Genetic conditions that disrupt anaplerotic flux — the metabolic pathways replenishing TCA cycle intermediates. Each entry maps the biochemical defect to its clinical consequences.
PC catalyzes pyruvate + CO₂ + ATP → oxaloacetate, the quantitatively most important anaplerotic reaction. Without OAA replenishment, the TCA cycle cannot accept acetyl-CoA, gluconeogenesis fails, and the urea cycle stalls (explaining hyperammonemia). This is the prototypical anaplerotic deficiency.
High-carbohydrate, low-fat diet; avoidance of fasting; citrate/aspartate supplementation to bypass OAA deficiency. Triheptanoin (odd-chain C7 triglyceride) provides propionyl-CoA for alternative anaplerosis via succinyl-CoA. Liver transplantation has been reported in severe cases.
The propionyl-CoA pathway normally feeds succinyl-CoA into the TCA cycle via D-methylmalonyl-CoA → L-methylmalonyl-CoA → succinyl-CoA. In PA, this route is blocked at the first step. Accumulated propionyl-CoA also inhibits N-acetylglutamate synthase (causing hyperammonemia) and citrate synthase (directly impairing TCA flux).
Protein-restricted diet limiting isoleucine, valine, methionine, and threonine; carnitine supplementation (carnitine conjugates propionyl-CoA for renal excretion); metronidazole to reduce gut propionate production. Liver transplantation reduces crisis frequency. mRNA therapy is in clinical trials.
Methylmalonyl-CoA mutase (requiring adenosylcobalamin/B12) catalyzes the final anaplerotic step: L-methylmalonyl-CoA → succinyl-CoA. This reaction directly feeds C4 units into the TCA cycle. In MMA, succinyl-CoA anaplerosis is impaired while toxic methylmalonic acid and propionyl-CoA derivatives accumulate.
Trial of hydroxocobalamin (B12) for cobalamin-responsive forms. Protein-restricted diet, carnitine supplementation. Combined liver-kidney transplant for severe mut⁰ forms. Gene therapy (AAV-based) is in advanced clinical trials with promising early results.
Long-chain fatty acid oxidation normally supplies acetyl-CoA (drives TCA cycle flux) and, from odd-chain fatty acids, propionyl-CoA (anaplerotic input to succinyl-CoA). In VLCAD deficiency, both inputs are diminished during fasting. The TCA cycle is starved of both oxidative fuel and anaplerotic carbon.
Avoidance of fasting and prolonged exercise. Medium-chain triglyceride (MCT) supplementation bypasses the VLCAD block. Triheptanoin (Dojolvi®) — FDA-approved for LC-FAOD — provides both acetyl-CoA (even-chain) and propionyl-CoA (odd-chain) for dual metabolic support, making it both an energy substrate and an anaplerotic agent.
Like VLCAD, LCHAD deficiency reduces acetyl-CoA and propionyl-CoA generation from long-chain fatty acids during fasting. Additionally, the accumulated hydroxy-fatty acid intermediates are directly toxic, creating both an energy deficit and a toxic metabolite problem. Anaplerotic supplementation addresses the former.
MCT supplementation, avoidance of fasting. Triheptanoin (Dojolvi®) is FDA-approved for this condition. DHA supplementation may slow retinopathy progression. Regular ophthalmologic and cardiac monitoring. Essential fatty acid supplementation with walnut oil.
CPT II sits on the inner mitochondrial membrane and is required for long-chain fatty acid entry into the matrix for β-oxidation. When blocked, the mitochondria cannot generate acetyl-CoA or propionyl-CoA from long-chain fats. During fasting or exercise, the TCA cycle loses both its primary fuel source and its anaplerotic input from odd-chain species.
High-carbohydrate, low-fat diet. Avoid prolonged exercise, fasting, and cold exposure. MCT oil supplementation (medium-chain fatty acids bypass CPT II). Triheptanoin provides anaplerotic support. Bezafibrate (PPARα agonist) has shown benefit in some myopathic cases by upregulating residual CPT II expression.
Biotin is the essential cofactor for two key anaplerotic enzymes: pyruvate carboxylase (OAA input) and propionyl-CoA carboxylase (succinyl-CoA input). Biotinidase deficiency starves both enzymes of their cofactor, creating a dual anaplerotic block. This makes it a uniquely broad anaplerotic disorder.
Biotin supplementation (5–20 mg/day) is curative if started early. Included on newborn screening panels worldwide. Treatment prevents all manifestations if initiated before symptom onset. Hearing loss and optic atrophy, if already present, may be irreversible. Lifelong treatment is required.
Like biotinidase deficiency, HLCS deficiency impairs both PC (OAA anaplerosis) and PCC (succinyl-CoA anaplerosis). The earlier onset and typically greater severity reflects the complete inability to activate any newly synthesized carboxylase, rather than failure to recycle biotin from degraded enzymes.
Pharmacologic doses of biotin (10–100 mg/day) can overcome the reduced enzyme affinity in many cases. Response is variable depending on the specific HLCS mutation. Earlier treatment correlates with better outcomes. Lifelong supplementation required.
Glutaric acidemia intersects anaplerosis at the level of α-ketoglutarate metabolism. The lysine degradation pathway normally funnels carbon toward α-KG and the TCA cycle. When GCDH is deficient, glutaryl-CoA accumulates and diverts carbon away from productive TCA cycle entry. Additionally, glutaric acid may interfere with glutamine-dependent anaplerosis by competing with α-KG at shared transporters.
Lysine-restricted diet, carnitine supplementation, and aggressive emergency protocols during illness to prevent encephalopathic crises. Identified on newborn screening via C5-DC acylcarnitine. Early treatment can prevent neurological damage entirely — one of the great success stories of expanded newborn screening.