Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up.
Study Goal
The researchers aimed to investigate the role of lysine degradation pathway disruption in pyridoxine-dependent epilepsy and explore potential treatments, including lysine restriction.
Results Summary
The study found that ATQ deficiency disrupts lysine catabolism, leading to toxic metabolite accumulation, and suggests that a lysine-restricted diet might mitigate toxicity. Pyridoxine and PLP treatments were effective in controlling seizures but did not fully prevent intellectual disability.
Population
Patients with pyridoxine-dependent epilepsy, particularly infants, neonates, and adults with ATQ deficiency.
Effective Dosage
Pyridoxine-HCl: 100 mg IV or 30 mg/kg/day orally/enterally; long-term: 15-30 mg/kg/day (infants), up to 200 mg/day (neonates), 500 mg/day (adults); PLP: up to 30 mg/kg/day.
Duration
Not specified
Interactions
None mentioned
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
pyridoxine | decrease | early onset epileptic encephalopathy | patients with Antiquitin (ATQ) deficiency | - | responsive to | #1 |
pyridoxine | increase | respiratory arrest | responders (first administration) | - | may result in | #2 |
pyridoxine | no change | late and masked response | patients being tested | - | should be continued until ATQ deficiency is excluded | #3 |
pyridoxal phosphate (PLP) | no change | treatment | patients with ATQ deficiency | up to 30 mg/kg/day | can be given alternatively | #4 |
maternal pyridoxine supplementation | increase | outcome | prenatal | - | possibly improves | #5 |
lysine restricted diet | decrease | potential toxicity of accumulating αAASA, P6C and pipecolic acid | patients with PDE (pyridoxine dependent epilepsy) | - | might address | #6 |
PLP | no change | treatment in patients with PNPO deficiency | patients with pyridox(am)ine phosphate oxidase (PNPO) deficiency | - | will not delay treatment | #7 |
Antiquitin (ATQ) deficiency is the main cause of pyridoxine dependent epilepsy characterized by early onset epileptic encephalopathy responsive to large dosages of pyridoxine. Despite seizure control most patients have intellectual disability. Folinic acid responsive seizures (FARS) are genetically identical to ATQ deficiency. ATQ functions as an aldehyde dehydrogenase (ALDH7A1) in the lysine degradation pathway. Its deficiency results in accumulation of α-aminoadipic semialdehyde (AASA), piperideine-6-carboxylate (P6C) and pipecolic acid, which serve as diagnostic markers in urine, plasma, and CSF. To interrupt seizures a dose of 100 mg of pyridoxine-HCl is given intravenously, or orally/enterally with 30 mg/kg/day. First administration may result in respiratory arrest in responders, and thus treatment should be performed with support of respiratory management. To make sure that late and masked response is not missed, treatment with oral/enteral pyridoxine should be continued until ATQ deficiency is excluded by negative biochemical or genetic testing. Long-term treatment dosages vary between 15 and 30 mg/kg/day in infants or up to 200 mg/day in neonates, and 500 mg/day in adults. Oral or enteral pyridoxal phosphate (PLP), up to 30 mg/kg/day can be given alternatively. Prenatal treatment with maternal pyridoxine supplementation possibly improves outcome. PDE is an organic aciduria caused by a deficiency in the catabolic breakdown of lysine. A lysine restricted diet might address the potential toxicity of accumulating αAASA, P6C and pipecolic acid. A multicenter study on long term outcomes is needed to document potential benefits of this additional treatment. The differential diagnosis of pyridoxine or PLP responsive seizure disorders includes PLP-responsive epileptic encephalopathy due to PNPO deficiency, neonatal/infantile hypophosphatasia (TNSALP deficiency), familial hyperphosphatasia (PIGV deficiency), as well as yet unidentified conditions and nutritional vitamin B6 deficiency. Commencing treatment with PLP will not delay treatment in patients with pyridox(am)ine phosphate oxidase (PNPO) deficiency who are responsive to PLP only.