Recent advancements in molecular genetics have expanded our understanding of the etiology of many neurological diseases and neurodevelopmental abnormalities. Having a comprehensive understanding of genetics is essential in treating patients with metabolic epilepsies. Genetic counseling has been defined as a process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. Some of the components of a genetic counseling interaction include interpretation of family and medical histories to assess the chance of disease occurrence or recurrence; education about inheritance, testing, management, prevention, resources, and research; and counseling to promote informed choices and adaptation to the risk or condition. The genetic counselor may also educate patients and their families about the underlying genetics of their epilepsy and the relevance of a genetic cause of epilepsy for family members, including recurrence risk, reproductive options and the possible teratogenic effect of antiepileptic drugs.
Your search for all content returned 43 results
This chapter presents a brief review of the enzymes, transporters, and cofactor producers of the urea cycle. Seizures have long been associated with urea cycle disorders (UCDs), thought to be caused by high levels of ammonia. Furthermore, the brain damage obtained during metabolic crisis has been thought to damage critical structures, leading to epilepsy after the conclusion of the crisis. The first and most critical step of successful treatment of UCDs is recognition. Neurologic monitoring is an essential part of the emergency management of UCDs. The neurological abnormalities observed in patients with urea cycle defects are vast. Controlling ammonia levels by dialysis and complementary medication are needed. EEG monitoring should be initiated early, as this may be very useful for clinical management and indication of untreated metabolic crises. Furthermore, aggressive treatment of clinical and subclinical seizure activity may be helpful in optimizing outcomes for these patients.
With the availability of the human genome sequence nearly 3 decades ago, the genetic research and diagnostic landscape has shifted immensely. Microarrays have been extensively used for single nucleotide polymorphism (SNP) and copy number variation (CNV) identification, as well as for genome-wide association studies (GWAS) and expression arrays. Next generation sequencing (NGS), in contrast to microarrays, does not require previous knowledge of the sequence in question. In order to compare and evaluate NGS technologies, a number of quality criteria and matrices have proven helpful. A basic understanding of the NGS vocabulary is indispensable for any physician who wants to incorporate the use of NGS technology into clinical practice. As genomic technologies are increasingly used in research and in clinical practice, logistical challenges, such as storage capacity, storage cost, data availability, and computational power, become more pronounced.
- Go to chapter: DEND Syndrome: Developmental Delay, Epilepsy, and Neonatal Diabetes, a Potassium Channelopathy
Potassium channels are crucial regulators of excitation in most tissues, their activation hastening membrane repolarization and damping down electrical activity. Many potassium channels are also specialized for specific functions. One of these is the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel, which couples the metabolic state of the cell to plasma membrane excitability and, thus, to a variety of cellular functions. In recent years, the discovery that mutations in the KATP channel are associated with various metabolic syndromes has highlighted the physiological importance of this channel. This chapter discusses how the most severe gain-of-function mutations lead to developmental delay, epilepsy and neonatal diabetes, a condition known as DEND syndrome. If activating KATP channel mutations work in a similar way to severe myoclonic epilepsy of infancy (SMEI) mutations, by suppressing GABA release from inhibitory neurons, it may be possible to treat DEND patients with combination therapies that enhance GABA transmission.
Inborn errors of metabolism (IEMs) are genetic disorders that disrupt biochemical processes in the human body by altering enzyme activity or cellular transport. This chapter utilizes a modified version of the classification proposed by Saudubray et al., which divides IEMs into categories on the basis of metabolic pathway and organelle: small molecule disorders, large molecular disorders, disorders of cerebral energy metabolism, and miscellaneous disorders. It also presents a diagnostic approach to IEMs in patients with epilepsy. Most IEMs are associated with an increased risk of seizures. Epileptogenic mechanisms in IEMs include energy failure (e.g., mitochondrial disorders), imbalance of excitation and inhibition (e.g., disorders of GABA metabolism), accumulation of toxic metabolites (e.g., urea cycle disorders), and malformations of cortical development (e.g., peroxisomal disorders). Neuroimaging may indicate a specific IEM. Several IEMs are associated with specific epilepsy syndromes that may facilitate diagnosis.
The metabolic disorders of epilepsy present many challenges for the child, caregivers, and their families. These disorders represent a range of presentations and severity and, therefore, often present very different burdens depending on diagnosis and symptoms. The most severely affected individuals share similar needs that include specialized care in the hospital and in the home, complex care coordination, and palliative care. This chapter highlights the potential psychosocial stressors that should be considered when treating the inherited metabolic epilepsies. These psychosocial stressors impact the afflicted children as well as their caregivers and the family unit. The chapter also highlights supports and resources to address these psychosocial stressors. The psychosocial stressors included in the chapter include financial, quality of life (QOL) and mental health, and educational stressors-agreed CR. Support and resources detailed include the multidisciplinary team, external peer supports, disease-specific support, and advocacy organizations.
Pyridox(am)ine 5’-phosphate oxidase (PNPO) deficiency is one of four known inborn errors of metabolism (IEM) that cause neonatal vitamin B6-dependent convulsions. This chapter summarizes the clinical peculiarities, the diagnostic biomarkers, and treatment aspects of PNPO deficiency. Following the initial description of PNPO deficiency, decreased pyridoxal 5’-phosphate (PLP) in CSF was recognized as a novel biomarker of this IEM, but warranted pretreatment samples. Later, it became clear that other vitamin B6-dependent epilepsies, including antiquitin (ATQ) deficiency, show similarly decreased concentrations prior to treatment. Decreased PLP in cerebrospinal fluid (CSF) must thus be seen as a common endpoint of the different mechanisms underlying IEM causing vitamin B6-dependent epilepsies. PNPO deficiency can be reliably diagnosed by the analysis of vitamin B6 vitamers in plasma (or CSF). Classical PNPO deficiency needs to be treated by oral (or intravenous) PLP supplementation.
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.
Altered metabolism has been implicated in the pathogenesis of diverse neurodegenerative disorders, including amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease. This chapter discusses (a) epilepsies arising from dysfunction of mitochondria; (b) epilepsies associated with metabolic dysfunction; and (c) metabolism-based therapeutic approaches. It highlights epilepsies associated with mutations occurring in the nuclear polymerase gamma (POLG) gene, which encodes the catalytic subunit of the mtDNA polymerase. The chapter largely focuses on non-mitochondrial mutations (mostly sporadic) that impair brain metabolic homeostasis and give rise to seizures. It discusses the disorders affecting glucose transport, proper functioning of voltage-gated ion channels, and antioxidant defense systems in detail. In addition, the chapter discusses metabolic dysfunctions associated with acquired epileptic phenotypes. Finally, it discusses the therapeutic approaches available for epilepsies arising from metabolic dysfunction, as well as upcoming methods of management of epilepsies.
Structural brain imaging including CT, MRI, and magnetic resonance spectroscopy (MRS) is part of the diagnostic workup for the patient presenting with seizures, and can assist with identifying underlying inborn errors of metabolism. This chapter focuses on the MRI and MRS features that need to be considered when evaluating a patient with epilepsy and a suspected metabolic disorder. Some metabolic diseases have relatively specific MRI imaging features, while other diseases are merely suggestive of the disease process. In addition to the MRI features on standard pulse sequences, proton magnetic resonance spectroscopy contributes further information in some metabolic diseases. MRI and MRS contribute to the diagnostic evaluation of patients with neurometabolic diseases. Careful evaluation of structures by T2, FLAIR, and diffusion imaging reveals patterns of findings that may indicate an etiology. Further correlation between imaging, clinical, and genetic evaluation should further enhance our diagnostic ability regarding phenotypic expression.