Abstracts

Summary: A selected group of eminently treatable but otherwise catastrophic epileptic encephalopathies will be highlighted. These epilepsies represent a vexing clinical challenge because a sufficiently low diagnostic threshold must be maintained for rare and esoteric diseases. Pyridoxine (vitamin B6) dependency is the prototype and recently identified as antiquitin deficiency involving lysine degradation. Urinary pipecolic acid is a valuable laboratory aid in addition to the standard concomitant administration of 100 mg IV during EEG. CSF monoamine metabolic analysis will show a characteristic pattern analogous to aromatic aminoacid decarboxylase deficiency. Empirical discontinuation of therapy as a diagnostic maneuver is inadvisable, and the diagnosis must be resuspected even in initial treatment failures. The enigmatic folinic acid dependency is allelic to pyridoxine dependency, and patients may respond to either or both therapies. Pyridoxal-5-phosphate dependency is a newly recognized variant which is due to pyridox(am)ine oxidase deficiency and requires supplementation with the biologically active form of pyridoxine. Newborn screening may lead to a misdiagnosis of PKU whereas an infant presenting with seizures may have a biopterin-responsive hyperphenylalaninemia. Dihydropteridine reductase deficiency additionally requires folinic acid which may result in resolution of basal ganglia calcifications. Cerebral folate deficiency, also treatable with folinic acid, is associated with decreased CSF 5-methyltetrahydrofolate with normal peripheral folate levels. Seizures (including infantile spasms or myoclonic) may be the sole feature in biotinidase deficiency, which is not universally covered in newborn screening. Glucose transporter 1 deficiency has an enlarging phenotype, requires CSF analysis for hypoglycorrhachia, and is treatable with the ketogenic diet, offering an alternative metabolic fuel to glucose. A neonate presenting with seizures and diabetes may have a potassium-regulated ATP channelopathy of pancreas and brain, DEND (developmental disorder, epilepsy, neonatal diabetes) whereas the hyperglycemia is corrected by insulin but a profound encephalopathy will result if treatment is not instead a sulfonylurea. In contrast, congenital hyperinsulinism with hyperammonemia (HI/HA), a mutation of glutamate dehydrogenase, is associated with generalized epilepsy and learning disabilities, and is treated with diazoxide and protein restriction. Serine biosynthesis disorders are treatable with combined L-serine and glycine but otherwise result in microcephaly and epilepsy. Creatine synthesis disorders feature intellectual disability and epilepsy, may be diagnosed with abnormal guanidinoacetic acid (GAA) levels in urine or plasma (or MR spectroscopy), and respond to creatine and ornithine supplementation and arginine restriction. Benzodiazepines appear to have an ameliorative role in hyperekplexia, an epilepsy mimicker due to mutations in the glycine inhibitory receptor or transport system associated with sudden death.