Review Question - QID 216408

This patient has homocystinuria, as evidenced by developmental delay, thromboembolic event (stroke) at a young age, features similar to Marfan syndrome (tall, thin, pectus excavatum, and fair skin), and inferonasal lens dislocation. Some patients with homocystinuria respond to supplementation with vitamin B6, also known as pyridoxine.

Homocystinuria is a rare autosomal recessive disorder caused by dysfunction in homocysteine metabolism. Homocysteine can be processed into either methionine or cystathionine. For the former, methionine synthase (also known as homocysteine methyltransferase) requires B12 as a cofactor to methylate homocysteine into methionine. Additionally, B9 is also important because it is a component of tetrahydrofolate that carries the methyl group that is eventually transferred to homocysteine. For the latter, cystathionine synthase requires B6 as a cofactor to process homocysteine. Deficiencies in either methionine synthase or cystathionine synthase will lead to homocysteine accumulation. In cases of decreased affinity of cystathionine synthase for its cofactor, excess B6 through supplementation can be beneficial because the increased availability of the cofactor increases the probability that cystathionine synthase will be bound to B6.

Wilcken et al. performed a retrospective analysis on patients with homocystinuria secondary to cystathionine synthase deficiency to investigate the relationship between vitamin administration (pyridoxine, folic acid, and hydroxocobalamin) and homocysteine levels and complications. Their investigation demonstrated that the aforementioned vitamins could lower homocysteine levels, and cardiovascular risk was markedly reduced. The authors recommend supplementation with vitamins B6, B9, and B12 to reduce the incidence of complications from homocystinuria.

Incorrect Answers:
Answer 1: Biotin is vitamin B7. It is a cofactor in many carboxylation enzymes such as pyruvate carboxylase, acetyl-CoA carboxylase, and propionyl-CoA carboxylase. Signs of deficiency are relatively nonspecific and include alopecia, dermatitis, lethargy, and brittle fingernails. Deficiency is relatively rare since many foods contain biotin. However, excessive ingestion of raw egg whites can lead to deficiency because they contain avidin, a biotin binder.

Answer 2: Niacin, also known as vitamin B3, is a precursor for both nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are cofactors in many redox reactions. Pellagra is caused by a deficiency of niacin and is characterized by diarrhea, photosensitive dermatitis, and delirium/dementia.

Answer 4: Riboflavin, also known as vitamin B2, is a precursor for flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are cofactors in a variety of processes: the electron transport chain (Complex I & II), fatty acyl CoA dehydrogenase, glutathione reductase, etc. Signs of deficiency are characterized by stomatitis and cheilosis.

Answer 5: Thiamine, also known as vitamin B1, is a cofactor in various enzymatic processes including pyruvate dehydrogenase, transketolase, and branched-chain AA dehydrogenase. Its deficiency can manifest as wet beriberi (heart failure and dilated cardiomyopathy) and dry beriberi (peripheral neuropathy and weakness).

Bullet Summary:
Depending on the specific pathophysiology, homocystinuria patients can benefit from supplementation with vitamins B6 (pyridoxine), B9 (folic acid), and/or B12 (cobalamin).