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Journal of Peking University (Health Sciences) ›› 2024, Vol. 56 ›› Issue (5): 781-787. doi: 10.19723/j.issn.1671-167X.2024.05.005

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Phenotype of infantile epileptic spasm syndrome in pyridoxin-dependent epilepsy

Xianru JIAO1,2, Pan GONG2, Yue NIU1, Zhao XU1, Zongpu ZHOU1, Zhixian YANG1,*()   

  1. 1. Department of Pediatrics, Peking University People's Hospital, Beijing 100044, China
    2. Department of Pediatrics, Peking University First Hospital, Beijing 100034, China
  • Received:2024-06-25 Online:2024-10-18 Published:2024-10-16
  • Contact: Zhixian YANG E-mail:zhixian.yang@163.com
  • Supported by:
    the National Natural Science Foundation of China(82171436);Beijing Health Promotion Research Fund Project(2020-2-4077);Beijing Clinical Key Specialty Construction Project-Pediatrics Foundation(2199000726);Peking University Medicine Fund of Fostering Young Scholars' Scientific & Technological innovation(中央高校基本科研业务费资助BMU2024YFJHPY005);Peking University People's Hospital School Construction Project(BMU2023XY016);Peking University People's Hospital Talent Introduction Start-up Fund(2023-T-02);Peking University People's Hospital R&D Fund Unveiling Project(RDGS2023-10)

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Abstract:

Objective: To analyze the clinical diagnosis, treatment, and prognosis of the patients with pyridoxine-dependent epilepsy (PDE) characterized by infantile epileptic spasm syndrome (IESS). Methods: A total of 75 PDE patients with ALDH7A1 variants were diagnosed at the Department of Pediatrics of Peking University First Hospital and Peking University People's Hospital from July 2012 to June 2024, and five PDE patients with the phenotype of IESS were selected. The clinical manifestations, treatment, blood biochemistry, metabolic screening, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and gene testing results of the five PDE patients were analyzed. Results: Among the five patients diagnosed with PDE, three were female and two were male, and the phenotype was consistent with IESS. The age at the last follow-up was from one year and 3 months to 11 years and 9 months. All the five cases were delivered at term. Two cases had anoxia and asphyxia at birth, and three cases had normal birth history. The onset age of seizure ranged from one day to 4 months after birth. One case presented with epileptic spasms (ES), and three cases presented with focal seizure and ES. The other patient was started with ES, followed by multiple seizure types, including focal seizure and generalized tonic-clonic seizure, and developed epileptic status which caused secondary brain injury. The interictal EEG results showed hypsarrhythmia in three cases, generalized and multifocal discharges in one cases, and multifocal discharges in one case. No abnormalities were found in brain MRI in three cases, and secondary cerebral atrophy and hydrocephalus were observed in two cases during the course of the disease. Gene analysis confirmed that the five patients carried compound heterozygous variants of ALDH7A1, and two of them carried exon deletion variants. High dose pyridoxine treatment started at the end of 2 days, 4 years, 3 years, 4 days. and 2 months after the onset of the disease. Up to the last follow-up, seizures of four cases were controlled, followed by normal EEG. One patient with brain atrophy had uncontrolled seizures and EEG remained abnormal. The neurodevelopment of the three patients were severely delayed, and two were mildly delayed. Conclusion: IESS could be a rare phenotype of PDE. High doses of pyridoxine can control or reduce the frequency of seizures. Delayed diagnosis and treatment, secondary brain injury, and the genotype, especially deletions variants, were associated with poor prognosis.

Key words: Pyridoxine-dependent epilepsy, Infantile epileptic spasm syndrome, Vitamin B6, ALDH7A1

CLC Number: 

  • R742.1

Table 1

Clinical characteristics of five patients with infantile epileptic spasm syndrome of pyridoxine-dependent epilepsy"

Case Current age/ Gender GA Birth history Age at seizure onset Age at the onset of ES Seizure type Age at which vitamin B6 treatment started Current medication Interictal EEG/Age Brain MRI Outcome
1 7y8m/F At term Normal 4m 4m ES 4m PN Hypsarrhythmia/4m Normal Severe ID/GDD
2 11y9m/F At term Normal 1m 7m FS, ES 4y PN Hypsarrhythmia/2y Normal Severe ID/GDD
3 7y4m/M At term Hypoxia 1m 1m ES, GTCS, FS, SE 3y PN, VPA, LEV, LTG Hypsarrhythmia/2y Brain atrophy Severe ID/GDD
4 1y6m/F At term Hypoxia < 24 h < 24 h ES, FS 4 d PN Generalized and multifocal discharges/4 d Abnormal white matter signal in both cerebral hemispheres, Intraventricular hemorrhage, bilateral ventricle fullness, subcutaneous hematoma/8 d; hydrocephalus/4m Mild ID/DD
5 1y3m/M At term Normal < 24 h 43 d FS, ES 2m PN Multifocal discharges/14 d Normal Mild ID/DD

Figure 1

EEGs of three pyridoxine-dependent epilepsy patient (case 1, 2 and 3) with the phenotype of infantile epileptic spasm syndrome A and B, case 1, hypsarrhythmia at the age of 4 months before pyridoxine used and normal electroencephalogram (EEG) after spasms controlled by pyridoxine for 9 months; C and D, case 2, hypsarrhythmia at the age of 2 years and 2 months before pyridoxine used and normal EEG after spasms controlled by pyridoxine for nearly 2 years; E and F, case 3, multifocal and generalized discharges were recorded at the age of 2 years and 11 months before pyridoxine used, and the episode of epileptic spasms was monitored."

Figure 2

Brain MRI of case 3 Brain magnectic resonance imaging (MRI) of case 3 revealed bilateral brain atrophy at the age of 2 years and 9 months."

Table 2

Genetic characteristics of five patients with infantile epileptic spasm syndrome of pyridoxine-dependent epilepsy"

Case ALDH7A1 variants (NM_001182.4) Source of variants Prediction resultsACMG
Polyphen2 SIFT Mutation taster
1c.563T>C p.(V188A) Paternal Probably damaging Deleterious Disease causing Variant of uncertain significance
Deletion exon 1 Maternal - - - Pathogenic
2c.1547A>G p.(Y516C) Paternal Probably damaging Deleterious Disease causing Likely pathogenic
c.1061A>G p.(Y354C) Maternal Probably damaging Deleterious Disease causing Pathogenic
3c.1553G>C p.(R518T) Paternal Probably damaging Deleterious Disease causing Likely pathogenic
c.1547A>G p.(Y516C) Maternal Probably damaging Deleterious Disease causing Likely pathogenic
4Deletion exons 8-13 Paternal - - - Pathogenic
c.871+5G>A Maternal - - - Pathogenic
5c.1061A>G p.(Y354C) Paternal Probably damaging Deleterious Disease causing Pathogenic
c.1112C>A p.(P371Q) Maternal Probably damaging Deleterious Disease causing Likely pathogenic
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