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The rett syndrome and CSF lactic acid patterns
SHORT COMMUNICATION
The Rett Syndrome and CSF Lactic Acid Patterns Toyojiro Matsuishi, MD, Fujiko Urabe, MD, Hironori Komori, MD, Yushiro Yamashita, MD, Etsuo Naito, MD, Yasuhiro Kuroda, MD, Mizuho Horikawa, MD and Etsuo Ohtaki, MD
We investigated both blood and cerebrospinal fluid (CSF) lactate and pyruvate levels in seven girls with the Rett syndrome (RS) and evaluated the relationship between CSF lactate and pyruvate levels and the clinical manifestations, particularly seizures, anticonvUlsant medication, and breathing dysfunction including breath holding, apnea and hyperventilation. Elevated lactate and pyruvate levels in CSF with normal serum lactate were found in two RS patients. Elevated CSF lactate correlated significantly with the clinical occu"ence of hyperventilation (Po = 0.048, Fisher exact probability). We measured native and dichloroacetate (DCA)-activated pyruvate dehydrogenase (PDH) complex activities in two patients (#1 and 2) using cultured lymphoblastoid cell lines which were transformed by EB virus and the results were normal. We also analyzed CSF citric acid intermediates from 7 RS patients including citric acid, cis-aconitate, CY.-ketoglutarate, succinate, fumarate, malate and oxaloacetate. These concentrations were not significantly different from those control patients (N = 21). An elevated lactate level may be a clue to clarify the etiology of RS. Key words: Rett syndrome, lactic acid, citric acid, pyruvate dehydrogenase complex, cerebrospinal fluid. Matsuishi T, Urabe F, Komori H, Yamashita Y, Naito E, Kuroda Y, Horikawa M, Ohtaki E. The Rett syndrome and CSF lactic acid patterns. Bntin Dev1992; 14:68-70
From the Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume (fM, FU, HK, YY, MH, EO); Department of Pediatrics, University of Tokushima School of Medicine, Tokushima (EN, YK). Received for pUblication: August 7, 1991. Accepted for pUblication: November 6,1991. Correspondence address: Dr. Toyojiro Matsuishi, Department of Pediatrics and Child Health, Kurume University School of Medicine 67 Asahi-machi, Kurume 830, Japan.
The Rett syndrome (RS) is a progressive neurodegenerative disorder of unknown etiology. Breathing abnormalities and epileptic seizures are also common [1]. Previous studies of amino acids, organic acids, lysosomal enzymes, biotin, biotinidase, neurotransmitters and their metabolites, neuropeptides and other biochemical parameters have failed to reveal consistent abnormalities. Recently, three reports suggest that the etiology of RS may be due to mitochondrial abnormalities [2-4] . Haas et al reported mild elevations of blood lactate and pyruvate levels in seven patients with RS [5]. However, lactate and pyruvate levels in cerebrospinal fluid (CSF) have not been reported. We report our CSF data and discuss the possibility of mitochondrial abnormalities. PATIENTS AND METHODS
Seven patients who fulfilled criteria for classical RS, were recruited for this study. Three of the patients were children aged 4-11, the other 4 adults ages 24-35 years. Cerebrospinal fluid (CSF) specimen were obtained from all RS patients and 21 control patients with informed consent either the parents or the control patients themselves. Control patients were as follows; 16 orthopedic or gynecologic patients, 2 others without any neurological symptoms, and 3 pediatric control patients including 2 meningismus and 1 mycoplama pneurnomia with normal CSF and without neurological symptoms and signs. Seven RS patients were evaluated in terms of clinical stage and magnetic resonance imaging (MRl) scans were performed in all with a 0.5 Tesla superconductive magnet (STM-50; Shirnazu, Japan). All RS patients were studied by analyzing both blood (enzyme method) and CSF lactate and pyruvate levels by high performance liquid chromatography (HPLC) and CSF citric acid intermediates using a modified method of Haas et al [6]. We performed HPLC twice, once at 36°C and a second time at 50°C using two Animex HPX-871 columns. For the analysis, both peak height and area were used to determine concentrations. The mobile phase was 0.002 M sulfuric acid, delivered at 0.7 ml/min. Column effluents were monitored spectrophotometrically at 205 nm. The mean (± SD) concentrations of the intermediates in controls at 36°C were as follows; citrate 266.18 (± 57.91) pg/ml, cis-aconitate 1.66 (± 0.28), fumarate 0.46 (± 0.25), malate 64.25 (± 16.55), oxaloacetate 3.07 (± 1.23), pyruvate 84.49 (± 10 .82), and lactate 1225.72 (± 134.28). The retention times for a-ketoglutarate and succinate were similar with that for oxaloacetate and lactate respectively, preventing separate determinations. At 50°C, we could separate them and found the mean (± SD) concentration to be, a-ketoglutarate 1.50 (± 0.83), and sccinate 385.37 (± 105.98). We evaluated the relationship between the concentrations of blood and CSF lactate, CSF pyruvate, and CSF citric acid intermediates and the following clinical
Table I Pyruvate and lactate concentration in blood and cerebrospinal fluid (CSF) Case
Age
1 2 3 4 5 6 7
11 4 10 24 35 26 31
controls
Blood (nmol/l) Lactate Pyruvate
CSF (mmol/l) Lactate Pyruvate
0.95 1.29 0.85 1.06 0.99 0.89 1.04
0.108 0.146 0.087 0.083 0.048 0.041 0.045
2.32 1.72 1.27 1.36 1.13 1.11 0.99
0.154 0.139 0.086 0.094 0.090 0.080 0.060
0.3-1.3
0.03-0.08
1.37 ± 0.34
0.087 ± 0.027
BH: Breath holding, HV: Hyperventilation,
2 3 4 5 6 7
pco 2
pa,
BE
BH
HV
7.59 7.42 7.41 7.42 7.39 7.40 7.41
15.8 40.1 42.4 40.0 41.4 39.0 35.2
76.6 69.8 51.9 77.0 92.0 86.0 91.0
-2.0 +2.2 +2.4 +1.9 +0.7 +0.1 -1.0
+
+ +
+
*
+
* (Po =0.048 Fisher exact probability).
Table 2 Clinical stage and MRI findings Case
Acid base balance PH
Stage
MRI findings
Pseudostationary Pseudostationary Pseudosta tionary Late motor deterioration Late motor deterioration Late motor deterioration Late motor deterioration
Normal Mild FCA Normal CFD, marked FTA, LVD Moderate FTA, LVD Moderate FTA, LVD CFD, Moderate FTA, LVD
FCA: Frontal cortical atrophy, CFD: Craniofacial disproportion, FTA: Frontal and temporal lobe atrophy, LVD: Lateral venticle dilation. (Stage: The Rett Syndrome Diagnostic Criteria Work Group, [1))
manifestations; seizures, anticonvulsant medications, breath holding, apnea and hyperventilation. If patients showed elevated lactate levels in blood or CSF, we measured native and dichloroacetate (DCA)activated pyruvate dehydrogenase (PDH) complex activities using cultured lymphoblastoid cell lines which were transformed by EB virus. RESULTS Elevated lactate and pyruvate levels in CSF with normal serum lactate were found in two RS patients (#1 and 2). Elevated CSF lactete correlated significantly with the clinical occurrence of hyperventilation (Po =0.048, Fisher exact probability) (Table 1) and not correlated with advanced clinical stage and MRI fmdings (Table 2). Native and dichloroacetate (DCA)-activated pyruvate dehydrogenase (PDH) complex activities in the two patients (#1 and 2) were normal. All citric acid intermediates in our seven patients were normal. Our patients had normal blood acid-base balance and mean PC0 2 values in the normal range with no evidence of alkalosis except patient 1.
DISCUSSION The Rdt syndrome is a progressive neurodegenerative disorder of unknown etiology. Our hypothesis is that mitochondrial dysfunction may play an important role in RS. The cause of elevated lactate and pyruvate concentration could be due to 1) abnormal carbohydrate metabolism such as PDH defiCiency, 2) tissue ischemia, 3) defects in citric acid cycle metabolism or phosphorylation, and 4) hyperventilation with alkalosis [7]. Tissue hypoxia and seizures also produce lactic acidosis and prominent apneic periods could elevate lactate levels. Our two patients (#1 and #2) did not manifest any seizure activity. Brain MRI would be helpful to eliminate the possibility that cerebral ischemia resulted in elevated lactate levels in CSF. Patient 1 showed normal MRI fmdings and patient 2 revealed mild frontal cortical atrophy (Table 2), therefore the possibility of a chronic hypoxic condition in the central nervous system might not play an important role. It is known that in steady state a diffusion eqUilibrium exists between CSF and cerebral tissue fluids [8]. We directly measured citric acid cycle intermediates and revealed normal results. Hyper~ ventilation with alkalosis was not likely the cause for the elevated CSF lactate and pyruvate in this case, because patients 2 showed normal acid base balance (Table 1). Carbohydrate metabolism in the central nervous system or abnormalities of oxidative phosphorylation could cause elevated lactate levels, and these two mechanisms could cause elevated lactic levels in the CNS in RS. Respiratory abnormalities including hyperventilation and/or apnea are well known signs of metabolic disorders such as PDH complex deficiency, pyruvate carboxylase deficiency, thiamine deficiency, the respiratory chain deficiency and Leigh disease. In 1988, Brown et al reported markedly elevated concentrations of CSF lactate and pyruvate, but normal or only slightly elevated blood lactate and pyruvate in six patients having neurological disabilities. This
Matsuishi et al: Rett syndrome and CSF lactate 69
led them to term the condition as "cerebral lactic acidosis [9]." Their patients revealed extremely high CSF lactate (6.7-8.6) and five of their six patients showed PDH complex defects in cultured fibroblast. Prick et al discribed a 16-month-old infant in whom lactate concentration was elevated in CSF with normal blood lactate content. They found PDH deficiency restricted to brain [10]. Elevated lactate concentration in CSF with normal serum lactate content might be considered consistent with altered mitochondrial function in the brain. Five of our patients did not show evidence of lactate elevation in CSF. This may indicate that RS could be a heterogeneous group of disorders or the finding could be age dependent. It is uncertain whether lactic acid is the primary or secondary phenomenon. The etiology of RS has so far been a mystery. Elevated CSF lactate levels may be a clue to clarify the etiology. Metabolic investigation, especially PDH complex activity of postmortem brain tissue, might give us an important information. ACKNOWLEDGMENTS Our work was partly supported by grant 2A-5B-32 from the National Center of Neurology & Psychiatry of the Ministry of Health and Welfare, Japan. We wish to thank Dr. Alan Percy and Dr. Makoto Yoshino for their valuable advice.
REFERENCES 1. The Rett Syndrome Diagnostic Criteria Work Group. Diagnostic Criteria for Rett syndrome. Ann Neurol 1988;23: 425-8. 2. Eeg-Qlofsson 0, AI-Zuhair AGH, Teebi AS, et al. Rett syndrome: a mitochondrial disease? J Child Neurol 1990;5: 210-4. 3. Wakai S, Kameda K, Ishikawa Y, et al. Rett syndrome: Findings suggesting axonopathy and mitochondrial abnormalities. Pediatr Neurol 1990;6: 339-43. 4. Coker SB, Melnyk AR. Rett syndrome and mitochondrial enzyme deficiencies. J Child Neurol 1991;6:164-6. 5. Haas RH, Rice MA, Trauner DA, et al. Therapeutic effects of a ketogenic diet in Rett syndrome. Am J Med Genet 1986;24 (suppl1): 225-46. 6. Haas RH, Breuer J, Hammen M. High performance liquid chroma tographic measurement of selected blood citric acid . cycle intermediates. J Chromatogr 1988;425:47-57. 7. Huckable WA. Relationship of pyruvate and lactate during anaerobic metabolism II. Exercise and formation O2 debt. J Clin Invest 1958;37: 255-63. 8. Levine R, Haft DE. Carbohydrate homeostasis. N Engl J Med 1970;283: 175. 9. Brown GK, Haan EA, Kirby DM, et al. "Cerebral" lactic acidosis: defects in pyruvate metabolism with profound brain damage and minimal systemic acidosis. Eur J Pediatr 1988; 147:10-4. 10. Prick M, GabreiHs F, Renier W, et al. Pyruvate dehydrogenase deficiency restricted to brain. Neurology 1981;31:398-404.
NATO Advanced Research Workshop and the Joseph Roger's Day The 4th International Workshop on Childhood Epilepsies will be held in Marseille, France, on June 23-26,1992. It is organized by Charlotte Dravet, Centre Saint-Paul (Marseille, France), Fritz Dreifuss,
Charlottesville (Virginia, USA) and Cesare Lombroso, Boston (Massachusetts, USA). The topic is "Epilepsies and generalized epileptic syndromes before the age of 6."
This workshop will be followed by a Scientific Day in honour of Joseph Roger, on June 27, 1992. For further information and registration please contact: Dr Michelle Bureau, AREP, 300 Bd de Sainte-Marguerite, 13009, Marseille, France.
70 Brain & Development, Vol 14, No 1, 1992
The Rett Syndrome and CSF Lactic Acid Patterns Toyojiro Matsuishi, MD, Fujiko Urabe, MD, Hironori Komori, MD, Yushiro Yamashita, MD, Etsuo Naito, MD, Yasuhiro Kuroda, MD, Mizuho Horikawa, MD and Etsuo Ohtaki, MD
We investigated both blood and cerebrospinal fluid (CSF) lactate and pyruvate levels in seven girls with the Rett syndrome (RS) and evaluated the relationship between CSF lactate and pyruvate levels and the clinical manifestations, particularly seizures, anticonvUlsant medication, and breathing dysfunction including breath holding, apnea and hyperventilation. Elevated lactate and pyruvate levels in CSF with normal serum lactate were found in two RS patients. Elevated CSF lactate correlated significantly with the clinical occu"ence of hyperventilation (Po = 0.048, Fisher exact probability). We measured native and dichloroacetate (DCA)-activated pyruvate dehydrogenase (PDH) complex activities in two patients (#1 and 2) using cultured lymphoblastoid cell lines which were transformed by EB virus and the results were normal. We also analyzed CSF citric acid intermediates from 7 RS patients including citric acid, cis-aconitate, CY.-ketoglutarate, succinate, fumarate, malate and oxaloacetate. These concentrations were not significantly different from those control patients (N = 21). An elevated lactate level may be a clue to clarify the etiology of RS. Key words: Rett syndrome, lactic acid, citric acid, pyruvate dehydrogenase complex, cerebrospinal fluid. Matsuishi T, Urabe F, Komori H, Yamashita Y, Naito E, Kuroda Y, Horikawa M, Ohtaki E. The Rett syndrome and CSF lactic acid patterns. Bntin Dev1992; 14:68-70
From the Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume (fM, FU, HK, YY, MH, EO); Department of Pediatrics, University of Tokushima School of Medicine, Tokushima (EN, YK). Received for pUblication: August 7, 1991. Accepted for pUblication: November 6,1991. Correspondence address: Dr. Toyojiro Matsuishi, Department of Pediatrics and Child Health, Kurume University School of Medicine 67 Asahi-machi, Kurume 830, Japan.
The Rett syndrome (RS) is a progressive neurodegenerative disorder of unknown etiology. Breathing abnormalities and epileptic seizures are also common [1]. Previous studies of amino acids, organic acids, lysosomal enzymes, biotin, biotinidase, neurotransmitters and their metabolites, neuropeptides and other biochemical parameters have failed to reveal consistent abnormalities. Recently, three reports suggest that the etiology of RS may be due to mitochondrial abnormalities [2-4] . Haas et al reported mild elevations of blood lactate and pyruvate levels in seven patients with RS [5]. However, lactate and pyruvate levels in cerebrospinal fluid (CSF) have not been reported. We report our CSF data and discuss the possibility of mitochondrial abnormalities. PATIENTS AND METHODS
Seven patients who fulfilled criteria for classical RS, were recruited for this study. Three of the patients were children aged 4-11, the other 4 adults ages 24-35 years. Cerebrospinal fluid (CSF) specimen were obtained from all RS patients and 21 control patients with informed consent either the parents or the control patients themselves. Control patients were as follows; 16 orthopedic or gynecologic patients, 2 others without any neurological symptoms, and 3 pediatric control patients including 2 meningismus and 1 mycoplama pneurnomia with normal CSF and without neurological symptoms and signs. Seven RS patients were evaluated in terms of clinical stage and magnetic resonance imaging (MRl) scans were performed in all with a 0.5 Tesla superconductive magnet (STM-50; Shirnazu, Japan). All RS patients were studied by analyzing both blood (enzyme method) and CSF lactate and pyruvate levels by high performance liquid chromatography (HPLC) and CSF citric acid intermediates using a modified method of Haas et al [6]. We performed HPLC twice, once at 36°C and a second time at 50°C using two Animex HPX-871 columns. For the analysis, both peak height and area were used to determine concentrations. The mobile phase was 0.002 M sulfuric acid, delivered at 0.7 ml/min. Column effluents were monitored spectrophotometrically at 205 nm. The mean (± SD) concentrations of the intermediates in controls at 36°C were as follows; citrate 266.18 (± 57.91) pg/ml, cis-aconitate 1.66 (± 0.28), fumarate 0.46 (± 0.25), malate 64.25 (± 16.55), oxaloacetate 3.07 (± 1.23), pyruvate 84.49 (± 10 .82), and lactate 1225.72 (± 134.28). The retention times for a-ketoglutarate and succinate were similar with that for oxaloacetate and lactate respectively, preventing separate determinations. At 50°C, we could separate them and found the mean (± SD) concentration to be, a-ketoglutarate 1.50 (± 0.83), and sccinate 385.37 (± 105.98). We evaluated the relationship between the concentrations of blood and CSF lactate, CSF pyruvate, and CSF citric acid intermediates and the following clinical
Table I Pyruvate and lactate concentration in blood and cerebrospinal fluid (CSF) Case
Age
1 2 3 4 5 6 7
11 4 10 24 35 26 31
controls
Blood (nmol/l) Lactate Pyruvate
CSF (mmol/l) Lactate Pyruvate
0.95 1.29 0.85 1.06 0.99 0.89 1.04
0.108 0.146 0.087 0.083 0.048 0.041 0.045
2.32 1.72 1.27 1.36 1.13 1.11 0.99
0.154 0.139 0.086 0.094 0.090 0.080 0.060
0.3-1.3
0.03-0.08
1.37 ± 0.34
0.087 ± 0.027
BH: Breath holding, HV: Hyperventilation,
2 3 4 5 6 7
pco 2
pa,
BE
BH
HV
7.59 7.42 7.41 7.42 7.39 7.40 7.41
15.8 40.1 42.4 40.0 41.4 39.0 35.2
76.6 69.8 51.9 77.0 92.0 86.0 91.0
-2.0 +2.2 +2.4 +1.9 +0.7 +0.1 -1.0
+
+ +
+
*
+
* (Po =0.048 Fisher exact probability).
Table 2 Clinical stage and MRI findings Case
Acid base balance PH
Stage
MRI findings
Pseudostationary Pseudostationary Pseudosta tionary Late motor deterioration Late motor deterioration Late motor deterioration Late motor deterioration
Normal Mild FCA Normal CFD, marked FTA, LVD Moderate FTA, LVD Moderate FTA, LVD CFD, Moderate FTA, LVD
FCA: Frontal cortical atrophy, CFD: Craniofacial disproportion, FTA: Frontal and temporal lobe atrophy, LVD: Lateral venticle dilation. (Stage: The Rett Syndrome Diagnostic Criteria Work Group, [1))
manifestations; seizures, anticonvulsant medications, breath holding, apnea and hyperventilation. If patients showed elevated lactate levels in blood or CSF, we measured native and dichloroacetate (DCA)activated pyruvate dehydrogenase (PDH) complex activities using cultured lymphoblastoid cell lines which were transformed by EB virus. RESULTS Elevated lactate and pyruvate levels in CSF with normal serum lactate were found in two RS patients (#1 and 2). Elevated CSF lactete correlated significantly with the clinical occurrence of hyperventilation (Po =0.048, Fisher exact probability) (Table 1) and not correlated with advanced clinical stage and MRI fmdings (Table 2). Native and dichloroacetate (DCA)-activated pyruvate dehydrogenase (PDH) complex activities in the two patients (#1 and 2) were normal. All citric acid intermediates in our seven patients were normal. Our patients had normal blood acid-base balance and mean PC0 2 values in the normal range with no evidence of alkalosis except patient 1.
DISCUSSION The Rdt syndrome is a progressive neurodegenerative disorder of unknown etiology. Our hypothesis is that mitochondrial dysfunction may play an important role in RS. The cause of elevated lactate and pyruvate concentration could be due to 1) abnormal carbohydrate metabolism such as PDH defiCiency, 2) tissue ischemia, 3) defects in citric acid cycle metabolism or phosphorylation, and 4) hyperventilation with alkalosis [7]. Tissue hypoxia and seizures also produce lactic acidosis and prominent apneic periods could elevate lactate levels. Our two patients (#1 and #2) did not manifest any seizure activity. Brain MRI would be helpful to eliminate the possibility that cerebral ischemia resulted in elevated lactate levels in CSF. Patient 1 showed normal MRI fmdings and patient 2 revealed mild frontal cortical atrophy (Table 2), therefore the possibility of a chronic hypoxic condition in the central nervous system might not play an important role. It is known that in steady state a diffusion eqUilibrium exists between CSF and cerebral tissue fluids [8]. We directly measured citric acid cycle intermediates and revealed normal results. Hyper~ ventilation with alkalosis was not likely the cause for the elevated CSF lactate and pyruvate in this case, because patients 2 showed normal acid base balance (Table 1). Carbohydrate metabolism in the central nervous system or abnormalities of oxidative phosphorylation could cause elevated lactate levels, and these two mechanisms could cause elevated lactic levels in the CNS in RS. Respiratory abnormalities including hyperventilation and/or apnea are well known signs of metabolic disorders such as PDH complex deficiency, pyruvate carboxylase deficiency, thiamine deficiency, the respiratory chain deficiency and Leigh disease. In 1988, Brown et al reported markedly elevated concentrations of CSF lactate and pyruvate, but normal or only slightly elevated blood lactate and pyruvate in six patients having neurological disabilities. This
Matsuishi et al: Rett syndrome and CSF lactate 69
led them to term the condition as "cerebral lactic acidosis [9]." Their patients revealed extremely high CSF lactate (6.7-8.6) and five of their six patients showed PDH complex defects in cultured fibroblast. Prick et al discribed a 16-month-old infant in whom lactate concentration was elevated in CSF with normal blood lactate content. They found PDH deficiency restricted to brain [10]. Elevated lactate concentration in CSF with normal serum lactate content might be considered consistent with altered mitochondrial function in the brain. Five of our patients did not show evidence of lactate elevation in CSF. This may indicate that RS could be a heterogeneous group of disorders or the finding could be age dependent. It is uncertain whether lactic acid is the primary or secondary phenomenon. The etiology of RS has so far been a mystery. Elevated CSF lactate levels may be a clue to clarify the etiology. Metabolic investigation, especially PDH complex activity of postmortem brain tissue, might give us an important information. ACKNOWLEDGMENTS Our work was partly supported by grant 2A-5B-32 from the National Center of Neurology & Psychiatry of the Ministry of Health and Welfare, Japan. We wish to thank Dr. Alan Percy and Dr. Makoto Yoshino for their valuable advice.
REFERENCES 1. The Rett Syndrome Diagnostic Criteria Work Group. Diagnostic Criteria for Rett syndrome. Ann Neurol 1988;23: 425-8. 2. Eeg-Qlofsson 0, AI-Zuhair AGH, Teebi AS, et al. Rett syndrome: a mitochondrial disease? J Child Neurol 1990;5: 210-4. 3. Wakai S, Kameda K, Ishikawa Y, et al. Rett syndrome: Findings suggesting axonopathy and mitochondrial abnormalities. Pediatr Neurol 1990;6: 339-43. 4. Coker SB, Melnyk AR. Rett syndrome and mitochondrial enzyme deficiencies. J Child Neurol 1991;6:164-6. 5. Haas RH, Rice MA, Trauner DA, et al. Therapeutic effects of a ketogenic diet in Rett syndrome. Am J Med Genet 1986;24 (suppl1): 225-46. 6. Haas RH, Breuer J, Hammen M. High performance liquid chroma tographic measurement of selected blood citric acid . cycle intermediates. J Chromatogr 1988;425:47-57. 7. Huckable WA. Relationship of pyruvate and lactate during anaerobic metabolism II. Exercise and formation O2 debt. J Clin Invest 1958;37: 255-63. 8. Levine R, Haft DE. Carbohydrate homeostasis. N Engl J Med 1970;283: 175. 9. Brown GK, Haan EA, Kirby DM, et al. "Cerebral" lactic acidosis: defects in pyruvate metabolism with profound brain damage and minimal systemic acidosis. Eur J Pediatr 1988; 147:10-4. 10. Prick M, GabreiHs F, Renier W, et al. Pyruvate dehydrogenase deficiency restricted to brain. Neurology 1981;31:398-404.
NATO Advanced Research Workshop and the Joseph Roger's Day The 4th International Workshop on Childhood Epilepsies will be held in Marseille, France, on June 23-26,1992. It is organized by Charlotte Dravet, Centre Saint-Paul (Marseille, France), Fritz Dreifuss,
Charlottesville (Virginia, USA) and Cesare Lombroso, Boston (Massachusetts, USA). The topic is "Epilepsies and generalized epileptic syndromes before the age of 6."
This workshop will be followed by a Scientific Day in honour of Joseph Roger, on June 27, 1992. For further information and registration please contact: Dr Michelle Bureau, AREP, 300 Bd de Sainte-Marguerite, 13009, Marseille, France.
70 Brain & Development, Vol 14, No 1, 1992