Pyridoxal phosphate dependency, a newly recognized treatable catastrophic epileptic encephalopathy

Abstract

Few conditions are as riveting to physicians as devastating encephalopathies that are treatable. In this issue of the Journal, Georg F. Hoffmann and colleagues describe the clinical syndrome of pyridoxal-phosphate dependent seizures with its inherent, and compelling, responsiveness to specific therapy. This story begins over fifty years ago, when Hunt and colleagues reported the successful treatment of infantile seizures with pyridoxine (vitamin B6) (Hunt et al 1954). Hence, pyridoxine-dependent seizures became the prototype of the severe but eminently treatable conditions that no clinician wants to miss. The cardinal diagnostic feature is the presence of refractory seizures, classically during the neonatorum, which cease only when pharmacological doses of pyridoxine are administered. While the condition is rare, with an estimated birth incidence between 1:400 000 and 1:750 000, the importance of early recognition is emphasized by an improved prognosis with early treatment (Baxter 2003). Patients will present with multiple seizure types in the neonatal period or even prenatally, with fetal seizures perceived by mothers as fluttering or hammering sensations beginning at 5 months_ gestation or later. Patients have an associated newborn encephalopathy which may include jitteriness, hypothermia, dystonia, and a prodrome of restlessness, irritability and emesis preceding seizures. The classic diagnostic procedure is intravenous administration of 100 mg of pyridoxine during EEG monitoring, aiming for resolution of a generalized or multifocal spike, or burstsuppression, pattern and cessation of clinical seizures. In an infant with pyridoxine dependency, the seizures and epileptiform EEG abnormalities will typically subside within 2–6 minutes after injection. However, some patients with pyridoxine dependency require up to 500 mg before clinical and electrographic responses are demonstrated. After receiving this initial treatment with pyridoxine, some neonates with pyridoxine dependency may become sleepy and hypotonic for a period of 24 hours. An alternative approach to diagnosis is to treat the patient with daily enteral doses of pyridoxine, 15 mg/kg. In pyridoxine-dependent patients, clinical seizures will resolve within a week of the initiation of this therapy. After a patient is clinically diagnosed by either the acute parenteral administration of pyridoxine or the daily enteral treatment with the vitamin, continued daily supplementation with pharmacological doses of pyridoxine is necessary, as the seizures tend to recur after a median delay of 9 days. Therefore, lifelong maintenance therapy is necessary (Gospe 2002). The classic neonatal phenotype may represent the tip of the iceberg. There are several atypical phenotypes J Inherit Metab Dis (2008) 30:2–4 DOI 10.1007/s10545-008-9974-1