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Concomitant administration of sodium dichloroacetate and vitamin B1 for lactic acidemia in children with MELAS syndrome
mitant administration of sodium acetate and vitamin B 1 for lactic acidemia in with MELAS syndrome Yasuhiro Kuroda, AID,PhD,Alichinori Ito, AID,PhD, Etsao Naito, AID,PhD,Ichiro Yokota, AID,PhD, Jan/co AIatsuda, AID, Takahiko Saijo, AID, PhD, Shaft Kondo, AID, Yoshihiro .Yoneda,AID,Alasahito Aliyazaki, AID,PhD,Kenfi Alori, AID,PhD,and Hiro/co Iwanwto
Myoclonic seizures, intractable abdominal pain, and headaches resolved during the concomitant administration of sodium dichloroacetate and vitamin B 1 in two Japanese siblings with the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike syndrome). (J Pediatr 1997; 131:450-2)
The NIELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) is progressive because adequate treatment is not available. 1,2 With the informed consent of the parents, we investigated the therapeutic effect of orally administered sodium dichloroacetate in combination with their previous drug regimens, including vitamin B 1, in two young Japanese siblings with the MELAS syndrome who exhibited progressive neurologic deterioration.
CASE REPORTS Case 1
A Japanese boy, now 6 years of age, had been born by aspiration delive W at the thirty-second week of gestation From the Depart.wat of Pedlao.ics, School of Medicine, University of Tokaahima, and the Kanaga~.a Chikgren'J Medical genre1;Yokohama, Japan. Submitted for publication Feb. 7, 1996; accepted
Nov. 20, 1996. Reprint requests: Yasuhiro Kuroda, MD, PhD, Department of Pediatrics, School of Medicine, University of Tokushlma, 3-Kuramoto-cho,Tokushima770, Japan. Copyright9 1997by Mosby-YearBook,Inc. 0022-3476/97/$5,00 +0 9/22/79487
450
(weight, 1464 gm). His psychomotor development was delayed. At the age of 2 years, he exhibited elevated plasma levels of lactate (8.7 mmol/L; normal range, 0.7 to 2.0) and of pyruvate (0.54 mmol/L; normal range, 0.08 to 0.14). Examination of a muscle biopsy specimen showed ragged red fibers and a reduction in the activity of complex I of the mitochondrial electron transport system (48.2 nmol/min per milligram of protein; control value, 148.2 _+25.5). An A-to-G transition at nucleotide 3243 in the tRNA-Leu(UUR) gene was identified in his leukocytes. At the age of 3 years, the patient suddenly had weakness on the left side, and myoclonic seizures of the left foot developed. Thereafter, he had repeated episodes of vomiting, lethargy, myoclonic seizures, and general elonic convulsions. His condition gradually deteriorated, with worsening of the myoclonic seizures. Therapy with sodium DCA (Tokyo Kasei Kogyo, Tokyo, Japan) was initiated, at a dose of 50 mg/kg body weight given orally every 12 hours. Vitamin B 1 administration was continued, along with previously administered medications (carbamazepine, 250 mg; thiamine hydrochloride, 250 mg; octotiamine, 100 rag; riboflavin phosphate,
30 rag; pyridoxine hydrochloride, 160 mg; cyanocobalamin, 1 mg; ubidecarenone, 40 rag; L-carnitine, 200 mg; sodium succinote, 2 gin; and denopamine, 5 mg. The plasma level of lactate decreased rapidly, falling to less than 5.6 mmol/L 2 days after the addition of DCA to the regimen, and was ultimately maintained in the range of 2.2 to 4.4 mmol/L. The plasma level of DCA fluctuated widely between 5 and 130 btg/ml (Figure). The frequency and severity of the myoclonie seizures decreased markedly during the first month of DCA therapy and virtually disappeared thereafter. The patient's general condition and appetite also improved markedly during treatment. No adverse effects of the drug were observed during administration for 25 months.
Case 2
A 9-year-old Japanese boy, the older brother of patient 1, exhibited normal development until the age of 6 years, when he had persistent headaches and a 3-day episode of vomiting. When he was 7 years of age, genetic study revealed the same Ato-G mutation in the mitochondrial DNA in leukocytes as that observed in his brother (patient 1). Plasma levels of lactate (3.5 mmol/L) and pyruvate (0.16
KURODA ET AL.
THE JOURNAL OF PEDIATRICS Volume 13 I, N u m b e r 3
mmol/L) were both elevated. At the age of 9 years, patient 2 complained of recurrent numbness of the left hand, and he had recurrent episodes of abdominal pain. He then had episodes of vomiting, seizures, and recurrent cerebral insults that resembled strokes and that caused hemiparesis, hemianopia, and cortical blindness. Sodium DCA, 50 mg/kg body weight, was given orally eve W 12 hours. No change was made in the drug regimen, including therapy with vitamin B 1, that had been initiated before the use of sodium DCA (carbamazepine, 200 rag; clonazepam, 0.5 rag; thiamine hydrochloride, 250 mg; octotiamine, 100 mg; riboflavin phosphate, S0 mg; pyridoxine hydrochloride, 160 mg; eyanoeobalamin, 1 mg; ubidecarenone, 60 mg; b-carnitine, 400 mg; sodium succinate, 2 gin; and potassium and sodium citrate, 85S mg). The plasma and eerebrospinal fluid levels of DCA increased, whereas the plasma and CSF levels of lactate decreased and remained within the normal range, even after gradual reduction of the close of sodium DCA to 25 mg/kg per day. No further strokelike episodes were observed after the initiation of sodium DCA therapy, and the patient's intractable abdominal pain and headaches virtually disappeared during continued therapy. No adverse effects of the drug were observed during observation for 22 months. In these studies, plasma and CSF levels of D C A were assayed by high-performance liquid chromatography by means of the modified method of Sakaldhara et aI. 3 The plasma and CSF concentrations of lactate were determined by an enzymatic method.
DISCUSSION DCA increases tile acti~dty of the pyrurate dehydrogenase complex in the brain and other tissues and reduces the plasma and brain levels of lactate in rats in vivo.4 Sodium DCA has been used to treat patients with chronic lactic acidosis related to various congenital defects, but its clinical efficacy varies. 5-9 The therapeutic effect of sodium DCA may perhaps depend
[] Blood DCA I
9 Blood (mmo
100 10
50
Attack 9
1994 Jul 'OOI
Au8
Sop
Oct
5, ,40 DCA (mg/kg/day)
Nov ~
Dec 1995 Jan
Feb
Mar Ap
5'
Figure. Changesin severity and frequency of myoclonic seizuresand in plasmaconcentrations of dichloroacetate and lactate in patient I. Vertical lines indicate severity of myocronic seizures,
on the underlying defects responsible for the lactic acidosis and on the severity of the preexisting neurologic damage. We previously reported that sodium DCA reduced the severity of lactic acidosis and increased the activity of the PDH, as well as tricarbox21ic acid cycle, in a patient with the MELAS syndrome, l~ More recently, De Stefano et al.ll reported that 1 week of D C A treatment reduced the plasma level of lactate and improved the indexes of brain oxidative metabolism and of neuronal and glial density or function in patients with the MELAS syndrome. We previously reported that a patient with the M E L A S syndrome who was having visual and andito W hallucinations responded to the oral administration of sodium DCA. 8 In the present study, sodium DCA was administered orally to two Japanese siblings with the MELAS syndrome because of progressive deterioration. This therapy reduced the plasma and CSF levels of lactate, halted the clinical deterioration, and ultimately improved the quality of life of both patients. DCA stimulates the activity of thiamine-dependent enzymes, including PDH. Long-term treatment with sodium D C A may deplete thiamine stores. The concomitant administration of sodium DCA and thiamine to rats significantly reduced the incidence and severity of toxic
effects of sodium DCA, including neuropathy. 12 Sodium DCA appeared to be safe, at least for short-term use, and to be well tolerated in the children described. 5 This agent is designated as an orphan drug for the long-term treatment of congenital lactic acidosis and homozygous familial hypercholesterolemia. 6 The concomitant administration of sodium DCA and vitamin B 1 may improve the clinical signs and symptoms, and thus the quality of life in children with the MELAS syndrome. Such combination treatment might be effective in treating patients with lactic acidemia of other causes. A prospective clinical trial should be conducted to investigate this possibility.
REFERENCES 1. Pavlalds SG, Phillips PC, DkMauro S, De Vivo DC, Rowland LR MJtochondrialmyopathy, encephalopathy,lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 1984;16:481-8. 2. Montagr~aE Gallassi R, Medori R, Govonl E, Zeviani M, DiMauro S, et al. MELAS syndrome: characteristic migrainous and epileptic features and maternal transmission. Neurology 1988;38:751-4. 3. Sakakihara Y, Nakamura G, Tokoeda Y, Abe T, KamoshitaS. A rapid microassayfor dichloroacetate in serum by gel-permea6on chromatography. Eur d Clin Chem Clin Biochem 1994;32:7%85. 4. Kuroda Y, Toshima K, Watanabe T,
451
KURODA ET AL.
THE JOURNAL OF PEDIATRICS SEPTEMBER 1997
Kobashi H, Ito IV[, Takeda E, et al. Effects of dichloroacetate on pyruvate metabolism in rat brain in vivo. Pediatr Res 1984; 18:936-8. Stacpoole PW. The pharmacology of dichloroacetate. Metabolism 1989;38:112d44. Stacpoole PW, Greene YJ. Dichloroacetate. Diabetes Care 1992;15:785-91. Elpelog ON, Ruitenbeek W,, 3akob C, Barash V, De Vivo DC, Amir N. Congenital lactic acidemia caused by lipoamide dehydrogenase deficiency with favorable outcome. J Pediatr 199b;126:72-q.
O
8. Saijo % Naito E, Ito M, Takeda E, Hashimoto T, Kuroda Y. Therapeutic effect of sodium dicliloroacetate on visual and auditory hallucinations in a patient with MELAS. Neuropediatrics 1991;22: 166-7. 9. Kuroda Y, Ito H, Toshima K, Takeda E, Naito E, Hwang TJ, et al. Treatment of chronic congenital lactic acidosis by oral administration of diehloroaeetate, d Inher Metab Dis 1986;9:244-52. 10. Naito E, Kuroda Y, Toshima K, Takeda E, Saijo T, Kobashi H, et al. Effect of sodium, dichloroacetate on human pyru-
vate metabolism. Brain Dev 1989; 11:1957. 11. De Stefano N, Matthews PM, Ford B, Genge A, Karpati G, Arnold DL. Shortterm dlchloroacetate treatment improves indices of cerebral metabolism in patients with mitochondrial disorders. Neurology 1995;45:1193-8. 12. Stacpoole PW,, Hatwood H J dr, Cameron DF, Curry SH, Samuelson DA, Cornwell PE, et al. Chronic toxicity of dichloroaccrate: possible relation to thiamine deficiency in rats. Fundamental Applied Toxicology 1990;14:327-37.
N THE MOVE? ~en
usyournewa
ressat
east six w e e k s a h e a d
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Myoclonic seizures, intractable abdominal pain, and headaches resolved during the concomitant administration of sodium dichloroacetate and vitamin B 1 in two Japanese siblings with the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike syndrome). (J Pediatr 1997; 131:450-2)
The NIELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) is progressive because adequate treatment is not available. 1,2 With the informed consent of the parents, we investigated the therapeutic effect of orally administered sodium dichloroacetate in combination with their previous drug regimens, including vitamin B 1, in two young Japanese siblings with the MELAS syndrome who exhibited progressive neurologic deterioration.
CASE REPORTS Case 1
A Japanese boy, now 6 years of age, had been born by aspiration delive W at the thirty-second week of gestation From the Depart.wat of Pedlao.ics, School of Medicine, University of Tokaahima, and the Kanaga~.a Chikgren'J Medical genre1;Yokohama, Japan. Submitted for publication Feb. 7, 1996; accepted
Nov. 20, 1996. Reprint requests: Yasuhiro Kuroda, MD, PhD, Department of Pediatrics, School of Medicine, University of Tokushlma, 3-Kuramoto-cho,Tokushima770, Japan. Copyright9 1997by Mosby-YearBook,Inc. 0022-3476/97/$5,00 +0 9/22/79487
450
(weight, 1464 gm). His psychomotor development was delayed. At the age of 2 years, he exhibited elevated plasma levels of lactate (8.7 mmol/L; normal range, 0.7 to 2.0) and of pyruvate (0.54 mmol/L; normal range, 0.08 to 0.14). Examination of a muscle biopsy specimen showed ragged red fibers and a reduction in the activity of complex I of the mitochondrial electron transport system (48.2 nmol/min per milligram of protein; control value, 148.2 _+25.5). An A-to-G transition at nucleotide 3243 in the tRNA-Leu(UUR) gene was identified in his leukocytes. At the age of 3 years, the patient suddenly had weakness on the left side, and myoclonic seizures of the left foot developed. Thereafter, he had repeated episodes of vomiting, lethargy, myoclonic seizures, and general elonic convulsions. His condition gradually deteriorated, with worsening of the myoclonic seizures. Therapy with sodium DCA (Tokyo Kasei Kogyo, Tokyo, Japan) was initiated, at a dose of 50 mg/kg body weight given orally every 12 hours. Vitamin B 1 administration was continued, along with previously administered medications (carbamazepine, 250 mg; thiamine hydrochloride, 250 mg; octotiamine, 100 rag; riboflavin phosphate,
30 rag; pyridoxine hydrochloride, 160 mg; cyanocobalamin, 1 mg; ubidecarenone, 40 rag; L-carnitine, 200 mg; sodium succinote, 2 gin; and denopamine, 5 mg. The plasma level of lactate decreased rapidly, falling to less than 5.6 mmol/L 2 days after the addition of DCA to the regimen, and was ultimately maintained in the range of 2.2 to 4.4 mmol/L. The plasma level of DCA fluctuated widely between 5 and 130 btg/ml (Figure). The frequency and severity of the myoclonie seizures decreased markedly during the first month of DCA therapy and virtually disappeared thereafter. The patient's general condition and appetite also improved markedly during treatment. No adverse effects of the drug were observed during administration for 25 months.
Case 2
A 9-year-old Japanese boy, the older brother of patient 1, exhibited normal development until the age of 6 years, when he had persistent headaches and a 3-day episode of vomiting. When he was 7 years of age, genetic study revealed the same Ato-G mutation in the mitochondrial DNA in leukocytes as that observed in his brother (patient 1). Plasma levels of lactate (3.5 mmol/L) and pyruvate (0.16
KURODA ET AL.
THE JOURNAL OF PEDIATRICS Volume 13 I, N u m b e r 3
mmol/L) were both elevated. At the age of 9 years, patient 2 complained of recurrent numbness of the left hand, and he had recurrent episodes of abdominal pain. He then had episodes of vomiting, seizures, and recurrent cerebral insults that resembled strokes and that caused hemiparesis, hemianopia, and cortical blindness. Sodium DCA, 50 mg/kg body weight, was given orally eve W 12 hours. No change was made in the drug regimen, including therapy with vitamin B 1, that had been initiated before the use of sodium DCA (carbamazepine, 200 rag; clonazepam, 0.5 rag; thiamine hydrochloride, 250 mg; octotiamine, 100 mg; riboflavin phosphate, S0 mg; pyridoxine hydrochloride, 160 mg; eyanoeobalamin, 1 mg; ubidecarenone, 60 mg; b-carnitine, 400 mg; sodium succinate, 2 gin; and potassium and sodium citrate, 85S mg). The plasma and eerebrospinal fluid levels of DCA increased, whereas the plasma and CSF levels of lactate decreased and remained within the normal range, even after gradual reduction of the close of sodium DCA to 25 mg/kg per day. No further strokelike episodes were observed after the initiation of sodium DCA therapy, and the patient's intractable abdominal pain and headaches virtually disappeared during continued therapy. No adverse effects of the drug were observed during observation for 22 months. In these studies, plasma and CSF levels of D C A were assayed by high-performance liquid chromatography by means of the modified method of Sakaldhara et aI. 3 The plasma and CSF concentrations of lactate were determined by an enzymatic method.
DISCUSSION DCA increases tile acti~dty of the pyrurate dehydrogenase complex in the brain and other tissues and reduces the plasma and brain levels of lactate in rats in vivo.4 Sodium DCA has been used to treat patients with chronic lactic acidosis related to various congenital defects, but its clinical efficacy varies. 5-9 The therapeutic effect of sodium DCA may perhaps depend
[] Blood DCA I
9 Blood (mmo
100 10
50
Attack 9
1994 Jul 'OOI
Au8
Sop
Oct
5, ,40 DCA (mg/kg/day)
Nov ~
Dec 1995 Jan
Feb
Mar Ap
5'
Figure. Changesin severity and frequency of myoclonic seizuresand in plasmaconcentrations of dichloroacetate and lactate in patient I. Vertical lines indicate severity of myocronic seizures,
on the underlying defects responsible for the lactic acidosis and on the severity of the preexisting neurologic damage. We previously reported that sodium DCA reduced the severity of lactic acidosis and increased the activity of the PDH, as well as tricarbox21ic acid cycle, in a patient with the MELAS syndrome, l~ More recently, De Stefano et al.ll reported that 1 week of D C A treatment reduced the plasma level of lactate and improved the indexes of brain oxidative metabolism and of neuronal and glial density or function in patients with the MELAS syndrome. We previously reported that a patient with the M E L A S syndrome who was having visual and andito W hallucinations responded to the oral administration of sodium DCA. 8 In the present study, sodium DCA was administered orally to two Japanese siblings with the MELAS syndrome because of progressive deterioration. This therapy reduced the plasma and CSF levels of lactate, halted the clinical deterioration, and ultimately improved the quality of life of both patients. DCA stimulates the activity of thiamine-dependent enzymes, including PDH. Long-term treatment with sodium D C A may deplete thiamine stores. The concomitant administration of sodium DCA and thiamine to rats significantly reduced the incidence and severity of toxic
effects of sodium DCA, including neuropathy. 12 Sodium DCA appeared to be safe, at least for short-term use, and to be well tolerated in the children described. 5 This agent is designated as an orphan drug for the long-term treatment of congenital lactic acidosis and homozygous familial hypercholesterolemia. 6 The concomitant administration of sodium DCA and vitamin B 1 may improve the clinical signs and symptoms, and thus the quality of life in children with the MELAS syndrome. Such combination treatment might be effective in treating patients with lactic acidemia of other causes. A prospective clinical trial should be conducted to investigate this possibility.
REFERENCES 1. Pavlalds SG, Phillips PC, DkMauro S, De Vivo DC, Rowland LR MJtochondrialmyopathy, encephalopathy,lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 1984;16:481-8. 2. Montagr~aE Gallassi R, Medori R, Govonl E, Zeviani M, DiMauro S, et al. MELAS syndrome: characteristic migrainous and epileptic features and maternal transmission. Neurology 1988;38:751-4. 3. Sakakihara Y, Nakamura G, Tokoeda Y, Abe T, KamoshitaS. A rapid microassayfor dichloroacetate in serum by gel-permea6on chromatography. Eur d Clin Chem Clin Biochem 1994;32:7%85. 4. Kuroda Y, Toshima K, Watanabe T,
451
KURODA ET AL.
THE JOURNAL OF PEDIATRICS SEPTEMBER 1997
Kobashi H, Ito IV[, Takeda E, et al. Effects of dichloroacetate on pyruvate metabolism in rat brain in vivo. Pediatr Res 1984; 18:936-8. Stacpoole PW. The pharmacology of dichloroacetate. Metabolism 1989;38:112d44. Stacpoole PW, Greene YJ. Dichloroacetate. Diabetes Care 1992;15:785-91. Elpelog ON, Ruitenbeek W,, 3akob C, Barash V, De Vivo DC, Amir N. Congenital lactic acidemia caused by lipoamide dehydrogenase deficiency with favorable outcome. J Pediatr 199b;126:72-q.
O
8. Saijo % Naito E, Ito M, Takeda E, Hashimoto T, Kuroda Y. Therapeutic effect of sodium dicliloroacetate on visual and auditory hallucinations in a patient with MELAS. Neuropediatrics 1991;22: 166-7. 9. Kuroda Y, Ito H, Toshima K, Takeda E, Naito E, Hwang TJ, et al. Treatment of chronic congenital lactic acidosis by oral administration of diehloroaeetate, d Inher Metab Dis 1986;9:244-52. 10. Naito E, Kuroda Y, Toshima K, Takeda E, Saijo T, Kobashi H, et al. Effect of sodium, dichloroacetate on human pyru-
vate metabolism. Brain Dev 1989; 11:1957. 11. De Stefano N, Matthews PM, Ford B, Genge A, Karpati G, Arnold DL. Shortterm dlchloroacetate treatment improves indices of cerebral metabolism in patients with mitochondrial disorders. Neurology 1995;45:1193-8. 12. Stacpoole PW,, Hatwood H J dr, Cameron DF, Curry SH, Samuelson DA, Cornwell PE, et al. Chronic toxicity of dichloroaccrate: possible relation to thiamine deficiency in rats. Fundamental Applied Toxicology 1990;14:327-37.
N THE MOVE? ~en
usyournewa
ressat
east six w e e k s a h e a d
Don't miss a single issue of the journal! To ensure prompt service when you change your address, please photocopy and complete the form below. Please send your change of address notification at least six weeks before your move to ensure continued service. We regret we cannot guarantee replacement of issues missed due to late notification.
JOURNAL TITLE: Fill in the rifle of the journal here.
OLD ADDRESS:
NEW ADDRESS:
Affix the address label from a recent issue of the journal here.
Clearly print your new address here. Name Address City/State/ZIP
COPY AND MAIL THIS FORM TO: Journal Subscription Services Mosby-Year Book, Inc. 11830 Westline Industrial Dr. St. Louis, MO 63146-3318
452
OR FAX TO:
OR PHONE:
314-432-1158
1-800-453-4351 Outside the U.S., call 314-453-4351
Mosby