Understanding Challenges of Genetic Testing on Neuromuscular Disorders from the Parental Lens.

Neuromuscular disorders, characterized by progressive muscle degeneration and weakness, present substantial challenges to both affected individuals and their families. Genetic testing assumes a pivotal role in facilitating early diagnosis, intervention, treatment, and informed family planning for these conditions. The objective of this qualitative study is to delve into the knowledge, awareness, and perceptions surrounding genetic testing within the cohort of parents caring for individuals with neuromuscular disorders in Malaysia. A semi-structured interview approach was employed to elicit data from parents of individuals diagnosed with neuromuscular disorders, encompassing those with clinical diagnoses and those diagnosed through genetic testing. Examination of the interview responses yielded nine overarching themes, which furnish invaluable insights into the perspectives of Malaysian parents concerning genetic testing. The study discerned several challenges associated with genetic testing, notably encompassing the limited awareness among parents, the financial constraints associated with genetic testing, and the perceived significance of genetic testing in the context of neuromuscular disorders. The findings suggest that the level of knowledge and awareness pertaining to genetic testing for neuromuscular disorders among parents in Malaysia varies, with initial levels of awareness ranging from relatively low to reasonably sufficient prior to and following the birth of an affected child. However, the investigation revealed that parents tended to cultivate more favorable perceptions regarding genetic testing subsequent to their experience with genetic counseling. This underscores the potential for heightened awareness and comprehension as a consequence of the personal experience of parenting an affected child confirmed through genetic testing and genetic counseling, ultimately influencing parental awareness.

Management of status epilepticus in Malaysia: A national survey of current practice and treatment gap.

INTRODUCTION: Early and effective treatment is fundamental in status epilepticus (SE) management. At the initiative of the Epilepsy Council of Malaysia, this study aimed to determine the treatment gap in SE across different healthcare settings in Malaysia. METHODS: A web-based survey was sent to clinicians involved in the management of SE, across all states and at all levels of healthcare services. RESULTS: A total of 158 responses were received from 104 health facilities, including 23 tertiary government hospitals (95.8% of all government tertiary hospitals in Malaysia), 4 (80.0%) universities, 14 (6.7%) private, 15 (11.5%) district hospitals and 21 clinics. Intravenous (IV) diazepam was available in 14 (93.3%) district and 33 (80.5%) tertiary hospitals for prehospital management. Non-IV benzodiazepine (rectal diazepam and intramuscular midazolam) was not widely available in prehospital services (75.8% and 51.5%). Intramuscular midazolam was underutilised (60.0% in district and 65.9% in tertiary hospitals). IV sodium valproate and levetiracetam were only available in 66.7% and 53.3% of the district hospitals, respectively. Electroencephalogram (EEG) services were available in only 26.7% of the district hospitals. Non-pharmacological therapies such as ketogenic diet, electroconvulsive therapy, and therapeutic hypothermia were not available in most district and tertiary hospitals for refractory and super-refractory SE. CONCLUSIONS: We identified several gaps in the current practice of SE management, including limited availability and underutilization of non-IV midazolam in prehospital services, underutilization of non-IV midazolam and other second-line ASMs, and lack of EEG monitoring in district hospitals and limited treatment options for refractory and super-refractory SE in tertiary hospitals.

Factors associated with outcomes of severe acute necrotizing encephalopathy: A multicentre experience in Malaysia.

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.

CYP3A5 genetic variants and their associations with carbamazepine and valproic acid response in Malaysian epileptic patients.

OBJECTIVE: Epilepsy is a common chronic neurological condition characterized by recurrent seizures. Approximately 30 - 40% of epileptic patients do not respond to antiepileptic drugs. Previous studies suggest that CYP3A5 polymorphisms affect carbamazepine metabolism. MATERIALS AND METHODS: To examine this hypothesis, in the present study, the associations between CYP3A5 variants (rs776746 and rs1419745) and response to carbamazepine and valproic acid monotherapy in Malaysian epileptic patients were evaluated. RESULTS: A total of 288 Malaysian epileptic patients were recruited and further reviewed, of whom 63 patients were on carbamazepine monotherapy, and 85 patients were on valproic acid monotherapy. There was no patient with drug hypersensitivity syndrome within the population. Subjects were genotyped by using Sequenom MassARRAY platform. This study found a significant association of CYP3A5 rs776746 with the carbamazepine treatment response in total patients (p = 0.026) and Malay ethnic subgroup (p = 0.006). In addition, a marginal significant association of CYP3A5 rs1419745 with carbamazepine treatment response was reported in the Malays. Similarly, CYP3A5 rs776746 was associated with valproic acid response in total patients (p = 0.037) and Malays (marginal p = 0.05). CONCLUSION: Our findings suggest that CYP3A5 polymorphisms affect carbamazepine and valproic acid response in Malaysian epileptic patients.

RORA gene rs12912233 and rs880626 polymorphisms and their interaction with SCN1A rs3812718 in the risk of epilepsy: a case-control study in Malaysia.

RAR-related orphan receptors A (RORA) and B (RORB) and voltage-gated sodium channel type 1 (SCN1A) genes play critical roles in the regulation of the circadian clock. Evidence has shown an association of RORA and RORB polymorphisms with susceptibility to autism and depression. Hence, we tested the association of RORA rs12912233, rs16943429, rs880626, rs2290430, and rs12900948; RORB rs1157358, rs7022435, rs3750420, and rs3903529; and SCN1A rs3812718 with epilepsy risk in the Malaysians. DNA was genotyped in 1789 subjects (39% epilepsy patients) by using MassARRAY (Sequenom). Significant association was obtained for rs12912233 in Malaysian Chinese (p=0.003). Interaction between rs12912233-rs880626 and rs3812718 was associated with the epilepsy risk in the subjects overall (p=0.001). Results show that RORA rs12912233 alone might be a possible risk variant for epilepsy in Malaysian Chinese, but that, together with RORA rs880626 and SCN1A rs3812718, this polymorphism may have a synergistic effect in the epilepsy risk in Malaysians.

Contribution of TIMP4 rs3755724 polymorphism to susceptibility to focal epilepsy in Malaysian Chinese.

Neuroinflammation can damage the brain and plays a critical role in the pathophysiology of epilepsy. Tissue inhibitor of metalloproteinase 4 (TIMP4) is an inflammation-induced apoptosis and matrix turnover factor involved in several neuronal disorders and inflammatory diseases. Evidence has shown linkage disequilibrium between rs3755724 (-55C/T) of this gene with synapsin 2 (SYN2) rs3773364 and peroxisome proliferator-activated G receptor (PPARG) rs2920502 loci, which contribute to epilepsy in Caucasians. The aim of this study was to examine the association of these loci alone or their haplotypes with the risk of epilepsy in the Malaysian population. Genomic DNA of 1241 Malaysian Chinese, Indian, and Malay subjects (670 patients with epilepsy and 571 healthy individuals) was genotyped for the candidate loci by using the Sequenom MassArray method. Allele and genotype association of rs3755724 with susceptibility to epilepsy was significant in the Malaysian Chinese with focal epilepsy under codominant and dominant models (C vs. T: 1.5 (1.1-2.0), p=0.02; CT vs. TT: 1.8 (1.2-2.8), p=0.007 and 1.8 (1.2-2.7), p=0.006, respectively). The T allele and the TT genotype were more common in patients than in controls. No significant association was found between rs2920502 and rs3773364-rs3755724-rs2920502 haplotypes for susceptibility to epilepsy in each ethnicity. This study provides evidence that the promoter TIMP4 rs3755724 is a new focal epilepsy susceptibility variant that is plausibly involved in inflammation-induced seizures in Malaysian Chinese.

Sleep disturbances in Malaysian children with cerebral palsy.

AIM: The aim of the study was to compare the frequency and type of sleep disturbances in a group of Malaysian children aged 4 to 18 years with cerebral palsy (CP) with their nearest-age, able-bodied siblings and to identify factors associated with sleep disturbances. METHOD: The study was a case-control study of 109 children with CP (61 males, 48 females; mean age 9 y, SD 3 y 11 mo, range 4-18 y) and their healthy siblings (56 males, 53 females; mean age 10 y, SD 3 y 9 mo, range 4-18 y). The Sleep Disturbances Scale for Children (SDSC) questionnaire was completed by the main caregiver. In children with CP, multiple regression analysis was be used to determine factors related to higher Total SDSC sleep scores. RESULTS: Ninety-seven children (89%) had spastic CP, 10 (9%) had dyskinetic CP, and two (2%) had mixed CP. Based on the Gross Motor Function Classification System (GMFSC), 34 patients (31%) were at GMFSC level I or II, 10 patients (9%) at level III, and 65 patients (60%) at level IV or V. Children with CP scored significantly higher than their siblings on Total SDSC and four SDSC subscale scores - difficulty in initiating and maintaining sleep, sleep breathing disorders, sleep-wake transition disorders, and sleep hyperhidrosis. Caregiver sleep duration of less than 7 hours (p=0.02) and caregiver sleep latency of more than 30 minutes (p=0.03) were significantly associated with higher Total SDSC scores. Co-sleeping was not a significant factor. INTERPRETATION: Sleep disturbances are more common in children with CP than in their siblings. Attention should be given to caregiver sleep when evaluating sleep disturbances in children with CP as this factor was shown to be associated with higher Total SDSC scores.

PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine.

OBJECTIVE: Whole genome sequencing and the screening of 103 families recently led us to identify PRRT2 (proline-rich-transmembrane protein) as the gene causing infantile convulsions (IC) with paroxysmal kinesigenic dyskinesia (PKD) (PKD/IC syndrome, formerly ICCA). There is interfamilial and intrafamilial variability and the patients may have IC or PKD. Association of IC with hemiplegic migraine (HM) has also been reported. In order to explore the mutational and clinical spectra, we analyzed 34 additional families with either typical PKD/IC or PKD/IC with migraine. METHODS: We performed Sanger sequencing of all PRRT2 coding exons and of exon-intron boundaries in the probands and in their relatives whenever appropriate. RESULTS: Two known and 2 novel PRRT2 mutations were detected in 18 families. The p.R217Pfs*8 recurrent mutation was found in ≈50% of typical PKD/IC, and the unreported p.R145Gfs*31 in one more typical family. PRRT2 mutations were also found in PKD/IC with migraine: p.R217Pfs*8 cosegregated with PKD associated with HM in one family, and was also detected in one IC patient having migraine with aura, in related PKD/IC familial patients having migraine without aura, and in one sporadic migraineur with abnormal MRI. Previously reported p.R240X was found in one patient with PKD with migraine without aura. The novel frameshift p.S248Afs*65 was identified in a PKD/IC family member with IC and migraine with aura. CONCLUSIONS: We extend the spectrum of PRRT2 mutations and phenotypes to HM and to other types of migraine in the context of PKD/IC, and emphasize the phenotypic pleiotropy seen in patients with PRRT2 mutations.

Lack of association between synapsin II (SYN2) gene polymorphism and susceptibility epilepsy: a case-control study and meta-analysis.

OBJECTIVE: The SYN2 rs3773364 A>G polymorphism has been proposed to be involved in susceptibility to epilepsy, but research results have been inconclusive. The aim of this study was to investigate the association between the SYN2 rs3773364 A>G polymorphism and susceptibility against epilepsy in a case-control study and a meta-analysis. METHODS: The SYN2 rs3773364 A>G polymorphism was successfully genotyped in 1182 samples (618 epilepsy patients) of Chinese, Indian, and Malay ethnicities. Meta-analysis of the related studies, including this case-control study, was performed under alternative genetic models. RESULTS: Data from the case-control study indicated no allelic and genotypic association of this locus with susceptibility to epilepsy in the tri-ethnic Malaysian population. Similar finding was obtained by stratified analysis by epilepsy syndrome for idiopathic epilepsy. These results were verified by meta-analysis of the related pooled data. CONCLUSIONS: Our study indicated that SYN2 rs3773364 A>G polymorphism is not a risk factor for susceptibility to epilepsy.

Association between ABCB1 polymorphism and response to sodium valproate treatment in Malaysian epilepsy patients.

Over-expression of P-glycoprotein, encoded by the ABCB1 gene, is proposed to be involved in resistance to antiepileptic drugs in about 30% of patients with epilepsy. Here, we investigated the possible association between ABCB1 polymorphisms and sodium valproate (VPA) treatment in Malaysian epilepsy patients. Genotypes were assessed in 249 drug-resistant and 256 drug-responsive Malaysian patients for C1236T, G2677T/A, and C 5T polymorphisms in the ABCB1 gene. No genotypes, alleles, or haplotypes were associated with the response to VPA in either the overall group or Chinese, Indian, and Malay subgroups. Our data suggest that C1236T, G2677T/A, and C3435T polymorphisms in the ABCB1 gene do not contribute to the response to VPA in patients with epilepsy.

Sturge-Weber syndrome without facial nevus: an unusual cause of neonatal seizures.

Sturge-Weber syndrome is a neurocutaneous syndrome characterised by facial port wine stain, ipsilateral leptomeningeal angioma and vascular eye abnormalities. We report a rare case of Sturge-Weber syndrome without facial nevus presenting with neonatal seizures.

Novel familial cases of ICCA (infantile convulsions with paroxysmal choreoathetosis) syndrome.

Epilepsy and paroxysmal dyskinesia are two episodic cerebral disorders that can share a common genetic basis. Rare families with infantile seizures and paroxysmal dyskinesia [predominantly paroxysmal kinesigenic dyskinesia (PKD)], co-inherited as a single autosomal dominant trait, have been described (infantile convulsions with paroxysmal choreoathetosis; ICCA syndrome) and a disease gene has been mapped at chromosome 16p12-q12 (ICCA region). We report the clinical picture of seven previously unreported families with ICCA syndrome. The identification of novel ICCA families should contribute to better knowledge regarding the clinical manifestations of ICCA syndrome as well as the search for the underlying genetic defect(s).

Episodic vomiting and headache in children: consider occipital epilepsy.

Children with occipital seizures often have ictal autonomic symptoms such as pallor and vomiting and lack motor manifestations. This has lead to misdiagnosis of occipital seizures in children. The following case report highlights the clinical features of a child with occipital epilepsy misdiagnosed as having migraine. The aetiology of symptomatic occipital epilepsy will be discussed.

Sleep habits and disturbances in Malaysian children with epilepsy.

AIMS: To compare sleep habits and disturbances between Malaysian children with epilepsy and their siblings (age range 4-18 years) and to determine the factors associated with greater sleep disturbance. METHODS: The Sleep Disturbance Scale for Children (SDSC) questionnaire was completed by the primary caregiver for 92 epileptic children (mean age 11.1 years, 50 male, 42 females) and their healthy siblings (mean age 11.1 years, 47 males, 45 females). Details of sleep arrangements and illness severity were obtained. Multiple regression analysis was used to determine factors associated with high Total SDSC scores in epileptic patients. RESULTS: Compared with their siblings, epileptic children had significantly higher total SDSC score (difference between means 8.7, 95% confidence interval (CI) 6.4-11.1) and subscale scores in disorders of initiating and maintaining sleep (3.9, 95% CI 2.8-5.2), sleep-wake transition disorders (2.1, 95% CI 1.3-2.9), sleep-disordered breathing (0.7, 95% CI 0.3-1.1) and disorders of excessive sleepiness (1.5, 95% CI 0.6-2.4). Epileptic children had a higher prevalence of co-sleeping (73.7% vs 31.5%) and on more nights per week (difference between means 3, 95% CI 2.0-3.9) than their siblings. Higher Epilepsy Illness Severity scores were associated with higher total SDSC scores (P= 0.02). CONCLUSION: Co-sleeping was highly prevalent in children with epilepsy, who also had more sleep disturbances (especially problems with initiating and maintaining sleep and sleep-wake transition disorders) than their siblings. Epilepsy severity contributed to the sleep disturbances. Evaluation of sleep problems should form part of the comprehensive care of children with severe epilepsy.