European Journal of
Pediatrics
Letters to the editors
9 Springer-Verlag1991
Eur J Pediatr (1991) 150 : 684 034061999100136L
Organic aciduria in Pearson syndrome
Table 1. Urinary organic acids excretion (mmol/mol creatinine) in patient with Pearson's syndrome
C. Jakobs, P. Danse, and A. J. P. Veerman
Organic acid
Patient
Controls
Department of Paediatrics, Free University Hospital, Postbus 7057, Amsterdam, The Netherlands
L 3HB 2-Ketoglutarate Fumarate Malate
160-8492 253-1560 100- 540 150-1020 144-1380
40-150 20-100 30-100 10- 50 5- 30
Sir: Pearson syndrome (McKusick 26056) is a fatal disorder involving the haemapoietic system, exocrine pancreas, liver and kidneys presenting with failure to thrive [2]. Recently the observation of high lactate/pyruvate ratios in plasma and abnormal oxidative phosphorylation in lymphocytes led to the postulation that Pearson syndrome belongs to the group of mitochondrial cytopathies, the first of non-neuromuscular expression [4]. Rotig et al. [3] have confirmed a mitochondrial (mt)D N A deletion, affecting mitochondrially encoded components of the respiratory chain. The demonstration that rearrangements of the mitochondrial genome between direct D N A repeats were consistently found in all tissues tested confirmed that this disease is in fact a multisystem disorder, as suggested by the clinical course [1]. We had the opportunity to study a patient with Pearson syndrome, presenting with the classic symptoms described above. A 3563 bp mitochondrial-DNA deletion was detected in fibroblasts involving the N A D H dehydrogenase subunits 4 and 4L and parts of subunits 3 and 5 of complex I of the mitochondrial respiratory chain. Metabolic investigations in our patient showed elevated blood lactate (L), pyruvate (P), 3-hydroxybutyrate (3HB) and acetoacetate (AA) with clearly increased L/P and 3 H B / A A ratios, L 2300-7000 gM/1 (controls [C] < 2000 pM/1); pyruvate 86-246 gM/l (C < 150 gM/1); 3HB 218-4165 gM/1 (C < 90 gM/1) and A A 43-212 pM/1 (C < 40 pM/1); L/P 16-38 (C < 20) and 3 H B / A A 5-20 (C < 3), as described in other cases [4]. Our biochemical investigations also included the analysis of amino acids and organic acids in urine. From the age of 1 year, in addition to the excretion of lactic acid and 3-hydroxybutyrate the child invariably showed hyperaminoaciduria and excreted elevated amounts of the citric acid cycle intermediates 2-ketoglutarate, fumarate and malate (Table 1). A mitochondrial respiratory chain defect results in an increase of reducing equivalents within both mitochon-
Abbreviations: AA = acetoacetate; C = controls; 3HB = 3-hy- I droxybutyrate; L = lactate; P = pyruvate
I
dria and the cytoplasm, therefore an increase of both ketone body and L/P molar ratio is to be expected in the plasma of affected individuals. The disturbed N A D H / N A D ratio in our patient clearly also affects the functioning of the citric acid cycle mainly at the level of the N A D H / N A D dependent malate dehydrogenase leading to increased production and excretion of organic acids. This has not been described before in Pearson Syndrome. We suggest that when a similar urinary organic acid profile is found upon routine metabolic screening the investigation of the respiratory chain and mitochondrial D N A is indicated. Furthermore in those patients with a clinical presentation suggesting Pearson syndrome or other mitochondrial cytopathies, the investigation of urinary organic acids should be included, along with blood L/P and ketone body molar ratio.
Acknowledgements. We are very grateful for the confirmation of the Mt-DNA deletion in the patients fibroblasts by Dr. A. R6tig and Dr. A.Munnich (Unit6 de Recherches sur les Handicaps Gdn6tiques de l'Enfant, INSERM U-12, H6pital des EnfantsMalades, Paris, France).
References 1. Cormier V, Rotig A, Quartino AR, Forni GL, Cerone R, Maier M, Saudubray JM, Munnich A (1990) Widespread multitissue deletions of the mitochondrial genome in the Pearson marrow-pancreas syndrome. J Pediatr 117:599-602 2. Pearson HA, Lobel JS, Kocoshis SA, Naiman JL, Windmiller J, Lammi AT, Hoffman R (1979) A new syndrome of refractory sideroblastic anemia with yacuolization of marrow precursors and exocrine pancreatic dysfunction. J Pediatr 95 : 976-984 3. R6tig A, Colonna M, Bonnefont JP, Blanche S, Fischer A, Saudubray JM, Munnich A (1989) Mitochondrial DNA deletion in Pearson's marrow-pancreas syndrome. Lancet I : 902-903 4. R6tig A, Cormier V, Blanche S, Bonnefont JP, Ledeist F, Romero N, Schmitz J, Rustin P, Fischer A, Saudubray JM, Munnich A (1990) Pearson's marrow-pancreas syndrome: a multisystem mitochondrial disorder in infancy. J Clin Invest 86: 1601-1608
Pediatrics
Letters to the editors
9 Springer-Verlag1991
Eur J Pediatr (1991) 150 : 684 034061999100136L
Organic aciduria in Pearson syndrome
Table 1. Urinary organic acids excretion (mmol/mol creatinine) in patient with Pearson's syndrome
C. Jakobs, P. Danse, and A. J. P. Veerman
Organic acid
Patient
Controls
Department of Paediatrics, Free University Hospital, Postbus 7057, Amsterdam, The Netherlands
L 3HB 2-Ketoglutarate Fumarate Malate
160-8492 253-1560 100- 540 150-1020 144-1380
40-150 20-100 30-100 10- 50 5- 30
Sir: Pearson syndrome (McKusick 26056) is a fatal disorder involving the haemapoietic system, exocrine pancreas, liver and kidneys presenting with failure to thrive [2]. Recently the observation of high lactate/pyruvate ratios in plasma and abnormal oxidative phosphorylation in lymphocytes led to the postulation that Pearson syndrome belongs to the group of mitochondrial cytopathies, the first of non-neuromuscular expression [4]. Rotig et al. [3] have confirmed a mitochondrial (mt)D N A deletion, affecting mitochondrially encoded components of the respiratory chain. The demonstration that rearrangements of the mitochondrial genome between direct D N A repeats were consistently found in all tissues tested confirmed that this disease is in fact a multisystem disorder, as suggested by the clinical course [1]. We had the opportunity to study a patient with Pearson syndrome, presenting with the classic symptoms described above. A 3563 bp mitochondrial-DNA deletion was detected in fibroblasts involving the N A D H dehydrogenase subunits 4 and 4L and parts of subunits 3 and 5 of complex I of the mitochondrial respiratory chain. Metabolic investigations in our patient showed elevated blood lactate (L), pyruvate (P), 3-hydroxybutyrate (3HB) and acetoacetate (AA) with clearly increased L/P and 3 H B / A A ratios, L 2300-7000 gM/1 (controls [C] < 2000 pM/1); pyruvate 86-246 gM/l (C < 150 gM/1); 3HB 218-4165 gM/1 (C < 90 gM/1) and A A 43-212 pM/1 (C < 40 pM/1); L/P 16-38 (C < 20) and 3 H B / A A 5-20 (C < 3), as described in other cases [4]. Our biochemical investigations also included the analysis of amino acids and organic acids in urine. From the age of 1 year, in addition to the excretion of lactic acid and 3-hydroxybutyrate the child invariably showed hyperaminoaciduria and excreted elevated amounts of the citric acid cycle intermediates 2-ketoglutarate, fumarate and malate (Table 1). A mitochondrial respiratory chain defect results in an increase of reducing equivalents within both mitochon-
Abbreviations: AA = acetoacetate; C = controls; 3HB = 3-hy- I droxybutyrate; L = lactate; P = pyruvate
I
dria and the cytoplasm, therefore an increase of both ketone body and L/P molar ratio is to be expected in the plasma of affected individuals. The disturbed N A D H / N A D ratio in our patient clearly also affects the functioning of the citric acid cycle mainly at the level of the N A D H / N A D dependent malate dehydrogenase leading to increased production and excretion of organic acids. This has not been described before in Pearson Syndrome. We suggest that when a similar urinary organic acid profile is found upon routine metabolic screening the investigation of the respiratory chain and mitochondrial D N A is indicated. Furthermore in those patients with a clinical presentation suggesting Pearson syndrome or other mitochondrial cytopathies, the investigation of urinary organic acids should be included, along with blood L/P and ketone body molar ratio.
Acknowledgements. We are very grateful for the confirmation of the Mt-DNA deletion in the patients fibroblasts by Dr. A. R6tig and Dr. A.Munnich (Unit6 de Recherches sur les Handicaps Gdn6tiques de l'Enfant, INSERM U-12, H6pital des EnfantsMalades, Paris, France).
References 1. Cormier V, Rotig A, Quartino AR, Forni GL, Cerone R, Maier M, Saudubray JM, Munnich A (1990) Widespread multitissue deletions of the mitochondrial genome in the Pearson marrow-pancreas syndrome. J Pediatr 117:599-602 2. Pearson HA, Lobel JS, Kocoshis SA, Naiman JL, Windmiller J, Lammi AT, Hoffman R (1979) A new syndrome of refractory sideroblastic anemia with yacuolization of marrow precursors and exocrine pancreatic dysfunction. J Pediatr 95 : 976-984 3. R6tig A, Colonna M, Bonnefont JP, Blanche S, Fischer A, Saudubray JM, Munnich A (1989) Mitochondrial DNA deletion in Pearson's marrow-pancreas syndrome. Lancet I : 902-903 4. R6tig A, Cormier V, Blanche S, Bonnefont JP, Ledeist F, Romero N, Schmitz J, Rustin P, Fischer A, Saudubray JM, Munnich A (1990) Pearson's marrow-pancreas syndrome: a multisystem mitochondrial disorder in infancy. J Clin Invest 86: 1601-1608
