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Fulltext Lack of meaningful genotype-phenotype association in SCN1A-related infantile-onset epileptic encephalopathies

Siti Aishah Abdul Wahab, Yusnita Yakob, Khoo,Teik-Beng, Sangita Dharshini Terumalay, Vigneswari Ganesan, Teh,Chee-Ming, et al.

Neurology Asia, 2017;22(2):99-111.
MyJurnal

Background & Objective: SCN1A gene which encodes for sodium channel alpha 1 subunit has been
found to be the most common mutated gene in patients with epilepsy. This study aims to characterize the
SCN1A mutations as well as to describe genotype and phenotype association in children with SCN1Arelated
infantile-onset epileptic encephalopathies in Malaysia.

Methods: Children with infantile-onset
epileptic encephalopathy mostly suspected to have Dravet syndrome who had mutational analysis for
SCN1A gene from hospitals all over Malaysia were included in the study. Their epilepsy syndrome
diagnosis was classified into severe myoclonic epilepsy in infancy and its variants. Polymerase chain
reaction and bidirectional sequencing were used to identify SCN1A mutations.

Results: A total of 38
children with heterozygous mutations were analysed, 22 (57.9%) of which were novel mutations.
Truncated mutations were the most common mutation type (19, 50%). Other mutation types were
missense mutations (14, 36.8%), splice site mutations (4, 10.5%) and in-frame deletion (1, 2.6%). The
mean age of seizure onset was 4.7 months. Seizure following vaccination was observed in 26.3% of
the children. All of them had drug resistant epilepsy. There was no significant association between
the type of mutation with the syndromic diagnosis, age of seizure onset, tendency of the seizures to
cluster or having status epilepticus, mean age when developmental delay was observed and response
to various antiepileptic drugs.

Conclusion: This study expands the spectrum of SCN1A mutations and proves the importance of
SCN1A gene testing in diagnosing infantile-onset epileptic encephalopathies patients. Although, our
study does not support any clinically meaningful genotype-phenotype association for SCN1A-related
infantile-onset epileptic encephalopathies, the clinical characteristics of our cohort are similar to those
that have been described in previous studies.
Neurologic manifestations and complications of pandemic influenza A H1N1 in Malaysian children: what have we learnt from the ordeal?

Muhammad Ismail HI, Teh CM, Lee YL, National Paediatric H1N1 Study Group

Brain Dev, 2015 Jan;37(1):120-9.
PMID: 24746706 DOI: 10.1016/j.braindev.2014.03.008

In 2009, pandemic influenza A H1N1 emerged in Mexico and subsequently spread worldwide. In Malaysia, there were more than a thousand of confirmed cases among children. The general clinical characteristics of these children have been well-published. However, the description of neurologic complications is scarce.
Congenital myasthenic syndrome with novel pathogenic variants in the COLQ gene associated with the presence of antibodies to acetylcholine receptors

Tay CG, Fong CY, Li L, Ganesan V, Teh CM, Gan CS, et al.

J Clin Neurosci, 2020 Feb;72:468-471.
PMID: 31831253 DOI: 10.1016/j.jocn.2019.12.007

Congenital myasthenic syndrome (CMS) is a heterogeneous group of inherited disorder which does not associate with anti-acetylcholine receptor (AChR) antibody. The presence of AChR autoantibody is pathogenic and highly sensitive and specific for autoimmune myasthenia gravis (MG). We describe 2 children from unrelated families who presented with hypotonia, ptosis and fatigability in early infancy with anti-AChR antibodies detected via ELISA on 2 separate occasions in the sera. Both were treated as refractory autoimmune MG due to poor clinical response to acetylcholinesterase inhibitor and immunotherapy. In view of the atypical clinical features, genetic studies of CMS were performed and both were confirmed to have novel pathogenic mutations in the COLQ gene. To the best of our knowledge, the presence of anti-AChR antibody in COLQ-related CMS has never been reported in the literature. The clinical presentation of early onset phenotype, and refractoriness to acetylcholinesterase inhibitor and immunotherapy should prompt CMS as a differential diagnosis.
Quality of life of children with tuberous sclerosis complex

Fong CY, Ng K, Kong AN, Ong LC, Rithauddin MA, Thong MK, et al.

Arch Dis Child, 2019 10;104(10):972-978.
PMID: 31122923 DOI: 10.1136/archdischild-2018-316394

AIM: Evaluation of impaired quality of life (QOL) of Malaysian children with tuberous sclerosis complex (TSC) and its possible risk factors.
METHOD: Cross-sectional study on 68 parents of Malaysian children aged 2-18 years with TSC. QOL was assessed using proxy-report Paediatric Quality of Life Inventory (PedsQL) V.4.0, and scores compared with those from a previous cohort of healthy children. Parents also completed questionnaires on child behaviour (child behaviour checklist (CBCL)) and parenting stress (parenting stress index-short form). Multiple regression analysis was used to determine sociodemographic, medical, parenting stress and behavioural factors that impacted on QOL.
RESULTS: The mean proxy-report PedsQL V.4.0 total scale score, physical health summary score and psychosocial health summary score of the patients were 60.6 (SD 20.11), 65.9 (SD 28.05) and 57.8 (SD 19.48), respectively. Compared with healthy children, TSC patients had significantly lower mean PedsQL V.4.0 total scale, physical health and psychosocial health summary scores (mean difference (95% CI): 24 (18-29), 20 (12-27) and 26 (21-31) respectively). Lower total scale scores were associated with clinically significant CBCL internalising behaviour scores, age 8-18 years and Chinese ethnicity. Lower psychosocial health summary scale scores were associated with clinically significant CBCL internalising behaviour scores, Chinese ethnicity or >1 antiepileptic drug (AED).
CONCLUSION: Parents of children with TSC reported lower PedsQL V.4.0 QOL scores in all domains, with psychosocial health most affected. Older children, those with internalising behaviour problems, of Chinese ethnicity or on >1 AED was at higher risk of lower QOL. Clinicians need to be vigilant of QOL needs among children with TSC particularly with these additional risk factors.
Factors associated with outcomes of severe acute necrotizing encephalopathy: A multicentre experience in Malaysia

Lee VWM, Khoo TB, Teh CM, Heng HS, Li L, Yusof YLM, et al.

Dev Med Child Neurol, 2023 Sep;65(9):1256-1263.
PMID: 36748407 DOI: 10.1111/dmcn.15536

This case series compared clinical variables and various combinations of immunotherapy received with outcomes of patients with severe acute necrotizing encephalopathy (ANE). We performed a retrospective review of clinical variables, immunotherapy received, and outcomes (based on the modified Rankin Scale) in Malaysia between February 2019 and January 2020. Twenty-seven children (12 male), aged 7 months to 14 years (mean 4 years) at diagnosis were included. Of these, 23 had an ANE severity score of 5 to 9 out of 9 (high risk). Eleven patients received tocilizumab (four in combination with methylprednisolone [MTP], seven with MTP + intravenous immunoglobulin [IVIG]) and 16 did not (two received MTP alone, 14 received MTP + IVIG). Nine died. Among the survivors, six had good outcomes (modified Rankin Score 0-2) at 6 months follow-up. All patients who received tocilizumab in combination with MTP + IVIG survived. Twenty children received first immunotherapy within 48 hours of admission. No significant association was found between the timing of first immunotherapy with outcomes. Those with brainstem dysfunction (p = 0.016) were observed to have poorer outcomes. This study showed a trend towards better survival when those with severe ANE were treated with tocilizumab in combination with MTP + IVIG. However, larger studies will be needed to determine the effect of this regime on the long-term outcomes.