1224
permanent blindness due to bilateral optic atrophy. Blood and muscle specimens showed a mitochondrial DNA mutation at nt 11778 of ND4. Electronmicroscopical analysis of muscle revealed clusters of abnormally numerous and somewhat enlarged mitochondria both between the myofibrils and below the sarcolemma.9 Later, he became alcoholic with epileptic seizures, alcohol gastritis, and pancreatitis. In 1981, he had primary syphilis, treated with antibiotics. In October, 1991, the patient was admitted with hallucinations and headache. He was conscious but disoriented. Temperature was 37-9°C. Apart from mild sinus tachycardia, physical examination was normal and laboratory tests were normal. There were no signs of infection in urine or on chest radiography. Cerebrospinal fluid (CSF) was normal. Semiquantitative serum analysis for benzodiazepines gave a weak positive reaction. Arterial blood gas analysis showed pH 7-35, PaC02 83 kPa, base excess + 65, and Pa02 60 kPa. After some hours he was alert and discharged himself. The next morning the patient returned and was increasingly restless. Incipient delirium tremens was suspected and a 50 mg tablet of oxazepam was given. After a couple of hours his respiratory rate slowed. He was cyanotic; blood gas analysis showed pH 7 31, PACO, 9 IkPa, and Pa02 60 kPa. In the intensive care unit, he was given intravenous flumazenil to antagonise the benzodiazepine. This treatment was initially beneficial, but eventually PACO, rose to 14 9 kPa. He was intubated and artificially ventilated. Repeated CSF tap was normal. Computed tomography of the brain showed only mild cortical atrophy. 24 hours later the patient recovered with no further need for artificial ventilation. When asked, he admitted having taken oxazepam at home before admission. The patient was transferred to a psychiatric ward because of delirium. Later he was instructed not to use benzodiazepines and was discharged. The acute episode of severe hypoventilation was associated with oxazepam administration. The biochemical nature of ND4 mutation is not clear, although decrease in the oxidation rate of NAD-linked substrates in patients with this mutation has been demonstrated.15,9 The defect is reflected also in structurally abnormal mitochondria in muscle biopsy specimens of patients with LHON,4,9 as seen in our case. The clinical symptoms of mitochondriopathies are ascribed to energy failure in selected tissues, especially in those with high oxidative energy production. LHON mainly affects optic nerves but the disease is not restricted to the visual pathways. Patients may develop severe cardiac and neurological symptoms. Apparently, in mitochondriopathies including LHON, various tissues function on the verge of failure. This is supported by sudden metabolic incompensations described in other n-jitochondriopathies.11 Departments of Ophthalmology and Internal Medicine; Department of Pathology, Division of Neuropathology; and Department of Clinical Genetics, University of Turku, Turku 20520,
Finland; and Department of Medical Chemistry, University of Helsinki, Helsinki
E. NIKOSKELAINEN M. ASOLA H. KALIMO M-L. SAVONTAUS A. MAJANDER
1. Nikoskelainen EK. Leber hereditary optic neuropathy. Curr Opin Ophthalmol 1991; 2: 531-37. 2. Brown MD, Voljavec AS, Lott MT, Torroni A, Yang CC, Wallace DC. Mitochondrial DNA complex I and III mutations associated with Leber’s hereditary optic neuropathy. Genetics 1992; 130: 163-73. 3. MajanderA, Huoponen K, Savontaus M-L, Nikoskelainen R, Wikstrom M. Electron transfer properties of NADH-ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON). FEBS Lett 1991; 292: 289-92. 4. Larsson N-G, Anderson O, Holme E, Oldfors A, Wahlström J. Leber’s hereditary optic neuropathy and complex I deficiency in muscle. Ann Neurol 1991; 30: 701-08. 5. Howell N, Bindoff LA, McCullough DA, et al. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet 1991; 49: 939-50 6. Bower SPC, Hawley I, Mackey DA. Cardiac arrhythmia and Leber’s hereditary optic neuropathy. Lancet 1992; 339: 1427-28. 7. Hunter AR. Idiopathic alveolar hypoventilation in Leber’s disease. Unusual sensitivity to mild analgesic and diazepam. Anaesthesia 1984; 39: 781-83.
8. Nikoskelainen E, Hoyt WF, Nummelin K. Ophthalmoscopic findings in Leber’s hereditary optic neuropathy II The fundus findings in the affected family members. Arch Ophthalmol 1983; 101: 1059-68. 9. Nikoskelainen E, Hassinen IE, Paljarvi L, Lang H, Kalimo H. Leber’s hereditary optic neuroretinopathy, a mitochondrial disease? Lancet 1984; ii: 1474. 10. Morgan-Hughes JA. Mitochondrial diseases. In: Mastaglia FL, Lord Walton of Detchant, eds. Skeletal muscle pathology. Edinburgh: Churchill Livingstone,
1992; 367-424.
Magnesium deficiency and cardiovascular disease SiR,—Iread with interest, and with some fulfillment, Dr Woods and colleagues’ article (the LIMIT-2 trial, June 27, p 1553) on the possible role of magnesium in the pathogenesis, prevention, and treatment of cardiovascular disease. Reviewing previous work, I was unable to find any studies predating our own that demonstrated rather convincingly the effect of magnesium deficiency not only in the pathogenesis of cardiovascular atherosclerosis in rats, dogs, and non-human primates but with the regressions of these lesions, on administration of high levels of dietary magnesium (4 to 6 x normal requirements) in animals with lesions induced by feeding and which were maintained on atherogenic diets.1-5 The basis of having undertaken these studies in the late 1950s and early 1960s was our previous observation that magnesium deficiency uncoupled oxidative phosphorylation in isolated mitochondria as did the administration of thyroxine which seemed to increase magnesium requirements Also, we noted defects in oxidative phosphorylation by heart mitochondria in young rats after only four days on a magnesium-deficient diet. At this time no change in the oxidative phosphorylation of liver or kidney mitochondria was shown.1 Thus, the metabolism of cardiac tissue seemed to be
peculiarly susceptible to magnesium deprivation. The mechanism by which magnesium deficiency exerts itself is not clear but there are several possibilities. One is, as we have shown, that magnesium deficiency enhances metastatic calcification, especially in the kidney, and could be expected to result in hypertension leading to cardiovascular atherosclerosis, which, indeed, occurred.2,7Another possibility is that the hypercholesterolaemia that arises with an atherogenic diet results in an increased magnesium requirement since the beneficial effects of high dietary magnesium occurred without affecting the serum cholesterol or lipid concentrations.1-5 Finally, magnesium deficiency may enhance the pathogenesis of coronary atherosclerosis not only by disrupting oxidative processes, potassium transport across cell membranes, and transmembrane potentials,5,8 but also by influencing the oxidation of low-densitylipoprotein cholesterol, which is receiving some attention as an enhancing mediator of coronary heart disease.9,10 I am not sure of its origin but the saying, "What goes around, comes around", remains appropriate. In 1976, the President’s Biological Research Panel (USA) addressed itself to the lags between initial discovery and clinical application in cardiovascular pulmonary medicine and surgery. In view of the lag times among the 132 discoveries listed and the first clinical application in just this one specialty, 43 were applied in less than 10 years; 27 in 10-24 years; 39 in 25-49 years; 18 in 50-90 years, and 5 in 100 years or more.lIs it not time to look beyond dietary cholesterol and eggs and fat, and so on, and perhaps look at micronutrients, anti-oxidants, and vitamins and their possible aetiological and therapeutic roles?
Department of Pathology, Nutrition Pathology Unit, Boston University School of Medicine, Boston, Massachusetts 02118, USA
JOSEPH J. VITALE
1. Vitale
JJ, White PL, Nakamura M, et al. Interrelationships between experimental hypercholesterolaemia, magnesium requirement and experimental atherosclerosis. J Exp Med 1957; 106: 757-66. 2. Hellerstein EE, Vitale JJ, White PL, et al. Influence ofdietary magnesium on cardiac and renal lesions in young rats fed an atherogenic diet.J Exp Med 1957; 106: 767-76.
3. Nakamura M, Vitale JJ, Hegsted DM, Hellerstein EE. The effect of dietary magnesium and thyroxine on progression and regression of cardiovascular lipid deposition in the rat, J Nutr 1960; 7: 347-55. 4. Vitale JJ, Hellerstein EE, Nakamura M, Lown B. Effects of magnesium-deficient diet upon puppies. Circ Res 1961; 9: 387-94.
1225
5.Vitale JJ, Velez H, Guzman C, Correa P. Cali-Harvard Nutrition Project IV, magnesium deficiency in the cebus monkey. Circ Res 1963; 12: 642-50. 6. Vitale JJ, Hegsted DM, Nakamura M, Connors P. The effect of thyroxine on magnesium requirement. J Biol Chem 1957; 226: 597-601. 7. Vitale JJ, Hellerstein EE, Hegsted DM, Nakamura M, Farbman A. Studies on the interrelatonships between dietary magnesium and calcium in atherogenesis and renal lesions. Am J Clin Nutr 1959; 7: 13-22. 8. Seta K, Kleiger R, Hellerstein EE, Lown B, Vitale JJ. Effect of potassium and
magnesium deficiency on the electrocardiogram and plasma electrolytes of pure-bred beagles. Am J Cardiol 1966; 17: 516-19. 9. Salonen JT, Ylä-Herttuala S, Yamamoto R, et al. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet 1992; 339: 883-87. 10. Regnstrom J, Nilsson J, Tornvall P, Landou C, Hamsten A. Susceptibility to low-density lipoprotein oxidation and coronary atherosclerosis in man. Lancet 1992; 339: 1183-86. 11. Vitale JJ. Issues and advances in human and clinical nutrition In: Vitale JJ, Broitman SA, eds. Advances in human and clinical nutrition. Boston: John Wright PSG,
pulmonary immunological defect in both regulatory T-cell and secretory B-cell functions. Despite hypergammaglobulinaemia, replacement therapy with intravenous IgG has much to recommend it,5 since it increases pulmonary IgG subclass concentrations in subjects with ALD and respiratory bacterial infections.2 a severe
Istituto di Clinica Medica 1, Università di Perugia, Policlinico Monteluce, I-06100 Perugia, Italy
FABRIZIO SPINOZZI ELISABETTA AGEA ROBERTO GERLI CHRISTOPHER MUSCAT ONELIA BISTONI
Istituto di Clinica Pediatrica, Universita di Perugia
ALBERTO BERTOTTO
1982: 1-6. 1. Umetsu R, Ambrosino DM, Quinti I, Siber GR, Geha RS. Recurrent sinopulmonary
infection and impaired antibody response to bacterial capsular polysaccharide antigen in children with selective IgG subclass deficiency. N Engl J Med 1985; 313:
Hypergammaglobulinaemia and IgG subclass deficiency
2.
SIR,-Dr Shield and colleagues (Aug 22, p 448) report hypergammaglobulinaemia and IgG2 subclass deficiency in children. They conclude that these patients may be one end of a clinical spectrum that includes others with recurrent infections and many similar clinical features but without abnormalities in
IgG
subclass distribution. These findings, which are similar to those of others,l might result from an abnormal or delayed maturation of the humoral immune system. As Shield et al point out, however, some cases may be explained on the basis of chronic immunological
challenge. We have documented IgG2 and IgG4 deficiency in five of fifteen patients with alcoholic liver disease (ALD) and a history of respiratory bacterial infections, in whom hypergammaglobulinaemia with raised total IgG and IgA concentrations was clearly evident.2 However, when the IgG concentrations were measured in bronchoalveolar lavage (BAL) fluid samples, 70% of cases proved to have a defect in IgG subclass distribution (IgGl, IgG2, and IgG4). All six ALD patients who had very low IgGl (
permanent blindness due to bilateral optic atrophy. Blood and muscle specimens showed a mitochondrial DNA mutation at nt 11778 of ND4. Electronmicroscopical analysis of muscle revealed clusters of abnormally numerous and somewhat enlarged mitochondria both between the myofibrils and below the sarcolemma.9 Later, he became alcoholic with epileptic seizures, alcohol gastritis, and pancreatitis. In 1981, he had primary syphilis, treated with antibiotics. In October, 1991, the patient was admitted with hallucinations and headache. He was conscious but disoriented. Temperature was 37-9°C. Apart from mild sinus tachycardia, physical examination was normal and laboratory tests were normal. There were no signs of infection in urine or on chest radiography. Cerebrospinal fluid (CSF) was normal. Semiquantitative serum analysis for benzodiazepines gave a weak positive reaction. Arterial blood gas analysis showed pH 7-35, PaC02 83 kPa, base excess + 65, and Pa02 60 kPa. After some hours he was alert and discharged himself. The next morning the patient returned and was increasingly restless. Incipient delirium tremens was suspected and a 50 mg tablet of oxazepam was given. After a couple of hours his respiratory rate slowed. He was cyanotic; blood gas analysis showed pH 7 31, PACO, 9 IkPa, and Pa02 60 kPa. In the intensive care unit, he was given intravenous flumazenil to antagonise the benzodiazepine. This treatment was initially beneficial, but eventually PACO, rose to 14 9 kPa. He was intubated and artificially ventilated. Repeated CSF tap was normal. Computed tomography of the brain showed only mild cortical atrophy. 24 hours later the patient recovered with no further need for artificial ventilation. When asked, he admitted having taken oxazepam at home before admission. The patient was transferred to a psychiatric ward because of delirium. Later he was instructed not to use benzodiazepines and was discharged. The acute episode of severe hypoventilation was associated with oxazepam administration. The biochemical nature of ND4 mutation is not clear, although decrease in the oxidation rate of NAD-linked substrates in patients with this mutation has been demonstrated.15,9 The defect is reflected also in structurally abnormal mitochondria in muscle biopsy specimens of patients with LHON,4,9 as seen in our case. The clinical symptoms of mitochondriopathies are ascribed to energy failure in selected tissues, especially in those with high oxidative energy production. LHON mainly affects optic nerves but the disease is not restricted to the visual pathways. Patients may develop severe cardiac and neurological symptoms. Apparently, in mitochondriopathies including LHON, various tissues function on the verge of failure. This is supported by sudden metabolic incompensations described in other n-jitochondriopathies.11 Departments of Ophthalmology and Internal Medicine; Department of Pathology, Division of Neuropathology; and Department of Clinical Genetics, University of Turku, Turku 20520,
Finland; and Department of Medical Chemistry, University of Helsinki, Helsinki
E. NIKOSKELAINEN M. ASOLA H. KALIMO M-L. SAVONTAUS A. MAJANDER
1. Nikoskelainen EK. Leber hereditary optic neuropathy. Curr Opin Ophthalmol 1991; 2: 531-37. 2. Brown MD, Voljavec AS, Lott MT, Torroni A, Yang CC, Wallace DC. Mitochondrial DNA complex I and III mutations associated with Leber’s hereditary optic neuropathy. Genetics 1992; 130: 163-73. 3. MajanderA, Huoponen K, Savontaus M-L, Nikoskelainen R, Wikstrom M. Electron transfer properties of NADH-ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON). FEBS Lett 1991; 292: 289-92. 4. Larsson N-G, Anderson O, Holme E, Oldfors A, Wahlström J. Leber’s hereditary optic neuropathy and complex I deficiency in muscle. Ann Neurol 1991; 30: 701-08. 5. Howell N, Bindoff LA, McCullough DA, et al. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet 1991; 49: 939-50 6. Bower SPC, Hawley I, Mackey DA. Cardiac arrhythmia and Leber’s hereditary optic neuropathy. Lancet 1992; 339: 1427-28. 7. Hunter AR. Idiopathic alveolar hypoventilation in Leber’s disease. Unusual sensitivity to mild analgesic and diazepam. Anaesthesia 1984; 39: 781-83.
8. Nikoskelainen E, Hoyt WF, Nummelin K. Ophthalmoscopic findings in Leber’s hereditary optic neuropathy II The fundus findings in the affected family members. Arch Ophthalmol 1983; 101: 1059-68. 9. Nikoskelainen E, Hassinen IE, Paljarvi L, Lang H, Kalimo H. Leber’s hereditary optic neuroretinopathy, a mitochondrial disease? Lancet 1984; ii: 1474. 10. Morgan-Hughes JA. Mitochondrial diseases. In: Mastaglia FL, Lord Walton of Detchant, eds. Skeletal muscle pathology. Edinburgh: Churchill Livingstone,
1992; 367-424.
Magnesium deficiency and cardiovascular disease SiR,—Iread with interest, and with some fulfillment, Dr Woods and colleagues’ article (the LIMIT-2 trial, June 27, p 1553) on the possible role of magnesium in the pathogenesis, prevention, and treatment of cardiovascular disease. Reviewing previous work, I was unable to find any studies predating our own that demonstrated rather convincingly the effect of magnesium deficiency not only in the pathogenesis of cardiovascular atherosclerosis in rats, dogs, and non-human primates but with the regressions of these lesions, on administration of high levels of dietary magnesium (4 to 6 x normal requirements) in animals with lesions induced by feeding and which were maintained on atherogenic diets.1-5 The basis of having undertaken these studies in the late 1950s and early 1960s was our previous observation that magnesium deficiency uncoupled oxidative phosphorylation in isolated mitochondria as did the administration of thyroxine which seemed to increase magnesium requirements Also, we noted defects in oxidative phosphorylation by heart mitochondria in young rats after only four days on a magnesium-deficient diet. At this time no change in the oxidative phosphorylation of liver or kidney mitochondria was shown.1 Thus, the metabolism of cardiac tissue seemed to be
peculiarly susceptible to magnesium deprivation. The mechanism by which magnesium deficiency exerts itself is not clear but there are several possibilities. One is, as we have shown, that magnesium deficiency enhances metastatic calcification, especially in the kidney, and could be expected to result in hypertension leading to cardiovascular atherosclerosis, which, indeed, occurred.2,7Another possibility is that the hypercholesterolaemia that arises with an atherogenic diet results in an increased magnesium requirement since the beneficial effects of high dietary magnesium occurred without affecting the serum cholesterol or lipid concentrations.1-5 Finally, magnesium deficiency may enhance the pathogenesis of coronary atherosclerosis not only by disrupting oxidative processes, potassium transport across cell membranes, and transmembrane potentials,5,8 but also by influencing the oxidation of low-densitylipoprotein cholesterol, which is receiving some attention as an enhancing mediator of coronary heart disease.9,10 I am not sure of its origin but the saying, "What goes around, comes around", remains appropriate. In 1976, the President’s Biological Research Panel (USA) addressed itself to the lags between initial discovery and clinical application in cardiovascular pulmonary medicine and surgery. In view of the lag times among the 132 discoveries listed and the first clinical application in just this one specialty, 43 were applied in less than 10 years; 27 in 10-24 years; 39 in 25-49 years; 18 in 50-90 years, and 5 in 100 years or more.lIs it not time to look beyond dietary cholesterol and eggs and fat, and so on, and perhaps look at micronutrients, anti-oxidants, and vitamins and their possible aetiological and therapeutic roles?
Department of Pathology, Nutrition Pathology Unit, Boston University School of Medicine, Boston, Massachusetts 02118, USA
JOSEPH J. VITALE
1. Vitale
JJ, White PL, Nakamura M, et al. Interrelationships between experimental hypercholesterolaemia, magnesium requirement and experimental atherosclerosis. J Exp Med 1957; 106: 757-66. 2. Hellerstein EE, Vitale JJ, White PL, et al. Influence ofdietary magnesium on cardiac and renal lesions in young rats fed an atherogenic diet.J Exp Med 1957; 106: 767-76.
3. Nakamura M, Vitale JJ, Hegsted DM, Hellerstein EE. The effect of dietary magnesium and thyroxine on progression and regression of cardiovascular lipid deposition in the rat, J Nutr 1960; 7: 347-55. 4. Vitale JJ, Hellerstein EE, Nakamura M, Lown B. Effects of magnesium-deficient diet upon puppies. Circ Res 1961; 9: 387-94.
1225
5.Vitale JJ, Velez H, Guzman C, Correa P. Cali-Harvard Nutrition Project IV, magnesium deficiency in the cebus monkey. Circ Res 1963; 12: 642-50. 6. Vitale JJ, Hegsted DM, Nakamura M, Connors P. The effect of thyroxine on magnesium requirement. J Biol Chem 1957; 226: 597-601. 7. Vitale JJ, Hellerstein EE, Hegsted DM, Nakamura M, Farbman A. Studies on the interrelatonships between dietary magnesium and calcium in atherogenesis and renal lesions. Am J Clin Nutr 1959; 7: 13-22. 8. Seta K, Kleiger R, Hellerstein EE, Lown B, Vitale JJ. Effect of potassium and
magnesium deficiency on the electrocardiogram and plasma electrolytes of pure-bred beagles. Am J Cardiol 1966; 17: 516-19. 9. Salonen JT, Ylä-Herttuala S, Yamamoto R, et al. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet 1992; 339: 883-87. 10. Regnstrom J, Nilsson J, Tornvall P, Landou C, Hamsten A. Susceptibility to low-density lipoprotein oxidation and coronary atherosclerosis in man. Lancet 1992; 339: 1183-86. 11. Vitale JJ. Issues and advances in human and clinical nutrition In: Vitale JJ, Broitman SA, eds. Advances in human and clinical nutrition. Boston: John Wright PSG,
pulmonary immunological defect in both regulatory T-cell and secretory B-cell functions. Despite hypergammaglobulinaemia, replacement therapy with intravenous IgG has much to recommend it,5 since it increases pulmonary IgG subclass concentrations in subjects with ALD and respiratory bacterial infections.2 a severe
Istituto di Clinica Medica 1, Università di Perugia, Policlinico Monteluce, I-06100 Perugia, Italy
FABRIZIO SPINOZZI ELISABETTA AGEA ROBERTO GERLI CHRISTOPHER MUSCAT ONELIA BISTONI
Istituto di Clinica Pediatrica, Universita di Perugia
ALBERTO BERTOTTO
1982: 1-6. 1. Umetsu R, Ambrosino DM, Quinti I, Siber GR, Geha RS. Recurrent sinopulmonary
infection and impaired antibody response to bacterial capsular polysaccharide antigen in children with selective IgG subclass deficiency. N Engl J Med 1985; 313:
Hypergammaglobulinaemia and IgG subclass deficiency
2.
SIR,-Dr Shield and colleagues (Aug 22, p 448) report hypergammaglobulinaemia and IgG2 subclass deficiency in children. They conclude that these patients may be one end of a clinical spectrum that includes others with recurrent infections and many similar clinical features but without abnormalities in
IgG
subclass distribution. These findings, which are similar to those of others,l might result from an abnormal or delayed maturation of the humoral immune system. As Shield et al point out, however, some cases may be explained on the basis of chronic immunological
challenge. We have documented IgG2 and IgG4 deficiency in five of fifteen patients with alcoholic liver disease (ALD) and a history of respiratory bacterial infections, in whom hypergammaglobulinaemia with raised total IgG and IgA concentrations was clearly evident.2 However, when the IgG concentrations were measured in bronchoalveolar lavage (BAL) fluid samples, 70% of cases proved to have a defect in IgG subclass distribution (IgGl, IgG2, and IgG4). All six ALD patients who had very low IgGl (
