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in Childhood Nutrition, F Lifshitz, ed. Boca Raton, FL 1995, Chapt. 17:197-224



Adjunct Professor, Department of Nutrition, School of Public Health, North Carolina University Medical Center, Chapel Hill, N.C.

Adjunct Professor, Department of Community and Preventive Medicine, New York Medical College, Valhalla, New York

The section headers of this paper are as follows:


Infantile cardiovascular lesions that have caused early serious disease or death, and that can contribute to the common arterial and cardiac diseases of later life have been studied for roles of nutritional or genetic factors. It is proposed, here, that absolute or relative dietary magnesium deficiency, which is common, (1-4), might contribute to the complications of these diseases, particularly in mothers and infants with genetic variations in handling magnesium. Reviewed elsewhere is substantial experimental evidence that diets low in magnesium, but otherwise adequate, produce microangiopathy and resultant cardiomyopathy (CMP), and that magnesium deficiency intensifies the thrombogenicity and macroangiopathy caused by atherogenic diets.(4-7) Analysis of reports on infants with cardiovascular lesions resembling those of ischemic heart disease of later life has disclosed abnormalities resembling those of induced magnesium deficiency.(4-8) Data on maternal magnesium inadequacy, as contributory to poor outcomes of pregnancy, have been considered elsewhere.(8-12) Familial patterns of the common cardiovascular diseases suggest that attention be paid to genetic factors in magnesium utilization in afflicted families. Severe metabolic errors, such as isolated malabsorption,(13-17) and renal tubular wasting of magnesium,(18-20) that are associated with hypomagnesemia usually requiring parenteral magnesium therapy to control convulsive and tetanic manifestations, have been shown to be familial.(15,17-20) That such abnormalities may not be an "all or none" phenomenon is suggested by genetic differences in plasma and cellular magnesium levels that have been elicited in different ethnic groups, in Types A and B subjects, in twin studies, and in genetically selected mice.(21-23) Not studied is whether these differences might be contributed to by malabsorption, renal wasting, or differences in membrane permeability to magnesium.

Since magnesium acts like a trace mineral as a cofactor for over 300 enzymes,(24,25) its possible contributory role in genetic diseases involving trace minerals and vitamins, in which arterial disease develops, should be explored. Suggested here is the possibility that the microangiopathy of the common genetic disease, diabetes mellitus, and the cardiomyopathies seen in several inborn errors of metabolism that entail vitamin-dependencies and abnormal mineral metabolism, might also involve function of enzymes in which magnesium is a cofactor.



Magnesium deficiency that results from generalized intestinal malabsorption - whether caused by chronic diarrhea, Crohn's disease, steatorrhea, celiac disease, or sprue, has long been recognized,(26) but is not the subject of this report. The metabolic error: isolated defect of intestinal absorption of magnesium, was first identified in a French Canadian baby.(13,27,28) Soon thereafter it was recognized in American,(29) French,(14-20) Swedish,(16,17) and Italian(30) infants, and then found to be familial when siblings developed the same syndrome.(15,17) As a result of efforts to repair the hypocalcemia by calcium, high dose vitamin D, and parathyroid hormone therapy, in the first identified case of magnesium malabsorption, glomerular and renal interstitial fibrosis developed, with calcification, which was described as a major complication of infantile hypomagnesemia.(13,27,28)

The risk of producing hypercalcemia by calcemic treatment of hypocalcemia in the presence of hypomagnesemia, was cautioned against in an early study of magnesium malabsorption.(26) That low serum magnesium levels could not be relied upon for diagnosis of severe magnesium deficiency of intestinal malabsorption was commented on in a 1981 study of 17 hospitalized patients with severe Crohn's disease, only six of whom had overt hypomagnesemia, but 15 of whom had low urine magnesium.(31)


More frequently diagnosed (generally in older children and in adults) is renal wastage of magnesium,(18-20,32-48) usually but not always in association with hypokalemia or hypocalcemia or both. Two families with members suffering from hypomagnesemia caused by renal magnesium loss were reported in 1966.(18,19) Each renal magnesium wasting syndrome has been reported in more than one family member.(18-20,33,41,43,45,47)

Hypochloremic Hypokalemic Alkalosis with Magnesium Wasting - Bartter's syndrome was diagnosed in a three month old febrile, sweating baby with apathy, weakness and growth failure, and laboratory findings characteristic of that syndrome: hypokalemic hypochloremic alkalosis, hyper-reninism, aldosteronism, and urinary wasting of sodium, as well as of potassium and chloride.(34) Despite only marginally low serum magnesium: mean of 1.7 mEq/L (range: 1.5-1.9), oral magnesium supplementation (6 mg of Mg/kg/day) was prescribed because a muscle biopsy disclosed subnormal magnesium levels (11.6 mEq/kg fat-free weight; normal = 20 +/-1.8). A renal biopsy disclosed hyperplasia of the juxtaglomerular apparatus and cloudy swelling of the proximal tubules. Sustained magnesium supplements lowered his high renin and aldosterone levels and corrected all of the electrolyte and clinical abnormalities, except for slow growth, by 16 months of age. Since this baby's magnesium deficit was not detectable by serum values, the authors suggested that low intracellular magnesium might be more common than suspected in Bartter's syndrome. In another family(47) three siblings had Bartter's syndrome with pronounced hypomagnesemia; necropsy findings of juxtaglomerular hyperplasia were similar to that reported from a renal biopsy from the infant with low muscle magnesium.(34) Renal magnesium wasting has been reported by others in patients with hypokalemic alkalosis as part of Bartter's syndrome [20,40]. In three siblings (two girls and a boy) with familial hypokalemic alkalosis with tubulopathy, rather than the glomerular abnormality generally considered part of Bartter's syndrome, oral magnesium supplements of 40-60 mEq/day as MgCl2 corrected the potassium loss, but had no effect on the elevated renin, and raised the aldosterone levell(41) The hypomagnesemia of two adult sisters in another family was associated with hypokalemic alkalosis, normotensive hyper-reninemism, and marginally high mineralocorticoids.(18)

Renal Tubular Acidosis with Magnesium Wasting - Renal magnesium leakage has also been associated with renal tubular acidosis, usually with hypocalcemia, hypercalciuria and nephrocalcinosis(33,39,40,45) and/or chondro-calcinosis.(32,36,39,42,46) Of two siblings with renal tubular acidosis and nephrocalcinosis, the sister exhibited weakness and trembling, and developed active rickets at ten years of age - manifestations of hypomagnesemia from the renal loss. Suggestive of the possibility that they might have had magnesium inadequacy from birth is the fact that their mother had a history of seven spontaneous abortions;(33) magnesium deficiency is contributory to abortions and preterm births.(4,8,9,11,12) A young boy with renal magnesium wasting, associated with aminoaciduria, glycosuria (at normal to low blood glucose levels), growth retardation and osteoporosis, without intestinal magnesium malabsorption, has been reported to respond well to high dosage oral magnesium supplements;(33) most patients with renal magnesium wasting have required parenteral magnesium treatment.

Renal Damage from Calcemic Therapy of Magnesium-Low Hypocalcemia - Tetany and convulsive seizures characterize both hypomagnesemia and hypocalcemia. The usual clinical pathological testing procedures disclose the calcium deficit, whereas the magnesium deficit is more difficult to detect,(49) an underlying magnesium inadequacy is apt to be missed, and treatment is directed to correction of the hypocalcemia. Since animal studies have shown that magnesium deficient rats, on high calcium intakes, develop calcific lesions in the corticomedullary area of the kidneys, and calcium microliths in the loop and the ascending limb of the loop of Henle (ALLH), the major site of magnesium reabsorption,(5,50-54) it is possible that calcemic therapy, given to hypocalcemic infants and children, who are magnesium deficient, might cause renal tubular lesions in such areas. The laboratory findings, and several clinical data support the premise that calcemic rather than magnesium treatment of hypocalcemia with underlying magnesium deficiency might play a role in long-lasting renal magnesium leakage.

Two of the renal magnesium wasting young men, with hypocalcemia, hypercalciuria and bilateral nephrocalcinosis, as well as chondrocalcinosis, also malabsorbed magnesium.(37) Another young man with chondrocalcinosis and renal magnesium wasting had his disease first diagnosed at the age of six, when hypocalcemic convulsions and hypokalemia failed to improve with calcium and potassium treatment.(36) At that time, a renal biopsy showed intraluminal tubular microliths in the renal corticomedullary area; possibly the ALLH was involved. He, too, was found to be a poor absorber of magnesium. The first reported case, in 1944, of hypomagnesemic osteochondrosis was a six year old boy who had been treated unsuccessfully with high dosage vitamin D for neonatal hypocalcemic tetany and convulsions.(55) His magnesium deficiency was not identified until he was six months of age. Parenteral magnesium then controlled the neuromuscular manifestations, but magnesium supplementation was not sustained. Perhaps magnesium malabsorption caused his early hypomagnesemic hypocalcemia; his later persistent magnesium deficit might have been caused by renal damage-induced magnesium wastage. Another young boy's renal magnesium wasting, that could not be compensated for by oral or parenteral magnesium supplements, developed osteochondritis, and later died of CMP.(32) A child with a comparable history, but without osteochondritis, died with hypertrophic CMP (at 13 years of age).(48) Autopsy of a five month old baby girl, whose convulsions had been unsuccessfully treated with high dose vitamin D and intravenous calcium, and who was found to have profound hypomagnesemia the last day of life,(56) disclosed renal calcinosis, with calcium deposits in proximal tubules and Henle's loop, as well as focal myocardial necrosis and calcium deposits, and coronary arterial calcification. This case report seems supportive of the premise that early calcemic therapy, in the presence of magnesium deficiency (possibly caused by malabsorption), can cause renal tubular damage that diminishes renal magnesium reabsorptive capability. In view of the history of infantile convulsions in four of her siblings, and death of another sibling from cerebral arterial calcification at three months, the metabolic disorder seems to be familial.

Patterns of Hereditary Renal Magnesium Wasting - Three types of hereditary renal hypomagnesemia have been suggested:(43) an autosomal dominant pattern of inheritance is believed to be present in patients with isolated familial hypomagnesemia; an autosomal recessive trait has been suggested in familial hypomagnesemia caused by a low renal magnesium threshold, that is associated with hypokalemia, metabolic alkalosis, hypocalciuria and moderate salt wasting; and familial hypomagnesemic hypercalciuria, caused by a defect in absorption of both magnesium and calcium at the ALLH, with renal calcinosis, also may be inherited as an autosomal recessive trait. This condition has not been clearly separated from hereditary distal renal tubular acidosis. A form of hypomagnesemic hypokalemia that may be transmitted by an autosomal recessive gene has been described in a young son of a woman suffering from chronic hypomagnesemia(57). He had no symptoms of his subnormal magnesium and potassium serum levels, other than carpopedal spasms, that were not relieved by magnesium or potassium therapy. This defect was postulated to be caused by inability to maintain a normal gradient between intraand extracellular magnesium and potassium.

Genetic Factors in Control of Magnesium Levels in Plasma and Erythrocytes - Studies of identical and fraternal twins have shown that red cell magnesium is significantly more similar in monozygotic than in dizygotic twins, and among family members than in unrelated subjects.(21-23,58) Association of major histocompatibility complex - human leukocyte antigens (HLA) alleles have been shown to regulate red blood cell magnesium in humans; H-2 alleles are involved in mice genetically selected for low red cell magnesium.(22,23) HLA-B38 carriers, among blood donors, have lower plasma and red cell magnesium levels than do other genetically related groups.(23,59)

The latent tetany syndrome of magnesium deficiency(60) has been associated with the HLA-B35 allele;(61); chondrocalcinosis, which has been found in renal wasters of magnesium, has been associated with the B15 antigen.(62) Type A behavior students, many of whom were in the HLA-Bw35 group,(63,64) had a lowered red cell level of Mg under stress, as well as lower plasma magnesium levels. Interestingly, they had higher red cell zinc levels (possibly linked with the GLO1 locus(63)), and excreted more urinary zinc under stress.(21) Mitral valve prolapse, which has also been associated with low magnesium levels, occurring more frequently in patients with the latent tetany syndrome,(65-67) also is associated with HLA-Bw35.(65-67) This allele is associated with lower red cell Mg and much greater antibody response to anti-influenza vaccination,(68) which might relate to the role of magnesium in immunologic disorders, in which the major histocompatability complex plays an important role.(69)



Neonatal Cardiovascular Damage - The early arterial lesions, that were reported in 154 individual case reports and in more than 500 infants reported in pathology summaries of abnormalities found in stillborn infants and in those dying in the first month of life Table 1(4,8))

Genetic Table 1

include small vessel intimal fibroblastic proliferation, elastica degeneration and calcification, changes such as have been produced by experimental magnesium deficiency in laboratory animals.(4-6) The coronary microcirculation was rarely examined in the fetuses and infants tabulated in the 1980 report, but the myocardial and endocardial lesions indicate probable damage to the small arteries of the heart (Table 2(4-8)).

Genetic Table II

To correlate such changes with magnesium deficiency of the fetus, which must reflect that of the mother, has to be inferential, few data having been reported on the mothers of the cited infants born with these or gross cardiovascular anomalies. In the few reports indicating the maternal condition, spontaneous abortions, toxemias, multiple births, frequent and/or multiple pregnancies and diabetes, were all associated with poor outcomes of pregnancy; in all magnesium inadequacy is likely.(4,8,11,12,70-87) Also, prenatal magnesium supplements have shown benefit; fewer toxemic pregnancies and low birth weight infants among supplemented versus control mothers, have been reported from extensive European retrospective,(88,89) epidemiologic(90) and prospective double blind studies.(91,92) Since preterm infants have low magnesium levels, much of the total fetal magnesium being accumulated in the last two lunar months(4,8,93) (Table 3),

Genetic Table III

fetal inadequacy of magnesium seems to be a plausible contributory factor to the higher incidence of cardiovascular abnormalities in such infants, than in term singleton infants born to mature normal non-multiparous mothers.

Maternal and Infant Cardiomyopathy - Microangiopathy/CMP has been reported both in infants,(94-98) and peripartally in mothers,(99-112) particularly with gestational conditions associated with magnesium deficiency. A 1971 study indicated that toxemic pregnancies were complicated by peripartum CMP about six times as frequently as were normal pregnancies, and that 7% of peripartal CMP occurred with twin pregnancies.(103) The much greater vulnerability of marginally malnourished multiparous and toxemic pregnant women to CMP, than of affluent mothers, who usually are better nourished, was editorially commented upon in 1968;(102) the condition is much rarer in the developed world(108,112) than in Africa.(107,110)

Among the primary "idiopathic" cardiomyopathies, listed in a 1970(99) paper systematizing the many conditions associated with CMP, were fibrotic CMP of infancy (suggested as possibly attributable to hypercalcemia), familial myocardial fibrosis of later childhood and adults, and CMP of pregnancy and the puerperium, in each of which magnesium inadequacy may participate. Magnesium deficiency or tissue loss also occurs in several of the conditions that were listed as contributory to secondary CMP: alcoholism, severe diarrhea, potassium deficiency or excess, abnormal calcium deposition including that of hyperparathyroidism, protein calorie malnutrition, beriberi (both thiamin responsive and resistant, or catecholamine-toxicity. Cited also were magnesium deficiency itself, and several dysrhythmias.

Magnesium Deficiency and the Heart: There is growing evidence that magnesium deficiency can contribute to a variety of arrhythmias and that magnesium treatment is increasingly being used for their management worldwide.(4,7,113-124) Although its therapeutic use is based predominantly on its pharmacologic effect, it may also be restoring a deficit.(117-121) Increased intravascular coagulation, a probable factor in CMP,(99) might be contributed to by a low ratio of magnesium to calcium.(12) And finally, the myocardial lesions of experimental magnesium deficiency in rats,(125-128) dogs,(129) and golden Syrian hamsters(130-132) resemble those of CMP.


The familial occurrence of CMP was commented on in 1957, when the term was first used to indicate myocardial disease without major coronary arterial involvement.(133) Familial myocardial fibrosis was listed as the commonest form of CMP in 1970;(99) that year 13 families with hypertrophic CMP were reported(134) and the following year 11 more such families were described, with findings compatible with an autosomal dominant gene with high penetrance.(135) The 1964(133) and 1970(99) reviews of genetic diseases associated with cardiovascular abnormalities did not include diabetes mellitus. However, in 1964 and 1967(137,138) the minute focal areas of myocardial degeneration and fibrosis of these diseases were attributed to medial necrosis of the small intramural arteries and their occlusion by platelet aggregation, which was then proposed as being partially explanatory of, not only the rare genetic cardiomyopathies, but of that of alcoholics and of juvenile diabetics; their similarity to that of experimental magnesium deficiency(129) was noted.(138)

Diabetic Cardiomyopathy - Proliferative lesions of the endothelium, that narrow or obliterate the lumina, were described in diabetics' intramural small coronary arteries in 1960,(139) Fibrotic CMP, stemming from microangiopathy of diabetes, was described a decade later.(140) In 1972, it was shown that 16 of 73 patients with diabetes mellitus had CMP; autopsies in several showed mural coronary microangiopathy and focal perivascular and interstital fibrosis of the endocardium and subendocardium.(141)

Relationship with Magnesium Loss: It has been known for almost half a century that poorly controlled insulin dependent diabetes (Type I) causes magnesium loss.(142) An early report also showed that those with juvenile diabetes are likely to have the lowest serum magnesium values.(143) A study with diabetic children, under strict medical and dietary control, found that a third had hypomagnesemia (less than 1.4 mEq/L of serum) as well as comparably low levels in red cells.(144) It thus appears that diabetic children are more likely to be magnesium deficient than are adult diabetics. As with adults, in a study of 95 Type I children, those not optimally controlled had the lowest serum magnesium values.145 This was verified in a subsequent study of 63 such children, which further demonstrated the deficit by retention of greater than 40% of a parenteral load of magnesium.(146) In both of those clinical studies, increased urinary magnesium output was noted, versus controls. Diabetic gastro-enteropathy was suggested as a cause of magnesium malabsorption that contributes to magnesium deficiency. Elevated serum levels of low-density lipids and depressed levels of high-density lipids, of poorly controlled diabetic children were shifted to an improved pattern with better control that was associated with higher serum magnesium.(144) This is in accord with the demonstration that magnesium deficiency causes substantial elevation of lowdensity and very low-density lipids and decreased high-density lipids, accompanied by increased platelet aggregation and thrombus formation, in rats fed a low fat diet.(147,148) Since increased magnesium intake protected against these effects, the authors suggested that the dyslipidemia of diabetes mellitus might be mediated, at least in part, by magnesium loss.(147,148)

Possible Relationship with Chromium: The dietary intake of chromium is suboptimal in the American diet, its loss is increased during pregnancy, and its deficiency has been linked to maturity onset diabetes and arterial disease, and its supplementation has increased high-density lipids levels.(150-152) It has been suggested that, although the major mineral abnormality in diabetes is that of magnesium, these effects of chromium justify trial of its supplementation, as well as that of magnesium, in juvenile diabetes.(153)

Congenital Deafness, Syncope, Arrhythmias, and Sudden Death (Jervell-Lange-Nielsen Syndrome) - First reported in 1957, as familial deaf-mutism with prolonged Q-T interval, CMP and attacks of syncope, no abnormal blood electrolytes (calcium, potassium and phosphorus) were then encountered.(154) In a 1964 paper on the obscure cardiomyopathies, involvement of the nutrient arteries of the sinus node and atrio-ventricular node was suggested to explain the high incidence of arrhythmias and conduction abnormalities in this condition,(137) by the investigator who later noted the similarity of the lesions of human CMP to that produced by experimental magnesium deficiency in dogs.(138) Among nine cases in six sibships, autopsies disclosed focal hemorrhages near the atrioventricular and sinoatrial nodes, with involvement of the left anterior descending coronary artery (from which the nodal arteries arise), and nodal fibrotic lesions.(155) Cochlear abnormalities (absent stria vascularis and spiral ganglion of the ear) were speculated to have been caused by fetal vascular damage. Since then, there have been additional reports of the complete familial syndrome,(156,157) of several members of a family with only sinus node involvement,(158) and of a family in which arrhythmias occurred alone or with deafness.(159)

Deafness Caused or Intensified by Experimental Magnesium Deficiency: Weanling rats, that survived magnesium deficiency that caused noise-induced convulsions and death in litter mates, were found to have markedly decreased response to sound,160 and to have cochlear damage (personal communication). That the infantile impairment of hearing might have been caused by magnesium deficiency is suggested by the significantly greater hearing loss of magnesium deficient guinea pigs exposed to very loud noise than did animals fed a magnesium rich diet, exposed to the same noise.(161) Suggested mechanisms of the combined noise plus magnesium deficiency-induced deafness were increased catecholamine release, with constriction of the cochlear artery, and decreased magnesium content of the fluid around the hair cells, which allowed for their increased permeability, with increased calcium and sodium influx and energy depletion in the hair cells.(162,163)

Progressive Muscular Dystrophy, Marfan's Syndrome, and Friedrich's Ataxia - Patients with the rare genetic disorders: Marfan's syndrome and ataxia, or with the more common Duchenne's muscular dystrophy are prone to CMP.(99,136-138) Almost all of those with muscular dystrophy, which is inherited as an X-linked trait, develop cardiac lesions,(164) which resemble those of skeletal muscle.(165) It is of interest that a patient with Duchenne's muscular dystrophy, who died suddenly, had medial degeneration of the nutrient artery to the sinus node and of the node, such as is seen in more generalized CMP, in addition to scattered sites of myocardial necrosis.(165) Electro-cardiographic study of 169 patients with this disease disclosed abnormalities in 75%.(166)

Magnesium and Calcium in Duchenne's Muscular Dystrophy: Markedly lower serum magnesium and higher serum calcium levels in dystrophic patients than control values were reported by one group of investigators,(167,168) but not by another, who found that pre-adolescent patients had significantly higher red blood cell magnesium than did postpubertal patients, which was the reverse of findings in controls.(169) Fetuses at risk of this disease, and a premature infant who later developed typical Duchenne's disease, had 3-6-fold increased muscle calcium and a lesser increase of muscle magnesium (18 to 57% above normal); no necrotic fibers were detected.(170) Comparably increased muscle calcium was seen in full blown dystrophy.(171) The increase in their muscle calcium was considered a non-specific part of the final common pathway leading toward cellular degeneration and death.(170,171)

Among the data on the myocardium from studies with patients with Duchenne's muscular dystrophy, although not directly illustrative of the magnesium status, are a few that can be correlated with animal models of hereditary muscular dystrophy that provide information on magnesium (below). Abnormal myocardial metabolism, suggestive of uncoupling of oxidative phosphorylation (indicated by high inorganic phosphate, increased glycolysis, and the high arteriovenous redox potential of anaerobic metabolism) were detected in 11 Duchenne patients whose blood samples were obtained by coronary sinus catherization.(172) Six patients' biopsied muscle, not yet irreparably damaged by the dystrophic disease, had excess catecholamine accumulation around arterioles.(173)

Magnesium and Calcium, Myocardial Metabolism, and Catecholamines in Models of Genetic Muscular Dystrophy: From a strain of golden Syrian hamsters that had hereditary muscular dystrophy, an inbred strain (BIO 14.6) was developed that consistently developed spontaneous CMP.(174) The authors commented that the lesions resembled those produced by excessive catecholamines in rats and other species: augmentation of oxygen consumption beyond requirements for cardiac work, and uncoupling of oxidative phosphorylation. The earliest cardiac abnormality in the CMP hamster, before myocardial necrosis developed, was markedly decreased myocardial magnesium as compared with normal hamsters (73 vs 115 mg/100 g dry weight), at 29 days of age.(175) At two months, when the cardiac damage was moderate to severe in the CMP strain, the myocardial Mg was the same (109 mg) as in the normal hamsters of the same age. The increase in myocardial calcium, over that of normals, however, was slight at the prenecrotic phase (17 vs 12 mg), but marked at two months (215 vs 15 mg). Fed magnesium deficient diets, the CMP hamsters and hybrids developed much more myocardial necrosis than did normal hamsters fed the deficient diet. Adding MgCl2 (1.0mM/d) to the low magnesium diet prevented myocardial necrosis of normal and hybrid hamsters, but not of the CMP strain.(175) Comparable myocardial mineral findings were reported in another study of this CMP strain, that also provided ultramicroscopic evidence of the progressive mitochondrial damage,(176) and in one that also reported trace mineral findings: high zinc levels, possibly in exchange for calcium.(177) The MDx mouse, which has a gene defect at the locus homologous to the defective one in Duchenne's muscular dystrophy,(178) also exhibited elevated myocardial calcium at 10 days, 30 days and 254-347 days of life,(178) and at 5,10, and 23 weeks.(179) As in the BIO 14.6 hamsters,(175,176) the magnesium changes were not notable. The energy metabolism studies of skeletal muscle of the CMP hamster,(180-182) and of myocardium of the MDx mouse,(179) yielded findings comparable to those from Duchenne patients.(172,173) Uncoupling of oxidative phosphorylation occurred in 50-80 day old CMP hamsters, the time of most necrosis. Addition of 3mM MgCl2 to abnormal mitochondria at the beginning of the experiment produced doubling of initial rate of respiration and restored phosphorylative coupling to near normal. This might bear on the lack of response to magnesium of the hamsters with most advanced disease. Mitochondria from MDx mice have decreased respiratory control, an observation also in the dystrophic hamsters and in Duchenne's muscular dystrophy.

Cardiac norepinephrine studies,(183) prior to and during development of congestive heart failure of the CMP hamster, showed that its formation was most above normal in the pre-necrotic phase, probably due to increased cardiac sympathetic nerve activity. Similar but lesser increases in the myocardial catecholamine were seen at the intermediate phase of cardiac damage. During the final phase, when congestive heart failure had developed, there was a markedly lower content possibly from a "dilution" effect of hypertrophy and focal destruction of adrenergic nerve terminals. Directly germane to the low myocardial magnesium/calcium ratio in the pre-necrotic myocardium of the CMP-hamster is the in vitro evidence that a low magnesium/calcium ratio in adrenals(184) and peripheral nerves(185) increases catecholamine secretion.

Vitamin E, Selenium, Zinc and Magnesium in Cardiomyopathy of Muscular Dystrophy: Among the abnormalities produced by experimentally induced vitamin E deficiency in several species is necrotizing myopathy, that has pathologic changes resembling those of human muscular dystrophy (which is not responsive to vitamin E). In swine, the manifestations of tocopherol deficiency include myocardial damage associated with fibrinoid necrosis of the arteries.(186) Apart from the histopathologic similarities between vitamin E deficiency-induced lesions, and those of hereditary muscular dystrophy, the deficiency-altered muscles also exhibit excessive oxygen utilization, possibly as a result of uncoupling of oxidative phosphorylation, even before the lesions are detectable.(186) Still another similarity is in the lowered muscle magnesium content of both vitamin E deficient dystrophic animals(187-189) and those with hereditary muscular dystrophy before development of the histologic lesions.(174-176)

Interrelationships between magnesium and vitamin E are indicated also by precipitation of signs and lesions of magnesium deficiency in vitamin E deficient normal rats,(190) and by prevention of respiratory decline of (hepatic) mitochondria from vitamin E deficient rats by administration of magnesium.(191) Additionally, lipid peroxidation, which has long been known to be counteracted by the anti-oxidant effect of vitamin E,(192) is increased by magnesium deficiency in rat liver, muscle, heart and other organs,(193,194) an effect suggesting that the magnesium deficiency-induced myocardial damage might be mediated by free radicals.(195) This premise has been substantiated by studies with magnesium deficient golden Syrian hamsters (not the CMP strain). Magnesium deficiency alone caused myocardial injury that was protected against by vitamin E.(132) Intensification of the myocardial damage by injection of the beta-catecholamine analog, isoproterenol, was interpreted as showing impairment of tolerance of oxidative stress by magnesium deficiency.(131,196) Direct evidence that free radicals participate in the myocardial damage caused by magnesium deficiency was provided by a study showing that vitamin E deficiency increased the number and extent of the lesions so induced and that its supplementation was protective.(132) Combined vitamin E and magnesium protected against (erythrocyte) membrane lipid peroxidation in magnesium deficient Syrian hamsters.(196)

Selenium also protects against peroxidation of lipids, and its deficiency (in China) causes CMP of Keshan disease.(197-199) Its interactions with vitamin E are being considered, as they affect muscle disease.(198-201) It has been found to spare vitamin E, decreasing the amount required by the Syrian golden hamster (after 120 days of E depletion), but it did not prevent the myopathy.(202) A study of the muscle damage (determined by increased release of creatine kinase) of vitamin E and selenium-low calves when transferred from enclosures to open pasture(203) recalls the intensification of neuromuscular signs of magnesium deficiency of ruminants shifted from barns to pasture,(204) which was attributed in part to the change from warmth of the enclosure to stress of exposure to cold, with catecholamine release.(205) The meaning of the increase in intracellular zinc, that is associated with increased calcium in the affected heart of dystrophic hamsters(177) is not clear. The investigators hypothesized that zinc might be co-transported with calcium across the cell membrane or substituted for calcium in pathways affected by the high-energy ATP-pump. The role of zinc, not as an antioxidant, but possibly through its ability to stabilize membranes exposed to oxidative stress(206) might have a protective function. Possibly pertinent zinc, magnesium, and pyridoxine interrelationships are considered, below, under homocystinuria.

Cystic Fibrosis and Cardiomyopathy; Interaction of Nutrient Deficiencies? - Cystic fibrosis, the most common lethal or semilethal genetic disease in the white population, is inherited in an autosomal recessive manner.(207) Loss of pancreatic enzyme activity is characteristic; complete loss occurs in 80-85% of patients.(207,208) Malabsorption, the degree of which depends on the extent of loss of pancreatic function, leads to nutritional deficiencies of vitamin E and other fat soluble vitamins; deficiencies of magnesium and selenium - also implicated in myopathies - can also develop. In about 10% of those with cystic fibrosis, CMP, characterized by patchy focal areas of necrosis and fibrosis, complicates the disease.(209) The lesions resemble those of "idiopathic" CMP, human muscular dystrophy, and the CMP induced by experimental vitamin E deficiency or magnesium deficiency.

Vitamin E, Magnesium, Calcium, and Selenium in Cardiomyopathy of Cystic Fibrosis: The shortened red blood cell survival of this disease responds to high dosage vitamin E (10-fold higher than the normal recommended dietary allowance,(209,210) but the muscle weakness (myopathy?) of cystic fibrosis, is not responsive. In an early report(211) (additional to those reviewed in 1988(209) of two brothers with cystic fibrosis, who had steatorrhea that developed at six months of age, one who died of pneumonia was found at autopsy to have not only pancreatic damage, but also endomyocardial fibroelastosis. In their discussion, the authors referred to eight additional reports of myocardial damage in infants and young children with pancreatic insufficiency of cystic fibrosis. Autopsy examination of two additional patients, who had had hypercalcemia, disclosed generalized arterial intimal proliferation and calcification and renal calcification; one had mild rickets.(212) These manifestations resemble those described above in patients with renal wasting of magnesium, with and without magnesium malabsorption.

Few data have been found on the magnesium status of cystic fibrosis patients. A study of erythrocyte levels of magnesium, calcium, zinc and sodium in eight children with cystic fibrosis, and in four of the parents, showed that the patients had the lowest magnesium, zinc and sodium values, and the highest calcium levels; the parents had higher magnesium levels than did the affected children, but lower than control adults values.(213) There were higher magnesium and lower zinc contents of hair, nails, and duodenal fluid from children with cystic fibrosis;(214) the significance is unknown. They had very high calcium content of their duodenal fluid. In this study the magnesium level in sweat was slightly elevated; in another(215) there was no difference between patients and normal children. Neonatal hair from most of the 13 infants with cystic fibrosis contained water soluble calcium versus less than 30% of controls, and over ten times as much insoluble calcium as controls.(216) There were similar findings with hair magnesium, but of lesser magnitude. It was speculated that inability (of patients' hair) to bind calcium and magnesium might be related to the basic defect.

Tremor, nervousness, weakness and anorexia (symptoms of latent tetany of magnesium deficiency(60)) developed in a young man with cystic fibrosis complicated by cor pulmonale, who had recently received furosemide (a loop diuretic that causes magnesium loss) for heart failure, but only for several days.(217) When his serum magnesium was found to be 1.4 mEq/L, and a magnesium load of 367 mg Mg disclosed urinary excretion of 612 mg in 48 hours, he was treated with 4 g/d of magnesium for five days, with disappearance of signs and symptoms of the deficiency. The renal excretion of so much magnesium in the face of hypomagnesemia suggests renal wasting. Acutely lowered serum magnesium developed in seven cystic fibrosis patients with bowel obstruction from meconium ileus, that had been treated with oral and rectal administration of the mucolytic agent, N-acetylcysteine, and a hypertonic solution of sodium diatrizoate.(218)

Considered above, under muscular dystrophy, are the data on the CMP of selenium deficiency, and its interactions with vitamin E.(197-203) A 1982 review of clinical data failed to support a premise that selenium deficiency might be implicated in the pathogenesis of cystic fibrosis.(198) However, since then, in a discussion of the CMP complication, it was pointed out that malabsorption with and without cystic fibrosis has caused low plasma selenium levels.(201) A study with the golden Syrian hamster showed that selenium prevented pancreatic atrophy induced by vitamin E depletion.(219)

Homocystinuria and Cardiomyopathy; Interaction of Nutrient Deficiencies? Pyridoxine-Dependence of Homocystinurics: One of the conditions listed as being associated with CMP is homocystinuria,(99) predominantly a vitamin B6-dependent disorder.(220-222) There are several metabolic abnormalities that give rise to homocystinuria, the most common of which is a Mendelian recessive trait that causes deficient activity of cystathionine beta-synthase, an enzyme that contains pyridoxal phosphate.(220)Almost half of the patients respond to very high dosage pyridoxine (up to 300 times more pyridoxine than is needed for correction of a simple deficiency; they may have slight (residual) activity of this enzyme.(220-221) Those with a more complete deficiency of the enzyme, or with a metabolic block after formation of cystathionine also require additional dietary modification and/or supplementation.

Among the pathologic changes in homocystinuric patients are several germane to development of CMP: the occurrence of thrombi, not only in large arteries but in the microvasculature, with fraying of the elastica and premature arteriosclerosis.(223) CMP is not frequently reported, but Marfan's syndrome, another condition associated with CMP,(99,137) has occurred in homocystinuric patients.(220,223)

Additional Nutritional Treatment of Homocystinuria: Folate B12, Amino Acid Intake Modification and Possibly Magnesium and Zinc: Patients with deficiency of cystathionine synthase, accompanied by abnormally low serum folate levels have the folate level further lowered by pyridoxine treatment, and folate repletion is necessary for the chemical response to pyridoxine.(220,224) Vitamin B12 supplements are necessary for those whose metabolic block is after formation of cystathionine. Those with methionine accumulation also require methionine restriction and cysteine or choline supplements. Perhaps vitamin B6 treatment from infancy might be effective.(222)

Pyridoxal phosphate, which is necessary for activity of cystathionine synthase, requires magnesium as a cofactor for this and for many other of its enzymatic reactions.(225) Studies in the 1960s(226-229) and more recently(230-233) have shown that vitamin B6 is necessary for the maintenance of magnesium and zinc tissue levels, and that the pyridoxine-dependent enzymes also require these minerals. Thus, adding magnesium and zinc to vitamin B6 supplementation of patients with unduly high vitamin B6 requirements seems worthy of trial.


Presented here is a postulate that magnesium deficiency caused by genetic variations in magnesium metabolism, in conjunction with marginal magnesium intake, is a contributory factor to gestational complications, including perinatal and neonatal CMP. Severe forms of familial magnesium deficiency: isolated malabsorption and renal wasting of magnesium have been identified. The possibility that the underlying inherited abnormality in the renal magnesium wasting syndromes is that of magnesium malabsorption is presented. It is suggested that renal magnesium wasting may be caused by damage at the major site of tubular magnesium reabsorption, when infants with hypomagnesemic hypocalcemia are provided calcemic treatment without magnesium repletion. It is proposed that there may be degrees of magnesium malabsorption, and that there are genetic differences in plasma and cellular magnesium levels in different ethnic groups; low values have been associated with specific HLA groups. These differences might be part of the metabolic basis of other inherited diseases.

The heritable diseases, that are complicated by cardiovascular damage, especially microangiopathy leading to generalized or nodal CMP, are of particular interest as regards the possibility of contributory magnesium inadequacy, because experimental magnesium deficiency causes similar arterial and myocardial lesions. There is direct evidence of abnormalities in magnesium retention and/or tissue levels in diabetes mellitus, especially in the juvenile form, in which microangiopathy causes serious early complications. Since chromium, like magnesium, participates in carbohydrate and lipid metabolism, and it seems to be linked to maturity onset diabetes, its role, with and without magnesium in pregnant diabetic women, and in infants born to such women might be worth exploring.

The familial syndrome of congenital deafness, syncope, arrhythmias, and sudden death has not been correlated with magnesium abnormality in the literature, but it bears similarity to manifestations produced by magnesium deficiency. The myocardial lesions involving the conducting tissue and nodes differ from those of the more commonly described cardiomyopathies, and those of magnesium deficiency, only in their location. The deafness has been presumed to be caused by cochlear damage, caused by damage of the nutrient arteries to the inner ear; it can be correlated with the hearing loss of magnesium deficient weanling rats and of noise-exposed magnesium deficient guinea pigs. Might magnesium supplementation during pregnancy of diabetics or of members of families with risk of the Jervell-Nielsen-Lange syndrome protect the infant, and might it slow or limit progression of the disease manifestations in those afflicted?

The skeletal muscle and myocardial lesions of Duchenne progressive muscular dystrophy, have been compared with those produced by magnesium deficiency, and are similar to those seen in models of genetic muscular dystrophy, which also have comparable metabolic findings. CMP hamsters were shown to lose skeletal and myocardial muscle magnesium and to gain large amounts of calcium before the necrosis developed, even when not fed a magnesium deficient diet. They also exhibited high myocardial catecholamine content and uncoupling of oxidative phosphorylation, abnormalities also seen in the human disease. Magnesium supplementation delayed, but did not prevent the damage in the CMP hamster, but prevented it in hybrid and normal magnesium deficient hamsters. The lesions of the human disease also resemble those of vitamin E deficient animals, which also have low muscle magnesium content. The CMP induced by magnesium deficiency in golden Syrian hamsters has been shown to be intensified by vitamin E deficiency and reduced by its supplementation. The capacity of magnesium deficient Syrian hamsters to withstand the oxidative stress of catecholamine challenge was diminished without prior supplementation with vitamin E, indicating free radical participation in magnesium deficiency-induced CMP. Treatment with high dosage vitamin E has not influenced Duchenne muscular dystrophy. Perhaps treatment with both vitamin E and magnesium might delay its progression.

The shortened erythrocyte survival time of mucoviscidosis or cystic fibrosis requires ten times the normal intake of vitamin E for correction; the CMP that develops in about 10% of the cases is unresponsive. The vitamin E deficiency is attributed to malabsorption, from steatorrhea resulting from loss of pancreatic enzymes that can be complete in up to 85% of the patients with cystic fibrosis. It can be presumed that this condition also interferes with absorption of other nutrients, including magnesium. Few data have been found on the magnesium status, other than magnesium deficiency in several patients under short-term diuretic treatment or other therapy not usually associated with magnesium depletion, for complications of mucoviscidosis. However, these few data suggest that these patients may be unduly vulnerable to magnesium loss. The interrelationships of magnesium with vitamin E, additional to those discussed in relation to Duchenne disease, are indicated by evidence that vitamin E deficiency has precipitated magnesium deficiency in rats, and magnesium has prevented vitamin E-induced respiratory decline and lipid peroxidation. Might vitamin E plus magnesium supplements prove helpful in management of cystic fibrosis? The observation that selenium prevented the pancreatic atrophy induced by vitamin E depletion in the golden hamster, might be worthy of exploration in humans.

Almost half of homocystinuric patients (those with some cystathionine synthase activity) require very high dosage pyridoxine (up to 300 times normal) for correction of the biochemical abnormality. The supplements or dietary restriction required by patients who have a more complete deficiency of the enzyme, or with a metabolic block after formation of cystathionine can include vitamin B12, folate, methionine restriction, and cysteine supplements. Progression of the disease despite the several nutritional approaches, has suggested that (pyridoxine) supplementation be instituted in infancy. CMP has not been reported in homocystinuria, but patients are subject to microvascular thrombosis, which can contribute to CMP, as well as to large artery thromboses. Homocystinuria has been reported in patients with Marfan's syndrome (associated with CMP), and premature arteriosclerosis with frayed elastica and medial degeneration is common. Both because the arteriopathy (and hypercoagulability) resemble that produced by magnesium deficiency, and because pyridoxal phosphate, which is necessary for activity of cystathionine synthase, requires magnesium as a cofactor, and is necessary for maintenance of tissue levels of magnesium, addition of magnesium to the therapeutic regimen deserves trial. Since tissue levels of zinc are also dependent on adequate pyridoxine, the effect of addition of zinc is worth determining.

The major emphasis in this paper has been on genetic disorders that are associated with CMP, to which magnesium deficiency, caused by higher than average magnesium requirements, might be contributory. Magnesium is protective against arterial and myocardial damage, and interacts with vitamins E and B6, dependencies or deficiencies of which have been implicated in the genetic diseases complicated by CMP. A few data have been presented on the trace minerals: selenium, chromium, and zinc that may also bear on these diseases.


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