Metachromatic Leukodystrophy Without Arylsulfatase a Deficiency

Abstract

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...

An Asn > Lys substitution in saposin B involving a conserved amino acidic residue and leading to the loss of the single N-glycosylation site in a patient with metachromatic leukodystrophy and normal arylsulphatase A activity

“…14,15 Mutation N215H has been identified in a patient described as a 4-year-old child with MLD. 13 Mutation T217I has been found in two siblings with a probably milder MLD phenotype than in patient PV, showing first symptoms at 4.5 and 6 years of age respectively, 16 whilst our patient showed walking difficulties at 2 years and mental retardation at 3. Interestingly, the Thr23 residue is conserved in human, porcine and chicken sap-B, but is not conserved in mouse or rat sap-B, whilst the Asn21 residue is conserved in the saposins B from all these five species (Figure 3).…”

Diagnosis of Metachromatic Leukodystrophy, Krabbe Disease, and Farber Disease after Uptake of Fatty Acid-labeled Cerebroside Sulfate into Cultured Skin Fibroblasts

“…This has not yet been reported for families who have a healthy family member with low levels of galactosylceramide B3-galactosidase. Shapiro et al (12) described a patient with MLD who did not have the very low levels of CS sulfatase in vitro usually measured in patients with MLD. We must be able to clearly differentiate patients who have the disease in question (and perhaps delayed onset of symptoms) from healthy people who have enzyme levels near those of affected patients.…”

“…To The media containing the compound to be tested was passed through a membrane filter (Millex-GS, 0.22 gm, Millipore (12,21), were found to have 27% of control activity using NCS and 21% of controls using CS as substrates.…”

Increasing Sulfatide Synthesis in Myelin-Forming Cells of Arylsulfatase A-Deficient Mice Causes Demyelination and Neurological Symptoms Reminiscent of Human Metachromatic Leukodystrophy

“…It is a negative regulator of oligodendrocyte differentiation (Bansal et al, 1999). MLD is caused by arylsulfatase A (ASA) deficiency, attributable to mutations in the ASA gene Arsa, resulting in the inability to degrade sulfatide and related sulfated lipids (Shapiro et al, 1979;Gieselmann, 2003). MLD patients suffer from a progressive loss of myelin and exhibit various neurological symptoms (von Figura et al, 2001).…”