2026-05-13 | RNA-LNP-mediated in vivo prime editing corrects disease phenotypes in a mouse model of citrullinemia type I.
Citrullinemia type I (CTLN1) is a severe urea cycle disorder caused by pathogenic variants in the ASS1 (argininosuccinate synthetase 1) gene, for which liver transplantation remains the only curative option. Here, we used prime editing to correct the Ass1fold mouse model of CTLN1. Adeno-associated virus (AAV)-mediated delivery of the PE7 prime editor with an optimized prime editing guide RNA (pegRNA) achieved 71 and 54% correction of the pathogenic Ass1 mutation in hepatocytes of neonates and juveniles, respectively. Delivery of mRNA-encoded PE7 and synthetic pegRNA via lipid nanoparticles (LNPs) resulted in 24% correction after a single 3 mg kg-1 dose in neonates and 13% after three 4 mg kg-1 doses in juveniles. All treated groups showed full normalization of survival and of blood citrulline and ammonia concentrations, with restored urea cycle function and correction of natural behavior defects. Consistent with these findings, immunostaining demonstrated restoration of wild-type-like ASS1 protein localization in functionally relevant periportal and intermediate-zone hepatocytes. Editing was confined to the liver, with minimal indel formation and off-target activity and only transient elevations in liver enzymes. In a cellular reporter system, 6 of 15 recurrent human pathogenic ASS1 mutations studied, including the most common ASS1G390R variant, were corrected with similar or higher efficiencies than Ass1fold. These findings highlight prime editing as a precise and potentially curative treatment strategy for individuals with CTLN1 and other genetic liver diseases.
Open article ↗
2026-02-28 | Dual rare genetic variants: case report of a child with SBIDDS syndrome and citrullinemia type 1.
BACKGROUND: The arginine methyltransferase 7 (PRMT7) gene plays a role in signal transduction and protein interactions and negatively regulates neuronal differentiation. Pathogenic variants of PRMT7 cause SBIDDS syndrome (Short stature, brachydactyly, intellectual developmental disability, and seizures). PRMT7 has been shown to interact with the argininosuccinate synthetase (ASS1) gene; biallelic pathogenic variants of ASS1 are associated with citrullinemia type 1. We report a patient with biallelic variants for SBIDDS syndrome and citrullinemia type 1. CASE PRESENTATION: The child exhibits severe intellectual disability, microcephaly, dysmorphisms, and seizures, consistent with the characteristics of these conditions. Exome sequencing identified variants c.1575 +1 G > A and c.232 dupT;p.Leu78Phefs*24 (NM_019023) in compound heterozygosity in the PRMT7 gene and variants c.1168G > A;p.Gly390Arg and c.-5-10C > G in exon 3 of the ASS1 gene (previously also identified in neonatal metabolic screening). The patient also has Wolf-Parkinson-White syndrome (WPW), behavioral issues, and brain morphological abnormalities, features that are poorly described in prior studies. CONCLUSIONS: It is not yet clear whether the clinical severity observed in this patient could also be partially due to interactions between these variants, as such interactions are not well-documented in the literature. Further research is necessary to elucidate the interplay between these two genes.
Open article ↗
2026-01-01 | Fatal Neonatal Citrullinemia Type I Unmasking a History of Recurrent Reproductive Loss in a Non-Consanguineous Indian Family: A Case Report
This case report describes a fatal neonatal presentation of Citrullinemia Type I (CTLN1) in a term male infant from a non-consanguineous Indian family, a diagnosis that eventually provided an explanation for a significant history of recurrent reproductive loss (G6P2A4L0). The neonate initially manifested with refractory hypoglycemia at 10 hours of life, necessitating glucose infusion rates up to 13~mg/kg/min$, before progressing to severe hyperammonemic encephalopathy with a peak ammonia level of 1280~\mu mol/L$. Despite intensive supportive care, the infant died on day 15; however, postmortem tandem mass spectrometry revealed a diagnostic citrulline elevation of 1100~\mu mol/L, and whole exome sequencing identified a homozygous pathogenic splice-site variant in the ASS1 gene (c.421-2A>G). The case underscores the critical need for expedited newborn screening infrastructure in India, as the 20-day turnaround for biochemical results arrived only after the patient’s death, while highlighting how community endogamy can mimic consanguinity to facilitate rare autosomal recessive disorders
Open article ↗
