Pyridoxine
Pyridoxine (PN) is a form of vitamin B6 found commonly in food and used as a dietary supplement. As a supplement it is used to treat and prevent pyridoxine deficiency, sideroblastic anaemia, pyridoxine-dependent epilepsy, certain metaboli ...
-dependent epilepsy (PDE) is a rare
genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...
characterized by intractable seizures in the prenatal and neonatal period. The disorder was first recognized in the 1950s, with the first description provided by Hunt et al. in 1954.
More recently, pathogenic variants within the
ALDH7A1
Aldehyde dehydrogenase 7 family, member A1, also known as ALDH7A1 or antiquitin, is an enzyme that in humans is encoded by the ''ALDH7A1'' gene. The protein encoded by this gene is a member of subfamily 7 in the aldehyde dehydrogenase gene family ...
gene have been identified to cause PDE.
Genetics
PDE is inherited in an
autosomal
An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosome ...
recessive manner and is estimated to affect around 1 in 400,000 to 700,000 births, though one study conducted in Germany estimated a prevalence of 1 in 20,000 births.
The ALDH7A1 gene encodes for the enzyme antiquitin or α-aminoadipic semialdehyde dehydrogenase, which is involved with the catabolism of
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...
.
Treatment
Patients with PDE do not respond to
anticonvulsant
Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...
medications, but seizures rapidly cease with therapeutic intravenous doses of
vitamin B6 and remission from seizures are often maintained on daily therapeutic doses of vitamin B
6.
An optimal dose has not yet been established, but doses of 50–100 mg/day or 15–30 mg/kg/day have been proposed.
Importantly, excessive doses of vitamin B
6 can result in irreversible neurological damage, and therefore several guidelines recommend between 200 mg (
neonates
In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to Juvenile (orga ...
) and 500 mg per day as the maximal daily dose.
Despite remission of seizure activity with vitamin B
6 supplementation, intellectual disability is frequently seen in patients with PDE.
Because the affected enzyme antiquitin is involved in the cerebral lysine degradation pathway, lysine restriction as an additional treatment modality has recently been explored. Studies have been published which demonstrate potential for improved biomarkers, development, and behavior in patients treated with lysine restriction in addition to pyridoxine supplementation.
In trial, lysine restriction of 70–100 mg/kg/day in children less than 1 year of age, 45–80 mg/kg/day in children between 1–7 years of age, and 20–45 mg/kg/day in children older than 7 years of age were prescribed.
Despite the potential of additional benefit from lysine restriction, vitamin B6 supplementation remains the main-stay of treatment given lack of studies thus far demonstrating the safety and efficacy of lysine restriction for this purpose.
Monitoring
Plasma and cerebrospinal fluid levels of
pipecolic acid are frequently elevated in patients with PDE, though it is a non-specific biomarker.
α-aminodipic semialdehyde is elevated in urine and plasma and is a more specific biomarker for PDE.
Improvements in these biomarkers have been reported with the implementation of a lysine-restricted diet.
Initial studies evaluating the safety and efficacy of lysine restriction evaluated developmental and cognitive outcomes by age-appropriate tests and parental observations.
See also
*
Early-onset vitamin B6-dependent epilepsy - pyridoxine-responsive epilepsy discovered in 2016 and caused by mutations of the
PROSC gene.
*
Hyperphosphatasia with mental retardation syndrome - in this rare syndrome, some patients have pyridoxine-dependent epilepsy.
References
External links
GeneReview/NCBI/NIH/UW entry on Pyridoxine-Dependent SeizuresPyridoxine-dependent epilepsy
''Genetics Home Reference''. June 17, 2013.
{{DEFAULTSORT:Pyridoxine-Dependent Epilepsy
Epilepsy types