P538: Hyperammonemia in the acute catabolic state

Treatment and Management: Both received neurorehabilitation since early childhood through early intervention.CDS01001 was trialed on a mitochondrial cocktail (ubiquinone, riboflavin, biotin, thiamine) and levocarnitine with no improvement.Seizure frequency improved in both cases with anti-epileptic medication.Outcome and Follow-Up: At their last clinical evaluation (aged 10-13 years), both have short stature, intellectual disability and are non-verbal.CDS01001 walks with support while CDS22601 walks independently.They attend special-needs education school where they receive neurorehabilitation therapy.Seizure occurrence has decreased from monthly to 4-monthly with levetiracetam in CDS01001 and mostly ceased with sodium valproate in CDS22601.Discussion: Our 2 cases expand the phenotype of RNU4-2 related NDD with features of oligohydramnios, behavioral issues, and physical anomalies (inverted nipples, adducted thumbs, prominent digit pads, clinodactyly, short halluces with lateral deviation).Conclusion: This report adds to the growing evidence of the role of non-coding genes in NDD.It also highlights the advantage of GS over ES, as well as repeated analysis in view of the continued discovery of novel gene-disease associations, including non-coding genes.Introduction: Genetic etiology of neurodevelopmental disorders (NDD) is fairly heterogenous with over 1400 protein coding genes implicated so far.Recently, a non-coding gene, RNU4-2, was implicated as a frequent cause of NDD.We reviewed our Singapore Undiagnosed Disease cohort and identified 2 individuals with de novo variants in RNU4-2.To date, no cases have been reported from Southeast Asia, and herein, we present our cases of RNU4-2 highlighting known as well as novel features of this newly described syndrome.Case Presentation: Both cases (CDS01001 and CDS22601) are male, of Chinese ethnicity and born to non-consanguineous parents.They were aged between 9 years and 12 years old at diagnosis.Antenatally, ventriculomegaly was present in both, while oligohydramnios and intrauterine growth restriction (IUGR) only in CDS01001.Both were delivered borderline premature at 36 and 37 weeks and CDS01001 was small-for-gestational-age with microcephaly, while CDS22601 was appropriate-for-gestational-age.Postnatally, CDS01001 had persistent pulmonary hypertension of the newborn (PPHN) and lactic acidosis requiring intubation and ventilation, inhaled nitric oxide and inotropes.He was discharged home with nasogastric tube feeding at 1-month old.Postnatal history for CDS22601 was unremarkable and discharged at 6-days old.Both had severe global developmental delay and seizures.CDS01001 presented at birth with hypotonia and developed seizures at 16 months old, while CDS22601 had later-onset symptoms of hypotonia at 3 months and seizures at 4 years old.Both had optic disc pallor, sensorineural hearing loss, delayed ambulation, non-verbal language disorder, behavioral issues (hand-flapping, aggression), and abnormal MRI brain findings.In addition, CDS01001 had bilateral cataracts and retinal detachments, atrial septal defect, and feeding difficulties; while CDS22601 had renal pelviectatsis, hypothyroidism, strabismus and sleep-wake reversal.CDS01001 had dysmorphic features noted at birth, of widely spaced eyes, posteriorly rotated ears and retrognathia, while CDS22601 had epicanthus, right protruding ear and tented upper vermillion which were observed by 2 years of age.Other physical features included inverted nipples, adducted thumbs, prominent digit pads, clinodactyly, and short halluces with lateral deviation.Diagnostic Workup: Both cases were extensively investigated with a normal karyotype, chromosome microarray analysis, methylation analysis for Prader Willi locus, and DMPK expansion analysis.In view of lactic acidosis in CDS01001, workup for mitochondrial (mt) disease including mitochondrial panel (22 mtDNA and 3 POLG variants) on leucocyte-extracted DNA, muscle biopsy, respiratory chain enzyme activity and mtDNA deletion/duplication analysis on muscle tissue all returned negative.Both cases were recruited into Singapore Undiagnosed Disease program (CIRB 2019/2243) and underwent further research testing (TruSightOne Panel, exome sequencing (ES), genome sequencing (GS) and/or PacBio HiFi long-read genome sequencing (lrGS) between 2015 and 2022 which returned negative.CDS01001 was reviewed at the Undiagnosed Hackathon (June 2024), performed through Radboud Medical Center, Nijmegen, where analysis of trio lrGS showed a de novo heterozygous variant (GRCh38, chr12:120,291,835; n.68_69insA) in RNU4-2.This variant is absent from population databases and has been reported in one other individual with a similar phenotype.CADD score was 19.Re-analysis of trio lrGS in CDS22601 revealed a de novo heterozygous variant in RNU4-2 (GRCh38, chr12:120,291,839:T:TA; n.64_65insT).Both variants and de novo occurrences were validated by Sanger sequencing.