Precision diagnosis and treatment of vitamin metabolism-related epilepsy

Abstract

Epilepsy is a chronic disorder of the nervous system caused by abnormal discharges from brain cells. Structural, infectious, metabolic, immunologic, and unknown causes can contribute to the development of seizures. In recent years, there has been increasing attention on epilepsy caused by genetic metabolic disorders. More than two hundred inherited metabolic disorders have been identified as potential cause of seizures, and they are mainly associated with energy deficiency in the brain, accumulation of toxic substances, abnormal neurotransmitter transmission, and deficiency of cofactors. Vitamins play a crucial role as components of several enzymes or coenzymes. Impaired metabolism of thiamine, biotin, vitamin B6, vitamin B12 and folic acid can contribute to early-onset seizures and developmental abnormalities in infants. However, timely supplementation therapy can significantly improve patient prognosis of affected patients. Therefore, a thorough understanding and investigation of the metabolic basis of epilepsy is essential for the development of precise therapeutic approaches, which could provide significant therapeutic benefits for patients.

Keywords: Epilepsy; Metabolism; Treatment; Vitamin.

Fig. 1

ALDH4A1 mutation leads to accumulation of P5C in mitochondria. P5C reacts with PLP to form PLP-P5C condensate, which reduces the concentration of PLP in the brain. Elevated P5C can be converted to proline, leading to mitochondrial stress

Fig. 2

Lysine metabolism. ALDH7A1 is involved in the oxidation of lysine and mutations in this gene lead to pathological accumulation of α-AASA, P6C and piperonylic acid. P6C accumulation can react with PLP to form a Knoevenagel condensate, which inactivates PLP and interferes with the metabolism of important neurotransmitters in the brain

Fig. 3

Metabolic pathways involving vitamin B12. Adenosylcobalamin is involved in the conversion of methylmalonyl coenzyme A to succinyl coenzyme A. In vitamin B12 deficiency, methylmalonyl coenzyme A and malonyl coenzyme A accumulate, leading to the synthesis of single-chain fatty acids, which are incorporated into the myelin sheath to cause myelin changes; homocysteine is converted to methionine in the presence of methylcobalamin, methionine is metabolized to S-adenosylmethionine, and S-adenosylmethionine (SAM) is demethylated and converted to S-adenosine homocysteine (SAH). The SAM : SAH ratio decreases in methylcobalamin deficiency, protein, lipid and neurotransmitter synthesis in the CNS is impaired, and DNA synthesis and cell division are inhibited