Abstract
Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder that causes seizures in neonates and infants. Mutations of the ALDH7A1 gene are now recognized as the molecular basis PDE and help to define this disease. Three Chinese children with PDE were clinically analyzed, followed by treatment and examination of the ALDH7A1 mutations. The seizures of the 3 patients were all resistant to multiple anticonvulsants (2 to 7 types). For case 1, onset of seizures was at the age of 2 months. His seizures were well controlled by intravenous pyridoxine for several days at the age of 3 months 20 days and recurred at intervals of 13, 14 and 38 days after pyridoxine withdrawn for 3 times. At the age of 7 months, symptoms of PDE appeared and uninterrupted oral pyridoxine started. For case 2, her seizures occurred at 8 days after birth. After administration of multiple antiepileptic drugs observed ineffective, high-dose pyridoxine continuous therapy was taken at the age of 10 months and the significant treatment effect induced a diagnostic PDE. Seizure onset in case 3 was at the first day of birth. He experienced inadvertently pyridoxine therapy several times (first time at 2 days after birth) and achieved good therapeutic effect, which was confirmed by physicians until 4 months 10 days. The treatment process in our 3 patients suggested that pyridoxine should be early and purposefully used in patients with early onset seizures. ALDH7A1 gene mutation analysis revealed compound heterozygous mutations in each case: heterozygous c.410G>A (p.G137E) and IVS11+1G>A in case 1, heterozygous c.952G>C (p.A318P) and heterozygous c.965C>T (p.A322V) in case 2, and heterozygous c.902A>T (p.N301I) and IVS11+1G>A in case 3. Only p.N301I was reported previously, all other mutations were novel. This is the first time to report cases of Chinese patients diagnosed with PDE by molecular genetic analysis.
Highlights
Pyridoxine-dependent epilepsy (PDE, OMIM 266100) is a rare autosomal recessive disorder that was first described in 1954 by Hunt et al [1]
Case 3: heterozygous c.902A.T (p.N301I) in exon10 that was inherited from the mother, and IVS11+1G.A in intron 11 inherited from the father
The mutations G137E, A322V and N301I all occur in regions that are highly conserved in antiquitin across species, suggesting their evolutional importance (Figure 2)
Summary
Pyridoxine-dependent epilepsy (PDE, OMIM 266100) is a rare autosomal recessive disorder that was first described in 1954 by Hunt et al [1]. It is characterized by recurrent seizures mainly during neonatal or early infantile periods and is refractory to common anticonvulsants but responsive to high doses of pyridoxine. Based on the above studies and by analyzing 13 individuals with PDE, Mills et al [5] confirmed that PDE was caused by ALDH7A1 gene mutations, and the concentration of alpha-aminoadipic semialdehyde was increased in cerebrospinal fluid, plasma or urine of PDE patients.
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