THE NATURAL-HISTORY OF HOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE DEFICIENCY

Abstract

An international questionnaire survey was conducted to define better the natural history of homocystinuria due to cystathionine .beta.-synthase deficiency and permit evaluation of treatment. Data were complied for 629 patients. Among patients not discovered by newborn screening, B6-responsive individuals on the average have significantly better mental capabilities (mean IQ, 79) than do B6-nonresponsive individuals (mean IQ, 57). Time-to-event curves are presented for the other major clinical abnormalities produced by this disease. Each occurred at significantly lower rates in untreated B6-responsive than in untreated B6-nonresponsive patients, as shown by the following examples: dislocation of optic lenses (at age 10, changes of dislocation: 55% and 82%, respectively); initial clinically detected thromboemolic events (at age 15, chances of having had such an event: 12% and 27%, respectively); radiologic detection of spinal osteoporosis (at age 15, changes of such osteoporosis were detected: 36% and 64%, respectively); and mortality (at age 30, chances of not surviving: 4% and 23%, respectively). Met restriction initiated neonatally prevented mental retardation, retarded the rate of lens dislocation, and may have reduced the incidence of seizures. Pyridoxine treatment of late-detected B6-responsive patients retarded the rate of occurrence of initial thromboembolic events. Following 586 surgical procedures, 25 postoperative thromboembolic complications occurred, 6 of which were fatal. Reproductive histories were reported predominately for B6-responsive patients. Living offspring of either men or women patients had few abnormalities. The evidence is inconclusive whether untreated maternal cystathionine .beta.-synthase deficiency leads to excessive fetal loss. Only 13% of patients detected in screening programs of newborns and classified as to B6-responsiveness were B6-responsive, compared to 47% among late-detected patients. Current screening programs that identify neonatal hypermethioninemia may be preferentially failing to detect B6-responsive patients.