Authors :
Presenting Author: Mohammed AlQahtani, MD – The Hospital for Sick Children (SickKids)
Ali Mir, MD – Pediatric Neurologist, King Fahad Specialist Hospital in Dammam; Raidah AlBaradie, MD – Executive Director, Neuroscince center, King Fahad Specialist Hospital in Dammam; Fouad Alghamdi, MD – King Fahad Specialist Hospital in Dammam; Wajd Alotaibi, MD – King Fahad Specialist Hospital in Dammam; Fawzia Amer, MD – King Fahad Specialist Hospital in Dammam; Shahid Bashir, PhD – King Fahad Specialist Hospital in Dammam; Gregory Costain, MD PhD – Medical Genetics Staff, The Hospital for Sick Children (SickKids); Liali Aljouda, MD – Medical Genetics Fellow, The Hospital for Sick Children (SickKids); Yousef Housawi, MD – Medical Genetics Staff, King Fahad Specialist Hospital in Dammam
Rationale:
Epileptic spasms (ES) can be caused by a variety of etiologies. A thorough patient history and physical examination combined with magnetic resonance imaging (MRI) of the brain can help identify a large proportion of these etiologies. However, in almost half of cases, the etiology is unidentified by initial work up. With the advent of next-generation sequencing (NGS), the recognition of genetic etiologies has increased. In the era of personalized genomics and therapeutics, early diagnosis of specific etiologies of ES is of paramount importance so that specific therapies can be initiated. We primarily aim at measuring the yield of each genetic testing modality and secondarily want to identify the most common genetic etiologies of ES.
Methods:
We performed a retrospective chart review of all patients under 16 years of age who were diagnosed with ES at King Fahad Specialist Hospital in Dammam (KFSH-D) between January 2009 and December 2022. Institutional review board approval was obtained prior to pursuance of data collection. Genetic testing details were reviewed by three clinical geneticists. Genetic testing included tests such as karyotyping, chromosomal micro-array analysis (CMA), a 343-gene NGS epilepsy gene panel (343-gene EP), exome sequencing, mitochondrial DNA (mtDNA) testing, and other targeted single-gene tests or panels. Metabolic testing included the following plasma tests: levels of ammonia, lactate, and pyruvate; an acylcarnitine profile, and amino acid levels. It also included the following urine tests: acylcarnitine profile and levels of amino acids, organic acids, and very long chain fatty acids. Additional tests, such as cerebrospinal fluid (CSF) levels of lactate, pyruvate, amino acids, and neurotransmitters, were reviewed when necessary and if available.
Results:
Our data show that in 52.8% of patients with ES, the etiology was unidentified after a standard clinical evaluation and neuroimaging. Of these patients, n= 34 (51.5%) received a genetic diagnosis after some form of genetic testing, and 3.3% of patients received a diagnosis after clues from specialized metabolic work indicated the need for genetic testing to confirm the diagnosis. Karyotyping led to a diagnosis in 3.8% of patients, and chromosomal microarray led to a diagnosis in 5.1%. An NGS epilepsy gene panel (EP) was done for 44 patients, leading to a diagnosis in 34.1% (n=15, P= 0.049, CI: 20.5-49.9). Exome sequencing was done for 27 patients, including n=15 with non-diagnostic panel testing; it led to a diagnosis in 55.6% (n=15, CI: 35.3-74.5). Exome sequencing led to a diagnosis in all 12 patients without a previous panel test and in only three patients who had previously had a negative panel testing.Conclusions:
In this project, we present the diagnostic evaluations of ES for a cohort of 125 patients and discuss the yield and priority of wider coverage NGS for evaluating ES to achieve cost-effective and timely diagnosis. Our findings suggest that exome sequencing has a higher diagnostic yield than other genetic tests for determining the etiology of ES in patients for whom the etiology is still unclear after an appropriate clinical assessment and a brain MRI.Funding: None