Pyridoxal 5'-phosphate-dependent epilepsy

Alternate names

Pyridoxine-5'-phosphate oxidase deficiency; PNPO Deficiency; Pyridoxamine 5-prime-phosphate oxidase deficiency; PNPO-related neonatal epileptic encephalopathy

Definition

Pyridoxal 5'-phosphate-dependent epilepsy is a rare genetic metabolic disorder. Babies born with this disorder are not able to make enough Vitamin B6 and this causes the baby to start having seizures soon after they are born (also called early onset or neonatal onset seizures). The seizures typically involve irregular involuntary muscle contractions (myoclonus), abnormal eye movements, and convulsions.

Epidemiology

Pyridoxal 5'-phosphate-dependent epilepsy is a rare condition; approximately 14 cases have been described in the scientific literature.

Cause

Mutations in the PNPO gene cause pyridoxal 5'-phosphate-dependent epilepsy. The PNPO gene provides instructions for producing an enzyme called pyridoxine 5'-phosphate oxidase. This enzyme is involved in the conversion (metabolism) of vitamin B6 derived from food (in the form of pyridoxine and pyridoxamine) to the active form of vitamin B6 called pyridoxal 5'-phosphate (PLP). PLP is necessary for many processes in the body including protein metabolism and the production of chemicals that transmit signals in the brain (neurotransmitters).

Gene mutation

PNPO gene mutations result in a pyridoxine 5'-phosphate oxidase enzyme that is unable to metabolize pyridoxine and pyridoxamine, leading to a deficiency of PLP. A shortage of PLP can disrupt the function of many other proteins and enzymes that need PLP in order to be effective. It is not clear how the lack of PLP affects the brain and leads to the seizures that are characteristic of pyridoxal 5'-phosphate-dependent epilepsy.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

The seizures typically involve irregular involuntary muscle contractions (myoclonus), abnormal eye movements, and convulsions. Most babies with this condition are born prematurely and may have a temporary, potentially toxic, increase in lactic acid in the blood (lactic acidosis). Additionally, some infants have a slow heart rate and a lack of oxygen during delivery (fetal distress).

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Epileptic encephalopathy
• Status epilepticus(Repeated seizures without recovery between them)

30%-79% of people have these symptoms

• Abnormality of eye movement(Abnormal eye movement)
• Abnormality of the amniotic fluid
• Decreased CSF homovanillic acid
• EEG with burst suppression
• Failure to thrive(Faltering weight)
• Feeding difficulties(Feeding problems)
• Global brain atrophy(Generalized brain degeneration)
• Global developmental delay
• High-pitched cry
• Hypertonia
• Hypoargininemia(Low blood arginine levels)
• Hypoglycemia(Low blood sugar)
• Increased serum lactate
• Low APGAR score
• Metabolic acidosis
• Muscular hypotonia of the trunk(Low muscle tone in trunk)
• Myoclonus
• Premature birth(Premature delivery of affected infants)
• Unsteady gait(Unsteady walk)

5%-29% of people have these symptoms

• Abnormal circulating glycine concentration
• Abnormal circulating histidine concentration
• Abnormal circulating threonine concentration
• Abnormal circulating tyrosine concentration
• Microcephaly(Abnormally small skull)
• Pyridoxine-responsive sideroblastic anemia

Diagnosis

Diagnosis is suspected by early onset of seizures which are not controlled by normal anti-seizure medications. Genetic testing is used to confirm the diagnosis.

Treatment

• The disorder is fatal without treatment. Early treatment is important to decrease the chance of long term developmental delays. Some babies with early treatment have developed normally without any intellectual disabilities.
• The normal drugs to treat seizures (anti-seizure medications or anti-convulsants) do not work for these babies, however seizures can be controlled by pyridoxal 5'-phosphate (the active form of Vitamin B6).
• Published studies in 2015 have shown that some babies with pyridoxal 5'-phosphate-dependent epilepsy also respond well to pyridoxene (a different form of Vitamin B6).

NIH genetic and rare disease info

• NIH info on Pyridoxal 5'-phosphate-dependent epilepsy

Pyridoxal 5'-phosphate-dependent epilepsy is a rare disease.

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