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The presence of inherited metabolic epilepsy in adulthood is increasing with more pediatric patients receiving diagnoses through newborn screening or expedited testing and increasing success with interventions. There are also the scenarios of existing diseases going unrecognized or misdiagnosed as more generic entities such as nonprogressive/static encephalopathy or autism spectrum disorder. In addition, these disorders have changing phenotypes across the life span, ranging from changes in the underlying seizures to systemic manifestations. Then morbidity and mortality shift in terms of etiology and prognosis. The adult lives of these patients may be dominated by very different medical problems than what had existed during their childhood. Further, the care of the adult metabolic patient, whether presenting with new onset disease or in transitioning from childhood, requires a high level of complexity in medical decision making and often a multidisciplinary care model.
The diagnosis of inherited metabolic epilepsies poses major challenges. Inherited metabolic epilepsies tend to have onset during the neonatorum, infancy, or early childhood periods. The history may provide relevant information regarding other common entities including prenatal or perinatal events, trauma, central nervous system infection, or systemic conditions. Family history is a key point for inherited conditions and genetically based epilepsies. A detailed physical exam should focus particularly on dysmorphic or neurocutaneous stigmata, micro or macrocephaly, and signs of systemic disease. This chapter provides diagnostic algorithm for inherited metabolic epilepsies. The algorithm serves as a guide to enable a logical approach to disease screening and to choose specific diagnostic tests that may be required to identify certain inborn errors. The focus of the algorithm is on metabolic disorders and is not exhaustive. Special emphasis, however, is afforded to identifying treatable disorders that, without timely intervention, may have dire prognoses.
Inherited metabolic epilepsies represent a diverse group of disorders of inborn errors of metabolism in which epilepsy is a clinically significant component. This book, organized into six parts containing 43 chapters, is based on a sequential exposition of general principles, basic science, clinical science, small molecule disorders, large molecule disorders, and conclusions. Part I describe recognition, scope, and implications of inherited metabolic epilepsies and provides an overview of metabolic disease. Part II covers principles and mechanisms of metabolic epilepsies, metabolic energetics, an approach to molecular pathways with emphasis on the ubiquitous mechanistic target of rapamycin (mTOR) pathway that governs cellular proliferation and has implications from central nervous system (CNS) development to degeneration, excitatory/inhibitory imbalance that is at the heart of epilepsy, chaperone proteins representing a novel approach to metabolism, and neurophysiologic studies aimed at measuring neurotransmission. Part III explores neuroimaging including spectroscopy, electroencephalography, neuropathology, genomic technology, and use of the ketogenic diet in metabolic epilepsies. Individual disorders are categorized with the small versus large molecule format, with special emphasis given to certain metabolic disorders to highlight their unique characteristics. Part IV describes small molecule diseases such as amino and organic acid disorders, urea cycle disorders, pyridoxamine 5´-phosphate oxidase (PNPO) deficiency, disorders of GABA metabolism, DEND syndrome, Lesch-Nyhan disease to name a few. Part V presents large molecule diseases such as congenital disorders of glycosylation, lysosomal storage diseases, peroxisomal diseases, and leukodystrophies. The conclusion part covers diagnostic and therapeutic approaches, genetic counseling, family resources, and an algorithmic clinical approach to inherited metabolic epilepsies. The book will educate physicians, particularly specialists and trainees in pediatric and adult neurology, neurodevelopmental disabilities, epilepsy, and genetics, while caring for patients with inherited metabolic epilepsies, as well as spur further research into basic mechanisms and clinical trials in this group of maladies.
Inherited metabolic epilepsies may be amenable to specific targeted treatment, representing the prototype of personalized medicine where rapid and efficient diagnosis and intervention can markedly impact outcome. This chapter focuses on inherited metabolic epilepsies with a profound and specific requirement for vitamin intervention. Epilepsy may be a prominent presenting feature, or major morbidity, of a variety of inborn errors of metabolism. The diagnostic evaluation and oftentimes therapeutic approach, however, are distinct from the traditional approach to evaluation and management of epilepsy. This is especially true in the case of amenably treatable pediatric epilepsies. For heuristic purposes, the treatable metabolic epilepsies were organized into disorders of vitamin dependencies, transport proteins, amino and organic acidopathies, mitochondria, urea cycle, neurotransmitters, and glucose homeostasis. These largely represent many of the categories of the small molecule disorders, which have a predilection to present with acute epilepsies and encephalopathies.
Epilepsy is an important problem in both known inherited disorders of GABA catabolism: succinic semialdehyde dehydrogenase (SSADH) deficiency and GABA-transaminase (GABA-T) deficiency. There is a paradox to this problem of epilepsy in hyperGABAergic disorders, as GABA is the major inhibitory neurotransmitter of the brain. Insights from these rare diseases may thus shed considerable light on the pathophysiology of epilepsy and the complex role of GABA. Treatment for SSADH deficiency remains symptomatic, including targeted antiepileptic drug therapy. Options include anxiolytic agents or selective serotonin reuptake inhibitors (SSRIs) and related medications for obsessive-compulsive disorder. Adults with SSADH deficiency appear to be more commonly affected with epilepsy than children. Correlation of murine and human data suggest that absence seizures are related to excessive gamma-hydroxybutyrate (GHB) and GABAB-mediated activity, and generalized convulsive seizures may be an effect of overuse-dependent down-regulation of GABAA and GABAB receptor activity.
Study of inherited metabolic epilepsies is necessary to merge the knowledge and advances in the worlds of epilepsy/neurology and metabolism/genetics. There are certain commonalities to the clinical presentation that suggest an especially high likelihood of an inherited metabolic epilepsy. Both traditional understanding and modern technological approaches to diagnosis and treatment are crucial in this expanding field of neurology and genetics-metabolism. The transformative value of next-generation sequencing has had particular impact on neurometabolic disorders. The inherited metabolic epilepsies represent a group of disorders of rare inborn errors of metabolism in which epilepsy is a presenting or ultimately prominent feature. While individually rare, in aggregate they demand special attention on the part of the clinician and represent an important nexus between neurology/epilepsy and genetics/metabolism. The diagnostic evaluation and oftentimes therapeutic approach may be so different than the classic epileptology approach to seizures that very different considerations apply.