precision medicine in epilepsy mangement

genetic testing role in epilepsy in limited resources countries

1. A. Classical examples of epilepsy precision medicine 1. Vitamin B6-responsive disorders Pyridoxine-dependent epilepsy due to ALDH7A1 variants Pyridoxine-dependent epilepsy (PDE) is an autosomal recessive neurometabolic disorder characterized by neonatal intractable seizures that are responsive pyridoxine (vitamin B6), but not controlled by classical antiepileptic drugs. Pyridoxine-dependent epilepsy was first described in the 1950s ( Hunt et al., 1954 ) and the treatment response can sometimes be dramatic when previously intractable neonatal seizures stop shortly after intravenous pyroxidine administration.

2. Pyridoxine-dependent epilepsy provides an ideal example of personalized medicine: a genetic alteration leading to an ongoing biochemical dysfunction that can be rectified, leading to resolution of clinical symptoms ( Plecko , 2013 ).

3. 2. GLUT1 deficiency and the ketogenic diet . GLUT1 deficiency syndrome is an important example of a genetic epilepsy amenable to targeted treatment. GLUT1 deficiency syndrome was first described in 1991 in two children with global developmental delay, seizures and hypoglycorrhachia, an unexplained low glucose in the cerebrospinal fluid ( De Vivo et al., 1991 ). In 1998, disease-causing variants in SCL2A1 , encoding a glucose transporter in the blood-brain barrier, were identified as the genetic cause of GLUT1 deficiency syndrome ( Seidner et al., 1998 ). Both dominant and recessive forms of this condition have since been described. GLUT1 deficiency syndrome has become an important differential diagnosis in severe neonatal encephalopathies, and screening for low CSF glucose is now standard practice in these patients ( Ito et al., 2015; Hewson et al., 2018 )

4. Biotinidase deficiency No need for genetic testing in cases of biotinidase deficiency as blood testing assay is enough for diagnosis. Individuals with biotinidase deficiency who are diagnosed before they have developed symptoms (e.g., by newborn screening) and who are treated with biotin have normal development. Symptoms including seizures, developmental delay, cutaneous manifestations (skin rash, alopecia), optic atrophy, hearing loss, and respiratory problems occur only in those individuals with biotinidase deficiency prior to biotin treatment.

5. B . Complex response patterns to precision medicine in genetic epilepsies 1. Sodium channel blockers in sodium channelopathies Neurons heavily rely on voltage-gated sodium channels for the initiation and propagation of action potentials, and these channels represent a major target of anti-seizure medications. Genes encoding voltage-gated ion channels represent a major contributor to genetic causes of epilepsy ( Lindy et al., 2018; Heyne et al., 2019 ). The four genes coding for voltage-gated sodium channels are SCN1A , SCN2A , SCN8A , and SCN3A in decreasing order of frequency in individuals with epilepsy ( Claes et al., 2001; Wolff et al., 2017; Gardella et al., 2018; Zaman et al., 2018 ).

6. Dravet syndrome is caused by de novo alterations in SCN1A and a significant proportion of SCN1A variants are protein-disrupting variants, resulting in haploinsufficiency. . SCN2A, SCN3A, and SCN8A-related epilepsies The epilepsies due to disease causing genetic changes in SCN2/3/8A will be discussed jointly in the context of precision medicine approaches as similar considerations apply to these three conditions with respect to the use of sodium channel blockers. These three conditions are clinically characterized by a wide range of clinical features, ranging from developmental delay without seizures to severe, early-onset epileptic encephalopathies ( Wolff et al., 2017; Gardella et al., 2018; Zaman et al., 2018 )

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13. Challenges and limitations Large-scale clinical and outcome data Because they apply to small patient groups or even single individuals, demonstrating the effectiveness of precision treatments has been best accomplished when the clinical effects were dramatic. The vitamin B6-responsive disorders or GLUT1 deficiency syndrome provide instructional examples of the history of epilepsy precision medicine. However, more recent studies in the complex nature of response to anti-seizures medications in channelopathies suggest that in many cases, the response pattern may be more complex. Clinical response may be gradual rather than binary, change over time, and only be present in subset of individuals due to a range of known and unknown confounding factors.

14. standardized phenotyping language for epilepsy outcome measures Even though the epilepsy community is continuously expanding the standardized description of seizure types and epilepsy syndrome ( Fisher et al., 2017; Scheffer et al., 2017 ), the language and concepts represented in these classifications only capture a small subset of the relevant clinical information, such as response to medication, outcome, imaging and EEG features. . One attempt that has been made to overcome this issue is the use of standardized language mapped to a common ontology such as the epilepsy and seizure ontology ( EpSO ) that allows for a multi-modal representation of the various clinical domains related to epilepsy ( Sahoo et al., 2014 ). The Human Phenotype Ontology (HPO) addressed the same issue, albeit in a more limited domain, representing the clinical symptoms in a unified approach ( Robinson et al., 2008; Kohler et al., 2014; Kohler et al., 2017 ).

15. Future directions: Using electronic medical records to extract standardized epilepsy phenotyping The systematic use of standardized data formats such as the Observational Medical Outcomes Partnership (OMOP) Common Data Model ( Informatics, 2018 ), PEDSnet ( Forrest et al., 2014 ), or PCORnet ( PCORnet , 2018 ), enable further standardization that will allow for collaboration across institutions, which in turn will enable large longitudinal studies assessing outcomes. Jointly, these frameworks have the unique promise of generating objective, longitudinal clinical data alongside expanding genetic datasets to add the missing phenotypic dimension to current and future epilepsy precision medicine approaches.

16. Conclusions Epilepsy precision medicine is an expanding field fueled by the increasing identification of causative genetic alterations. We have highlighted some of the early successes in epilepsy precision medicine, as well as the current challenges in translating these paradigms to disorders with variable expressivity and largely unknown natural history. We recommend genetic testing for individuals with unexplained epilepsy. This evidence-based guideline is based on literature demonstrating the high diagnostic yields of GS, ES, MGP, and CMA, as well as the clinical utility of genetic testing to guide treatment/ medical management, revise, or establish prognosis and/or provide reproductive risk counseling.

17. Additionally, we recommend that th genetic testing in the unexplained epilepsy population be implemented by a qualified healthcare provider with appropriate pretest and post-test genetic counseling and interpretation of results.