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Better medicine through biochemistry.

When I was in medical school, a number of my classmates disliked biochemistry class. To them, biochemistry had little relevance to clinical medicine; it was just something they had to get through to move on to their clinical years. My view was the opposite. To me, most diseases had a molecular basis, and the more we understood about biochemistry, the more likely we would be to develop effective treatment strategies.

For example, research has demonstrated that mitochondrial energy production is impaired in patients who suffer from recurrent migraines. Nutrients or other substances that enhance energy production are therefore of potential value for migraine patients. Two such nutrients are riboflavin (a component of flavin adenine dinucleotide [FAD], a coenzyme involved in the electron-transport chain) and magnesium (which is essential for the synthesis of adenosine triphosphate [ATP] from adenosine diphosphate [ADP]). Randomized controlled trials have demonstrated that each of these nutrients, when taken individually, can substantially decrease the recurrence rate of migraines. The results of those trials strengthened the hypothesis that improving impaired energy production is beneficial for migraine sufferers. Investigators therefore began looking at coenzyme Q10 (CoQ10), another substance involved in the electron-transport chain. Some, though not all, studies have demonstrated that CoQ10 is also beneficial for migraine prophylaxis. The findings regarding magnesium, riboflavin, and CoQ10 would lead one to predict that niacinamide (a component of nicotinamide adenine dinucleotide [NAD], another coenzyme involved in the electron-transport chain) might also be useful. Moreover, since different individuals have different biochemical weaknesses, one might expect that the combination of magnesium, riboflavin, CoQ10, and niacinamide would be more effective than any of these nutrients by themselves. Those possibilities are fertile areas for future research.

A recently published study provided an elegant example of how knowledge of biochemistry can be used to improve clinical outcomes. Pyridoxine-dependent epilepsy is an inherited disorder that usually presents with intractable seizures in the first 6 months of life. The seizures can be completely controlled by administering large doses of vitamin B; but despite pyridoxine treatment, most patients with pyridoxine-dependent epilepsy suffer developmental delay or low IQ.

Patients with pyridoxine-dependent epilepsy have been found to have a genetic deficiency of antiquitin (alpha-aminoadipic semialdehyde dehydrogenase), an enzyme that facilitates cerebral lysine catabolism. Antiquitin deficiency results in the accumulation of lysine degradation products proximal to the deficient enzyme. One of these degradation products inactivates pyridoxal-5'-phosphate (P5P), the biologically active form of vitamin B6. Treatment with pyridoxine compensates for the inactivation of PLP, but it does not sufficiently decrease the concentration of potentially neurotoxic lysine degradation products. Researchers therefore considered the possibility that dietary lysine restriction would decrease the accumulation of these degradation products, thereby improving neurological development and cognitive function.

Seven children with pyridoxine-dependent epilepsy and documented antiquitin deficiency were placed on a low-lysine diet (70-100 mg per kg of body weight per day, 4580 mg/kg/day, and 20-45 mg/kg/day for children aged less than 1 year, 1-7 years, and above 7 years, respectively). (1) At the time the study was published, the patients had been on the diet for 4 months to 4.2 years. The diet was well tolerated, with good compliance and no adverse events. Reduction in plasma and urinary biomarker levels ranged from 20% to 72%, depending on the patient and the biomarker measured. Improvement in age-appropriate skills was observed in 4 of 5 patients who had pre-diet delays.

The best-documented examples of how knowledge of biochemistry can be used to improve health are with various rare but serious genetic diseases. However, a large body of evidence indicates that many common diseases also have a genetic component. For example, 5% to 15% of various human populations are homozygous for the methylenetetrahydrololate reductase (MTHFR) 677C [right arrow] T polymorphism (TT genotype), which results in reduced enzyme activity. Most of the research on the MTHFR 677C [right arrow] T polymorphism has focused on hyperhomocysteinemia and increased folate requirements. However, it has also been demonstrated that the MTHFR enzyme of people with the 677TT genotype is 10 times as likely as the wild type to dissociate from its FAD cofactor and become inactivated. As noted above, riboflavin is a component of FAD, and it has been shown that individuals with the MTHFR 677TT genotype develop hyperhomocysteinemia only if they have poor riboflavin status. (2)

Hypertensive patients with the MTHFR 677TT genotype tend to have an inadequate response to antihypertensive medication. However, randomized controlled trials have shown that adjunctive treatment with a very modest dose of riboflavin (1.6 mg per day) substantially lowers blood pressure in this subgroup of hypertensive patients. (3)

So, all you medical students, biochemistry is here to stay. And thank you to the many researchers who have conducted the basic-science and clinical research that helps us take better care of our patients.

Notes

(1.) Van Karnebeek CDM et al. Lysine restricted diet for pyridoxine-dependent epilepsy: first evidence and future trials. Mol Genet Metab. 2012;107:335-344.

(2.) McNulty H et al. Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements. Am J Clin Nutr. 2002;76:436-441.

(3.) Wilson CP et al. Riboflavin offers a targeted strategy for managing hypertension in patients with the MTHFR 677TT genotype: a 4-y follow-up. Am J Clin Nutr. 2012;95:766-772.

Alan R. Gaby, MD
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Author:Gaby, Alan R.
Publication:Townsend Letter
Article Type:Editorial
Geographic Code:1USA
Date:Dec 1, 2013
Words:882
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