The natural history of homocystinuria due to cystathionine beta-synthase deficiency

• Published in: American journal of human genetics Vol. 37; no. 1; pp. 1 - 31
• Main Authors: Mudd, S H, Skovby, F, Levy, H L, Pettigrew, K D, Wilcken, B, Pyeritz, R E, Andria, G, Boers, G H, Bromberg, I L, Cerone, R
• Format: Journal Article
• Language: English
• Published: United States 01.01.1985
• Subjects: Adolescent; Adult; Child; Child, Preschool; Clinical Enzyme Tests; Cystathionine beta-Synthase - deficiency; Female; Fertility; Follow-Up Studies; Genetic Testing; Homocystinuria - complications; Homocystinuria - diagnosis; Homocystinuria - diet therapy; Homocystinuria - genetics; Humans; Infant; Infant, Newborn; Intellectual Disability - etiology; Lens Subluxation - etiology; Male; Methionine - administration & dosage; Original; Osteoporosis - etiology; Pregnancy; Pregnancy Complications; Pyridoxine; Seizures - etiology; Surveys and Questionnaires; Thromboembolism - etiology
• ISSN: 0002-9297; 1537-6605

An international questionnaire survey has been conducted to define better the natural history of homocystinuria due to cystathionine beta-synthase deficiency and permit evaluation of treatment. Data were compiled 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: (1) dislocation of optic lenses (at age 10, chances of dislocation: 55% and 82%, respectively); (2) initial clinically detected thromboembolic events (at age 15, chances of having had such an event: 12% and 27%, respectively); (3) radiologic detection of spinal osteoporosis (at age 15, chances of such osteoporosis having been detected: 36% and 64%, respectively); and (4) mortality (at age 30, chances of not surviving: 4% and 23%, respectively). Methionine 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, six of which were fatal. Reproductive histories were reported predominantly 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.