Metabolic Disorders

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Various diseases with underlying inborn metabolic abnormalities may cause epilepsy characterized by a particular EEG abnormality (40). Early identification and appropriate treatment of these specific disorders frequently leads to the best treatment of seizures and optimal developmental outcome. AEDs, however, are sometimes necessary adjuncts.

Urea Cycle Disorders

Urea cycle disorders occur in 1 in 30,000 births. Seizure activity may be the presenting symptom associated with hyperammonemia, which can be precipitated or worsened by valproate therapy in unrecognized ornithine transcar-bamylase deficiency (41). Deficiencies of ornithine trans-carbamylase and arginosuccinic acid lyase have resulted in abnormal EEG activity characterized mainly by multiple spikes, spike waves, or slow-and-sharp-wave activity. The EEG normalizes with successful treatment of the metabolic disorder (42). Citrullinemia also has presented with seizure activity and an EEG with multifocal spikes (43). However, there is a lag in EEG normalization after treatment (peritoneal dialysis) in this condition. Neurologic deficits persist in reported cases (44).


Phenylketonuria, when untreated, may be associated with infantile spasms and hypsarrhythmia. Phenylketonuria is caused by a deficiency in hepatic phenylalanine hydroxy-lase, whose gene is located at 12.q24.1 (45). In treated phenylketonuria there is an increased prevalence of EEG abnormalities manifesting as generalized slowing with or without spikes (46). With advancing age, the EEG abnormalities increase but lack any relationship to IQ or dietary treatment (47).

Menkes Disease

Menkes kinky hair disease, a sex-linked disorder with its gene located on the long arm of the X chromosome, causes a marked reduction of serum copper and serum cerulo-plasmin levels. Patients typically present at 2-3 months of age. The clinical findings consist of mental retardation, poorly pigmented fragile hair, hypotonia, and generalized seizure activity, frequently infantile spasms (48). Milder forms have been described with less or minimal neurologic sequelae; the mildest Menkes variant is known as occipital horn syndrome, in reference to the pathogno-monic wedge-shaped calcification that forms within the trapezius and sternocleidomastoid muscles at their attachment to the occipital bone in affected individuals (49). Parenteral copper benefits some patients with Menkes disease. This may reflect preservation of some activity of certain copper ATPase alleles (50).

Glycine Encephalopathy

Glycine encephalopathy, also known as nonketotic hyper-glycinemia, is an autosomal recessive disorder caused by defective function of the multimeric glycine cleavage enzymes. The most common defect, affecting the P protein, is encoded by a gene localized to 9p22. Glycine is elevated in the plasma, urine, and cerebrospinal fluid (CSF). The lack of ketones helps differentiate between nonketotic hyperglycinemia and organic acidurias such as methylmalonic acidemia and propionic acidemia. Infants with the classic form of the disease present in the first week after birth with apnea, lethargy, and hypotonia (51). Intractable seizures develop; the EEG demonstrates burst-suppression or hypsarrhythmia (52). Brain imaging in nearly one half of patients with glycine encephalopathy shows congenital abnormalities including atrophy and agenesis of the corpus callosum (41C). Valproate is con-traindicated, because it induces hyperglycinemia (53).

GM2 Gangliosidoses

GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) have seizures as a frequent complication, particularly in the infantile form. The first symptom is an excessive startle in response to noise, tactile stimuli, or light flashes. This startle response in patients with Tay-Sachs disease, which differs from the Moro response of normal infants, consists of a quick extension of the arms and legs, frequently with clonic movements. There is arrest in development, and axial hypotonia ensues. During the second year after birth, macrocephaly develops, and seizures become more prominent. These may be myoclonic or gelastic and can be induced by auditory or tactile stimulation (54). Later, blindness develops and patients become increasingly less responsive. Autonomic dysfunction is a frequent finding including apnea. In Sandhoff disease the only clinical differences compared to Tay Sach's disease are mild hepa-tosplenomegaly, secondary to storage of globoside, and bony deformities (54).

Pyridoxine-Dependent Seizures

Seizures beginning in the first week after birth may have pyridoxine dependency. Associated symptoms may include episodes of restlessness, irritability, and feeding difficulties. The seizures are refractory to standard anticonvulsant medications but respond well to pyri-doxine administration (55). Atypical forms are common and may outnumber the classical form. Features include late onset after the first week but typically in the first months after birth, transient response to standard therapy, and atypical seizures (56). Very late forms have been described (57), as well as response following failed trials during infancy (58). Some cases have localized to the gene at chromosome 5q31.2-q31.3 (59).


Although porphyria does not become symptomatic until after puberty, it occasionally affects older adolescents. Seizures commonly occur in 15 percent of patients with porphyria, usually during an acute attack. Seizures may be partial or generalized. Therapy of chronic seizures in these patients must avoid drugs that increase porphyria precursors and induce attacks. This includes all commonly used AEDs (60), although gabapentin and leveti-racetam should be safe and effective.

Biotinidase Deficiency

Skin rashes and striking neurologic symptoms with seizures are prominent signs of biotinidase deficiency. Hypotonia, developmental delay, and seizures are presenting features in the neonatal form. In the late-onset type, 1 week to 2 years onset, the most common presenting feature is seizures. The most common seizure type is myoclonus, although generalized tonic-clonic and focal clonic seizures have been described (61). Ataxia and hypotonia are present, as are rash and alopecia. Hearing loss may occur. Treatment is oral biotin with rapid response within 24 hours (61, 62).

Other Inborn Errors of Metabolism

Other inborn errors of metabolism may be associated with generalized seizure activity. These include maple syrup urine disease, galactosemia, organic acidurias, hyperammonemia, and peroxisomal disorders, to mention only a few.

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