824 Respiratory Compromise as a Major Cause of Morbidity and Mortality in Hunter Syndrome

Abstract

. Department of P e d i a t r i c s , university o f California, san Diego, La J o l l a , C A 92093 3-Methylglutaconic a c i d u r i a has been described i n 7 p a t i e n t s i n whom urinary excretion of 3-methylglutaconic (3-MGC) and 3-methylglutaric (3-MGR) a c i d s were elevated. I n two s i b l i n g s t h e only manifestation was speech r e t a r d a t i o n . Combined excret i o n of 3-MGC and 3-MGR was 520-940 mmol/mol c r e a t i n i n e (normal l e s s than 6). The o t h e r p a t i e n t s had a p i c t u r e of severe neurol o g i c degeneration and profound mental r e t a r d a t i o n . Combined excretion of 3-MGC and 3-MGR ranged from a low o f 40 t o 800 m o l / m O l c r e a t i n i n e . The a c t i v i t y o f 3-methylulutaconyl-CoA (3-MGCoA) hydratase i n f i b r o b l a s t l y s a t e s derived from t h e s i b l i n g s with speech r e t a r d a t i o n was l e s s than 3% of t h e c o n t r o l l e v e l . In c o n t r a s t t h e a c t i v i t y of t h i s enzyme was normal i n t h r e e p a t i e n t s with t h e o t h e r c l i n i c a l phenotype. W e have postulated t h a t t h e excretion of 3-MGC and 3-MGR i n t h e p a t i e n t s with neurol o g i c a l abnormality i s a secondary accumulation i n response t o another primary d e f e c t not only because of t h e normal a c t i v i t y of t h e enzyme but because they a l s o excrete l a r g e q u a n t i t i e s of c i t r i c a c i d cycle intermediates. W e conclude t h a t t h e mild c l i ni c a l presentation of t h e s i b l i n g s we have s t u d i e d i s t h e c l i n i c a l p i c t u r e of 3-MG-CoA hydratase deficiency. These observations i n d i c a t e t h a t n e i t h e r t h e presence of nor t h e l e v e l of excretion of 3-MGC and 3-MGR c o r r e l a t e s with 3-MG-CoA hydratase deficiency. (Sponsored by Mark Ballow). Eleven p a t i e n t s with Hunter Syndrome (MPS f1) have been followed a t t h e University of Connecticut, of which 10 have been placed on a monthly leukocyte transfusion protocol. P o s i t i v e e f f e c t s of t h e transfusions have included softening of t h e skin and h a i r with r e s o l u t i o n of nodular skin l e s i o n s and diarrhea. W e have a l s o noted marked s u b j e c t i v e improvement of j o i n t d i scomfort i n those individuals who a r e a b l e t o communicate. No s i g n i f i c a n t improvement of macroglossia, organomegaly, s k e l e t a l , cardiovascular o r pulmonary changes have been noted.Previously, i t was f e l t t h a t m o r t a l i t y i n Hunter syndrome was frequently secondary t o cardiovascular complications. Our recent experience with 11 p a t i e n t s has shown t h a t t h e major morbidity i s r e l a t e d t o r e s p i r a t o r y disease, e s p e c i a l l y with regard t o upper airway compromise. Because of t h e unusual t r a c h e a l c a r t i l a g e conformation which develops i n these individuals, tracheostomy has been necessary i n 5/11 p a t i e n t s includi n g 213 individuals with t h e mild form of Hunter syndrome. Tr...