No evidence for mevalonate shunting in moderately affected children with Smith‐Lemli‐Opitz syndrome

Abstract

Summary Smith-Lemli-Opitz syndrome (SLOS) is caused by a genetic deficiency in 7-dehydrocholesterol (7-DHC) reductase (EC 1.3.1.21), the last enzyme of the cholesterol synthetic pathway. In SLOS, plasma cholesterol concentration is reduced and immediate precursor concentration (7-DHC) is elevated. Surprisingly, total sterol synthesis is reduced but HMG-CoA reductase activity, a rate-limiting enzyme in cholesterol synthesis is unaltered as judged by normal urinary excretion of mevalonic acid (MVA) (Pappu, 2002). These findings raise the possibility of increased diversion of MVA into the MVA shunt pathway away from sterol synthesis, by activation of the shunt pathway enzymes. To test this hypothesis, we measured the urinary excretion of 3-methylglutaconic acid (U-3MGC), a by-product of the shunt pathway, in 19 mild-to-moderately severely affected SLOS subjects (10 males, 9 females) receiving either a cholesterol-free or a high cholesterol diet, and in 20 age- and sex-matched controls. U-3MGC was similar in SLOS and controls, and was unaffected by dietary cholesterol intake. Further, no change in U-3MGC was observed in a subset of SLOS subjects (n=9) receiving simvastatin. In contrast, U-MVA was reduced by cholesterol supplementation (~54%, p<0.05) and by simvastatin (~50%, p<0.04). There was no correlation between U-3MGC and either plasma sterol concentrations, urinary isoprenoids, or the subjects’ clinical severity score. However U-3MGC was inversely correlated with age (p<0.04) and body weight (p<0.02), and higher in females than in males (~65%, p<0.025). The data show that DHCR7 deficiency does not result in 3MGC accumulation in SLOS and suggest that the MVA shunt pathway is not activated in patients with the condition.

Hepatic Isoprenoid Metabolism in a Rat Model of Smith‐Lemli‐Opitz Syndrome

“…1). However, a recent report from Steiner’s group [14] appears to refute this possibility. They demonstrated that feeding Chol to SLOS patients reduced urinary mevalonate levels (as a result of suppression of HMG-CoA reductase (HMGR) activity by Chol), but had no significant effect on urinary MGA levels, thereby arguing against shunting to MGA.…”

“…They demonstrated that feeding Chol to SLOS patients reduced urinary mevalonate levels (as a result of suppression of HMG-CoA reductase (HMGR) activity by Chol), but had no significant effect on urinary MGA levels, thereby arguing against shunting to MGA. Interestingly, this group has also found a 4- to 7-fold elevation in the levels of urinary dolichol and coenzyme Q (a.k.a., ubiquinone) [11, 14] as well as an increase in dolichol chain lengths [14] in SLOS patients, compared to controls. These findings suggested that some of the mevalonate in SLOS patients is shunted not toward leucine degradation, but rather to the nonsterol isoprenoid branches of the pathway.…”

Leucine Loading Test is Only Discriminative for 3-Methylglutaconic Aciduria Due to AUH Defect

“…Two possible shuntways are known, the Popjak shunt linking dimethylallyl-PPi in the cholesterol biosynthesis with 3-methylcrotonyl-CoA in the Sum of 3-methylglutaric and 3-methylglutaconic acid leucine catabolism and the HMG Salvage pathway, linking 3-hydroxy-3-methylglutaryl-CoA with 3-methylglutaconylCoA. Recently we and others have shown that there is no 3-MGA-uria in a total of 27 (treated and untreated) Smith Lemli Opitz patients as well as in three patients with mevalonate kinase deficiency (Roullet et al 2012;Wortmann et al 2013b). This makes significant shunting via the mevalonate shunt as source of 3-MGA-uria unlikely.…”

A Pilot Study of the Association of Markers of Cholesterol Synthesis with Disturbed Sleep in Smith-Lemli-Opitz Syndrome

“…Since cholesterol supplementation impacts serum cholesterol levels in SLOS patients (19), the treatment may have influenced the sterol-sleep relationships reported in Table 3. It is, however, reasonable to assume that at the time the sleep behavior assessments were made, serum cholesterol levels had reached a steady-state level that reflected homeostatic adaptation to cholesterol supplementation.…”