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 ... -  《-》

Genetic Advancements in Infantile Epileptic Spasms Syndrome and Opportunities for Precision Medicine.

Snyder HE ，Jain P ，RamachandranNair R ，Jones KC ，Whitney R ... -  《-》

Genotype-phenotype correlates of infantile-onset developmental & epileptic encephalopathy syndromes in South India: A single centre experience.

A paucity of literature exists on genotype- phenotype correlates of 'unknown-etiology' infantile-onset developmental-epileptic encephalopathies (DEE) from India. The primary objective was to explore the yield of genetic testing in identifying potential disease causing variants in electro-clinical phenotypes of DEE METHODS: An observational hospital-based study was undertaken on children with unexplained refractory seizure-onset ≤12 months age and developmental delay, whose families consented and underwent genetic testing during a three year time period (2016-2018) by next-generation sequencing (NGS) or multiplex ligand protein amplification. Yield was considered based on demonstration of pathogenic/likely pathogenic variants only and variants of unknown significance (VUS) were documented. Pathogenic/likely pathogenic variants were identified in 26 (31.7 %) out of 82 children with DEE. These included those variants responsible for primarily DEE- 21(76.7 %); neuro-metabolic disorders- 3(18.6 %) and chromosomal deletions- 2(4.7 %). Of these patients, early-infantile epilepsy onset ≤ 6 months age was noted in 22(84.6 %). The DEE studied included Ohtahara syndrome associated with STXBP1 and SCN8A variants with yield of 50 % (2/4 tested); early myoclonic encephalopathy (no yield in 2); West syndrome with CDKL5, yield of 13.3 % (2/15 tested); epilepsy of infancy with migrating partial seizures due to CACNA1A and KCNT1 variants, yield of 67 % (2/3 tested); DEE-unclassified with KCNQ2, AP3B2, ZEB2, metabolic variants (SUOX, ALDH7A1, GLDC) and chromosome deletions (chr 1p36, chr2q24.3); yield of 32 % (8/25 tested). Patients with Dravet syndrome/Dravet-like phenotypes (N = 33) had variants in SCN1A (N = 10), SCN1B, CHD2; yield of 36.4 % (12/33 tested; 57.1 % from NGS). Eighteen patients with potential variants (SCN1A, SCN2A, SCN8A, KCNQ2, ALDH7A1 which also included VUS) could be offered targeted therapy. Our study confirms a good yield of genetic testing in neonatal and infantile-onset DEE provided robust phenotyping of infants is attempted with prognostic and therapeutic implications, particularly relevant to centres with resource constraints.

Mitta N ，Menon RN ，McTague A ，Radhakrishnan A ，Sundaram S ，Cherian A ，Madhavilatha GK ，Mannan AU ，Nampoothiri S ，Thomas SV ... -  《-》

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 ... -  《-》

Late infantile epileptic encephalopathy: A distinct developmental and epileptic encephalopathy syndrome.

Within the spectrum of developmental and epileptic encephalopathy (DEE), there are a group of infants with features that are distinct from the well-recognized syndromes of early infantile developmental and epileptic encephalopathy (EIDEE), infantile epileptic spasm syndrome (IESS), and Lennox-Gastaut syndrome (LGS). We refer to this condition as late infantile epileptic encephalopathy (LIEE). Our objective was to highlight the characteristics of this group by analyzing patients who exhibit prototypical features. From July 2022 to May 2023, we searched for LIEE features in pediatric patients who underwent epilepsy follow-up at the University of Chicago Comer Children's Hospital. Out of 850 patients evaluated, thirty patients (3.5%) were identified with LIEE based on electroclinical characteristics. These patients had an average onset of epilepsy at 6.8 months and an average onset of LIEE features at 18.1 months. The epilepsy etiology was most commonly genetic and metabolic (50%), followed by congenital cortical malformations (23%), acquired structural abnormalities (20%), and unknown (7%). The predominant seizure types were myoclonic-tonic (70%), spasm-tonic (50%), epileptic spasms (47%), tonic (43%), and myoclonic (43%) seizures. All patients reported a history of either spasm-tonic or myoclonic-tonic seizures in addition to other types. All patients had EEGs showing discontinuity, electrodecrements, or both along with diffuse slowing, background voltages between 100 and 300 μV, and superimposed multifocal, diffuse epileptiform discharges. Every patient, except one, fulfilled the definition of drug-resistant epilepsy, and all reported either moderate-to-severe or severe developmental delay. Late infantile epileptic encephalopathy (LIEE) is characterized by several unique clinical and electrographic features. Typically, LIEE manifests in patients during the second year of life and occurs before two years of age, hence late infantile onset. The condition is commonly observed in infants with symptomatic epilepsy. Myoclonic-tonic and spasm-tonic seizures are the quintessential seizure types. The inter-ictal EEG exhibits more organization and lower voltages than seen with hypsarrhythmia and lacks the defining EEG characteristics of EIDEE, IESS, or LGS. We propose that LIEE is a distinct electroclinical syndrome within the spectrum of developmental and epileptic encephalopathies.

Kacker S ，Phitsanuwong C ，Oetomo A ，Nordli DR Jr ... -  《-》