u l a t i o n o f t h e U n i t e d S t a te s , t h e o c c u r r e n c e o f N T D sin s ib li n g s i s a p p r o x im a te ly 3 , a n d it r o u g h ly d o u -b l e s w i th t h e b i r t h o f e a c h a d d i t i o n a l c h i l d w i th a nNT D. 35 In second-deg ree re la tives , the recur rence dropsto 0 .5 , and in th i rd-degree re la tives , it i s approxi -m a t e l y e q u a l t o t h e g e n e r al p o p u l a t i o n ' s b a c k g r o u n drisk (~1 p er 2 000) . 36

    A n e x c e ss o f f e ma le s h as b e e n s e e n a mo n g c h i ld r e nwi th NT Ds. 32 How ever , an equa l sex ra t io of c h i ldrena f fec ted wi th sp ina b i f ida was obse rved in a s tud y of 2p r e d o min a n t ly H i sp a n i c c o u n t i es b o r d e r in g Me x ic o a n din a n a d d i t i o n a l s t u d y p u b l i sh e d o n H i sp a n i c s i nHou ston , Texas . 37,38 I f a f ema le p redom inanc e of th istype of b i r th de fec t ex is ts , i t c o u ld r e su l t f ro m in u t e r o

    Cur r P rob l P ed ia t r Nove mb er /Dec em ber 20 00 321

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    6/16

    T A B LE 1 . G e n e t i c a n d e n v i r o n m e n t a l f a c t o rs a s s o c i a t e d w i t h n e u r a l t u b e defectsGen et ic fac tors nvironmental factorsNT D inc idenc e v a r i es am ong e t hn i c g r ou psNT D inc idenc e v a r i es w i t h geo g r aph i c a l l oc a t i onFami l ia l recur rence risksA l t e r ed s ex r a t i o *NT E ~ s usc ep ti b le an im a l m ode l s s ee T ab le 3 )G ene ti c s y nd r om es as s oc ia t ed w i t h NT Ds

    M a t e r n a l a n d p a t e r n a l a g e *L o w s o c i o e co n o m i c c l a s s *P ar en ta l oc c u pa t i on*M a t e r na l obes i t y and d iabe t esM at e r na l hy pe r t he r m ia and i l lnes sM at e r na l an t i c onv u l s an t d r ug us e

    *Conf l ic t ing resul ts f rom m ul t ip le s tudies as to ef fec t o f these var iab les .

    s e l e c t i o n a g a i n s t a f f e c t e d m a l e s , l e a d i n g t o a n i n c r e a s ei n m i s c a r r i a g e r a te s a n d a d e c r e a s e i n t h e m a l e - t o - f e m a l er a t i o o f s i b l i n g s . 3 9 I n c o n t r a s t , i f a m a l e p r o t e c t i v e m e c h -a n i s m a g a i n s t N T D s e x i s t s , t h e p r e s e n c e o f a m a l ep r o b a n d s u g g e s t s h i g h e r g e n e t i c s u s c e p t i b i li t y in a f a m -i l y . S i m i l a r l y , f a m i l i e s w i t h m u l t i p l e a f f e c t e d m e m b e r sa r e t h o u g h t t o h a v e g r e a t e r s u s c e p t ib i l it y t o t h e s e N T D s .T h e r e f o r e , f a m i l i e s w i t h m a l e p r o b a n d s o r m u l t i p l ea f f e c t e d m e m b e r s h a v e b e e n i n v e s t i g a t e d t o d e t e r m i n ew h e t h e r t h e s e f a m i l i e s h a v e a h i g h e r f e t a l m o r t a l i t y ra t e ,p r e s u m a b l y o f a f f e c t e d c hi l dr e n . T h e r a t e o f m i s c a r r ia g eh a s n o t b e e n f o u n d t o b e s i g n if i c a n tl y h ig h e r i n f a m i l i e sw i t h a m a l e p r o b a n d o r m u l t i p l e a f f e c t e d m e m b e r s . 39

    S e v e r a l a n i m a l m o d e l s t h a t a re s u s c e p ti b le t o N T Dm a l f o r m a t i o n s f u r t h e r s u g g e s t a n e t i o l o g i c r o l e f o rg e n e t i c s i n t h e o c c u r r e n c e o f t h is b i r t h d e f e c t . F i r s t,h o m o z y g o u s m i c e w i t h m u t a t i o n s i n th e L o o p - t a i l Lp)g e n e h a v e c r a n i o r a c h i s c h i s i s , i n w h i c h t h e n e u r a l t u b er e m a i n s o p e n f r o m t h e m i d b r a i n t o t h e t a i l. 4 S e c o n d l y ,c u r l y - ta i l m u t a n t m i c e a r e m o r e l i k e l y to d e v e l o p e x e n -c e p h a l y w i t h o r w i t h o u t l u m b o s a c r a l s p i n a b i f i d a . 31N e x t , t h e m o u s e m u t a n t s p l ot c h , w h i c h d e v e l o p s e x e n -c e p h a l y , m e n i n g o c e l e , a n d s p i n a b i f id a , h a s a m u t a t i o ni n t h e Pax3 g e n e . 41 F i n a l l y , a s t u d y b y H e l w i g e t a 1 42s h o w e d t h a t d i g e n i c i n h e r i t a n c e i s o n e p o s s i b l e m e c h -a n i s m t o e x p la i n t h e i n h e ri t a n c e o f N T D s . B y c r o s s in gt h e P a t c h a n d u n d u l a t e d m u t a n t m i c e , i t w a s d e m o n -s t ra t e d th a t m i c e , w h o w e r e h o m o z y g o u s f o r th e u n d u -l a te d m u t a t i o n a n d h e m i z y g o u s f o r t h e P a t c h m u t a t io n ,d e v e l o p e d s p i n a b i fi d a. N e i t h e r o f t h e s e m u t a n t m o u s es t ra i n s i n d e p e n d e n t l y h a v e a n i n h e r i t e d s u s c e p t i b i l i tyf o r d e v e l o p i n g t h i s t y p e o f N T D . 4 2

    S p e c i f i c c h r o m o s o m e a b n o r m a l i t i e s a n d g e n e t i c s y n -d r o m e s a r e a s s o c i a t e d w i t h N T D s , f u r th e r s u g g e s t i n g a ne t i o l o g i c r o l e f o r g e n e t i c s . S p i n a b i f i d a o c c u r s m o r eo f t e n t h a n e x p e c t e d i n b o t h t r i s o m y 1 3 a n d t r i s o m y 1 8 . 4 3A d d i t i o n a l l y , N T D s a r e a s s o c i a t e d w i t h m a n y g e n e t i cs y n d r o m e s , i n c l u d i n g a c r o c a l l o s a l s y n d r o m e , c e r e b r o -c o s t o m a n d i b u l a r s y n d r o m e , C H I L D s y n d r o m e , F r a s e rs y n d r o m e , J a r c h o - L e v i n s y n d r o m e , M e c k e l - G r u b e r s y n -d r o m e , a n d W a a r d e n b u r g s y n d r o m e t y p e s I a n d 1 I.43

    n v i r o n m e n t a l F a c t o r sI n a d d i t i o n t o g e n e t i c f a c t o r s , e n v i r o n m e n t a l i n f l u -

    e n c e s a r e a l s o i m p o r t a n t f o r u n d e r s t a n d i n g t h e e t i o l o -g y o f N T D s T a b le 1 ). I n th e e p i d e m i o l o g i c s t u d y o fN T D s , a b ro a d c o n c e p t o f t h e e n v i r o n m e n t h a s b e e nu t i l i z e d t o e m b r a c e a l l n o n g e n e t i c a s p e c t s o f e t i o l o g y ,i n c l u d i n g m a t e r n a l a g e , s o c i a l c l a s s , a n d m e t a b o l i cd i s e a s e . 44 P a r e n t a l a g e , o c c u p a t i o n , e d u c a t i o n , a n ds o c i o e c o n o m i c s ta t us h a v e b e e n e x p l o r e d a s p o t e n t ia lr i s k f a c t o r s . A d d i t i o n a l l y , p r e g n a n c y h i s t o r i e s , m a t e r -n a l h e a l t h , a n d m a t e r n a l n u t r i t i o n a l s t a t u s h a v e b e e ni n v e s t i g a t e d t o e x a m i n e t h e i r p o t e n t i a l r o l e s .

    T h e r o l e o f m a t e r n a l a n d p a t e r n a l a g e i n t h e e t i o l o -g y o f N T D s i s p o o r l y u n d e r s t o o d . M u l t i p l e s t u d ie sh a v e e x a m i n e d m a t e r n a l a n d / o r p a te r n a l a g e i n N T D s .S e v e r a l s t ud i e s h a v e s h o w n a n i n c r e a s e d r i s k w i t h a ni n c r e a s e d m a t e r n a l a g e . S t r a s s b u r g e t a129 n o t e d a g e n -e r a l p a t te r n o f i n c r e a s i n g r i s k w i t h i n c r e a s i n g m a t e r n a la g e f o r s p i n a b i f i d a in a s t u d y i n L o s A n g e l e s C o u n t y .I n c o n t r a s t , o t h e r s t u d i e s f o u n d n o r e l a t i o n s h i pb e t w e e n N T D s a n d m a t e r n a l a g e . 2 ,3 ,3 8,4 5 B e c a u s e o ft h e s e c o n f l i c t in g r e p o r ts , t h e i m p o r t a n c e o f m a t e r n a la g e i n ri s k f o r N T D o c c u r r e n c e i s u n c le a r . M a n y s t ud -i e s h a v e a l s o c o n s i d e r e d p a t e r n a l a g e , o n l y o n e o fw h i c h f o u n d a g e n e r a l p a t te r n o f i n c r e a s i n g r is k f o rN T D s a s s o c i a t e d w i t h a d v a n c i n g p a t e r n a l a g e . 46 T h em a j o r i t y o f s t u d i e s h a v e f a i l e d t o s h o w a r e l a t i o n s h i pb e t w e e n p a t e r n a l a g e a n d r i s k f o r N T D s. 29 30 32 35 47 48L o w s o c i o e c o n o m i c c la s s , as m e a s u r e d b y p a r e n ta lo c c u p a t i o n a n d e d u c a t i o n , h a s b e e n f o u n d t o b e a s s o -c i a t e d w i t h a n i n c r e a s e d r i s k f o r h a v i n g a n o f f s p r in gw i t h a n N T D i n s o m e s t u d ie s . L o w m a t e r n a l e d u c a -t i o na l l e v e l w a s f o u n d t o b e a s s o c i a te d w i t h a n e n -c e p h a l y , b u t n o t s p i n a b i f i d a , i n a s t u d y o n r i s k f a c t o r si n t h e H i s p a n i c p o p u l a t i o n o f H a r r i s C o u n t y , T e x a s . 38A c a s e - c o n t ro l s t u d y i n L o s A n g e l e s r e v e a l e d n o a s s o -c i a t io n b e t w e e n s o c i o e c o n o m i c cl a ss , a s m e a s u r e d b yi n c o m e a n d p a r e n t a l e d u c a t io n , a n d r i sk f o r N T D -a f f e c t e d o f f s p r i n g . 29 A d d i t i o n a l ly , n o a s s o c i a t i o n w a sf o u n d b e t w e e n r i s k a n d s o c i o e c o n o m i c c l a s s in a n

    3 2 2 C u r r P r o bl P e d i a tr , N o v e m b e r / D e c e m b e r 2 0 0 0

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    7/16

    i n v e s t i g a ti o n i n C a m e ro n C o u n t y , T e x a s . 45 T h e m i x e dre s u l t s o f t h e a v a i l a b l e s t u d i e s m a k e i t d i f fi c u l t t o d r a wc o n c l u s i o n s a b o u t a r e l a t i o n s h i p b e t we e n s o c i o e c o -n o m i c s t a tu s a n d r i s k fo r NT D s .

    T h e i n f l u e n c e o f p a re n ta l o c c u p a t i o n o n t h e r i s k fo ro ffsp r ing wi th congen i ta l anomal ies o f the cen t ra l ner -vous sy s tem has bee n inves t iga ted , bu t no def in i t ive con-c l u s i o n s h a v e b e e n r e a c h e d . An i n c re a s e d r i s k a m o n gch i ld ren o f paren ts wi th occupat ions invo lv ing exposureto so lven ts , such as indus t r ia l workers o r pa in te rs , hasbee n reporte d. 3,44,49,50 He alth car e wor kers , prim ari lyf e m a l e n u r s e s , h a v e b e e n s h o wn t o h a v e a n i n c re a s e dr i sk fo r o f fsp r ing wi th NTDs 44 Agricu l tu ra l occupat ionsh a v e a l s o b e e n s h o wn t o b e a s s o c i a te d w i t h a n i n c re a s e dr i sk fo r th i s type o f b i r th defec t .44,5 Fina lly, a signifi-c a n t l y i n c re a s e d ri s k fo r NT Ds h a s b e e n s e e n a m o n g o f f -sp r ing o f bo th mothe rs and fa thers work in g in trans -por ta t ion -re la ted occupat ions . 5

    T wo l i n e s o f e v i d e n c e s u p p o r t t h e i m p o r t a n c e o f g l u -c o s e m e t a b o l i s m i n t h e f o r m a t i o n o f N T D s : o b e s ew o m e n a r e m o r e l i k e l y to h a v e o f f s p r in g w i t h N T D s(e s p e c i a l l y s p in a b i fi d a ) , a n d wo m e n wi t h d i a b e t e s a r em o re l i k e l y t o h a v e o f f s p r i n g w i t h NT Ds . S e v e ra lr e c e n t r e p o r t s h a v e p r o v i d e d e v i d e n c e t h a t m a t e r n a lo b e s i t y i s a r i s k f a c t o r fo r c o n g e n i t a l m a l fo rm a t i o n si n v o l v i n g t h e c e n t r a l n e rv o u s s y s t e m . T h e a s s o c i a t i o na p p e a r s t o b e i n d e p e n d e n t o f fo la t e i n t a k e ( s e e fo ll o w-i n g ) a n d i s n o t r e a d i l y e x p l a i n e d b y a n y k n o w n s o c i a l,d i e t a ry , o r m e d i c a l c o n fo u n d e r s , t h e r e fo re s u g g e s t i n gt h e i n c re a s e d r i s k m i g h t a r i s e f ro m a s p e c i f i c p a t h o -phys io log ic d i s tu rb anc e o f obes i ty . 51-53 A s tudy byW a l l e r e t a 15 1 d e m o n s t r a t e d t h a t , w h e n c o m p a re d t ow o m e n o f n o rm a l w e i g h t, w o m e n w h o w e r e o b e seb e f o r e p r e g n a n c y ( b o d y m a s s i n d e x > 2 9 k g / m )s h o w e d a s i g n i f i c a n t l y i n c re a s e d r i s k o f h a v i n g a ni n fa n t w i t h a n NT D (o d d s r a ti o [OR ] = 1 .8 ). T h e e f f e c twas par t i cu la r ly s t rong fo r sp ina b i f id a (O R = 2 .6 ) . 51A r e c e n t s t u d y b y S h a w e t a 15 3 c o n f i r m e d th e s e f i n d -i n g s . T h e s t u d y b y S h a w e t a l a l s o e x a m i n e d p o t e n -t i a l ly c o n fo u n d i n g f a c t o r s s u c h a s m a t e rn a l n o n -u s e o fv i t a m i n s c o n t a i n i n g fo l i c a c i d , u s e o f d i e t p i ll s , l o we rd i e t a ry fo la t e in t a k e , d i a b e te s , a n d a n NT D -p re g n a n c yh i s to ry . I t wa s d e t e r m i n e d t h a t n o n e o f t h e s e f a c t o r sa c c o u n t e d fo r t h e f i n d i n g s. 53

    M a t e rn a l d i a b e t e s is k n o w n t o b e a s s o c i a t e d w i t h a ni n c re a s e d r i s k fo r o f f s p r i n g w i t h NT Ds . T h e r i s k h a sb e e n e s t i m a t e d t o r a n g e f ro m a s l o w a s 2 i n t h eUn i t e d S t a t e s t o a s h i g h a s 8 i n B i rm i n g h a m ,E n g l a n d . 54,55 In c re a s e d r i s k fo r b o t h a n e n c e p h a l y a n ds p i n a b i f i d a h a s b e e n n o t e d . 56 An e n c e p h a l y o c c u r s i n

    2 t o 5 o f o f f s p r i n g o f m o t h e r s w i t h p r e g e s t a t i o n a ld i a b e t e s (b o t h T y p e I a n d T y p e I I ) . Ad d i t i o n a l l y , t h er i s k i s i n c r e a s e d a m o n g b o t h w h i t e a n d A f r i c a nAm e r i c a n p o p u l a t i o n s i n t h e Un i t e d S t a te s . 54,57 T h ere c u r r e n c e r i sk fo r m o t h e r s w i t h d i a b e t e s i n t h e Un i t e dS t a t e s i s 4 , s i m i l a r to t h e r i s k fo r m o t h e r s w i t h o u td i a b e te s . 56 T h e e t i o l o g y u n d e r l y i n g t h e i n c re a s e d r i s kh a s y e t t o b e e l u c i d a t e d . M e t a b o l i c d e r a n g e m e n t s , p a r -t i c u l a r l y a l t e r e d g l u c o s e m e t a b o l i s m d u r i n g o rg a n o -g e n e s i s , a r e t h o u g h t t o b e t h e m e c h a n i s m ; fo r e x a m -p le , abe rran t g lyc osy la t ion in ra t s resu l t s in b i r thd e fe c t s s i m i l a r t o t h o s e s e e n i n c h i l d r e n b o rn t o m o t h -ers wi th d iabe tes .

    Nu t r i t i o n a l f a c t o r s h a v e b e e n a s s o c i a t e d w i t h NT Dfo rm a t i o n . R e s e a rc h d a t a s u g g e s t t h a t m a t e rn a l v i t a -m i n d e f i c i e n c i e s , e s p e c i a l l y o f fo l a t e , p l a y a ro l e i n t h ep a t h o g e n e s i s o f NT Ds . In f a c t , s e v e ra l s t u d i e s h a v ed e m o n s t r a t e d t h a t f o l a t e s u p p l e m e n t a t i o n b o t h b e fo rea n d d u r i ng e a rl y p r e g n a n c y m a y p r e v e n t u p to 7 0 o fa l l NT Ds . 58-61 Fo la te ac t s bo th as a co fa c to r fo r e n -z y m e s i n v o l v e d i n D N A a n d R N A s y n t he s i s a n d in t h es u p p l y o f m e t h y l g ro u p s t o t h e m e t h y l a t i o n c y c l e .T h u s , a fo l a t e d e f i c i e n c y c a n l e a d t o d e fe c t i v e c e l l p ro -l i f e r a t io n a n d c e l l d e a t h d u e t o t h e i n h i b i t io n o f DN As y n t h e s i s a n d c a n c a u s e a s h o r t a g e o f m e t h i o n i n e ,wh i c h w i l l p r e v e n t c e l l s f ro m m e t h y l a t i n g p ro t e i n s ,l ip ids , and myel in .58,62 In fac t , mi nor def ic ienc ie s o fa n y e s s e n t i a l n u t r i e n t m a y r e s u l t i n m a l fo rm a t i o n s o ft h e d e v e l o p i n g f e t u s . 58 De s p i t e t h e o b v i o u s r e l a t i o n -s h ip b e t w e e n m a t e rn a l f o l a t e s t at u s a n d o c c u r r e n c e o fNT D s , i t i s u n c l e a r h o w fo l a t e is i n v o l v e d i n t h e p a t h o -g e n e s is o f N T D s .

    Z i n c i s a n a d d i t i o n a l n u t r i e n t e s s e n t i a l f o r n o rm a lf e t a l g ro wt h a n d d e v e l o p m e n t b e c a u s e i t f a c il i ta t e sg e n e t r a n s c r i p t i o n a n d i s n e c e s s a ry fo r c e l l d i v i s i o n ,d e v e l o p m e n t , a n d d i f f e r e n t i a t i o n .63,64 Ina deq uate z inci n t a k e h a s b e e n a s s o c i a t e d w i t h NT D s i n b o t h a n i m a l sa n d h u m a n s . I n la b o ra t o ry a n i m a l s , s e v e re l y r e d u c e dz i n c i n t a k e fo r 1 t o 2 d a y s e a r l y i n g e s t a t i o n wa s a s s o -c i a t e d w i t h t h e d e v e l o p m e n t o f NT Ds . 65 In h u m a n s ,w o m e n w i t h a n e x t r e m e l y r a re g e n e t i c d i s o r d e r o f zi n cm e t a b o l i s m - - a c r o d e r m i t i t i s e n t e r o p a t h i c a - - a r e a th i g h r i s k fo r b e a r i n g c h i l d r e n w i t h N T Ds . 66 In a r e c e n ts t u d y b y Ve l i e e t a l6 7 i n c re a s e d t o t a l p r e c o n c e p t i o n a lz i n c i n t a k e , a s we l l a s i n c re a s e d s e rv i n g s o f a n i m a lp ro d u c t s ( t h e m o s t b i o a v a i l a b l e fo o d s o u rc e o f z i n c ) ,w a s a s s o c ia t e d w i t h a r e d u c e d r i s k f o r N T D s . T h e i ra n a l y s e s i n d i c a t e t h a t r i s k o f NT D s i n f e t u s e s d e c re a s -e s w i t h i n c r e a s e d m a t e r n a l p r e c o n c e p t i o n a l z i n ci n t a k e ; h o we v e r , i t r e m a i n s u n c l e a r wh e t h e r i n c re a s e d

    C u rr P r ob l P e di at r N o v e m b e r / D e c e m b e r 2 0 0 0 3 2 3

  • 8/12/2019 Curr Prob Ped Northrup 2000

    8/16

    TABLE 2 . A l l e l e f re q u e n c i e s o f th e M T H F R C 6 7 7 T m u t a t i o n a m o n g N T D p a t i e n t s a n d c o n t r o l s i n d i f f e r e n t e t h n i c p o p u l a t i o n sExamined 77T a l le le S ignificantPopulation persons f r e q u e n c y f T ) a s s o c i a t i o n

    Dut c h 82 S B pa t i en t s 0 . 3 65 Y esM o t h e r s 0 . 3 5 1 Y e sC o n t r o l s 0 . 2 5 7

    B r it is h 83 NT D pa t i en t s 0 . 3 05 NoC o n t r o l s 0 . 3 5 5

    U S A m e r i ca n s6 N T D p a t i e n ts 0 . 4 0 5 N oC o n t r o l s 0 . 2 1 5

    French8 7 S B p a t i e n t s 0 . 3 2 5 N oC o n t r o l s 0 . 3 6 1

    G e r m a n84 S B pa t i en t s 0 . 3 60 NoC o n t r o l s 0 . 3 1 0

    I ta l ian 88 S B pa t i en t s 0 . 4 75 Y esC o n t r o l s 0 , 4 3 5

    H is pan i c 89 S B pa t i en t s 0 . 5 05 NoC o n t r o l s 0 . 4 2 0

    T ur ki sh 9 NT D pa t i en t s 0 . 30 5 NoM o t h e r s 0 . 3 9 0 N oC o n t r o l s 0 . 2 8 7

    C a n a d i a n91 NT D pa t i en t s 0 . 4 30 NoM o t h e r s 0 . 3 9 6 N oC o n t r o l s 0 . 3 3 8

    Irish85 NT D pa t i en t s 0 . 40 6 Y esM o t h e r s 0 , 3 8 6 Y e sC o n t r o l s 0 . 3 0 5

    H is pan i c 86 Lev e l 1 S B pa t i en t s 0 . 52 7 NoM o t h e r s 0 . 5 9 2 Y e sC o n t r o l s 0 . 4 7 3

    SB Spina bif ida.

    z i n c i n t a k e o r a n o t h e r n u t r i e n t o r c o m b i n a t i o n o f n u tr i -e n t s c o r r e l a t e d w i t h d i e t a ry z i n c i n t a k e i s c a u s a l l ya s s o c i a t e d w i t h r e d u c e d N TD r i sk . 67M a t e rn a l i l ln e s s e s a n d h y p e r t h e rm i a h a v e b e e n a s s o -c i a t e d w i t h a n i n c r e a s e d r i s k o f N TD s . I n 1 9 92 ,M i l u n s k y e t a 1 68 i n v e s t i g a t e d t h e e f f e c t o f m a t e rn a lh y p e r t h e r m i a o n N T D r i s k a n d f o u n d t h a t e x p o s u r e toa sauna , fever , e lec t r i c b lanke t , o r ho t tub in ear lyp r e g n a n c y i n c r e a s e d t h e r i s k o f N T D - a f f e c t e d o f f -s p r i n g . I n a r e t ro s p e c t i v e , i n t e rv i e w , c a s e - c o n t ro ls tudy , Sand fo rd e t a169 fou nd tha t a s ign i f i can t ly h igh -e r n u m b e r o f w o m e n r e p o r t e d t a k in g h o t b a th s d u r i n gt h e c r i t i c a l p e r i o d o f n e u ra l t u b e fo rm a t i o n . F i n a l l y , ar e p o r t f r o m t h e m e t r o p o l i t a n A t l a n t a a r e a f o u n d a ni n c r e a s e d r i s k f o r N T D t o b e a s s o c ia t e d w i t h m a t e r n a lr e p o r t s o f h a v i n g f l u w i t h f e v e r o v e r p e r i o d s r a n g i n gf r o m 1 m o n t h b e f o r e c o n c e p t i o n to 2 m o n t h s a f t e rconc ep t ion . 7

    A n t i c o n v u l s a n t u s e h a s b e e n fo u n d t o b e a s s o c i a te dw i t h a n i n c r e a s e d r i s k fo r m a l fo rm e d o f f s pr i n g.71 Them a l fo rm a t i o n s d o c u m e n t e d i n t h e c h i l d r e n o f m o t h e r sw i t h e p i l e p s y d o n o t g e n e ra l l y i n c lu d e N TD s ; h o w e v e r ,m a t e rn a l v a l p ro ic a c i d u s e d u r i n g e a r l y p r e g n a n c y h a sb e e n d e m o n s t r a t e d t o i n c r e a s e a w o m a n ' s r i s k o f h a v i n g

    a ch i ld w ith spina bifida. 71-73 Valp roic ac id , o r so diu mvalp roa te , was the on ly an t iconvu lsan t as soc ia ted wi than increa sed r i sk fo r o f fsp r ing wi th sp ina b i f ida repor t -ed in on e in te rna t iona l s tudy .26 Add i t iona l ly , the as soc i -a t i o n b e t w e e n v a l p ro i c a c i d a n d s p i n a b i f id a h a s b e e nconf i rm ed in separa te s tud ies in Spa in , France , I t a ly ,a n d W e s t e rn A u s t r a l i a . 74 -77 Th e m a j o r i t y o f t h e s er e p o r ts a r e o f s p i n a b i fi d a i n v o lv i n g t h e l o w e r l u m b a r o rsacra l reg ions o f the sp ine .

    Research for Disease C ausing Gen eso l a te M e t a b o l i s mT h e m o s t r e c e n t d e v e l o p m e n t i n u n c o v e r i n g t h e

    m o l e c u l a r b a s is o f N TD s i s t h e d i s c o v e ry o f a g e n e t i cl i nk t o t h e m o s t w e l l - k n o w n e n v i r o n m e n t a l c a u s e o fN T D f o r m a t io n , f o l a te d e f i c i e n c y i n p r e g n a n t w o m e n ,I t w a s d e f i n i t i v e l y p ro v e n a l m o s t 1 0 y e a r s a g o t h a tp e r i c o n c e p t i o n a l f o l i c a c i d s u p p l e m e n t a t i o n d e c re a s e st h e r e c u r r e n c e o f N T D s , a s w e l l a s t h e f i rs t o c c u r r e n c eo f N TD s . 78,79 Th e s t u d y b y t h e M e d i c a l R e s e a rc hC o u n c i l V i t a m i n S t u d y R e s e a rc h G ro u p 78 a s s i g n e d1 81 7 w o m e n a t h i g h r i s k o f h a v in g a p r e g n a n c y w i t h

    3 2 4 C u r r P r o bl P e d i a tr , N o v e m b e r / D e c e m b e r 2 0 0 0

  • 8/12/2019 Curr Prob Ped Northrup 2000

    9/16

    T B L E 3 . M o u s e m o d e l s o f n e u r a l t u b e d e fe c t s , t h e i r sy n t e n ic c h r o m o s o m a l l o c a t io n i n h u m a n s, a n d t h e g e n e s i n v o lv e d ( w h e n k n o w n )H u m a n c h r o m o s o m eM o u s e m o d e l M o u s e m o d e l p h e n o ty p e l o c a t i o n Ge n e

    V a cu o la t e d l e ns Op a q u e w h i t e l e nse s ; w h i t e b e ll y sp o t ; 1 q 2 1 -q 2 2 - -ca u d a l sp i n a b i f id a

    Cur l y ta i l Exencepha ly; mye losch is is ; k inked ta i l l p 36 .3 - -Sp lo tch Mye lomeningoce le ; exencepha ly 2q 36 PAX3Undula ted Ver tebra l co lumn abno rma l i t ies 20p 11 .2 PAXPatch Wh i te fu r pa tches; me sode rmal de f ic iency 4q1 1-q1 2 PDGFRARach i te ra ta Smal l body s i ze ; sho r t k inked ta i l ; 2q23 -q31 - -

    t h o ra c~ l u m b a r m a l f o rm a t io n s ; a b n o rm a l a x i sT ru n cat e S h o r t / a b se n t t a i l ; m i ss in g sa c ra l / 2 p 1 3 -p 1 2 - -

    l umba r ver teb rae; degenera t ion o f no tochordT(Brachyury) Poster io r mes ederm al de fec ts; 6q2 7 T

    sh o r t / a b s e n t t a i l ; g u t a n d n e u ra l t u b e f u s io n sLOOl~Tail Cran io rach isch is is 1q21 -q23 - -Dan for th s Sh or t Ta i l Sho r t k inked ta i l ; d i scont inuous no tochord ; lO p - -

    k idney de fects

    a n N T D ( d u e to t h e i r h a v i n g a p r e vi o u s N T D - a f f e c t e dp re g n a n c y ) t o 1 o f 4 g ro u p s : f o l i c a c i d , o t h e r v i t a m i n s ,b o t h fo l i c a c i d a n d o t h e r v i t a m i n s , o r n e i t h e r fo l i c a c i dn o r o t h e r v i t a m i n s . Af t e r 1 1 9 5 o f t h e s e h i g h - r i s kw o m e n h a d a c o m p l e t e d p r e g n a n c y w i th a k n o w n o u t -c o m e , i t w a s f o u n d t h a t 2 7 h a d a n N T D - a f f e c t e d p r e g-n a n c y ; 6 o c c u r r i n g i n t h e fo l i c a c i d g ro u p s a n d 2 1 i nt h e 2 g ro u p s n o t i n c l u d i n g fo l i c a c i d . T h e re fo re , f o l i ca c i d g a v e a 7 2 p ro t e c t i v e e f f e c t .78 A subse quen ts t u d y b y C z e i z e l a n d D u d a s 79 wa s d e s i g n e d t o d e t e r -m i n e w h e t h e r f o l ic a c i d s u p p l e m e n t a t i o n c o u l d r e d u c et h e r i sk o f f i r st o c c u r r e n c e o f N T D s . A r a n d o m i z e d ,c o n t ro l l e d t r ia l o f p e r i c o n c e p t i o n a l m u l t i v i t a m i n s u p -p l e m e n t a t i o n wa s e s t a b l i s h e d a n d t h e r e s u l t s i n c l u d e d2 1 0 4 w o m e n w h o r e c e i v e d v it a m i n s u p p l e m e n t a ti o na n d 2 0 5 2 w o m e n w h o r e c e i v e d tr a c e e l e m e n t s u p pl e -m e n t a t io n . T h o s e w o m e n w h o r e c e i v e d t r ac e e l e m e n ts u p p l e m e n t a t io n h a d 6 c a s e s o f N T D s a s o p p o s e d t on o c a s e s o f N T D s i n t h e v i t a m i n s u p p l e m e n t a t io ng ro u p , w i t h t h e d i f f e r e n c e b e i n g s t a t is t i c a ll y s i g n i f i-c a n t . 79 T h e e f f i c a c y o f fo l a t e i n p r e v e n t i o n o f NT Ds i sn o w s o w i d e l y a c c e p t e d t h e d e c i s i o n h a s b e e n m a d eb y t h e F D A t o s u p p l e m e n t f o o d s i n t h e U n i t e d S t a te swi th fo la te .

    T h e e x a c t m e c h a n i s m f o r t h e a c t i on o f f o l a t e i n p r e -v e n t i o n o f N T D s h a s b e e n a p r e d o m i n a n t f o c u s ; h o w -ever , i t i s s t i l l unc lear how fo la te i s invo lved in thep a t h o g e n e s i s o f NT D s . I t i s k n o w n t h a t e l e v a t e d le v e l so f t h e a m i n o a c i d h o m o c y s t e i n e in p r e g n a n t w o m e ni n c r e a se s r is k f o r N T D s , a n d b e c a u s e t h e m e t a b o l i s mo f h o m o c y s t e i n e a n d f o l a te a r e i n t e r d e p e n d e n t, i t h a sb e e n p o s t u l a t e d t h a t t h e s e r i s k f a c t o r s a r e c o n n e c t -ed . 8'81 In 1995 , v an t i e r Pu t e t a182 repo r ted a th erm o-l a bi le m u t a t io n i n t h e e n z y m e 5 , 1 0 - m e t h y l e n e t e t r a h y -

    d ro fo l a t e r e d u c t a s e (M T H F R ) , wh i c h r e s u lt s i n a 5 0r e d u c t i o n in e n z y m e a c ti v it y . M T H F R i s i m p o r ta n tb e c a u s e i t c o n v e r t s 5 , 1 0 -m e t h y l e n e t e t r a h y d ro fo l a t e t o5 -m e t h y l t e t r a h y d ro fo l a t e , wh i c h , a l o n g w i t h v i t a m i nB 1 2, a ct s a s a c o fa c t o r w i t h m e t h i o n i n e s y n t h a s e i n t h ec o n v e r s io n o f h o m o c y s t e i n e to m e t h i o n in e . T h e m u t a -t i o n i n M T H F R (C 6 7 7 T , s u b s t i t u ti o n o f v a l i n e fo r a la -n i n e a t n u c l e o t i d e p o s i t i o n 6 7 7 ) i s a s s o c i a t e d w i t hd e c re a s e d e n z y m e a c t i v i t y , l o w p l a s m a fo l a t e , a n dh i g h p l a s m a h o m o c y s t e i n e . Va n d e r P u t e t a 182 s t u d i e dt h e f r e q u e n c y o f t he C 6 7 7 T M T H F R m u t a t i o n in aDu t c h p o p u l a t i o n o f s p i n a b i f i d a -a f f e c t e d i n d i v i d u a ls ,a s we l l a s p a re n t s o f s p i n a b i f i d a -a f f e c t e d i n d i v id u a l s ,a n d c o m p a r e d t h e m to a c o n t r o l g r o u p. O n l y 5 o fc o n t ro l p a t i e n t s we re h o m o z y g o u s fo r t h e m u t a t i o n ,wh e re a s 1 6 o f m o t h e r s , 1 0 o f f a t h e r s , a n d 1 3p a t i e n t s w e r e h o m o z y g o u s f o r t h e M T H F R m u t a -t i on . s 2 A fo l l o w-u p s t u d y t e s t e d g e n o t y p e s o f 4 1f i b ro b la s t c u l tu r e s f ro m NT D-a f f e c t e d f e t u s e s a n dc o m p a re d t h e m wi t h g e n o t y p e s o f 1 0 9 i n d i v i d u a l s i nt h e g e n e r a l p o p u la t io n ; h o m o z y g o s i t y f o r t h e m u t a t i o nwa s a s s o c i a t e d w i t h a 7 . 2 - fo l d i n c re a s e d r is k o fNT Ds . 60

    Ov e r t h e l a s t s e v e ra l y e a r s , d a t a f ro m s e v e ra l s t u d ie so n d i f f e r e n t e t h n i c g ro u p s h a v e r e s u l t e d i n d i f f e r e n tc o n c l u si o n s a b o u t t h e r o le o f t h e C 6 7 7 T m u t a t i o n o ft h e M T H F R g e n e a s a r is k f a c t o r fo r NT D s (T a b l e 2 ) .F o r e x a m p l e , t h e C 6 7 7 T M T H F R v a r i a n t h a s b e e ns h o w n t o b e a r i s k f a c t o r fo r NT D s i n I r i s h a n d Du t c hp o p u l a t i o n s , b u t n o c o r r e s p o n d i n g a s s o c i a t i o n h a sbee n d e tec ted in B r i t i sh o r Ge rm an po pu la t ions . 82-85E p i d e m i o l o g i c s t u d ie s o f N T D s i n t h e U n i t e d S t a t e sh a v e d e m o n s t r a t e d t h a t H i s p a n i c s e x p e r i e n c e a p r e v a -l e n c e o f s p i n a b i f i d a t h a t i s 2 . 5 t i m e s o r g r e a t e r t h a n

    C u r r P r o b l P e d i a tr , N o v e m b e r / D e c e m b e r 2 0 0 0 3 2 5

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    r e p o r t e d i n 1 7 U S f a t u it i es a n d 1 4 D u t c h f a m i l i e s a n d n ol i n k a g e w a s d e t e c t e d . 1 9

    M i c e h o m o z y g o u s f o r th e u n d u l a t e d m u t a t i o n d is p l a ya b n o r m a l i t i e s a l o n g t h e v e r t e b r a l c o l u m n b u t d o n o th a v e s p i n a b i f i d a a s p a r t o f t h e i r p h e n o t y p e . U n d u l a t e dm i c e h a v e a p o i n t m u t a t i o n i n t h e Pax l g e n e .H e t e r o z y g o u s p a t c h m i c e a r e c h a r a c te r iz e d b y p a t c h e so f w h i t e f ur , a n d h o m o z y g o u s m i c e d i e d u r i n g m i d g e s -t a t io n a s a r e s u l t o f g e n e r a l m e s o d e r r n a l d e f i c i e n c y . T h ep a t c h p h e n o t y p e is s e c o n d a r y t o a 4 0 0 k b d e l e t i o n t h a ti n c l u d e s PDGFRA a n d s o m e a d d i t i o n a l l o c i . A l t h o u g hn e i t h e r u n d u l a te d n o r p a t c h m u t a n t m i c e a l o n e e x h i b its p i n a b i f i d a , d o u b l e - m u t a n t m i c e w i t h b o t h c o p i e s o fPaxl m u t a t e d a n d o n l y o n e c o p y o f PDGFRA p r e s e n ta l l s h o w s p i n a b i f id a a s t h e i r p h e n o t y p e . 42

    T h e h o m o z y g o u s r a c h i te r a t a ( rh ) m u t a n t m o u s e i ss m a l l i n s i z e , h a s a s h o r t t a il w i t h d i s t a l k i n k s , a n d h a sa m i s s i n g o r a b n o r m a l a x i s , f u s e d fi b s, a n d m a l f o r m a -t i o n s o f t h e t h o r a c o - l u m b a r r e g i o n . 1 1 I n a d d i t i o n ,t h e s e m i c e h a v e 6 c e r v i c a l v e r t e b r a e i n s t e a d o f th en o r m a l 7 . T h e m a l f o r m a t i o n s o f t h e t h o r a c o - l u m b a rr e g i o n r e f l e c t a p r i m a r y d i s t u r b a n c e f i r s t d e t e c t a b l e a t1 1 d a y s o f g e s t a t i o n , d u e t o a n a l t e r e d a r r a n g e m e n t o fs o m it e s. 1 11 T h e r h g e n e h a s b e e n l o c a l i z e d t o a r e g i o no f m o u s e c h r o m o s o m e 2 b e t w e e n t he Gcg a n d Hoxdg e n e s . T h i s r e g i o n o f m o u s e c h r o m o s o m e 2 is s y n t e n i ct o h u m a n 2 q 2 3 - q 3 1 .

    M i c e h o m o z y g o u s f o r t h e r e c e s s i v e t r u n c a t e tc)g e n e h a v e s h o r t o r a b s e n t t ai ls , a n d m a n y m u t a n t m i c eh a v e m i s s i n g s a c ra l o r l u m b a r v e r t e b ra e . T h e p r i m a r ye f f e c t in t r u n c a t e m i c e i s d e g e n e r a t i o n o f t h e n o t o -c h o r d a t 9 . 5 t o 1 0 d a y s o f g e s t a t i o n , l e a d i n g t o i n t e r -r u p t i o n o f t h e s p i n e , p a r a l y s i s o f t h e h i n d l e g s , a n da b s e n c e o f t h e m e d i a n v e n t r a l f i ss u r e o f t h e s p i n a lc o r d . 1 12 T h e tc g e n e is lo c a t e d o n m o u s e c h r o m o s o m e6 i n a r e g i o n s y n t e n i c t o h u m a n 2 p 1 3 - p 1 2 .

    T h e T m u t a n t Brachyury w a s o n e o f t h e e a r l ie s t d e v e l -o p m e n t a l l o c i t o b e c h a r a c t e r i z e d i n t h e m o u s e . B e c a u s eo f f in d i n g s in b o t h h o m o z y g o u s a n d h e t e r o z y g o u s m i c ew i t h t h e m u t a t i o n , i n v e s t i g a t o r s h a v e l o n g c o n s i d e r e dt h e l o c u s a s p o t e n t i a l l y i m p o r t a n t i n h u m a n s f o r d e v e l -o p m e n t o f N T D s . H o m o z y g o u s m i c e d i e i n m i d g e s t a -t i o n a n d d i s p l a y s e v e r e d e f e c t s i n p o s t e r io r m e s o d e r m a lt is s ue s . H e t e r o z y g o u s m i c e w i t h o n e r e m a i n i n g f u n c -t i o n a l T g e n e a r e v i a b le , b u t h a v e s h o r t e n e d o r n o n e x i s -t e n t ta i ls , f u s i o n s b e t w e e n t h e g u t a n d n e u r a l t u b e ,l o c a l i z e d d u p l i c a t i o n s o f o n e o r b o t h s t r u c t u r e s , a n do c c a s i o n a l m a l f o r m a t i o n s o f t h e s a c r a l v e r t e b r a e . 113H u m a n T h a s b e e n c l o n e d a n d m a p s t o 6q 2 7 . T h e in v e s-t ig a to r s w h o c l o n e d T s t u d i e d a p o l y m o r p h i s m t h e y

    d e t e c t e d i n i n t r o n 7 f o r a g e n e t i c a s s o c i a t i o n s t u d y i ns p i n a b i f i d a - a f f e c t e d f a m i l i e s . E v i d e n c e f o r a s i g n i f i -c a n t ( P = . 0 2) a s s o c i a t i o n b e t w e e n o n e o f t h e a l l e le s( T I V S 7 - 2 ) a n d s p i n a b i f i d a w a s d e t ec t e d. a 1

    H o m o z y g o u s m i c e f o r t h e L o o p - ta i l Lp) g e n e h a v ec r a n i o r a c h i s c h i s i s , i n w h i c h t h e n e u r a l t u b e r e m a i n so p e n f r o m t h e m i d b r a i n t o t h e t ai l. 4 M a p p i n g s t u d ie si n t h e m o u s e i n i t i a l l y p l a c e d t h e Lp g e n e o n d i s t a lm o u s e c h r o m o s o m e 1 , a n d re c e n t s t u d ie s u s i n g n e w e rr e c o m b i n a n t D N A t e c h n o l o g y h a v e b e e n a b l e t o f u r-t h e r l o c a l i z e t h e Lp g e n e t o t h e r e g i o n o f m o u s e c h r o -m o s o m e 1 sy n t en i c to h u m a n l q 2 1 -q 2 3 .

    D a n f o r t h s s h o r t t a il Sd) i s a s e m i d o m i n a n t m u t a -t i o n o f t h e m o u s e t h a t a ff e c ts d e v e l o p m e n t o f t h e v e r -t e b r a l c o l u m n a n d t h e u r o g e n i t a l s y s t e m . H e t e r o z y -g o u s m i c e h a v e s h o r t e n e d ta i ls a n d k i d n e y d e f e c ts .H o m o z y g o u s m i c e d i e a t o r s h o r t l y a f t e r b i r t h , a r ec o m p l e t e l y t a i ll e s s , a n d a r e o f t e n m i s s i n g s a c r a l a n dl u m b a r v e r t e b r a e . 114 B o t h h e t e r o z y g o u s a n d h o m o z y -g o u s Sd m u t a n t m i c e l a c k a f l o o r p l a t e i n t h el u m b o s a c r a l r e g i o n o f th e s p i n a l c o r d a n d s h o wd e g e n e r a t i v e c h a n g e s a l o n g t h e e n t i r e l e n g t h o f t h en o t o c h o r d . 115 A l t e r a t i o n s i n t h e n o t o c h o r d o f Sdh o m o z y g o t e s f ir s t a p p e a r b e t w e e n d a y s 9 . 5 a n d 1 0 . 5o f g e s t a ti o n , d u r i n g w h i c h t i m e t h e n o t o c h o r d u n d e r -g o e s a d e g e n e r a t i v e c h a n g e i n t h e c e r v i c a l a n d t h o -r a c ic r e g i o n , a n d f o r m a t i o n o f t h e n o t o c h o r d i s n e v e ra c h i e v e d i n t h e p r o s p e c t i v e l u m b o s a c r o c a u d a lr e g i on . 114 T h e p r o x i m a l p o r t i o n o f t h e c h r o m o s o m a lr e g i o n c o n t a i n i n g Sd s h o w s h o m o l o g y w i th h u m a nc h r o m o s o m e 1 0 p . 116

    dvances in Prenatal SurgeryD e s p i t e a d v a n c e m e n t a n d i m p r o v e m e n t o f o ve r a ll

    p a t i e n t c a r e, l i tt le p r o g r e s s h a s b e e n m a d e i n t h e p o s t -n a t a l s u r g i c a l m a n a g e m e n t o f c h i l d r e n w i t h s p i n a b i f i -d a . T h e g o a l o f f e t a l s u r g i c a l i n t e r v e n t i o n i n t h e t r e a t -m e n t o f m e n i n g o m y e l o c e l e is t o c o r r e c t t h e s t r u c tu r a ld e f e c t a t a t i m e w h e n s i g n i f i c a n t n e u r o n a l d a m a g e h a se i t h e r n o t y e t o c c u r r e d o r s t i l l h a s t h e p o t e n t i a l t o b er e v e r s e d . 17 O l u t o y e a n d A d z i c k 17 e x p l a i n t h a t t h e n e u ,r a l d a m a g e t o t h e e x p o s e d s p i n a l c o rd i n m e n i n g o m y -e l o c e l e s e c o n d a r i l y r e s u l t s f r o m f a i lu r e o f m e s o d e r m a lm i g r a t i o n , w h i c h c a n p o t e n t i a l l y b e p r e v e n t e d i f a na d e q u a t e p r e n a t a l c o v e r i n g c a n b e p r o v i d e d b e f o r e t h eo n s e t o f i rr e v e r s ib l e n e u r a l d a m a g e . O t h e r t y p e s o f s e c -o n d a r y , o r l a t e , n e u r a l d a m a g e i n c l u d e t r a u m a t o t h ee x p o s e d s p i n a l c o r d d u r i n g p a s s a g e t h r o u g h t h e b i r t hc a n a l , d i r e c t a b r a s io n o f t h e e x p o s e d s p i n a l c o r d a g a i n s t

    Cur r P robl Ped ia t r Novem ber /Decemb er 2000 327

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    the u te r ine wa l l a s we l l a s exposu re to subs tances in thea mn io t i c f l u id w h ic h ma y p r o d u c e c h e mic a l i n ju r yw h e n i n c o n t a c t w i th t h e u n p r o t e c t e d n eu r a l t is s u e s o fthe meningomyelocele .117-120 Th erefore cov erag e ofthe exp osed sp ina l cord in u te ro c ould theore t ica l ly pre -v e n t t h e s e f o r ms o f s e c o n d a r y i n ju r y o r p o t e n t i a l l yreve r se any d am age tha t has poss ib ly occur red . 17

    A c c o r d in g t o O lu to y e a n d A d z i c k ~7 f o r i n u t e r oin t e r v e n t i o n to h a v e t h e b e s t p o s s ib l e o u t c o m e re p a i rs h o u ld b e p e r f o r me d b e f o r e t h e o c c u r r e n c e o f i r r e -v e r s ib l e d a ma g e . A d d i t i o n a ll y i f i n t e r v e n t i o n o c c u r sb e f o r e t h e o n s e t o f my e l i n i z a t i o n t h e d a ma g e d s p in a lc o r d ma y r e t a in t h e a b i l i t y t o u n d e r g o r e g e n e r a t i v erepa i r a s we l l a s be p ro tec te d f rom fur the r in jury . 17P r e l im i n a r y r e su l ts w i t h h u m a n f e t al m e n i n g o m y e l o -c e l e r e p a i r s u g g e s t t h a t r e s o lu t i o n o f h y d r o c e p h a lu sa n d A r n o l d -C h i a r i ty p e I I m a l fo r m a t i o n t w o a n o m -a l ie s c o m m o n ly a s s o c i a t e d w i th s p in a b i f id a m a y b ea n u n e x p e c t e d b e n e f i t o f i n u t e ro r e p ai r e s p e c i a l l yw hen a lo ng ges ta t ion pe r io d fo l low s the r epa i r. 121O l u t o y e a n d A d z i c k 17 s u g g e s t i n u t e r o m e n i n g o m y -e lo c e l e re p a i r b e p e r f o r m e d o n f e tu s e s b e f o r e t h e e n do f t h e 2 4 th w e e k o f g e s t a ti o n t h u s t a k in g a d v a n t a g e o ft h e h e a l i n g p r o p e r t i e s o f y o u n g e r f e tu s e s p o t e n t i a l l yp r e s e r v in g t h e r e g e n e r a t iv e p o t e n t i a l o f u n m y e l in a t e ds p in a l c o r d e l imin a t i n g t h i rd t r ime s t e r d a ma g e t o t h es p in a l c o rd a n d i n t e r v e n in g e a r ly i n t h e c o u r s e o f p r o -g r e s s iv e h y d r o c e p h a ly a n d A r n o ld - C h ia r i ma l f o r ma -t i o n o f t e n s e e n i n f e tu s e s w i th me n in g o m y e lo c e l e .F e t a l s u r g e ry f o r me n in g o m y e lo c e l e i s p e r f o r me da f t er a d m in i s t e r in g ma te r n a l g e n e r a l a n d e p id u r a l a n e s -thes ia prov id ing adequa te fe ta l anes thes ia and u te r inere laxa t ion for the f e ta l surge ry . A low t r ansv e r se ma te r -n a l l a p a r o to my i s ma d e t o e x p o s e t h e u t e r u s a n dth e b a c k o f t h e f e tu s i s t h e n p o s i t i o n e d t o e x p o s e t h em e n i n g o m y e l o c e l e w h i l e k e e p i n g t h e f et u s w i t h i nt h e u t er u s. T h e c y s ti c m e m b r a n e o f t h e m e n i n g o m y e -loce le is ca re fu l ly exc ised the a t tachm ents of theme n in g e s a r e d e t a c h e d a n d t h e s p in al co r d is a l l o w e d

    o f a l l back in to the ve r tebra l cana l . Because of thec o n c e r n f o r t e t h e r i n g o f t h e s p in a l c o r d t o t h e o v e r ly in gskin c losure an ace l lu la r de rm a l gra f t i s p laced be -tw e e n t h e s p in a l c o r d a n d t h e s k in a n d t h e b i la t e ra ls k in f l a p s a r e s u b s e q u e n t l y e l e v a te d a n d c lo s e d o v e rthe patc h. ~7

    P o s to p e r a t i v e f o l l o w - u p i n c lu d e s a n u l t r a s o n o g r a p h ytwice a wee k in orde r to a ssess f e ta l we l l -be ing a s we l la s a f e t al ma g n e t i c r e so n a n c e im a g in g p e r f o r m e d e v e r y3 week s to fur the r eva lua te bra in and sp ina l cord deve l -o p m e n t . P r e g n a n c y i s c o n t i n u e d u n ti l 3 6 w e e k s o f g e s -

    ta t ion a t which t im e an e lec t ive cesa rean sec t ion i splan ned . 17Oluto ye and A dz ick 17 repor t tha t the i r g roup was the

    f i rs t t o d o c u m e n t imp r o v e d n e u r o lo g i c o u t c o m e a f te r i nu t e r o f e t al m e n in g o my e lo c e l e r e pa i r. T h e y p e r f o r me da n o p e n f e t al s u r g ic a l re p a i r o f a l a r g e me n in g o m y e lo -ce le in a 23-week -ges ta t ion fe tus tha t was sub sequent lyde l ive red by cesa rean sec t ion a f te r the ons e t o f pre te rmlabor a t 30 weeks of ges ta t ion . Pos tna ta l ly they repor tt h a t th e r e w a s n o h y d r o c e p h a lu s a n d h in d b r a in h e rn i a -t i o n w a s n o l o n g e r p r e s e n t . T h e n e u r o lo g i c o u t c o mesugges ted the e f fec t iveness of in u te ro f e ta l menin-g o m y e lo c e l e re p a i r i n p r e v e n t i n g f u rt h e r d a ma g e t o t h eexpo sed neura l t i s sue and poss ib ly a l lowing re s tora t iono f f u n c t i o n o r r e g e n e r a t i o n b e c a u s e o f t h e p l a s t ic i ty o fthe fe ta l nervous system.17

    ummaryN T D s r e s u l t in g f r o m f a i l u re o f t h e n e u r al t u b e t o

    c lo s e d u r in g t h e f o u r th w e e k o f e mb r y o g e n e s i s a r e t h emo s t c o mmo n s e v e r e ly d i s a b l i n g b i r t h d e f e c t s i n t h eU n i t e d S t a t es w i th a f r e q u e n c y o f a p p r o x ima te ly 1 o fe v e r y 2 0 0 0 b i r t h s . N e u r a l t u b e m a l f o r ma t io n s i n v o lv -ing the sp ina l cord a nd ve r tebra l a rches a re r e fe r red toa s s p in a b i f id a w i th s e v e r e t y p e s o f s p in a b i f i d a in v o lv -in g p r o t r u s io n o f t h e s p in a l c o r d a n d /o r me n in g e sth r o u g h a d e f e c t in t h e v e r t e b r a l a rc h . D e p e n d in g o nth e l e v e l o f t h e l e si o n i n t e r r u p t i o n o f t h e s p in a l c o r d a tt h e s i t e o f t h e s p in a b i f id a d e f e c t c a u s e s p a r a ly s is o f t h el e g s i n c o n t i n e n c e o f u r in e a n d f ec e s a n e s th e s i a o f t h es k in a n d a b n o r ma l i t ie s o f t h e h ip s k n e e s a n d fe e t .T w o a d d i t i o n a l a b n o r ma l i t i e s o f t e n s e e n i n c h i l d r e nw i t h s p i n a b i f i d a i n c l u d e h y d r o c e p h a l u s a n d t h eA r n o ld - C h ia r i t y p e I I ma l f o r ma t io n . D e s p i t e t h e p h y s -ica l and pa r t icu la r lea rn ing d isab i l i t ie s ch i ldren wi ths p in a b i fi d a mu s t c o p e w i th p a r t i c ip a t i o n i n i n d iv id u -a l i z ed e d u c a t i o n a l p r o g r a ms c a n a l l o w th e s e c h i l d r e nto d e v e lo p s k i l ls n e c e s s a r y f o r a u to n o my in a d u l t h o o d .

    A d v a n c e s i n r e s e a r c h t o u n c o v e r t h e mo le c u l a r b a s iso f N T D s i s e n h a n c e d b y k n o w l e d g e o f t h e li n k b e tw e e nb o th t h e e n v i r o n m e n ta l a n d g e n e t i c f a cto r s i n v o lv e d i nt h e e t i o lo g y o f N T D s . T h e m o s t r e c e n t d e v e l o p m e n t i nN T D r e s e a r c h f o r d i s e a s e - c a u s i n g g e n e s i s t h ed i s c o v e r y o f a g e n e t i c l i n k t o t h e mo s t w e l l - k n o w ne n v i r o n me n ta l c a u s e o f n e u r a l t u b e ma l f o r ma t io nf o l at e d e f i ci e n c y in p r e g n a n t w o me n . N e a r ly a d e c a d ea g o p e r i c o n c e p t i o n a l f o l ic a c id s u p p l e me n ta t i o n w a sp r o v e n t o d e c r e a se b o th t h e r e c u r r en c e a n d o c c u r r e n c eo f N T D s . T h e s t u d y o f f o la t e a n d i t s a s s o c i a ti o n w i th

    32 8 Cur r P rob l P ed ia t r Nove mb er /Dec em ber 200 0

  • 8/12/2019 Curr Prob Ped Northrup 2000

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    NT Ds i s an ongo ing endeavor tha t has led to num erouss tud ies o f d i f f erent genes invo lved in the fo la te metab-o l i sm pa thway , inc lud ing the most commonly s tud iedthermolab i le muta t ion (C677T ) in the MTH R gene .An addi t iona l focus for NT D research invo lves mousemodels that exhibit both naturally occurring NTDs, aswel l a s those crea ted by exper im enta l des ign . We ho pethe search for genes invo lved in the r i sk and/or deve l -opm ent o f NT Ds wi l l l ead to the deve lopm ent o f s t ra te-g ies for prevention and treatment .

    T he most recent ach ievement in t rea tment o f NT Dsi n v o l v e s t h e r e pa ir o f m e n i n g o m y e l o c e l e t h r o u g hadvancements in feta l surgery. Con vincin g experimentalevid ence exists that in utero repair preserves ne urolog icfunct ion, as well as resolv ing the hydrocephalus andA r n o l d - C h i a r i m a l f o r m a t i o n t h a t o f t e n a c c o m p a n yme ningo my eloce le defect s . However , f o l low-up is need-ed to com plete ly eva lua te long - t erm neuro log ic funct ionand overall impr oved quality o f l i fe . An d in the words o fOlutoye and Adzic k , 17 unt il the benef i t s o f f e ta l[meningomyelocele] repair are carefully elucidated,we ighe d against maternal and feta l risks, and comparedto conventional postnatal therapy, this procedu re sho uldbe restricted to a few centers that are committed (cl ini-cally and experimentally) to investigating these issues.

    eferences1 . C a m p b e l l L R , D a y t o n D H , S o h a l G S . N e u r a l t u b e d e f ec t s :