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Metabolic stroke in methylmalonic acidemia five years after liver transplantation
Metabolic stroke in methylmalonic acidemia five years after liver transplantation Anupam Chakrapani, MD, MRCP, MRCPCH, P. Sivakumar, MRCS, MRCP, FRCPCH, DCH, P. J. McKiernan, BSc, MRCP, FRCPCH, and J. V. Leonard, PhD, FRCP, FRCPCH It is believed that liver transplantation may improve the outcome of early onset methylmalonic acidemia. We report a case of methylmalonic acidemia in which successful liver transplantation in infancy failed to prevent neurologic damage caused by a metabolic stroke. (J Pediatr 2002;140:261-3)
Conventional treatment of methylmalonic acidemia (MMA) includes dietary protein restriction, bicarbonate, carnitine, and metronidazole, but complications are frequent and the outcome disappointing.1 The course of severely affected patients is characterized by recurrent life-threatening episodes of metabolic decompensation.2 Permanent neurologic damage may occur during these episodes, resulting in extrapyramidal signs such as hypertonicity, loss of speech, dystonic posturing, and dysphagia.3-5 On neuroimaging, such patients are found to have symmetrical changes in the basal ganglia that may involve the internal capsules.6 The poor outlook for severely affected patients receiving conventional treatment has prompted a search for more effective forms of therapy, one of which is liver transplantation (LT). Though experience with LT in MMA is limited, it is already clear that the procedure carries a very high perioperative risk.7 However, patients who have sur-
vived the procedure appear to have done relatively well.7-9 We report a case of neonatal-onset MMA in which successful LT in infancy failed to prevent basal ganglia injury.
CASE REPORT The patient is the fourth child of consanguineous Asian parents who have 3 other healthy children. She became symptomatic on the 5th day of life with poor feeding, tachypnea, and seizures. Initial biochemical investigations showed hypoglycemia (blood glucose, 1.2 mmol/L), hyperammonemium (peak blood ammonium, 497 µmol/L), and metabolic acidosis (bicarbonate, 13 mmol/L). A large peak of methylmalonic acid was present in the urine, but there was no hyperhomocystinemia. The diagnosis of MMA was confirmed, as propionate incorporation studies on cultured fibroblasts were markedly abnormal (propionate
From The Liver Unit, Birmingham Children’s Hospital, Luton and Dunstable Hospital, Luton, and the Biochemistry, Endocrinology, and Metabolism Unit, Institute of Child Health, London, United Kingdom.
Submitted for publication Apr 26, 2001; revision received Aug 15, 2001; accepted Nov 12, 2001. Reprint requests: A. Chakrapani, MD, Consultant in Inherited Metabolic Disease, Birmingham Children’s Hospital, Birmingham B5 6NH, United Kingdom. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/22/121698 doi:10.1067/mpd.2002.121698
incorporation without vitamin B12 = 8.2 mmol propionate/mmol phenylalanine; with vitamin B12 = 9.4 mmol/mmol phenylalanine; normal controls = 122.0-235.0 mmol/mmol phenylalanine). There was no reduction in urine methylmalonate after a trial of parenteral vitamin B12. Fibroblast methylmalonyl coenzyme A mutase activity was normal, indicating that the underlying biochemical defect involved adenosylcobalamin metabolism (most probably cblB). LT Liver transplantation MMA Methylmalonic acidemia
Despite optimal conventional therapy, the patient had several early episodes of severe decompensation. Developmental delay and hypotonia became evident in infancy. A decision to list her for LT was made, and at 9 months of age, she received a suitable donor liver. After surgery, she had metabolic acidosis and hyperammonemia requiring hemofiltration as well as renal dysfunction and seizures, but these resolved rapidly. Subsequent complications included an episode of rejection, cyclosporine nephrotoxicity, an episode of bronchiolitis requiring ventilation, and portal vein thrombosis with portal hypertension and variceal bleeding. However, there were no episodes of metabolic decompensation after transplantation, and she continued to receive a normal diet. Because the plasma and urine methylmalonate levels were persistently elevated (Fig 1), treatment with bicarbonate and carnitine was continued. There was no further neuroregression, and she had a developmental quotient (Bayley Scales of Infant De261
CHAKRAPANI ET AL
THE JOURNAL OF PEDIATRICS FEBRUARY 2002 speak, or swallow, and there was evidence of established symmetrical damage affecting the basal ganglia on magnetic resonance imaging (Fig 2, B).
DISCUSSION
Fig 1. Urine methylmalonate (MMA) levels before and after transplantation.
Fig 2. A, Axial T2-weighted magnetic resonance imaging scan of the brain 1 week after onset of acute neurologic deterioration shows bilateral symmetrical swelling and abnormal high signal intensity of the basal ganglia (arrows). B, Axial T2-weighted magnetic resonance imaging scan of the brain 3 months later shows persistent symmetrical hyperintensity of the basal ganglia (arrows).
velopment, 2nd ed) of 50 at 3 years of age, in keeping with the pretransplantation developmental assessment. During the next few years her language and social development progressed, and she was able to start schooling, though problems with ataxia, tremor, and incoordination persisted. At the age of 5 years and 6 months, the patient was admitted to the hospital with an episode of pneumonia. Even at the height of the respiratory illness, she had no metabolic acidosis and only mild hyperammonemia (123 µmol/L). One week later, while metabolically stable 262
and clinically improving on intravenous antibiotic therapy, she had an unexpected episode of acute neurologic deterioration with sudden onset of altered consciousness, loss of speech, and hypotonia. A computed tomographic scan at that time was unremarkable. During the next few days, she had severe residual limb and bulbar dystonia. Repeat neuroimaging 1 week after the acute episode revealed bilateral basal ganglia changes (Fig 2, A). Three months later, the patient had intermittent dystonic posturing and evidence of quadriparesis on examination. She was unable to sit,
Patients with the severe forms of MMA are at considerable risk of damage to the basal ganglia; however, the mechanism that is responsible is unknown. Because the onset of severe dystonia in MMA has been associated with acute metabolic decompensation,4,5 it has been proposed that acidosis and hypovolemia secondary to electrolyte depletion are possible etiologic factors.2 However, in our patient this was clearly not the case, which suggests that intrinsic factors are probably the most important. The basal ganglia have high energy requirements in childhood,10 and this may render them particularly vulnerable to damage in conditions associated with impaired brain energy metabolism. Several mechanisms have been proposed that may adversely affect brain energy production in MMA, including inhibition of aerobic oxidation by methylmalonate, inhibition of succinate dehydrogenase, secondary hypoglycemia, and impaired ketone body utilization.11 In addition, methylmalonate and other accumulating metabolites may have direct neurotoxic effects through glutaminergic mechanisms.12 LT (with or without kidney transplantation) has been proposed as a potentially curative treatment for MMA. However, although the transplanted liver is a source of enzymes, it only partially corrects the biochemical defect as the enzyme is expressed in most cells. The procedure has been carried out in a small number of patients and is associated with a very high perioperative mortality rate,13 but those who have survived transplantation appear to have a much reduced risk of recurrent metabolic decompensation. They also tolerate more relaxed protein diets.7
CHAKRAPANI ET AL
THE JOURNAL OF PEDIATRICS
VOLUME 140, NUMBER 2 However, even after LT, these patients continue to excrete large amounts of organic acids in the urine, presumably as a result of persistent enzyme deficiency in other tissues. In particular, MMA levels in cerebrospinal fluid after transplantation remain unchanged.8 With the added potential toxicity of immunosuppressive therapy, patients with MMA remain at risk of neurologic and renal damage even after transplantation.7 Our patient was severely affected, was symptomatic in the neonatal period, had recurrent early metabolic crises, and had transplantation in infancy. Though she had several transplant-related complications, her metabolic condition remained relatively stable for nearly 5 years. She did not decompensate despite having had episodes of severe infections and gastrointestinal bleeding. She was able to tolerate a normal diet, and she made developmental progress. Alkali and carnitine supplements were continued after transplantation. Despite these measures, she had a severely disabling metabolic stroke during an episode of pneumonia, in the absence of signs of overt biochemical decompensation. We would have to conclude that LT only partially corrects the defect in MMA. The enzyme deficiency in the brain is unchanged, and the kidneys are only partially protected at best. The benefits of an improved quality of life with abo-
lition of episodes of decompensation and better protein tolerance must be weighed against the potential for neurologic injury. The decision to perform transplantation in such a patient is therefore a complex one, and a better understanding of the long-term outcome of LT in this condition is necessary. Future studies should focus on the prevention of striatal damage.
6.
7.
8.
9.
REFERENCES 1. Leonard JV. The management and outcome of propionic and methylmalonic acidaemia. J Inherit Metab Dis 1995; 18:430–4. 2. Rosenberg LE, Fenton WA. Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease, 7th ed. New York: McGraw-Hill; 1995. p. 1423-50. 3. Nicolaides P, Leonard J, Surtees R. Neurological outcome of methylmalonic acidaemia. Arch Dis Child 1998;78:508-12. 4. Heindreich R, Natowicz M, Hainline BE, Berman P, Kelly RI, Hillman RE, et al. Acute extrapyramidal syndrome in methylmalonic acidaemia: “metabolic stroke” involving the globus pallidus. J Pediatr 1988;113:1022-7. 5. de Souza C, Peisowicz AT, Brett EM, Leonard JV. Focal changes in the globi pallidi associated with neurological dys-
10.
11.
12.
13.
function in methylmalonic acidaemia. Neuropediatrics 1989;20:199-201. Brismar J, Ozand PT. CT and MR of the brain in disorders of the propionate and methylmalonate metabolism. Am J Neuroradiol 1994;15:1459-73. van’t Hoff W, McKiernan PJ, Surtees RAH, Leonard JV. Liver transplantation for methylmalonic acidaemia. Eur J Pediatr 1999;158(suppl 2):S70-4. Goyens P, Brasseur D, Otte JB, Marchau F, De Laet C, Cavatorta E, et al. Liver transplantation for methylmalonyl CoA mutase deficiency. J Inherit Metab Dis 1997;20(suppl 1):38. Kaplan P, Mazur AM, Smith R, Olthoff K, Maller E, Palmieri M, et al. Transplantation for maple syrup urine disease (MSUD) and methylmalonic acidopathy (MMA). J Inherit Metab Dis 1997;20(suppl 1):37. Smith CB, Sokoloff L. The energy metabolism of the brain. In: Davidson AN, Thompson RHS, editors. The molecular basis of neuropathology. London: Edward Arnold Limited; 1981. Wajner M, Coelho JC. Neurological dysfunction in methylmalonic acidaemia is probably related to the inhibitory effect of methylmalonate on brain energy production. J Inherit Metab Dis 1997;20:761-8. de Mello CF, Begnini J, Jiminez-Bernal RE, Rubin MA, de Bastiani J, de Costa E Jr, et al. Instrastriatal methylmalonic acid administration induces rotational behaviour and convulsions through glutaminergic mechanisms. Brain Res 1996;721:120-5. Leonard JV, Walter JH, McKiernan PJ. The management of organic acidaemias: the role of transplantation. J Inherit Metab Dis 2001;24:309-11.
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263
Conventional treatment of methylmalonic acidemia (MMA) includes dietary protein restriction, bicarbonate, carnitine, and metronidazole, but complications are frequent and the outcome disappointing.1 The course of severely affected patients is characterized by recurrent life-threatening episodes of metabolic decompensation.2 Permanent neurologic damage may occur during these episodes, resulting in extrapyramidal signs such as hypertonicity, loss of speech, dystonic posturing, and dysphagia.3-5 On neuroimaging, such patients are found to have symmetrical changes in the basal ganglia that may involve the internal capsules.6 The poor outlook for severely affected patients receiving conventional treatment has prompted a search for more effective forms of therapy, one of which is liver transplantation (LT). Though experience with LT in MMA is limited, it is already clear that the procedure carries a very high perioperative risk.7 However, patients who have sur-
vived the procedure appear to have done relatively well.7-9 We report a case of neonatal-onset MMA in which successful LT in infancy failed to prevent basal ganglia injury.
CASE REPORT The patient is the fourth child of consanguineous Asian parents who have 3 other healthy children. She became symptomatic on the 5th day of life with poor feeding, tachypnea, and seizures. Initial biochemical investigations showed hypoglycemia (blood glucose, 1.2 mmol/L), hyperammonemium (peak blood ammonium, 497 µmol/L), and metabolic acidosis (bicarbonate, 13 mmol/L). A large peak of methylmalonic acid was present in the urine, but there was no hyperhomocystinemia. The diagnosis of MMA was confirmed, as propionate incorporation studies on cultured fibroblasts were markedly abnormal (propionate
From The Liver Unit, Birmingham Children’s Hospital, Luton and Dunstable Hospital, Luton, and the Biochemistry, Endocrinology, and Metabolism Unit, Institute of Child Health, London, United Kingdom.
Submitted for publication Apr 26, 2001; revision received Aug 15, 2001; accepted Nov 12, 2001. Reprint requests: A. Chakrapani, MD, Consultant in Inherited Metabolic Disease, Birmingham Children’s Hospital, Birmingham B5 6NH, United Kingdom. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/22/121698 doi:10.1067/mpd.2002.121698
incorporation without vitamin B12 = 8.2 mmol propionate/mmol phenylalanine; with vitamin B12 = 9.4 mmol/mmol phenylalanine; normal controls = 122.0-235.0 mmol/mmol phenylalanine). There was no reduction in urine methylmalonate after a trial of parenteral vitamin B12. Fibroblast methylmalonyl coenzyme A mutase activity was normal, indicating that the underlying biochemical defect involved adenosylcobalamin metabolism (most probably cblB). LT Liver transplantation MMA Methylmalonic acidemia
Despite optimal conventional therapy, the patient had several early episodes of severe decompensation. Developmental delay and hypotonia became evident in infancy. A decision to list her for LT was made, and at 9 months of age, she received a suitable donor liver. After surgery, she had metabolic acidosis and hyperammonemia requiring hemofiltration as well as renal dysfunction and seizures, but these resolved rapidly. Subsequent complications included an episode of rejection, cyclosporine nephrotoxicity, an episode of bronchiolitis requiring ventilation, and portal vein thrombosis with portal hypertension and variceal bleeding. However, there were no episodes of metabolic decompensation after transplantation, and she continued to receive a normal diet. Because the plasma and urine methylmalonate levels were persistently elevated (Fig 1), treatment with bicarbonate and carnitine was continued. There was no further neuroregression, and she had a developmental quotient (Bayley Scales of Infant De261
CHAKRAPANI ET AL
THE JOURNAL OF PEDIATRICS FEBRUARY 2002 speak, or swallow, and there was evidence of established symmetrical damage affecting the basal ganglia on magnetic resonance imaging (Fig 2, B).
DISCUSSION
Fig 1. Urine methylmalonate (MMA) levels before and after transplantation.
Fig 2. A, Axial T2-weighted magnetic resonance imaging scan of the brain 1 week after onset of acute neurologic deterioration shows bilateral symmetrical swelling and abnormal high signal intensity of the basal ganglia (arrows). B, Axial T2-weighted magnetic resonance imaging scan of the brain 3 months later shows persistent symmetrical hyperintensity of the basal ganglia (arrows).
velopment, 2nd ed) of 50 at 3 years of age, in keeping with the pretransplantation developmental assessment. During the next few years her language and social development progressed, and she was able to start schooling, though problems with ataxia, tremor, and incoordination persisted. At the age of 5 years and 6 months, the patient was admitted to the hospital with an episode of pneumonia. Even at the height of the respiratory illness, she had no metabolic acidosis and only mild hyperammonemia (123 µmol/L). One week later, while metabolically stable 262
and clinically improving on intravenous antibiotic therapy, she had an unexpected episode of acute neurologic deterioration with sudden onset of altered consciousness, loss of speech, and hypotonia. A computed tomographic scan at that time was unremarkable. During the next few days, she had severe residual limb and bulbar dystonia. Repeat neuroimaging 1 week after the acute episode revealed bilateral basal ganglia changes (Fig 2, A). Three months later, the patient had intermittent dystonic posturing and evidence of quadriparesis on examination. She was unable to sit,
Patients with the severe forms of MMA are at considerable risk of damage to the basal ganglia; however, the mechanism that is responsible is unknown. Because the onset of severe dystonia in MMA has been associated with acute metabolic decompensation,4,5 it has been proposed that acidosis and hypovolemia secondary to electrolyte depletion are possible etiologic factors.2 However, in our patient this was clearly not the case, which suggests that intrinsic factors are probably the most important. The basal ganglia have high energy requirements in childhood,10 and this may render them particularly vulnerable to damage in conditions associated with impaired brain energy metabolism. Several mechanisms have been proposed that may adversely affect brain energy production in MMA, including inhibition of aerobic oxidation by methylmalonate, inhibition of succinate dehydrogenase, secondary hypoglycemia, and impaired ketone body utilization.11 In addition, methylmalonate and other accumulating metabolites may have direct neurotoxic effects through glutaminergic mechanisms.12 LT (with or without kidney transplantation) has been proposed as a potentially curative treatment for MMA. However, although the transplanted liver is a source of enzymes, it only partially corrects the biochemical defect as the enzyme is expressed in most cells. The procedure has been carried out in a small number of patients and is associated with a very high perioperative mortality rate,13 but those who have survived transplantation appear to have a much reduced risk of recurrent metabolic decompensation. They also tolerate more relaxed protein diets.7
CHAKRAPANI ET AL
THE JOURNAL OF PEDIATRICS
VOLUME 140, NUMBER 2 However, even after LT, these patients continue to excrete large amounts of organic acids in the urine, presumably as a result of persistent enzyme deficiency in other tissues. In particular, MMA levels in cerebrospinal fluid after transplantation remain unchanged.8 With the added potential toxicity of immunosuppressive therapy, patients with MMA remain at risk of neurologic and renal damage even after transplantation.7 Our patient was severely affected, was symptomatic in the neonatal period, had recurrent early metabolic crises, and had transplantation in infancy. Though she had several transplant-related complications, her metabolic condition remained relatively stable for nearly 5 years. She did not decompensate despite having had episodes of severe infections and gastrointestinal bleeding. She was able to tolerate a normal diet, and she made developmental progress. Alkali and carnitine supplements were continued after transplantation. Despite these measures, she had a severely disabling metabolic stroke during an episode of pneumonia, in the absence of signs of overt biochemical decompensation. We would have to conclude that LT only partially corrects the defect in MMA. The enzyme deficiency in the brain is unchanged, and the kidneys are only partially protected at best. The benefits of an improved quality of life with abo-
lition of episodes of decompensation and better protein tolerance must be weighed against the potential for neurologic injury. The decision to perform transplantation in such a patient is therefore a complex one, and a better understanding of the long-term outcome of LT in this condition is necessary. Future studies should focus on the prevention of striatal damage.
6.
7.
8.
9.
REFERENCES 1. Leonard JV. The management and outcome of propionic and methylmalonic acidaemia. J Inherit Metab Dis 1995; 18:430–4. 2. Rosenberg LE, Fenton WA. Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease, 7th ed. New York: McGraw-Hill; 1995. p. 1423-50. 3. Nicolaides P, Leonard J, Surtees R. Neurological outcome of methylmalonic acidaemia. Arch Dis Child 1998;78:508-12. 4. Heindreich R, Natowicz M, Hainline BE, Berman P, Kelly RI, Hillman RE, et al. Acute extrapyramidal syndrome in methylmalonic acidaemia: “metabolic stroke” involving the globus pallidus. J Pediatr 1988;113:1022-7. 5. de Souza C, Peisowicz AT, Brett EM, Leonard JV. Focal changes in the globi pallidi associated with neurological dys-
10.
11.
12.
13.
function in methylmalonic acidaemia. Neuropediatrics 1989;20:199-201. Brismar J, Ozand PT. CT and MR of the brain in disorders of the propionate and methylmalonate metabolism. Am J Neuroradiol 1994;15:1459-73. van’t Hoff W, McKiernan PJ, Surtees RAH, Leonard JV. Liver transplantation for methylmalonic acidaemia. Eur J Pediatr 1999;158(suppl 2):S70-4. Goyens P, Brasseur D, Otte JB, Marchau F, De Laet C, Cavatorta E, et al. Liver transplantation for methylmalonyl CoA mutase deficiency. J Inherit Metab Dis 1997;20(suppl 1):38. Kaplan P, Mazur AM, Smith R, Olthoff K, Maller E, Palmieri M, et al. Transplantation for maple syrup urine disease (MSUD) and methylmalonic acidopathy (MMA). J Inherit Metab Dis 1997;20(suppl 1):37. Smith CB, Sokoloff L. The energy metabolism of the brain. In: Davidson AN, Thompson RHS, editors. The molecular basis of neuropathology. London: Edward Arnold Limited; 1981. Wajner M, Coelho JC. Neurological dysfunction in methylmalonic acidaemia is probably related to the inhibitory effect of methylmalonate on brain energy production. J Inherit Metab Dis 1997;20:761-8. de Mello CF, Begnini J, Jiminez-Bernal RE, Rubin MA, de Bastiani J, de Costa E Jr, et al. Instrastriatal methylmalonic acid administration induces rotational behaviour and convulsions through glutaminergic mechanisms. Brain Res 1996;721:120-5. Leonard JV, Walter JH, McKiernan PJ. The management of organic acidaemias: the role of transplantation. J Inherit Metab Dis 2001;24:309-11.
Receive tables of contents by e-mail To receive the tables of contents by e-mail, sign up through our Web site at http://www.mosby.com/jpeds. Choose E-mail Notification. Simply type your e-mail address in the box and click the Subscribe button. Alternatively, you may send an e-mail message to [email protected]. Leave the subject line blank and type the following as the body of your message: subscribe jpeds_toc You will receive an e-mail to confirm that you have been added to the mailing list. Note that table of contents e-mails will be sent out when a new issue is posted to the Web site.
263