Clinical Diagnosis, Treatment, and ALDH7A1 Mutations in Pyridoxine-Dependent Epilepsy in Three Chinese Infants

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for several days at the age of 3 months 20 days and recurred at intervals of 13, 14 and 38 days after pyridoxine withdrawn for 3 times.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.

Expression and regulation of aldehyde dehydrogenases in prostate cancer

“…ALDH7A1, which has also been related to the stemness of CSCs [88] , is mainly localised in the cytosol, but it has also been found expressed to a lesser degree in the mitochondria and nucleus [32,45] . In addition to catalysing aldehyde metabolism, ALDH7A1 also plays a role in protecting tissues from the damaging effects of osmotic stress [89] while mutation of the ALDH7A1 gene has been related to pyridoxinedependent epilepsy [90,91] . In cancer, ALDH7A1 is expressed in nodular melanoma (NM) [92] , ovarian [93] and lung cancers [94] while in PCa the isoform has been shown to be involved in intra-bone growth and induced bone metastasis [64] as well as zoledronic acid resistance [95] .…”

Clinical and genetic features in pyridoxine‐dependent epilepsy: a Chinese cohort study

“…Genetic analysis of ALDH7A1 was performed as described previously. 18 Genetic analysis of PLPBP was performed as described by Plecko et al 5 The study was approved by the Biomedical Research Ethical Committee of Peking University First Hospital.…”

“…[4][5][6][7][8][9][10][11][12][13][14][15][16] Here, we report the clinical, electrophysiological, biochemical, and genetic spectrum of 33 patients with PDE from 31 unrelated families, including 12 patients (patient 1-6, patient 8-13) who were reported previously. [17][18][19] Thirty-one patients were PDE-ALDH7A1, and the other two patients were PDE-PLPBP.…”

Pyridoxine dependent epilepsy: Seizure onset, seizure types and EEG features

“…In 20% of the patients, there were either unilateral or bilateral focal discharges on EEG [11,18,25,38,40,49,52,55,56,59,60]. Eight percent of the patients had normal EEG [11,36,48,52,56].…”

“…Seventy-four percent of the patients presented with seizures within the first week of life, almost two third of those within the first day of life [1, 11, 15, 18, 21, 25-30, 32-34, 37, 38, 40, 42-45, 47-56]. Ten percent of the patients presented with seizures between 1-4 wk of life [2,11,21,23,40,[46][47][48][56][57][58]. The neonatal onset seizures within the first 4 wk of life have been reported in 84% of the patients in total.…”