Maternal pyridoxine non‐responsive homocystinuria: the role of dietary treatment and anticoagulation

Abstract

A 19 year old girl with pyridoxine non-responsive homocystinuria due to cystathionine β-synthase deficiency, became pregnant. She had been diagnosed through newborn screening and was commenced on a methionine restricted, cystine supplemented diet since the ninth day of life. Mutational analysis for cystathionine β-synthase showed that she was a compound heterozygote of G307S / A354P. Her methionine tolerance was approximately 225 mg/day, equivalent to 9g /day of dietary (natural) protein. A synthetic amino acid mixture was prescribed at 1 g/kg body weight/day. Supplementation with cofactors included pyridoxine 200 mg three times daily, folic acid 5 mg/day, vitamin B12 4 μg three times daily and betaine anhydrous, a remethylating agent, 1.5 g three times daily. As a consequence of her poor compliance with treatment, she has suffered dislocation of the lens and learning difficulties. She had a lifetime free homocystine concentration of 18 (0–81) μmol/L [median range] prior to conception8. She was seen at six weeks of gestation and remained on her maintenance treatment throughout the pregnancy with necessary adjustments to her intake of dietary and synthetic proteins. Previous mutational analysis for other genetic thrombophilic factors were negative, for Factor V Leiden, thermolabile-methylenetetrahydrofolate reductase and prothrombin 20210A. Her serum concentrations of free homocystine, total homocysteine, methionine and cystine, and her coagulation profile including fibrinogen levels, were monitored, initially fortnightly and then weekly in the third trimester. Serum B12 and folate levels were measured monthly. The pregnancy was uneventful and she maintained normal serum B12, folate, coagulation profile, platelet count and fibrinogen levels throughout her pregnancy. Supplementation with cofactors and betaine anhydrous were continued. Her methionine tolerance gradually increased from 225 mg to 575 mg/day (9–23 g dietary protein) before delivery. The synthetic protein was prescribed at 1 g/kg body weight/day and the total protein intake was approximately 1.25 g/kg body weight/day (Fig. 1). The dietary protein intake was titrated to maintain a free homocystine of < 5 μmol/L. She maintained fairly good compliance with this dietary regimen with mean levels (SD) of free homocystine of 8.2 (5.5) μmol/L, total homocystine 74.8 (20.6) μmol/L and methionine 61.8 (33.9) μmol/L during her pregnancy. Subcutaneous heparin 5000U twice daily was given from one-week before birth until six weeks after birth. Maternal protein intake, betaine, heparin and plasma amino acid profiles during pregnancy and post-partum. She was admitted at 38 weeks of gestation in spontaneous labour and had an uncomplicated vacuum delivery of a life male infant. Apgar scores were nine at one minute and ten at five minutes. His birthweight was 4 kg (90th centile), length was 48 cm (<50th centile) and head circumference was 36.5 cm (90th centile). An obligate heterozygote, he had a normal physical examination, cranial ultrasound and echocardiogram. His total homocysteine was normal on the first, third and seventh days of life while fed on a proprietary baby formula. The infant was developmentally normal at 22 months of age. After her delivery the young woman remained clinically well and was continued on all her medications including subcutaneous heparin, for six weeks. Her methionine intake was immediately reduced after delivery to her pre-pregnancy methionine tolerance of 200 mg (8 g of dietary protein) and was gradually reduced thereafter to 125 mg at seven weeks postpartum. Despite the immediate reduction in the methionine intake after her delivery, her free homocystine remained markedly elevated until seven weeks postpartum, when it was <5 μmol/L (Fig. 1). Deproteinised amino acids were monitored daily in the first week and on alternate days on the second week, then weekly until seven weeks postpartum. Thereafter, she received routine care for her homocystinuria8: she continued on dietary methionine restriction with supplementation with cofactors and betaine anhydrous. Homocystinuria due to cystathionine β-synthase deficiency is clinically characterised by mental retardation, ectopia lentis, osteoporosis and thromboembolism. Biochemically, there is severe hyperhomocysteinaemia, hypermethioninaemia and hypocysteinaemia. The natural history predicts a 30% chance of a thromboembolic event by age 20 and this further increases to 50% by age 30 years1. Worldwide, 50% of patients are responsive to pyridoxine and have a milder phenotype. The ability of women with cystathionine β-synthase deficiency to survive pregnancy, particularly those with the more severe pyridoxine non-responsive phenotype, has always been guarded due to the maternal risk of thrombosis and miscarriage1,2. Fatal or near-fatal thromboembolic events in untreated maternal pyridoxine-responsive homocystinuria have been previously reported3,4,5. For women who are treated and responsive to pyridoxine, the results are encouragingly normal with regard to pregnancy and its outcome6,7. Caution must still remain in predicting a normal outcome of pregnancy in pyridoxine non-responsive women with high plasma homocysteine and methionine1. We describe the treatment of a young woman with pyridoxine non-responsive homocystinuria, treated with dietary methionine restriction, supplementation with synthetic amino acids and co-factors as homocysteine-lowering therapy, and anticoagulation during pregnancy, resulting in good maternal and fetal outcome. In 1971 the national newborn screening programme for cystathionine β-synthase deficiency was implemented in Ireland9. Based on newborn screening and clinically detected cases, the incidence is one in 50,000 The reported worldwide incidence of one in 344,000 is almost certainly an under-estimate as milder phenotypes due to pyridoxine responsiveness may not be diagnosed until they become apparent, most commonly, with a life-threatening thromboembolic event. The Celtic mutation, G307S, of the cystathionine β-synthase gene heralds the more severe pyridoxine non-responsive phenotype and predominates in Irish patients. This is the first reported case of a pregnant woman with pyridoxine non-responsive homocystinuria and it illustrates several features concerning dietary treatment and anticoagulation which are important in achieving a good maternal and fetal outcome. There is undoubtedly a high incidence of thrombotic episodes in untreated homocystinuria, and this risk is increased by the thrombotic tendencies of pregnancy and the puerperium. In addition, folate and pyridoxine depletion tends to be exaggerated in pregnancy, leading to an increase in hyperhomocysteinaemia5. As the young woman in our case report did not respond to pyridoxine, dietary methionine restriction was the only alternative homocysteine-lowering therapy available. While frequent monitoring of maternal homocysteine levels is essential, it is also necessary to monitor the methionine levels to prevent any deficiency in the fetus, as methionine is an essential amino acid. Cystine becomes an essential amino acid in cystathionine β-synthase deficiency and hence is supplemented in the synthetic amino acid mixture. In restricting dietary protein intake, the maternal protein intake is severely curtailed without the addition of a synthetic amino acid mixture lacking in methionine and enhanced with cystine. Betaine anhydrous has been used in the last 10 years to remethylate homocysteine back to methionine and was used throughout this pregnancy without any apparent fetal side effects. Careful monitoring of vitamin B12 and folate levels and their supplementation is also required to minimise hyperhomocysteinaemia and the associated risk of thrombosis. Ritchie and Carson reported the rise of fibrinogen to maximal levels of 700 mg/dL at twelve weeks of gestation and hypothesised that the rise may be the cause of the threatened abortion at 11 week of gestation in their pyridoxine-responsive patient, who subsequently aborted at 22 weeks2. It is now recognised that high homocysteine inhibits the activation of protein C in the anticoagulation cascade10 thus potentiating the coagulopathy, as indicated by the rising fibrinogen. The young woman in our case report maintained normal fibrinogen levels throughout pregnancy. Despite reducing the dietary protein intake immediately after delivery to the amount taken before conception, close monitoring of plasma deproteinised amino acids revealed severe hyperhomocystinaemia, which returned to the therapeutic range of <5 μmol/L seven weeks postpartum. The process of uterine involution, which normally takes six to seven weeks, may have contributed to this. Postpartum monitoring of deproteinised amino acids in our case has also revealed that the woman is most at risk of a thrombotic episode for seven weeks postpartum due to the severe hyperhomocystinaemia and despite maximum treatment. This finding provides the biochemical background to support anticoagulation during this period. Total homocysteine measurements have only been in use since the late 1980s. There are no reports yet on its use as a variable for long term biochemical control in patients with homocystinuria. Although free homocystine was used principally in determining biochemical control in this young woman, by measuring both free homocystine and total homocysteine concurrently we were able for the first time to document the biochemical control using both parameters. This suggests that a maternal free homocystine mean of 8 μmol/L and total homocysteine mean of 75 μmol/L during pregnancy are compatible with good maternal and fetal outcomes. Our main recommendation, resulting from the treatment of this young woman, is that appropriate homocysteine-lowering therapy with close biochemical monitoring throughout pregnancy be instituted. Avoidance of dehydration and rapid mobilisation are important in minimising the risk of thrombosis. Subcutaneous heparin should be given before birth and continued postnatally until the effects of pregnancy on the clotting mechanism have ceased. This case illustrates the prophylactic measures that should be undertaken for a good maternal and fetal outcome in maternal pyridoxine non-responsive homocystinuria. It is important to be aware of the condition and its possible consequences, as it is treatable. Homocysteine should be included in the investigation of a thrombotic episode in women during pregnancy or the puerperium. Thrombosis may be the only sign of this treatable condition. The authors would like to thank Ms M. Irranca and Ms M. Bradley (dieticians) and the laboratory staff, nurses, doctors and social workers for their contribution to the successful care of this young woman.