Metabolic epilepsies: approaches to a diagnostic challenge

Although inborn errors of metabolism (IEM) are a relatively rare cause of epilepsy in children, their diagnosis is important with respect to treatment, prognosis and genetic counselling. In addition to seizures and epilepsy, IEM may produce a complex clinical picture in which epilepsy is only one of the various neurologic manifestations including developmental delay/regression, mental retardation, movement disorders, micro-/macrocephaly, as well as cerebral grey and white matter changes. Dysmorphic features and cerebral dysgenesis may also be part of a metabolic epilepsy syndrome (e.g. disorders of peroxisomal biogenesis, glutaric aciduria type 2, pyruvate dehydrogenease complex deficiency). Metabolic epilepsies may dominate the clinical presentation (e.g. pyridoxine dependent epilepsy) or may precede further neurologic deterioration (e.g. neuronal ceroid lipofuscinosis) and additional organ involvement (e.g. liver failure in Alpers (POLG1) disease). Metabolic epilepsies often present with myoclonic seizures (e.g. Gaucher Disease type 3, mitochondrial syndromes) and, as a rule, patients presenting with predominantly myoclonic seizures should be carefully investigated for these types of metabolic epilepsies. Patients with very early onset of epilepsy are considered at high risk for an underlying IEM as well. In this review we present an overview of metabolic epilepsies based on various criteria such as treatability, age of onset, seizure type, and pathogenetic background. Exemplary disorders will be described in more detail including cerebral glucose transporter (GLUT1) deficiency, pyridoxine dependent epilepsy, neuronal ceroid lipofuscinosis, cathepsin D deficiency, Alpers syndrome (POLG deficiency), and guanidinoacetate methyltransferase (GAMT) deficiency.