Abstracts

Rationale: Early myoclonic encephalopathy (EME) is a rare disorder characterized by epileptic myoclonus in the neonatal period or early infancy, which often progresses to epileptic spasms. Sequelae include developmental arrest & severe cognitive impairment. Inborn errors of metabolism may be causative; however, an underlying etiology is not identified in many cases. We report a case of EME associated with a novel heterozygous variant in the Pumilio-2 gene. Methods: A retrospective chart review was conducted for a patient currently receiving care at this author’s institution. Clinical history, demographic history, laboratory data and neurodiagnostics were obtained. Results: An 11-year-old ex-38 week male is followed in the outpatient pediatric neurology clinic for medically-refractory epilepsy, remote epileptic spasms and global developmental delay. Onset of myoclonic seizures occurred by 3 months of age. At 15 months of age, continuous video EEG monitoring (cEEG) captured myoclonic seizures during wakefulness and nocturnal tonic seizures; within 1 month, the patient developed epileptic spasms. By 29 months of age, cEEG revealed diffuse slowing of the background, relative attenuation with a paucity of faster frequencies over the right anterior temporal region, biposterior sharp waves, and bursts of generalized paroxysmal fast activity interictally; ictally, numerous myoclonic-atonic seizures were captured. At present, the patient has failed multiple anti-seizure medications including clonazepam, topiramate, divalproex, and levetiracetam, and continues to experience intractable myoclonic, myoclonic-atonic, tonic and tonic-clonic seizures. Physical examination is notable for mildly dysmorphic facies and diffuse hypertonia with hyperreflexia. MRI brain without contrast at 3 years of age revealed markedly delayed myelination of the cerebral white matter without other structural abnormalities. Complete metabolic panel, CBC, serum lactate, pyruvate, carnitine, acylcarnitine, creatine/creatinine ratio, plasma amino acids, urine organic acids, urinary purine panel, CSF amino acids, and CSF neurotransmitters were within normal limits. Storage disease enzyme assays for GM1 ganglioside, Tay-Sachs, metachromatic leukodystrophy and Krabbe disease were unremarkable. A karyotype, chromosomal microarray, Angelman/Prader-Willi methylation analysis, Fragile X testing, mitochondrial panel, carbohydrate-deficient transferrin, and sequencing of CDKL5, CLN1 and CLN2 were unrevealing. Ultimately, exome trio testing revealed a de-novo heterozygous c.2454delA variant in the Pumilio-2 (PUM2) gene. The variant identified in this patient is a deletion of one base leading to a frame shift and early termination of the protein sequence.  Conclusions: In this case, we describe a patient with EME associated with a previously undescribed heterozygous nonsense mutation in the PUM2 gene. Mutations in the PUM2 gene have not previously been reported in association with human disease. Pumilio, a translational regulator, appears to play a role in neuronal homeostasis in Drosophila; its mammalian homolog PUM2 has been implicated in regulation of excitability in hippocampal neurons, differential expression of SCN1A, SCN2A, SCN8A, and GABRA2 mRNA, and the development of spontaneous epileptic seizures in murine gene-trap models. These mammalian models suggest a potential role for PUM2 in human epileptogenesis, and may elucidate the molecular mechanisms involved in the development of myoclonic encephalopathy. In an appropriate clinical setting, gene sequencing of PUM2 might be considered for cases of early myoclonic encephalopathy when conventional metabolic and genetic testing is non-diagnostic.  Funding: None