Hypomagnesemia, Hypertension, And Hypercholesterolemia, Mitochondrial

A number sign (#) is used with this entry because of evidence that this phenotype is caused by a mutation in the mitochondrial tRNA(Ile) gene (590045).

Clinical Features

Wilson et al. (2004) identified a Caucasian kindred (K129) ascertained through a proband with hypermagnesemia. Evaluation of her extended kindred revealed a high prevalence of hypomagnesemia, hypertension, and hypercholesterolemia. Wilson et al. (2004) performed a detailed clinical evaluation of 142 blood relatives in the kindred. Including the index case, 38 members had hypertension (blood pressure greater than 140/90 mm Hg or on treatment for hypertension), 33 had hypercholesterolemia (with total cholesterol greater than 200 mg/dl or on treatment for hypercholesterolemia), and 32 had clinically significant hypomagnesemia (range 0.8 to 1.7 mg/dl, normal 1.8 to 2.5 mg/dl). Hypomagnesemic individuals were distributed through 4 generations and 16 sibships, and both genders were affected; there was no significant effect of age on magnesium levels, and no hypomagnesemic subjects were taking magnesium-altering medications. All 32 members with hypomagnesemia were on the same maternal lineage. Affected fathers never transmitted the trait to their offspring (0 of 17 offspring), whereas affected mothers transmitted the trait to a high fraction of their offspring (16 of 21). Because of these features mitochondrial inheritance was deemed likely, with a chi square value of 49, p less than 10(-11). Members of the maternal lineage had a marked increase in urinary fractional excretion of magnesium (p = 0.0001); this effect was most pronounced among subjects with hypomagnesemia, establishing impaired renal magnesium absorption as the cause of hypomagnesemia in the K129 kindred. Hypokalemia due to inappropriate renal loss was also more frequently seen on the maternal lineage, predominantly among hypomagnesemic subjects. Urinary sodium excretion was equivalent in both groups. Hypertension also segregated with the maternal lineage. Thirty of 53 adults on the maternal lineage had blood pressure greater than 140/90 or were being treated with antihypertensive medication, versus 8 of 53 on the nonmaternal lineage (p less than 0.00001). The prevalence of hypertension on the maternal lineage showed a marked age dependence, increasing from 5% in subjects under age 30 (1 of 20) to 44% in those from age 30 to 50 (10 of 23 subjects), and to 95% in those over age 50 (19 of 20 subjects). Among adults age 18 to 60, maternal lineage increased systolic blood pressure by an average of 13 mm Hg and diastolic blood pressure by 5 mm Hg. On the maternal lineage, 24 of 46 had fasting total cholesterol greater than 200 or were being treated with cholesterol-lowering medication, versus 9 of 49 on the nonmaternal lineage (p = 0.0004). The relationship remained highly significant when the analysis was restricted to adults age 18 to 60. Quantitative analysis of total cholesterol among adults age 18 to 60 after adjustment for age, sex, and BMI revealed that maternal lineage increased total cholesterol by an average of 26 mg/dl. This increase was attributable to elevations in LDL and VLDL, with no effect on fasting HDL or triglycerides. In sum, of 45 adults on the maternal lineage who were evaluated for all 3 traits, 38 had 1 or more of hypertension, hypercholesterolemia, or hypomagnesemia, 26 had 2 or more, and 7 had all 3.

Wilson et al. (2004) carefully evaluated members of K129 for the presence of additional clinical phenotypes commonly associated with mitochondrial dysfunction. Prevalence of migraine headache, sensorineural hearing loss, and hypertrophic cardiomyopathy were increased on the maternal lineage. Measures of fasting HDL, triglycerides, insulin resistance, BMI, and diabetes mellitus were not significantly different between the 2 lineages. Immunohistochemistry of a skeletal muscle biopsy from a member of the maternal lineage revealed an increase in ragged-red fibers and subsarcolemmal succinate dehydrogenase staining, characteristic features of individuals carrying mitochondrial mutations. Electron microscopy demonstrated cytoplasmic lipid accumulation, increased glycogen stores, and dysmorphic mitochondrial cristae, further signs of mitochondrial dysfunction. In vivo nuclear magnetic resonance (NMR) spectroscopy of skeletal muscle in this patient demonstrated normal tricarboxylic acid cycle flux but reduced adenosine triphosphate production, suggesting impaired coupling of these processes.

Molecular Genetics

All affected individuals in the kindred K129 studied by Wilson et al. (2004) were found to have a thymidine-to-cytidine transition at nucleotide 4291 (590045.0007), which lies within the mitochondrial tRNA isoleucine gene. The mutation was found only on the maternal lineage in K129, did not appear among thousands of mitochondrial genomes previously sequenced, and was absent among 170 unrelated control individuals. The mutation was homoplasmic in all members of the maternal lineage regardless of phenotype, with the assay sufficiently sensitive to detect 1% heteroplasmy. Uridine at the position immediately 5-prime to the tRNA isoleucine anticodon is one of the most extraordinarily conserved bases in the biologic world. It is conserved in every sequenced isoleucine tRNA, including 242 different species of archaebacteria, eubacteria, unicellular and multicellular eukaryotes, animals, plants, chloroplasts, and mitochondria.

Wilson et al. (2004) commented that hypomagnesemia, hypertension, and hypercholesterolemia each showed approximately 50% penetrance among patients on the maternal lineage. The nearly stochastic distributions of these traits on the maternal lineage and the nonsignificant correlations among their quantitative values on the maternal lineage suggests that these are independent, pleiotropic effects of the mitochondrial mutation. Wilson et al. (2004) concluded that the results of this study suggest that loss of mitochondrial function with age could contribute to the characteristic age-related increase in blood pressure and to its clustering with hypercholesterolemia in the general population.