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hnRNP-U deficiency is caused by pathogenic variants in HNRNPU, which encodes the heterogeneous nuclear ribonucleoprotein U (HNRNPU), a highly conserved protein responsible for assisting spliceosomes in mediating transcription and alternative splicing activity. HnRNPs are responsible for the regulation of translation at the presynaptic sites as well as the transportation of stabilized mRNAs along the axonal cytoskeleton. Here, we report a 2-year-old-male with a HNRNPU variant with a new presentation of apparent recurrent apneic spells with an underlying epileptic origin. These were described as apnea followed by desaturation and tachycardia in the 180's-200 range prior to resolution of symptoms. He also had autistiform behaviors, hypotonia, global developmental delay, heart defects, and unique facial features. The anesthetist professional parents describe multiple BRUE. At 26 months, he presented to the hospital with hypotonia and unique facial features, global developmental delay, autistiform behaviors, dyspraxia with cognitive disability and a change in mental status. On physical exam, the proband had telecanthus, a broad nasal bridge, short palpebral fissures, mild nevus flammeus changes on his face, a single right palmar crease, and a modified single crease on the left. EKG showed a sinus rhythm with intermittent 1st degree AV block, blocked premature atrial contractions, left axis deviation, right bundle branch block, and an ejection fraction of 67%. Echocardiography re-identified an atrial septal defect. Brain MRI showed a T2/FLAIR hyperintense signal in the white matter of the parietal lobes, left greater than right. EEG identified generalized slowing indicative of a mild nonspecific encephalopathy. History of episodes were determined to be consistent with partial onset seizures with eye opening, deviation, and tachycardia with apnea and medical treatment ensued.
Genetic testing including microarray and an epilepsy panel that identified no genomic dosage anomalies and a de novo nonsense mutation (c.803+2T>C; p. unknown in HNRNPU), classified as pathogenic. The study of hnRNP complexes have gained momentum in neurodegenerative and tumorigenesis disease research. hnRNPs have a key role in mediating transcription, alternative splicing, and translation activity. Recently, Durkin et al, 2020 (PMID: 32319732) reported 21 previously unreported probands; nearly doubling the recorded patient population. Probands in the literature to date have had variable presentation, but usually with hypotonia, global developmental delays, and seizures. This suggests the addition of HNRNPU to all seizure-related diagnostic panels. We would also recommend including the HNRNPU-related disorders in a differential diagnosis of BRUE and recurrent apneic episodes as any underlying clonic activity may be profoundly subtle.
Scheffler, Jonah; Fishler, Kristen P.; and Starr, Lois J., "Expanding the phenotype of HNRNPU-related disorders to include brief, resolved, unexplained events (BRUE)" (2021). Child Health Research Institute Pediatric Research Forum. 16.