Metabolic etiologies in children with infantile epileptic spasm syndrome: Experience at a tertiary pediatric neurology center.

Infantile epileptic spasm syndrome (IESS), including West syndrome (WS) and infantile spasm (IS), causes a challenging prognosis, particularly when associated with metabolic etiologies. This study, conducted at a tertiary pediatric neurology center, explored the prevalence and clinical features of inborn errors of metabolism in 112 children with IESS over 10 years. Most patients presented with seizures, primarily flexor spasms, and the median age at onset was 5 months. Comprehensive clinical evaluation and neuroimaging revealed structural-acquired causes as the most common etiology. Notably, inborn errors of metabolism were identified in 5.4 % of cases, with six distinct diagnoses including nonketotic hyperglycinemia, pyridoxine-dependent epilepsy, primary coenzyme Q10 deficiency 7, congenital disorder of glycosylation type IIM, 6-pyruvoyl tetrahydrobiopterin synthase deficiency, and argininosuccinate lyase deficiency. The prevalence of inborn errors of metabolism in this cohort was consistent with global variations reported in the literature. Genetic testing, including karyotype analysis and whole exome sequencing, was performed in a subset of cases with no clear diagnosis, revealing abnormalities in approximately 50 % of cases. Adrenocorticotropic hormone emerged as the most frequently prescribed antiseizure medication. This study provides insight into the diagnostic challenges associated with IESS and highlights the importance of metabolic investigations, especially in cases without a clear etiology. The findings emphasize the need for further genetic and metabolic studies to enhance prognostic accuracy and guide potential treatment options for children with IESS, particularly in populations with high rates of consanguinity.

Yüksel MF ，Doğulu N ，Yıldırım M ，Köse E ，Bektaş Ö ，Eminoğlu FT ，Teber S ... -  《-》

Hereditary neurometabolic causes of infantile spasms in 80 children presenting to a tertiary care center.

Infantile spasms are a devastating infantile epileptic syndrome with multiple etiologies. Hereditary neurometabolic disorders are rarely recognized causes of infantile spasms. The aim of this study was to identify hereditary neurometabolic disorders when they were the cause of infantile spasms in patients presenting to a tertiary care center in Saudi Arabia. We conducted a retrospective review of children presenting to the Pediatric Department of King Abdulaziz Medical City in Riyadh, Saudi Arabia over a 15-year interval. Eighty patients with infantile spasms were identified. A hereditary neurometabolic disorder was diagnosed in 10 patients (12.5%). Of these patients, two had a Leigh-like disorder and one patient had each of the following diagnoses: ethylmalonic aciduria, nonketotic hyperglycinemia, hyperinsulinemic hypoglycemia, leukodystrophy, short-chain acyl-coenzyme A dehydrogenase deficiency, molybdenum cofactor deficiency, primary carnitine deficiency, and neonatal hypoglycemia due to panhypopituitarism. This article is the first to report the association of the last three conditions with infantile spasms. Compared with the other etiologies, the hereditary neurometabolic disorder group had a strong history of similar disease in the same family (P = 0.002), and most of the patients were born of consanguineous parents (P = 0.021). In addition, a typical hypsarrhythmia pattern was more common in the hereditary neurometabolic disorder group (P = 0.003). Furthermore, this group had a poor response to therapy (P = 0.04). Otherwise, there were no significant differences regarding the type of spasms, neuroimaging or outcome; however, there was a trend toward poorer outcomes and death in the hereditary neurometabolic disorder group. Hereditary neurometabolic disorders are relatively common causes of infantile spasms in this subpopulation of Saudi patients. An early diagnosis via proper metabolic and genetic testing has significant implications for applying specific treatments and for facilitating proper family counseling.

Alrifai MT ，AlShaya MA ，Abulaban A ，Alfadhel M ... -  《-》

Landscape of genetic infantile epileptic spasms syndrome-A multicenter cohort of 124 children from India.

Literature on the genotypic spectrum of Infantile Epileptic Spasms Syndrome (IESS) in children is scarce in developing countries. This multicentre collaboration evaluated the genotypic and phenotypic landscape of genetic IESS in Indian children. Between January 2021 and June 2022, this cross-sectional study was conducted at six centers in India. Children with genetically confirmed IESS, without definite structural-genetic and structural-metabolic etiology, were recruited and underwent detailed in-person assessment for phenotypic characterization. The multicentric data on the genotypic and phenotypic characteristics of genetic IESS were collated and analyzed. Of 124 probands (60% boys, history of consanguinity in 15%) with genetic IESS, 105 had single gene disorders (104 nuclear and one mitochondrial), including one with concurrent triple repeat disorder (fragile X syndrome), and 19 had chromosomal disorders. Of 105 single gene disorders, 51 individual genes (92 variants including 25 novel) were identified. Nearly 85% of children with monogenic nuclear disorders had autosomal inheritance (dominant-55.2%, recessive-14.2%), while the rest had X-linked inheritance. Underlying chromosomal disorders included trisomy 21 (n = 14), Xq28 duplication (n = 2), and others (n = 3). Trisomy 21 (n = 14), ALDH7A1 (n = 10), SCN2A (n = 7), CDKL5 (n = 6), ALG13 (n = 5), KCNQ2 (n = 4), STXBP1 (n = 4), SCN1A (n = 4), NTRK2 (n = 4), and WWOX (n = 4) were the dominant single gene causes of genetic IESS. The median age at the onset of epileptic spasms (ES) and establishment of genetic diagnosis was 5 and 12 months, respectively. Pre-existing developmental delay (94.3%), early age at onset of ES (<6 months; 86.2%), central hypotonia (81.4%), facial dysmorphism (70.1%), microcephaly (77.4%), movement disorders (45.9%) and autistic features (42.7%) were remarkable clinical findings. Seizures other than epileptic spasms were observed in 83 children (66.9%). Pre-existing epilepsy syndrome was identified in 21 (16.9%). Nearly 60% had an initial response to hormonal therapy. Our study highlights a heterogenous genetic landscape and phenotypic pleiotropy in children with genetic IESS.

Nagarajan B ，Gowda VK ，Yoganathan S ，Sharawat IK ，Srivastava K ，Vora N ，Badheka R ，Danda S ，Kalane U ，Kaur A ，Madaan P ，Mehta S ，Negi S ，Panda PK ，Rajadhyaksha S ，Saini AG ，Saini L ，Shah S ，Srinivasan VM ，Suthar R ，Thomas M ，Vyas S ，Sankhyan N ，Sahu JK ... -  《-》

Nutritional vitamin B12 deficiency-associated Infantile epileptic spasms syndrome: Clinico-neurophysiological presentation, response to treatment, and neurodevelopmental outcome.

Nutritional vitamin B12 deficiency has been shown to cause Infantile epileptic spasms syndrome (IESS) in infants in anecdotal studies. In this retrospective cohort study, we intended to study the clinical presentation, neurophysiological, laboratory abnormalities, treatment, and neurodevelopmental outcome at 6-months in infants presenting with IESS secondary to nutritional vitamin B12 deficiency (NVBD) and to compare these variables from the rest of the infants with IESS without vitamin B12 deficiency. We included only spasm-free cases or those who showed at least a 50% reduction in spasm frequency on D7 after starting oral/parenteral vitamin B12. We used well-validated measurement tools like the Developmental Assessment Scale for Indian Infants (DASII), Child Feeding Index (CFI), Burden of amplitudes and epileptiform discharges (BASED) score, countable Hypsarrhythmia paroxysm index (cHPI), durational Hypsarrhythmia paroxysm index (dHPI), and Early childhood epilepsy severity scale (E-CHESS) score for documenting these variables. Data from 162 infants with IESS (21 caused by NVBD) were included in our study. The NVBD group had more patients residing in the rural region, with lower socioeconomic status, vegetarian mothers and poor complementary feeding index (p<0.001 for all). The NVBD group also had less number of patients requiring antiseizure medications (ASMs) and hormonal therapy(p<0.001), remained seizure free at six months (p=0.008), lower number of clusters per day (p=0.02) and the number of spasms per clusters at presentation (p=0.03), lower BASED score (p=0.03) and cHPI, dHPI at presentation (p<0.001). All of them remained spasm-free, with normal electroencephalogram at 6-months. Development quotient at baseline, at 6-months, and improvement in development quotient between these two-time points were more in the vitamin B12 deficiency group (p<0.001). All of them had clinical features of pre-ITS (infantile tremor syndrome) or ITS and it was found to be the only independent predictor of NVBD in infants with IESS. Mothers of all these infants had low serum vitamin B12 levels (<200 pg/ml). Nutritional vitamin B12 deficiency may cause IESS in infants. Hence, vitamin B12 deficiency needs to be ruled out in patients with IESS without any definite etiology.

Sharawat IK ，Ramachandran A ，Elwadhi A ，Tomar A ，Panda PK ... -  《-》

Infantile spasms (West syndrome) in children with inborn errors of metabolism: a review of the literature.

Gkampeta A ，Pavlou E 《-》