Chapter 15 - Genetic-Metabolic Disorders Presenting as Acute, but Reversible, Severe Epilepsies

Abstract

Multiple genetic-metabolic epilepsies are amenable to treatment that markedly improves the disease course. Knowledge of these amenably treatable severe pediatric epilepsies allows for early identification, testing, and treatment. These disorders present with various phenotypes, ranging from early-onset epileptic encephalopathy (including refractory neonatal seizures, early myoclonic encephalopathy, and early infantile epileptic encephalopathy) to infantile spasms and mixed generalized seizure types in infancy, childhood, or even adolescence and adulthood. A typical clinical presentation is that of a newborn with impaired feeding who is noted to ultimately become encephalopathic with hypotonia, lethargy, or respiratory distress. Myoclonic seizures are classic, although apneic episodes, oculofacial movements, grunting, and epileptic spasms are also well-described ictal events. EEGs may show discontinuous patterns characterized by burst-suppression, continuous or frequent intermittent generalized sharp or spike wave activity, hypsarrhythmia, or multifocal spike discharges superimposed on background disorganization including loss of normal sleep architecture. The clinical task of identifying these disorders is made more complicated, however, by nonspecific presentations that include failure-to-thrive, developmental delay, or recurrent vomiting and by varying presentations of the same disorder. The disorders are presented as vitamin-responsive epilepsies including pyridoxine, pyridoxal-5-phosphate, folinic acid, biotin, and cobalamin; transportopathies including glucose transporter 1 deficiency, cerebral folate deficiency, and biotin thiamine responsive disorder; amino and organic acidopathies including serine synthesis defects, creatine synthesis disorders, molybdenum cofactor deficiency; mitochondrial disorders; urea cycle disorders; neurotransmitter defects including biopterin synthesis/recycling defects; and disorders of glucose homeostasis with neonatal diabetes or congenital hyperinsulinism. In each case, targeted intervention directed toward the underlying metabolic pathophysiology affords for the opportunity to significantly impact the outcome and prognosis of otherwise severe pediatric epilepsy.