SummaryPrenatal diagnosis was requested by a family at risk for metachromatic leukodystrophy (MLD). An examination of the family leukocyte arylsulfatase A profile revealed that the mother had pseudo arylsulfatase A deficiency. Cultured amniotic fluid cells were deficient in arylsdfatase A, so two possibilities were indicated. the fetus was affected with MLD or had the pseudodeficiency phenotype. The only known biochemical test to differentiate the two enzyme deficient phenotypes is cerebroside sulfate loading of growing fibroblasts. The pseudodeficient cells hydrolyze the incorporated sulfatide as efficiently as control cells, whereas MLD cells show no hydrolysis. Application of this test to the at risk cultured amniotic fluid cells resulted in appreciable uptake of the sulfolipid, but no hydrolysis. Control amniotic fluid cell cultures hydrolyzed 82 to 95% of the incorporated sulfatide. Therefore, an affected fetus was indicated. Fibroblasts derived from the aborted fetus sbowed a deficiency of arylsulfatase A and a similar inability to hydrolyze cerebroside sulfate i n the loading test. The loading technique allowed the prenatal diagnosis of MLD when the arylsulfatase A analysis was equivocal. Speculation I n metachromatic leukodystrophy families with pseudo arylsulfatase A deficiency, the usual enzyme assays on cultured amniotic fluid cell extracts fail to differentiate between the fetus with the affected phenotype and the fetus with the pseudodeficiency phenotype. The cerebroside sulfate loading test in growing cultured amniotic fluid cells allowed this discrimination. I t is important to examine the family enzyme profile for the peudodeficiency phenotype as a prerequisite in the prenatal diagnosis of metachromatic leukodystrophy to avoid the erroneous identification of a pseudodeficient fetus as a metachromatic leukodystrophy fetus.In metachromatic leukodystrophy (MLD), the profound deficiency of arylsulfatase A (ajlsuifaie ~ulfohydrola&, EC 3.1.6.1) leads to the accumulation of cerebroside sulfate in neural tissue ~ resulting in progressive neurological degeneration (5). Based on the age of onset of symptoms, three classical types of MLD are recognized: late infantile, juvenile, and adult. Each type appears to be an independent autosomal recessive disorder, so allelism is implied. Although no treatment is available, the disorder can be prevented in at risk families because MLD is amenable to prenatal diagnosis. In affected pregnancies, cultured amniotic fluid cells are deficient in arylsulfatase A (10,14,17,(21)(22)(23)(24).Dubois el al. (3, 4). Lott el al. (15). and Fluharty el al. (8) described four MLD families in which one of the parents and some of the unaffected children had very low arylsulfatase A activities which overlapped the range of probands. These individuals showed no neurologic dysfunction and were healthy, so it would be appropriate to iypifi the apparent enzyme deficikncy as a ~seudodeficiencv. The attenuated enzyme activity was observed in' leukocyte anda fibroblast extracts khether thk ...
SUMMARY"Wo s i b l l n g s of consanguinous p a r e n t s were noted t o have a neurologic syndrome parked by Zevelopmeptal d e l a y , r e q r e s s l o n of p s y c h o m t o r performance, marked s p a s t i c i t y and p m g r e s s l v e c e n t r a l nervous system degeneration. Markedly delayed nerve conduction t i r e s and a s u r a l nerve h i o p y which d e~o n s t r a t f d changes t y p l c a l of metachromatic leuku2ystrophy (MLD) were evldent. Impairment of s u l f a t e d a l y c o l l p i d metabolism was d o c m e n t e d by a n a l y s i s of glycosplngol~p l E I" u r l n a r y sediment. I n s p i t e o f t h e s e fini.inos, a c t i v i t i e s of a r y ls u l f a t a s e E and c e r e b r o s l d e s u l f a t i d a s e m whlte blood c e l l s and c u l t u r e d s k i n f r b r a b l a s t s were near normal. However, wher, i n t a c t qrowlng f i b r o b l a s t s were loaded wlth 3 5~~4 -s t~l f a t i d e a c l e a r d e f e c t i n s u l f a t i d e cleavage, comparable t o t h a t seen 1~1 MLD p a t i e n t s , was observed. Thus, t h e s e p a t i e n t s r e p r e s e n t a new form of s u l f a t i d e s t o r a g e d i s e a s e -MLD c h a r a c t e r i z e d by i n t a c t enzyme a c t i v i t y l n c e l l h~~o g e n a t e s but d e f e c t i v e s u l f o l i p r d metabolism & viw and i n i n t a c t fibroblasts.Since c e l l homogenates from t h e s e p a t i e n t s can c l e a v e s u l f a t l d e i n t h e presence of l e t e r g e r t s while t h e p a t l e n t s themselves and t h e i r i n t a c t c e l l s cannot, some e x p l a n a t i o n o t h e r than d e c r e a s e s a c t i v i t y of t h e r e l e v a n t lysosomal enzyme must be lnvoked t o e x p l a i n t h l s s t o r a r e d i s e a s e . The two most p l a u s i b l e hypotheses are t h a t e l t h e r t h e s e p a t i e n t s have a d e f e c t which p r e v e n t s enzyme and s u b s t r a t e l n t e r a c t l o n I" t h e p r o p e r s u b c e l l u l a r l o c a t i o n , o r t h a t t h e s e p a t i e n t s are missing t h e p u t a t i v e g l y m p r o t e i n " a c t i v a t i n g factor'' necessary Metachromatic leukodystrophy (MLD) i s a w e l l known e r r o r of s u l f a t e d g l y c o s p h i n g o l i p i d metabolism(8). Deficiency o f c e r e b r o s i d e s u l f a t i d a s e a c t i vi t y i n a f f e c t e d p a t i e n t s l e a d s t o t h e i n t r a l y s o s o m a l accumulation of s u l f a t e d g l y c o l i p i d s i n a number of t l s s u e s .m e t o t h e normally s u b s t a n t i a l c o n t e n t of such s u l f o l~p i d s zn b r a r n white m a t t e r and p e r i p h e r a l nerves, d e f e c t s i n s u lf a t i d e deoradation l e a d t o t i s s u e s t o r a q e and consequent neumpathology i n c l u d i n g hemispheric demyelination as w e l l as changes i n t h e b a s a l g a n g l i a , d e n t a t e n u c l e u s , and hrainstem.Lesions I" t h e p e r i p h e r a l nervous system are c h a r a c t e r i z e d by intralysosomal accumulation o f netachrom...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.