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Cerebral edema associated with betaine treatment in classical homocystinuria
CEREBRAL EDEMA ASSOCIATED WITH BETAINE TREATMENT IN CLASSICAL HOMOCYSTINURIA A. M. DEVLIN, MBBS, MD, MRCPCH, L. HAJIPOUR, MRCS, A. GHOLKAR, MBBS, FRCR, H. FERNANDES, MBBS, MD, FRCS, V. RAMESH, MBBS, FRCPCH, AND A. A. M. MORRIS, BM, BCH, PHD, FRCPCH
A child with cystathionine b-synthase deficiency developed cerebral edema 4 to 6 weeks after starting betaine therapy. There was no evidence of intracranial thrombosis, but there was widespread edema of the white matter. He recovered fully after emergency decompressive craniotomy and withdrawal of betaine. (J Pediatr 2004;144:545-8)
lassical homocystinuria is an autosomal recessive condition caused by deficiency of cystathionine b-synthase (CBS), the enzyme responsible for converting homocysteine to cystathionine (Fig 1). The incidence varies in different populations and is not known accurately; in England, it is >1:126,000.1 Neonatal screening has a low sensitivity and is not currently undertaken in the United Kingdom. Complications of classical homocystinuria include ectopia lentis, mental retardation, skeletal abnormalities, and thromboembolism, which is the most common cause of death. CBS requires pyridoxal-phosphate as a cofactor, and ~50% of patients respond to treatment with large doses of pyridoxine.1 In pyridoxine-unresponsive patients, homocysteine levels are controlled by a low-methionine diet, vitamins (folate and B12), and/or betaine therapy. Betaine is formed naturally during choline catabolism. It is involved in the maintenance of cell volume against osmotic stress and acts as a chemical chaperone, protecting proteins against denaturation. It is also a substrate for the hepatic enzyme betainehomocysteine methyltransferase (Fig 1). For >20 years, pharmacological doses of betaine have been used to lower homocysteine concentrations in homocystinuria.2 The usual dose in children has been 250 mg/kg/d,3,4 but recent studies suggest that there is little benefit from increasing >150 mg/kg/d.5 The response to betaine is variable. Plasma homocysteine concentrations often fall by $50%.2,3 Plasma methionine concentrations usually rise, sometimes only slightly but sometimes as high as 1000 to 1200 lmol/ L.2,4 There have been few clinical problems, but cerebral edema was reported in a patient treated with betaine.6 We report a second patient with CBS deficiency who had this complication while receiving betaine.
C
METHODS Amino acids were measured by ion exchange chromatography (H. Wastell, unpublished data, 2001) and total homocysteine (tHcy) by fluorescent polarization immunoassay. Betaine was assayed by an unpublished method by using liquid chromatography/electrospray ionisation/mass spectrometry (M.-H. Mar and S. H. Zeisel, unpublished data, 2001). N,N-dimethylglycine concentrations and CBS activity were measured as reported previously.7,8
CASE HISTORY A 4.5-year-old boy was diagnosed with homocystinuria after presenting with dislocated lenses. He had poor speech articulation, clumsiness, and frequent falls, but development was otherwise normal. Baseline plasma tHcy concentrations ranged from 334 to 430 lmol/L (normal, 5–17). The plasma methionine concentration was 203 lmol/L (normal, 10–54) with a normal vitamin B12 level and a normal urinary organic acid profile. CBS activity in fibroblasts was undetectable, with no change after the addition of pyridoxal-phosphate or S-adenosylmethionine. Clinically, there was only a partial response CBS CSF CT
Cystathionine b-synthase Cerebrospinal fluid Computed tomography
MRI tHcy
Magnetic resonance imaging Total homocysteine
From the Departments of Paediatric Neurology and Neurosurgery, Newcastle General Hospital, Newcastleupon-Tyne, and Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Manchester, United Kingdom. Submitted for publication June 17, 2003; last revision received Oct 14, 2003; accepted Dec 18, 2003. Reprint requests: A. A. M. Morris, BM, BCh, PhD, FRCPCH, Willink BiochemicalGeneticsUnit,RoyalManchester Children’s Hospital, Manchester M27 4HA, United Kingdom. E-mail: [email protected]. 0022–3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2003.12.041
545
Fig 1. Pathways of methionine and homocysteine metabolism. 1, Methionine synthase; 2, betaine-homocysteine methyltransferase; 3, cystathionine b-synthase; THF, tetrahydrofolate.
Table. Biochemical results in our patient around the time of the third lumbar puncture
Plasma
CSF
Methionine tHcy Betaine N,N-dimethylglycine Methionine Betaine
Concentration in our patient
Normal range
CBS deficient patients on betaine
1190 239 98 64 235 6.6
10-54 5-17 18-73 1.4-5.3 1-5
<1200 167-657 33-250
Values are expressed in lmol/L. The plasma sample was obtained 12 hours before the lumber puncture; both plasma and CSF were obtained 8 hours after the preceding dose of betaine. Normal ranges relate to normal subjects who were not taking betaine. Reference ranges for plasma betaine and N,N-dimethylglycine are from reference 7.
to pyridoxine (500 mg/d) and folic acid (5 mg/d) with plasma tHcy concentrations of 253 to 340 lmol/L. At age 5 years, betaine (Special Products, Surrey, UK) was started and increased gradually to 3 g/d (150 mg/kg), and dietary protein was restricted (methionine intake 500 mg/d). Four weeks after starting betaine, the patient began having morning headaches and vomiting, which increased in frequency and severity. Two weeks later, he presented to the hospital with papilledema but with no other neurological signs. Cranial MRI with magnetic resonance angiography and venography showed no evidence of sinovenous thrombosis. 546
Devlin et al
There was, however, a widespread abnormal signal from the white matter in both cerebral hemispheres (Fig 2, A). Lumbar puncture revealed an opening pressure of 48 cm of cerebrospinal fluid (CSF) but was otherwise normal and resulted in a marked reduction in symptoms. Four days later, symptoms returned and were relieved by a second lumbar puncture (opening pressure 47 cm CSF). Aspirin, dexamethasone, and acetazolamide were started. The betaine dose was doubled to 3 g twice daily. After another 4 days, symptoms worsened, and lumbar puncture showed an opening pressure >80 cm CSF. Relevant plasma and CSF results are shown in the Table. The Journal of Pediatrics April 2004
Fig 2. A, Cranial MRI (FLAIR sequence) showing widespread abnormal signal from the white matter in the cerebral hemispheres indicated by the arrows. B, Cranial CT showing diffuse brain swelling with loss of the basal cisterns. C, Repeat cranial MRI (FLAIR sequence) showing resolution of the white matter changes. FLAIR, Fluid attenuated inversion recovery.
Four hours after the third lumbar puncture, the patient became hypertensive and bradycardic with a falling level of consciousness and unilateral pupillary dilatation. Computed tomography (CT; Fig 2, B) showed diffuse brain swelling with loss of the basal cisterns. The patient was intubated, ventilated, and given mannitol, after which bilateral frontotemporal decompressive craniotomies were performed. Invasive angiography revealed no evidence of sinovenous or corticovenous thrombosis. Betaine was discontinued. Pupillary responses normalized within 6 hours of surgery. Ventilation and fluid Cerebral Edema Associated with Betaine Treatment in Classical Homocystinuria
restriction were continued for 48 hours, after which the patient recovered consciousness. Neurological examination was normal at discharge 8 days later and at follow-up after 9 months. Psychomotor development has progressed normally. Cranial MRI after 6 months showed resolution of the edema and the white matter signal abnormalities (Fig 2, C). Satisfactory levels of plasma tHcy (<50 lmol/L) and methionine (43-111 lmol/ L) have been achieved by using a low methionine diet (200 mg/d) with methionine-free amino acid supplements (XMet Maxamaid, SHS International, Liverpool, UK). 547
DISCUSSION Intracranial sinovenous and arterial thromboses are the most common causes of raised intracranial pressure in homocystinuria. In this case, there was no evidence of thrombosis, and the imaging results and time course suggest cerebral edema. It is uncertain whether anything else contributed to the reversible white matter abnormality on MRI. The onset of the problem soon after betaine was introduced and its resolution once betaine was withdrawn strongly suggest that the drug was responsible. Moreover, there has been one previous report of similar problems in a patient receiving betaine.6 The patient was a 10-year-old girl with pyridoxine-unresponsive CBS deficiency who had previously taken betaine erratically. Betaine was restarted at 6 g/ d (200 mg/kg) after an episode of pancreatitis. Three months later, she was admitted with headaches and signs of raised intracranial pressure. CT and MRI showed evidence of cerebral edema with increased signal from the white matter on T2 weighted imaging. Her symptoms and signs resolved within 4 weeks of stopping betaine and on dietary methionine restriction, and repeat MRI after 4 months was normal. Why did betaine treatment lead to cerebral edema in these two patients when hundreds of other patients have taken it without problems? The patient of Yaghmai et al6 had exceptionally high plasma methionine concentrations (22723037 lmol/L) while taking betaine, and the authors suggested that methionine toxicity might have caused the cerebral edema. Acute cerebral problems have also been associated with very high methionine concentrations in a normal control after a methionine load (plasma methionine 5760 lmol/L)9 and in infants with a high methionine intake (plasma concentrations 6830 and 2154 lmol/L).10 In contrast, our patient’s plasma methionine levels were no higher than in some patients who tolerate betaine without problems. The concentration was 1190 lmol/L on the day before craniotomy and 1205 lmol/L 5 days previously, though it might have been higher before admission. There are few data for CSF methionine concentrations during betaine therapy. Surtees et al3 found a mean CSF methionine concentration of 78 lmol/L in five children on betaine. This is much lower than the concentration of 235 lmol/L in our patient, but in their patients, the plasma methionine levels were relatively low. Patients with high plasma methionine concentrations on betaine therapy may have CSF methionine concentrations similar to our patient’s value. Could the cerebral edema have been caused directly by betaine or its metabolites? In the previous patient, the plasma betaine concentration (264 lmol/L) was within the range seen in other patients on this drug, but the plasma N,N-dimethylglycine concentration was high (883 lmol/L).6 Our patient’s plasma betaine and N,N-dimethylglycine concentrations were both relatively low (Table), and his CSF betaine concentration was similar to that seen in other patients on betaine (R. A. Iles, personal communication, 2002). However, it is conceivable that intracellular betaine con-
548
Devlin et al
centrations might have been high. If the patient had a variant form of the transporter that carries betaine into cells, betaine therapy might have led to high intracellular concentrations, which might have caused the cerebral edema. In summary, it is uncertain why our patient had this adverse response to betaine therapy, but elevated methionine concentrations are the prime suspect. Betaine remains a useful agent in the treatment of homocystinuria, but clinicians should be aware that, in a few patients, it can be associated with the development of cerebral edema. Complete recovery is possible if the drug is discontinued promptly. Plasma methionine concentrations should be monitored in patients taking betaine. Until we understand the cause of the cerebral edema, plasma methionine concentrations should be kept <1000 lmol/L by modifying the diet or reducing the betaine dose. We are grateful to Brian Fowler, PhD, at the University Children’s Hospital, Basel, for measurement of CBS activity; Steven Zeisel, MD, PhD, at the University of North Carolina at Chapel Hill, for betaine measurements; and Sally Stabler, MD, at the University of Colorado Health Sciences Center for N,Ndimethylglycine measurements.
REFERENCES 1. Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet A, Sly W, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th ed. Vol. 1. New York: McGraw-Hill; 1995. p. 1279-327. 2. Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuria—the effect of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med 1983;309:448-53. 3. Surtees R, Bowron A, Leonard J. Cerebrospinal fluid and plasma total homocysteine and related metabolites in children with cystathionine ß-synthase deficiency: the effect of treatment. Pediatr Res 1997;42:577-82. 4. Walter JH, Wraith JE, White FJ, Bridge C, Till J. Strategies for the treatment of cystathionine b-synthase deficiency: the experience of the Willink Biochemical Genetics Unit over the past 30 years. Eur J Pediatr 1998;157(suppl 2):S71-6. 5. Matthews A, Johnson TN, Rostami-Hodjegan A, Chakrapani A, Wraith JE, Moat SJ, et al. An indirect response model of homocysteine suppression by betaine: optimising the dosage regimen of betaine in homocystinuria. Br J Clin Pharmacol 2002;54:140-6. 6. Yaghmai R, Kashani AH, Geraghty MT, Stabler SP, Tangerman A, Wagner C, et al. Progressive cerebral oedema associated with high methionine levels and betaine therapy in a patient with cystathionine ß-synthase deficiency. Am J Med Genet 2002;108:57-63. 7. Allen RH, Stabler SP, Lindenbaum J. Serum betainem N, Ndimethylglycine and N-methylcysteine levels in patients with cobalamin and folate deficiency and related inborn errors of metabolism. Metabolism 1993;42:1448-60. 8. Fowler B, Kraus J, Packman S, Rosenberg LE. Homocystinuria: evidence for three distinct classes of cystathionine beta-synthase mutants in cultured fibroblasts. J Clin Invest 1978;61:645-53. 9. Cottington EM, LaMantia C, Stabler SP, Allen RH, Tangerman A, Wagner C, et al. Adverse event associated with methionine loading test. Arterioscler Thromb Vasc Biol 2002;22:1046-50. 10. Mudd SH, Braverman N, Pomper M, Tezcan K, Kronick J, Jayakar P, et al. Infantile hypermethioninaemia and hyperhomocystinaemia due to high methionine intake: a diagnostic trap. Mol Genet Metab 2003;79:6-16.
The Journal of Pediatrics April 2004
A child with cystathionine b-synthase deficiency developed cerebral edema 4 to 6 weeks after starting betaine therapy. There was no evidence of intracranial thrombosis, but there was widespread edema of the white matter. He recovered fully after emergency decompressive craniotomy and withdrawal of betaine. (J Pediatr 2004;144:545-8)
lassical homocystinuria is an autosomal recessive condition caused by deficiency of cystathionine b-synthase (CBS), the enzyme responsible for converting homocysteine to cystathionine (Fig 1). The incidence varies in different populations and is not known accurately; in England, it is >1:126,000.1 Neonatal screening has a low sensitivity and is not currently undertaken in the United Kingdom. Complications of classical homocystinuria include ectopia lentis, mental retardation, skeletal abnormalities, and thromboembolism, which is the most common cause of death. CBS requires pyridoxal-phosphate as a cofactor, and ~50% of patients respond to treatment with large doses of pyridoxine.1 In pyridoxine-unresponsive patients, homocysteine levels are controlled by a low-methionine diet, vitamins (folate and B12), and/or betaine therapy. Betaine is formed naturally during choline catabolism. It is involved in the maintenance of cell volume against osmotic stress and acts as a chemical chaperone, protecting proteins against denaturation. It is also a substrate for the hepatic enzyme betainehomocysteine methyltransferase (Fig 1). For >20 years, pharmacological doses of betaine have been used to lower homocysteine concentrations in homocystinuria.2 The usual dose in children has been 250 mg/kg/d,3,4 but recent studies suggest that there is little benefit from increasing >150 mg/kg/d.5 The response to betaine is variable. Plasma homocysteine concentrations often fall by $50%.2,3 Plasma methionine concentrations usually rise, sometimes only slightly but sometimes as high as 1000 to 1200 lmol/ L.2,4 There have been few clinical problems, but cerebral edema was reported in a patient treated with betaine.6 We report a second patient with CBS deficiency who had this complication while receiving betaine.
C
METHODS Amino acids were measured by ion exchange chromatography (H. Wastell, unpublished data, 2001) and total homocysteine (tHcy) by fluorescent polarization immunoassay. Betaine was assayed by an unpublished method by using liquid chromatography/electrospray ionisation/mass spectrometry (M.-H. Mar and S. H. Zeisel, unpublished data, 2001). N,N-dimethylglycine concentrations and CBS activity were measured as reported previously.7,8
CASE HISTORY A 4.5-year-old boy was diagnosed with homocystinuria after presenting with dislocated lenses. He had poor speech articulation, clumsiness, and frequent falls, but development was otherwise normal. Baseline plasma tHcy concentrations ranged from 334 to 430 lmol/L (normal, 5–17). The plasma methionine concentration was 203 lmol/L (normal, 10–54) with a normal vitamin B12 level and a normal urinary organic acid profile. CBS activity in fibroblasts was undetectable, with no change after the addition of pyridoxal-phosphate or S-adenosylmethionine. Clinically, there was only a partial response CBS CSF CT
Cystathionine b-synthase Cerebrospinal fluid Computed tomography
MRI tHcy
Magnetic resonance imaging Total homocysteine
From the Departments of Paediatric Neurology and Neurosurgery, Newcastle General Hospital, Newcastleupon-Tyne, and Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Manchester, United Kingdom. Submitted for publication June 17, 2003; last revision received Oct 14, 2003; accepted Dec 18, 2003. Reprint requests: A. A. M. Morris, BM, BCh, PhD, FRCPCH, Willink BiochemicalGeneticsUnit,RoyalManchester Children’s Hospital, Manchester M27 4HA, United Kingdom. E-mail: [email protected]. 0022–3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2003.12.041
545
Fig 1. Pathways of methionine and homocysteine metabolism. 1, Methionine synthase; 2, betaine-homocysteine methyltransferase; 3, cystathionine b-synthase; THF, tetrahydrofolate.
Table. Biochemical results in our patient around the time of the third lumbar puncture
Plasma
CSF
Methionine tHcy Betaine N,N-dimethylglycine Methionine Betaine
Concentration in our patient
Normal range
CBS deficient patients on betaine
1190 239 98 64 235 6.6
10-54 5-17 18-73 1.4-5.3 1-5
<1200 167-657 33-250
Values are expressed in lmol/L. The plasma sample was obtained 12 hours before the lumber puncture; both plasma and CSF were obtained 8 hours after the preceding dose of betaine. Normal ranges relate to normal subjects who were not taking betaine. Reference ranges for plasma betaine and N,N-dimethylglycine are from reference 7.
to pyridoxine (500 mg/d) and folic acid (5 mg/d) with plasma tHcy concentrations of 253 to 340 lmol/L. At age 5 years, betaine (Special Products, Surrey, UK) was started and increased gradually to 3 g/d (150 mg/kg), and dietary protein was restricted (methionine intake 500 mg/d). Four weeks after starting betaine, the patient began having morning headaches and vomiting, which increased in frequency and severity. Two weeks later, he presented to the hospital with papilledema but with no other neurological signs. Cranial MRI with magnetic resonance angiography and venography showed no evidence of sinovenous thrombosis. 546
Devlin et al
There was, however, a widespread abnormal signal from the white matter in both cerebral hemispheres (Fig 2, A). Lumbar puncture revealed an opening pressure of 48 cm of cerebrospinal fluid (CSF) but was otherwise normal and resulted in a marked reduction in symptoms. Four days later, symptoms returned and were relieved by a second lumbar puncture (opening pressure 47 cm CSF). Aspirin, dexamethasone, and acetazolamide were started. The betaine dose was doubled to 3 g twice daily. After another 4 days, symptoms worsened, and lumbar puncture showed an opening pressure >80 cm CSF. Relevant plasma and CSF results are shown in the Table. The Journal of Pediatrics April 2004
Fig 2. A, Cranial MRI (FLAIR sequence) showing widespread abnormal signal from the white matter in the cerebral hemispheres indicated by the arrows. B, Cranial CT showing diffuse brain swelling with loss of the basal cisterns. C, Repeat cranial MRI (FLAIR sequence) showing resolution of the white matter changes. FLAIR, Fluid attenuated inversion recovery.
Four hours after the third lumbar puncture, the patient became hypertensive and bradycardic with a falling level of consciousness and unilateral pupillary dilatation. Computed tomography (CT; Fig 2, B) showed diffuse brain swelling with loss of the basal cisterns. The patient was intubated, ventilated, and given mannitol, after which bilateral frontotemporal decompressive craniotomies were performed. Invasive angiography revealed no evidence of sinovenous or corticovenous thrombosis. Betaine was discontinued. Pupillary responses normalized within 6 hours of surgery. Ventilation and fluid Cerebral Edema Associated with Betaine Treatment in Classical Homocystinuria
restriction were continued for 48 hours, after which the patient recovered consciousness. Neurological examination was normal at discharge 8 days later and at follow-up after 9 months. Psychomotor development has progressed normally. Cranial MRI after 6 months showed resolution of the edema and the white matter signal abnormalities (Fig 2, C). Satisfactory levels of plasma tHcy (<50 lmol/L) and methionine (43-111 lmol/ L) have been achieved by using a low methionine diet (200 mg/d) with methionine-free amino acid supplements (XMet Maxamaid, SHS International, Liverpool, UK). 547
DISCUSSION Intracranial sinovenous and arterial thromboses are the most common causes of raised intracranial pressure in homocystinuria. In this case, there was no evidence of thrombosis, and the imaging results and time course suggest cerebral edema. It is uncertain whether anything else contributed to the reversible white matter abnormality on MRI. The onset of the problem soon after betaine was introduced and its resolution once betaine was withdrawn strongly suggest that the drug was responsible. Moreover, there has been one previous report of similar problems in a patient receiving betaine.6 The patient was a 10-year-old girl with pyridoxine-unresponsive CBS deficiency who had previously taken betaine erratically. Betaine was restarted at 6 g/ d (200 mg/kg) after an episode of pancreatitis. Three months later, she was admitted with headaches and signs of raised intracranial pressure. CT and MRI showed evidence of cerebral edema with increased signal from the white matter on T2 weighted imaging. Her symptoms and signs resolved within 4 weeks of stopping betaine and on dietary methionine restriction, and repeat MRI after 4 months was normal. Why did betaine treatment lead to cerebral edema in these two patients when hundreds of other patients have taken it without problems? The patient of Yaghmai et al6 had exceptionally high plasma methionine concentrations (22723037 lmol/L) while taking betaine, and the authors suggested that methionine toxicity might have caused the cerebral edema. Acute cerebral problems have also been associated with very high methionine concentrations in a normal control after a methionine load (plasma methionine 5760 lmol/L)9 and in infants with a high methionine intake (plasma concentrations 6830 and 2154 lmol/L).10 In contrast, our patient’s plasma methionine levels were no higher than in some patients who tolerate betaine without problems. The concentration was 1190 lmol/L on the day before craniotomy and 1205 lmol/L 5 days previously, though it might have been higher before admission. There are few data for CSF methionine concentrations during betaine therapy. Surtees et al3 found a mean CSF methionine concentration of 78 lmol/L in five children on betaine. This is much lower than the concentration of 235 lmol/L in our patient, but in their patients, the plasma methionine levels were relatively low. Patients with high plasma methionine concentrations on betaine therapy may have CSF methionine concentrations similar to our patient’s value. Could the cerebral edema have been caused directly by betaine or its metabolites? In the previous patient, the plasma betaine concentration (264 lmol/L) was within the range seen in other patients on this drug, but the plasma N,N-dimethylglycine concentration was high (883 lmol/L).6 Our patient’s plasma betaine and N,N-dimethylglycine concentrations were both relatively low (Table), and his CSF betaine concentration was similar to that seen in other patients on betaine (R. A. Iles, personal communication, 2002). However, it is conceivable that intracellular betaine con-
548
Devlin et al
centrations might have been high. If the patient had a variant form of the transporter that carries betaine into cells, betaine therapy might have led to high intracellular concentrations, which might have caused the cerebral edema. In summary, it is uncertain why our patient had this adverse response to betaine therapy, but elevated methionine concentrations are the prime suspect. Betaine remains a useful agent in the treatment of homocystinuria, but clinicians should be aware that, in a few patients, it can be associated with the development of cerebral edema. Complete recovery is possible if the drug is discontinued promptly. Plasma methionine concentrations should be monitored in patients taking betaine. Until we understand the cause of the cerebral edema, plasma methionine concentrations should be kept <1000 lmol/L by modifying the diet or reducing the betaine dose. We are grateful to Brian Fowler, PhD, at the University Children’s Hospital, Basel, for measurement of CBS activity; Steven Zeisel, MD, PhD, at the University of North Carolina at Chapel Hill, for betaine measurements; and Sally Stabler, MD, at the University of Colorado Health Sciences Center for N,Ndimethylglycine measurements.
REFERENCES 1. Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet A, Sly W, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th ed. Vol. 1. New York: McGraw-Hill; 1995. p. 1279-327. 2. Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuria—the effect of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med 1983;309:448-53. 3. Surtees R, Bowron A, Leonard J. Cerebrospinal fluid and plasma total homocysteine and related metabolites in children with cystathionine ß-synthase deficiency: the effect of treatment. Pediatr Res 1997;42:577-82. 4. Walter JH, Wraith JE, White FJ, Bridge C, Till J. Strategies for the treatment of cystathionine b-synthase deficiency: the experience of the Willink Biochemical Genetics Unit over the past 30 years. Eur J Pediatr 1998;157(suppl 2):S71-6. 5. Matthews A, Johnson TN, Rostami-Hodjegan A, Chakrapani A, Wraith JE, Moat SJ, et al. An indirect response model of homocysteine suppression by betaine: optimising the dosage regimen of betaine in homocystinuria. Br J Clin Pharmacol 2002;54:140-6. 6. Yaghmai R, Kashani AH, Geraghty MT, Stabler SP, Tangerman A, Wagner C, et al. Progressive cerebral oedema associated with high methionine levels and betaine therapy in a patient with cystathionine ß-synthase deficiency. Am J Med Genet 2002;108:57-63. 7. Allen RH, Stabler SP, Lindenbaum J. Serum betainem N, Ndimethylglycine and N-methylcysteine levels in patients with cobalamin and folate deficiency and related inborn errors of metabolism. Metabolism 1993;42:1448-60. 8. Fowler B, Kraus J, Packman S, Rosenberg LE. Homocystinuria: evidence for three distinct classes of cystathionine beta-synthase mutants in cultured fibroblasts. J Clin Invest 1978;61:645-53. 9. Cottington EM, LaMantia C, Stabler SP, Allen RH, Tangerman A, Wagner C, et al. Adverse event associated with methionine loading test. Arterioscler Thromb Vasc Biol 2002;22:1046-50. 10. Mudd SH, Braverman N, Pomper M, Tezcan K, Kronick J, Jayakar P, et al. Infantile hypermethioninaemia and hyperhomocystinaemia due to high methionine intake: a diagnostic trap. Mol Genet Metab 2003;79:6-16.
The Journal of Pediatrics April 2004