Diagnostic evaluation of patients with epileptic spasms in the era of next-generation sequencing.

OBJECTIVE: Epileptic spasms (ES) can be caused by a variety of etiologies. However, in almost half of cases, the etiology is unidentified. With the advent of next-generation sequencing (NGS), the recognition of genetic etiologies has increased. METHODS: We retrospectively reviewed the medical records of patients with ES who were evaluated in the comprehensive epilepsy program at King Fahad Specialist Hospital Dammam between 2009 and 2022. RESULTS: Our data show that in 57.7% of patients with ES, the etiology was unidentified after a standard clinical evaluation and neuroimaging. Of these patients, n = 25 (35.2%) received a genetic diagnosis after some form of genetic testing, and 3.1% of patients from specialized metabolic work indicated the need for genetic testing to confirm the diagnosis. Karyotyping led to a diagnosis in 3.6% of patients, and chromosomal microarray led to a diagnosis in 7.1%. An NGS epilepsy gene panel (EP) was done for 45 patients, leading to a diagnosis in 24.4% (n = 11). Exome sequencing was done for 27 patients, including n = 14 with non-diagnostic panel testing; it led to a diagnosis in 37.3% (n = 10). Exome sequencing led to a diagnosis in 61.5% of patients without a previous panel test and in only two patients who had previously had a negative panel testing. SIGNIFICANCE: In this article, we present the diagnostic evaluations of ES for a cohort of 123 patients and discuss the yield and priority of NGS for evaluating ES. Our findings suggest that exome sequencing has a higher diagnostic yield for determining the etiology of ES in patients for whom the etiology is still unclear after an appropriate clinical assessment and a brain MRI.

Clinical and Molecular Characteristics of Neuronal Ceroid Lipofuscinosis in Saudi Arabia.

BACKGROUND: Neuronal ceroid lipofuscinoses (NCLs) represent a heterogeneous group of inherited metabolic lysosomal disorders characterized by neurodegeneration. This study sought to describe the clinical and molecular characteristics of NCLs in Saudi Arabia and determine the most common types in that population. METHODS: A retrospective review of electronic medical records was conducted for 63 patients with NCL (55 families) from six tertiary and referral centers in Saudi Arabia between 2008 and 2022. Clinical, radiological, and neurophysiological data as well as genetic diagnoses were reviewed. RESULTS: CLN6 was the predominant type, accounting for 45% of cases in 25 families. The most common initial symptoms were speech delay (53%), cognitive decline (50%) and/or gait abnormalities (48%), and seizure (40%). Behavioral symptomatology was observed in 20%, whereas visual impairment was less frequently (9.3%) encountered. Diffuse cerebral and cerebellar atrophy was the predominant finding on brain magnetic resonance imaging. Electroencephalography generally revealed background slowing in all patients with generalized epileptiform discharges in 60%. The most common genotype detected was the p.Ser265del variant found in 36% (20 of 55 families). The most rapidly progressive subtypes were CLN2 and CLN6. Two patients with each died at age five years. The earliest age at which a patient was nonambulatory was two years in a patient with CLN14. CONCLUSIONS: This is the largest molecularly confirmed NCL cohort study from Saudi Arabia. Characterizing the natural history of specific NLC types can increase understanding of the underlying pathophysiology and distinctive genotype-phenotype characteristics, facilitating early diagnosis and treatment initiation as well as genetic counseling for families.

Constitutional Mismatch Repair Deficiency Syndromes, a Neurofibromatosis 1 Mimicker That Hinders Timely Management.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a rare, autosomal recessive disease caused by a biallelic germline mutation in one of the DNA mismatch repair genes ( MLH1 , MSH2 , MSH6 and PMS2 ). In addition to colorectal, brain, and hematological malignancies, many additional premalignant and non-malignant features that can point toward the diagnosis of CMMRD have been reported. The report from the CMMRD consortium revealed that all children with CMMRD have café-au-lait macules (CALMs) but the number of CALMs does not reach > 5 in all CMMRD patients, which is one of the diagnostic criterions of NF1. About half of the patients with CMMRD develop brain tumors and up to 40% develop metachronous second malignancies. METHODS: This is an observational retrospective case series describing five pediatric patients with CMMRD. RESULTS: All the five patients in our cohort developed brain tumors and showed a predilection to the frontal lobe. In our cohort, multiple Mongolian spots, coloboma, obesity, CHD, dysmorphism, and clubfoot were also encountered. In all our patients, NF1 and other tumorigenic predisposing syndromes were initially suspected. CONCLUSION: Increasing awareness of this condition and its shared reminiscent NF1 features, particularly CALMs among child neurologists, oncologists, geneticists, and dermatologists can help uncover the tip of the iceberg of CMMRD that carries an important consequence on management.

Continuous Spikes and Waves During Sleep (CSWS), Severe Epileptic Encephalopathy, and Choreoathetosis due to Mutations in FRRS1L.

Background. Biallelic pathogenic variants in the FRRS1L gene are now known to cause developmental and epileptic encephalopathy-37 (DEE37). It can also be associated with chorea and continuous spikes and waves during sleep (CSWS). CSWS is a rare age-related epileptic encephalopathy syndrome of childhood that is characterized by seizures, neurocognitive regression and electrical status epilepticus during sleep (ESES) on electroencephalogram (EEG) that evolves in four stages. Seizures start during the prodromal phase but the ESES on EEG appears only during acute stage and this is the stage when the diagnosis of CSWS can be made. Methods. We present two patients with FRRS1L mutation causing DEE37 with CSWS. We also review twenty-nine cases of DEE37 described in the literature before and discuss its association with CSWS in the total cohort of thirty-one cases. Results. Developmental regression was found in 80% of the patients, mean age of seizure onset was 18 months, ESES or slow spike and wave on the EEG were reported mostly in the older patients (median age of 11 years) and hypsarrhythmia was reported in younger patients (median age of 4 years). This could suggest that if the younger patients were followed longer their EEG would have evolved into ESES during the acute stage of this syndrome and a diagnosis of CSWS could be made. Conclusion. Recognizing ESES and the natural evolution of CSWS is important in diagnosis and proper management of these patients. More detailed report of EEG findings and the evolution of epilepsy and development are needed to further characterize this syndrome.

SLC gene mutations and pediatric neurological disorders: diverse clinical phenotypes in a Saudi Arabian population.

The uptake and efflux of solutes across a plasma membrane is controlled by transporters. There are two main superfamilies of transporters, adenosine 5'-triphosphate (ATP) binding cassettes (ABCs) and solute carriers (SLCs). In the brain, SLC transporters are involved in transporting various solutes across the blood-brain barrier, blood-cerebrospinal fluid barrier, astrocytes, neurons, and other brain cell types including oligodendrocytes and microglial cells. SLCs play an important role in maintaining normal brain function. Hence, mutations in the genes that encode SLC transporters can cause a variety of neurological disorders. We identified the following SLC gene variants in 25 patients in our cohort: SLC1A2, SLC2A1, SLC5A1, SLC6A3, SLC6A5, SLC6A8, SLC9A6, SLC9A9, SLC12A6, SLC13A5, SLC16A1, SLC17A5, SLC19A3, SLC25A12, SLC25A15, SLC27A4, SLC45A1, SLC46A1, and SLC52A3. Eight patients harbored pathogenic or likely pathogenic mutations (SLC5A1, SLC9A6, SLC12A6, SLC16A1, SLC19A3, and SLC52A3), and 12 patients were found to have variants of unknown clinical significance (VOUS); these variants occurred in 11 genes (SLC1A2, SLC2A1, SLC6A3, SLC6A5, SLC6A8, SLC9A6, SLC9A9, SLC13A5, SLC25A12, SLC27A4, and SLC45A1). Five patients were excluded as they were carriers. In the remaining 20 patients with SLC gene variants, we identified 16 possible distinct neurological disorders. Based on the clinical presentation, we categorized them into genes causing intellectual delay (ID) or autism spectrum disorder (ASD), those causing epilepsy, those causing vitamin-related disorders, and those causing other neurological diseases. Several variants were detected that indicated possible personalized therapies: SLC2A1 led to dystonia or epilepsy, which can be treated with a ketogenic diet; SLC6A3 led to infantile parkinsonism-dystonia 1, which can be treated with levodopa; SLC6A5 led to hyperekplexia 3, for which unnecessary treatment with antiepileptic drugs should be avoided; SLC6A8 led to creatine deficiency syndrome type 1, which can be treated with creatine monohydrate; SLC16A1 led to monocarboxylate transporter 1 deficiency, which causes seizures that should not be treated with a ketogenic diet; SLC19A3 led to biotin-thiamine-responsive basal ganglia disease, which can be treated with biotin and thiamine; and SLC52A3 led to Brown-Vialetto-Van-Laere syndrome 1, which can be treated with riboflavin. The present study examines the prevalence of SLC gene mutations in our cohort of children with epilepsy and other neurological disorders. It highlights the diverse phenotypes associated with mutations in this large family of SLC transporter proteins, and an opportunity for personalized genomics and personalized therapeutics.

Epilepsy in patients with EAST syndrome caused by mutation in the KCNJ10.

OBJECTIVE: EAST syndrome comprises of epilepsy, ataxia, sensorineural deafness, and tubulopathy. It is caused by a mutation in KCNJ10 gene. Less than thirty cases have been reported in the literature with emphasis on genetic mutation and renal tubulopathy. In this article, our goal is to present a comprehensive description of epilepsy and its management. A literature review is also presented to consolidate and compare our findings with the previously reported cases. METHODS: Retrospective chart review was done to collect patient data. Research clinic was organized to obtain missing data. Molecular genetic testing was done at the CGC Genetics Laboratory. Electroencephalogram (EEG) was done for all patients and interpreted by a pediatric epileptologist and brain MRI was reviewed by a pediatric neuroradiologist. Developmental assessment was done by a developmental pediatrician using Griffiths Mental Developmental Scale. RESULTS: In patients with EAST syndrome, seizure is the first symptom occurring around 3-4 months of age. Most common seizure type was generalized tonic clonic (GTC). Usually, the seizures were brief lasting <3 min but few patients also presented with status epilepticus especially when the medication was weaned. Carbamazepine (CBZ) was found to be effective in most cases. Lamotrigine (LTG), valproic acid (VPA), and topiramate (TPM) were also found to be helpful. Routine EEGs were usually normal or showed non-specific findings. In few patients, EEG showed background slowing. Brain MRI revealed hyperintensity in the dentate nuclei in some patients, and quantitative volumetric analysis studies showed volume loss in different regions of the brain especially the cerebellum. All our five patients have the same homozygous c.170C>T (p.Thr57Ile) missense mutation in KCNJ10 gene. CONCLUSION: This article provides the readers with an understanding of the natural history of epilepsy in this syndrome to help in early recognition, avoid unnecessary investigations, and provide the best treatment for seizures. It also helps the physicians to share the prognosis of this rare syndrome with the parents.

Screening for Lynch syndrome in young Saudi colorectal cancer patients using microsatellite instability testing and next generation sequencing.

Individuals with Lynch syndrome (LS) have germline variants in DNA mismatch repair (MMR) genes that confer a greatly increased risk of colorectal cancer (CRC), often at a young age. Identification of these individuals has been shown to increase their survival through improved surveillance. We previously identified 33 high risk cases for LS in the Saudi population by screening for microsatellite instability (MSI) in the tumor DNA of 284 young CRC patients. The aim of the present study was to identify MMR gene variants in this cohort of patients. Peripheral blood DNA was obtained from 13 individuals who were at high risk of LS due to positive MSI status and young age (<60 years at diagnosis). Next generation sequencing, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification were used to screen for germline variants in the MLH1, MSH2, MSH6 and PMS2 MMR genes. These were cross-referenced against several variant databases, including the International Society for Gastrointestinal Hereditary Tumors Incorporated database. Variants with pathogenic or likely pathogenic significance were identified in 8 of the 13 high risk cases (62%), comprising 4 in MLH1 and 4 in MSH2. All carriers had a positive family history for CRC or endometrial cancer. Next generation sequencing is an effective strategy for identifying young CRC patients who are at high risk of LS because of positive MSI status. We estimate that 7% of CRC patients aged <60 years in Saudi Arabia are due to LS, potentially involving around 50 new cases per year.

Loss-of-Function Mutations in KIF15 Underlying a Braddock-Carey Genocopy.

Braddock-Carey Syndrome (BCS) is characterized by microcephaly, congenital thrombocytopenia, Pierre-Robin sequence (PRS), and agenesis of the corpus callosum. BCS has been shown to be caused by a 21q22.11 microdeletion that encompasses multiple genes. Here, we report a BCS genocopy characterized by congenital thrombocytopenia and PRS that is caused by a loss-of-function mutation in KIF15 in a consanguineous Saudi Arabian family. Mutations of mitotic kinesins are a well-established cause of microcephaly. To our knowledge, KIF15 is the first kinesin to be associated with congenital thrombocytopenia.

Benign familial and non-familial infantile seizures (Fukuyama-Watanabe-Vigevano syndrome): a study of 14 cases from Saudi Arabia.

PURPOSE: Benign infantile seizures [BIS], familial and non-familial, represent a benign, age-related idiopathic syndrome of infancy. The aim of the current paper is to document the presence of the syndrome in Saudi Arabia and in Arab populations and to discuss the characteristic electroclinical features and the benign nature of this syndrome. PATIENTS AND METHODS: A case series of 275 patients with epileptic seizures (age range: 2 months-13 years) were followed over a period of 3 years and 7 months. The inclusion criteria for BIS were as follows (1) age of seizure onset between 2 and 24 months, (2) normal development before, during and after the onset of seizures, (3) normal interictal EEG, (4) normal brain imaging, and (5) good response to treatment. We analyzed these infants with respect to age at seizure onset, sex, physical and neurological examination, consanguinity, frequency and type of convulsions, associated conditions and laboratory and radiological investigations. A waking and sleeping interictal EEG was performed on all patients, and for one patient (No. 1), ictal EEG and video clips were recorded. RESULTS: Fourteen infants (12.0%) showed electroclinical features consistent with BIS. Eleven patients fulfilled the criteria of benign non-familial infantile seizures (BNFIS), and for three patients, their family pedigrees showed the possibility of benign familial infantile seizures (BFIS). All of the patients responded to anti-epileptic treatment, and 50% of them responded within 3 months. CONCLUSIONS: To our knowledge, this is the first study to document the presence of BIS (Fukuyama-Watanabe-Vigevano syndrome) in Saudi Arabian and Arab populations. We highlighted the characteristic features of BIS and demonstrated the benign nature of the syndrome.