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Infantile spasms in a Malaysian population. Clinical and EEG studies at initial presentation

Vignaendra V, Raju L, Lee C, Ghee T

J Trop Pediatr Environ Child Health, 1976 Oct;22(5):220-4.
PMID: 1051827
Matched MeSH terms: Spasms, Infantile/complications; Spasms, Infantile/diagnosis*
Epidemiology of West syndrome in Singapore

Lee WL, Ong HT

Brain Dev, 2001 Nov;23(7):584-5.
PMID: 11701260

The incidence of West syndrome (WS) was determined by a search of reports of electroencephalograms (EEG) recorded in 1998 and 1999 in all public hospitals in Singapore. Amongst records of patients born in 1998, nine were found with EEG features of hypsarrhythmia or modified hypsarrhythmia with onset of seizures between January 1,1998 and December 31, 1999. The medical records of these patients were reviewed. The population of children born in 1998 was 43,664. In 1998 and 1999, 67% of all hospital admissions for patients 2 years or younger in Singapore were in public hospitals. The cumulative incidence of WS in Singapore corrected for the percentage of hospital admissions to public hospitals was 3.1/10,000 live births. The corrected cumulative incidences in Chinese, Malays and Indians were 2.7, 3.1 and 3.3 per 10,000, respectively. Three cases were idiopathic; three were due to congenital structural lesions of the brain; one each had periventricular leucomalacia, intracranial hemorrhage and severe intrauterine growth retardation. None of the patients were normal at follow up. The three patients with idiopathic WS had mild global developmental delay and the other six cases had cerebral palsy and severe mental retardation. With the best modern medical treatment, possibly only two of the nine cases of WS may have been prevented.

Matched MeSH terms: Spasms, Infantile/epidemiology*
A novel homozygous truncating variant of NECAP1 in early infantile epileptic encephalopathy: the second case report of EIEE21

Mizuguchi T, Nakashima M, Moey LH, Ch'ng GS, Khoo TB, Mitsuhashi S, et al.

J Hum Genet, 2019 Apr;64(4):347-350.
PMID: 30626896 DOI: 10.1038/s10038-018-0556-2

We report the second case of early infantile epileptic encephalopathy (EIEE) arising from a homozygous truncating variant of NECAP1. The boy developed infantile-onset tonic-clonic and tonic seizures, then spasms in clusters. His electroencephalogram (EEG) showed a burst suppression pattern, leading to the diagnosis of Ohtahara syndrome. Whole-exome sequencing revealed the canonical splice-site variant (c.301 + 1 G > A) in NECAP1. In rodents, Necap1 protein is enriched in neuronal clathrin-coated vesicles and modulates synaptic vesicle recycling. cDNA analysis confirmed abnormal splicing that produced early truncating mRNA. There has been only one previous report of a mutation in NECAP1 in a family with EIEE; this was a nonsense mutation (p.R48*) that was cited as EIEE21. Decreased mRNA levels and the loss of the WXXF motif in both the families suggests that loss of NECAP1 function is a common pathomechanism for EIEE21. This study provided additional support that synaptic vesicle recycling plays a key role in epileptogenesis.

Matched MeSH terms: Spasms, Infantile/genetics*; Spasms, Infantile/physiopathology
Novel biallelic SZT2 mutations in 3 cases of early-onset epileptic encephalopathy

Tsuchida N, Nakashima M, Miyauchi A, Yoshitomi S, Kimizu T, Ganesan V, et al.

Clin Genet, 2018 02;93(2):266-274.
PMID: 28556953 DOI: 10.1111/cge.13061

The seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that is associated with epileptogenesis. In mice, Szt2 is abundantly expressed in the central nervous system. Recently, biallelic SZT2 mutations were found in 7 patients (from 5 families) presenting with epileptic encephalopathy with dysmorphic features and/or non-syndromic intellectual disabilities. In this study, we identified by whole-exome sequencing compound heterozygous SZT2 mutations in 3 patients with early-onset epileptic encephalopathies. Six novel SZT2 mutations were found, including 3 truncating, 1 splice site and 2 missense mutations. The splice-site mutation resulted in skipping of exon 20 and was associated with a premature stop codon. All individuals presented with seizures, severe developmental delay and intellectual disabilities with high variability. Brain MRIs revealed a characteristic thick and short corpus callosum or a persistent cavum septum pellucidum in each of the 2 cases. Interestingly, in the third case, born to consanguineous parents, had unexpected compound heterozygous missense mutations. She showed microcephaly despite the other case and previous ones presenting with macrocephaly, suggesting that SZT2 mutations might affect head size.

Matched MeSH terms: Spasms, Infantile/genetics*; Spasms, Infantile/pathology
De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms

Nakashima M, Kato M, Matsukura M, Kira R, Ngu LH, Lichtenbelt KD, et al.

J Hum Genet, 2020 Sep;65(9):727-734.
PMID: 32341456 DOI: 10.1038/s10038-020-0758-2

The ubiquitin-proteasome system is the principal system for protein degradation mediated by ubiquitination and is involved in various cellular processes. Cullin-RING ligases (CRL) are one class of E3 ubiquitin ligases that mediate polyubiquitination of specific target proteins, leading to decomposition of the substrate. Cullin 3 (CUL3) is a member of the Cullin family proteins, which act as scaffolds of CRL. Here we describe three cases of global developmental delays, with or without epilepsy, who had de novo CUL3 variants. One missense variant c.854T>C, p.(Val285Ala) and two frameshift variants c.137delG, p.(Arg46Leufs*32) and c.1239del, p.(Asp413Glufs*42) were identified by whole-exome sequencing. The Val285 residue located in the Cullin N-terminal domain and p.Val285Ala CUL3 mutant showed significantly weaker interactions to the BTB domain proteins than wild-type CUL3. Our findings suggest that de novo CUL3 variants may cause structural instability of the CRL complex and impairment of the ubiquitin-proteasome system, leading to diverse neuropsychiatric disorders.

Matched MeSH terms: Spasms, Infantile/complications; Spasms, Infantile/genetics*
Early epileptic encephalopathies including West syndrome: a 3-year retrospective study from Klang Hospital, Malaysia

Thambyayah M

Brain Dev, 2001 Nov;23(7):603-4.
PMID: 11701263

It is difficult to give a country report from Malaysia. A study done in 1999 reported the incidence of West Syndrome to be 3% among newly diagnosed cases of epilepsy. In this 3 year retrospective hospital-based study (1997-1999), the prevalence of early epileptic encephalopathy (EEE) and West Syndrome were 4.1 and 2.5% respectively. There is difficulty classifying EEE cases into distinct sub-groups of EIEE (early infantile epileptic encephalopathy), WS (West Syndrome) and SMEI (severe myoclonic epilepsy of infancy), using a combination of clinical features, EEG and CT/MRI findings.

Matched MeSH terms: Spasms, Infantile/epidemiology*
De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy

Nakashima M, Kato M, Aoto K, Shiina M, Belal H, Mukaida S, et al.

Ann Neurol, 2018 04;83(4):794-806.
PMID: 29534297 DOI: 10.1002/ana.25208

OBJECTIVE: The cytoplasmic fragile X mental retardation 1 interacting proteins 2 (CYFIP2) is a component of the WASP-family verprolin-homologous protein (WAVE) regulatory complex, which is involved in actin dynamics. An obvious association of CYFIP2 variants with human neurological disorders has never been reported. Here, we identified de novo hotspot CYFIP2 variants in neurodevelopmental disorders and explore the possible involvement of the CYFIP2 mutants in the WAVE signaling pathway.
METHODS: We performed trio-based whole-exome sequencing (WES) in 210 families and case-only WES in 489 individuals with epileptic encephalopathies. The functional effect of CYFIP2 variants on WAVE signaling was evaluated by computational structural analysis and in vitro transfection experiments.
RESULTS: We identified three de novo CYFIP2 variants at the Arg87 residue in 4 unrelated individuals with early-onset epileptic encephalopathy. Structural analysis indicated that the Arg87 residue is buried at an interface between CYFIP2 and WAVE1, and the Arg87 variant may disrupt hydrogen bonding, leading to structural instability and aberrant activation of the WAVE regulatory complex. All mutant CYFIP2 showed comparatively weaker interactions to the VCA domain than wild-type CYFIP2. Immunofluorescence revealed that ectopic speckled accumulation of actin and CYFIP2 was significantly increased in cells transfected with mutant CYFIP2.
INTERPRETATION: Our findings suggest that de novo Arg87 variants in CYFIP2 have gain-of-function effects on the WAVE signaling pathway and are associated with severe neurological disorders. Ann Neurol 2018;83:794-806.

Matched MeSH terms: Spasms, Infantile/genetics*