J. Inher. Metab. Dis. 15 (1992) 939-940
(c) SSIEM and Kluwer AcademicPublishers. Printed in the Netherlands
CASE REPORT Oral vitamin B12 treatment of eobalamin-responsive methylmalonic aciduria Z K. Ninan, H. Thorn and G. Russell
The inherited methylmalonic acidurias include various specific defects resulting in decreased activity of the cobalamin-dependent enzyme L-methylmalonyl-CoA mutase (Mahoney and Blick, 1987). When there is deficiency of the mutase coenzyme 5'deoxyadenosylcobalamin (McKusick 251100, 251110), patients may respond to pharmacological doses of vitamin B12. We describe the treatment of such a child using an oral preparation containing 1.5 mg/ml hydroxocobalamin (Roche). The patient, classified as a CblB variant, presented at 6 months with poor feeding, failure to thrive and metabolic acidosis. Investigation of urinary organic acids showed methylmalonic acid (MMA) in five random specimens at a level of t.44 _+ 0.13 tool/tool creatinine (mean _+ SEM). He responded immediately to protein restriction and intramuscular vitamin B12 (initially i rag/day tailed off to 1 rag/week). M M A output over the next year averaged 0.75 +_0.12tool/tool creatinine (n = 10). At 2 years of age treatment was changed to the oral preparation (vitamin B12 10rag/day) and MMA output stabilized around 2.44 + 0.24 mot/mol creatinine; 2.19 ± 0.27mmol/24h (n = 12). The child continued well and at 4 years dietary restriction, which was difficult, was abandoned. Vitamin B12 was increased to 15 rag/day. At age 7 years MMA output had a mean value of 3.03 _+ 0.22 tool/tool creatinine; 11.2 ± 1.3 retool/24 h (n = 6). He remained extremely well on this simple regimen and his parents questioned the necessity for continuing treatment. On parental insistence vitamin BI2 was reduced stepwise over 3 months then stopped. MMA excretion started to rise when the vitamin B12 dosage fell to 7.5rag/day and levelled off at 7.55 + 1.27 tool/tool creatinine (28.3 ± 3.20 retool/24 h) (n = 4) over the next 3 months. By this time the child was obviously deteriorating clinically and an acidotic crisis ensued 9 weeks after vitamin B12 had been stopped. Output of MMA was 16.4 tool/tool creatinine; 74 retool/24 h. Vitamin B~2 2 mg was then given intramuscularly, and oral therapy was restored, but MMA excretion stabilized at 14.6 _+ 2.9 tool/tool creatinine; 49.6 ± 0.9 retool/24 h (n = 2). Continuing lethargy was overcome only by administration of 2 mg vitamin B12 intramuscularly at 2-day intervals for 14 days. Over the next 6 months with oral therapy only, at the pre-withdrawal level, MMA output eventually stabilized at a mean level of 4.37 ± 1.04 tool/tool creatinine; 17.0 ± 4.6mmol/24h (n = 3). Aspects of a carnitine challenge prior to the withdrawal of vitamin B12 (deSousa et al 1985) and of creatine metabolism over the withdrawal period (Davies et al 1990) have been recorded. Department of Child Health, University of Aberdeen, Aberdeen AB9 2ZG, UK 939
940
Case Reports
The boy is now aged 15 years and over the past 5 years his output of MMA monitored 6 monthly has been 2.77 +_ 0.35 mol/mol creatinine; 14.0 +_ 1.7 mmol/24 h (n = 10). Childhood infections have caused no undue problems. Psychometric assessment indicates that he functions at the average range of ability with performance tests slightly above average. We strongly recommend a trial of oral therapy, which is simple and well tolerated, althoughthese are the attributes which caused the parents to question its necessity. Although it might be argued that confirmation of vitamin B12 responsiveness requires withdrawal of therapy with subsequent relapse, this may be dangerous. Our experience shows how long it may take to restore control.
REFERENCES Davies SEC, Isles RA, Stacey TE, Chalmers RA (1990) Creatine metabolism during metabolic perturbations in patients with organic acidurias. Clin Chim Acta 194: 203-218. deSousa C, Chalmers RA, Tracey Bet al (1985) Changes in carnitine and methylmatonate followingwithdrawal of vitamin B12 in B12 responsive methylmalonicaciduria. Pediatr Res 19: 1074. Mahoney MJ, Blick D (1987) Recent advances in the inherited methylmatonicacidemias. Acta Paediatr Scand 76: 689-696.
J. Inher. Metab. Dis. 15 (1992) 940-941
© SSIEM and KluwerAcademicPublishers. Printed in the Netherlands
SHORT REPORT Estimates of uridine diphosphate glucose in human erythrocytes H. N. K i r k m a n Jr.
Ng and coworkers (1989) claim that patients with galactosaemia (galactose-1phosphate uridyltransferase deficiency; McKusick 230400) have a major deficiency of uridine diphosphate galactose (UDPGal), the product of the transferase that is deficient in galactosaemia. In the hope of preventing or reversing some of the latemanifesting complications of galactosaemia, they have proposed giving galactosaemic children uridine, which is said to raise the level of UDPGal. Kirkman (1992), however, has stated the following: (a) There is no biochemical reason why there should be such a deficiency when an unaffected enzyme, epimerase, is able to make UDPGal. (b) He found no major deficiency of UDPGat when he used an enzymic assay similar to that of Ng and coworkers. (c) The normal values of erythrocytic UDPGal and uridine diphosphate glucose (UDPG) are only 1/5 of the values claimed by Ng and coworkers. Using HPLC methods, members of the laboratory of Dr Stanton Segal have Brain and Development Research Center and Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7250, USA J. lnher. Metab. Dis. 15 (1992)
(c) SSIEM and Kluwer AcademicPublishers. Printed in the Netherlands
CASE REPORT Oral vitamin B12 treatment of eobalamin-responsive methylmalonic aciduria Z K. Ninan, H. Thorn and G. Russell
The inherited methylmalonic acidurias include various specific defects resulting in decreased activity of the cobalamin-dependent enzyme L-methylmalonyl-CoA mutase (Mahoney and Blick, 1987). When there is deficiency of the mutase coenzyme 5'deoxyadenosylcobalamin (McKusick 251100, 251110), patients may respond to pharmacological doses of vitamin B12. We describe the treatment of such a child using an oral preparation containing 1.5 mg/ml hydroxocobalamin (Roche). The patient, classified as a CblB variant, presented at 6 months with poor feeding, failure to thrive and metabolic acidosis. Investigation of urinary organic acids showed methylmalonic acid (MMA) in five random specimens at a level of t.44 _+ 0.13 tool/tool creatinine (mean _+ SEM). He responded immediately to protein restriction and intramuscular vitamin B12 (initially i rag/day tailed off to 1 rag/week). M M A output over the next year averaged 0.75 +_0.12tool/tool creatinine (n = 10). At 2 years of age treatment was changed to the oral preparation (vitamin B12 10rag/day) and MMA output stabilized around 2.44 + 0.24 mot/mol creatinine; 2.19 ± 0.27mmol/24h (n = 12). The child continued well and at 4 years dietary restriction, which was difficult, was abandoned. Vitamin B12 was increased to 15 rag/day. At age 7 years MMA output had a mean value of 3.03 _+ 0.22 tool/tool creatinine; 11.2 ± 1.3 retool/24 h (n = 6). He remained extremely well on this simple regimen and his parents questioned the necessity for continuing treatment. On parental insistence vitamin BI2 was reduced stepwise over 3 months then stopped. MMA excretion started to rise when the vitamin B12 dosage fell to 7.5rag/day and levelled off at 7.55 + 1.27 tool/tool creatinine (28.3 ± 3.20 retool/24 h) (n = 4) over the next 3 months. By this time the child was obviously deteriorating clinically and an acidotic crisis ensued 9 weeks after vitamin B12 had been stopped. Output of MMA was 16.4 tool/tool creatinine; 74 retool/24 h. Vitamin B~2 2 mg was then given intramuscularly, and oral therapy was restored, but MMA excretion stabilized at 14.6 _+ 2.9 tool/tool creatinine; 49.6 ± 0.9 retool/24 h (n = 2). Continuing lethargy was overcome only by administration of 2 mg vitamin B12 intramuscularly at 2-day intervals for 14 days. Over the next 6 months with oral therapy only, at the pre-withdrawal level, MMA output eventually stabilized at a mean level of 4.37 ± 1.04 tool/tool creatinine; 17.0 ± 4.6mmol/24h (n = 3). Aspects of a carnitine challenge prior to the withdrawal of vitamin B12 (deSousa et al 1985) and of creatine metabolism over the withdrawal period (Davies et al 1990) have been recorded. Department of Child Health, University of Aberdeen, Aberdeen AB9 2ZG, UK 939
940
Case Reports
The boy is now aged 15 years and over the past 5 years his output of MMA monitored 6 monthly has been 2.77 +_ 0.35 mol/mol creatinine; 14.0 +_ 1.7 mmol/24 h (n = 10). Childhood infections have caused no undue problems. Psychometric assessment indicates that he functions at the average range of ability with performance tests slightly above average. We strongly recommend a trial of oral therapy, which is simple and well tolerated, althoughthese are the attributes which caused the parents to question its necessity. Although it might be argued that confirmation of vitamin B12 responsiveness requires withdrawal of therapy with subsequent relapse, this may be dangerous. Our experience shows how long it may take to restore control.
REFERENCES Davies SEC, Isles RA, Stacey TE, Chalmers RA (1990) Creatine metabolism during metabolic perturbations in patients with organic acidurias. Clin Chim Acta 194: 203-218. deSousa C, Chalmers RA, Tracey Bet al (1985) Changes in carnitine and methylmatonate followingwithdrawal of vitamin B12 in B12 responsive methylmalonicaciduria. Pediatr Res 19: 1074. Mahoney MJ, Blick D (1987) Recent advances in the inherited methylmatonicacidemias. Acta Paediatr Scand 76: 689-696.
J. Inher. Metab. Dis. 15 (1992) 940-941
© SSIEM and KluwerAcademicPublishers. Printed in the Netherlands
SHORT REPORT Estimates of uridine diphosphate glucose in human erythrocytes H. N. K i r k m a n Jr.
Ng and coworkers (1989) claim that patients with galactosaemia (galactose-1phosphate uridyltransferase deficiency; McKusick 230400) have a major deficiency of uridine diphosphate galactose (UDPGal), the product of the transferase that is deficient in galactosaemia. In the hope of preventing or reversing some of the latemanifesting complications of galactosaemia, they have proposed giving galactosaemic children uridine, which is said to raise the level of UDPGal. Kirkman (1992), however, has stated the following: (a) There is no biochemical reason why there should be such a deficiency when an unaffected enzyme, epimerase, is able to make UDPGal. (b) He found no major deficiency of UDPGat when he used an enzymic assay similar to that of Ng and coworkers. (c) The normal values of erythrocytic UDPGal and uridine diphosphate glucose (UDPG) are only 1/5 of the values claimed by Ng and coworkers. Using HPLC methods, members of the laboratory of Dr Stanton Segal have Brain and Development Research Center and Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7250, USA J. lnher. Metab. Dis. 15 (1992)
