Inborn errors of metabolism (IEMs) are a group of disorders resulting from defects in enzymes in metabolic pathways. These disorders impact the processing of metabolites, leading to a wide array of effects on each organ system. Advances in genetic screening have allowed for the early identification and intervention of IEMs, traditionally in the form of enzyme replacement or vitamin supplementation. However, many IEMs disrupt essential metabolic pathways where simple supplementation proves ineffective, resulting in substantial disease burden. In the case of renal IEMs, metabolic pathway disruption leads to the onset of chronic kidney disease (CKD). For these diseases, genetic therapy provides hope. Over the past few decades, the technology for genetic therapy has emerged as a promising solution to these disorders. These therapies aim to correct the source of the defect in the genetic code so that patients may live full, unencumbered lives. In this review, we searched a large database to identify IEMs that affect the kidney and investigated the current landscape and progression of gene therapy technology. Multiple promising genetic therapies were identified for IEMs affecting the kidney, including primary hyperoxaluria, argininemia, glycogen storage diseases Ia and Ib, and Fabry disease. Emerging gene therapy approaches using adeno-associated virus (AAV) vectors, lentiviral vectors, and CRISPR/Cas9 techniques hold promising potential to provide curative treatments for additional single-mutation disorders.

Argininemia (OMIM: 207800), as well as arginase deficiency, a disorder of the urea cycle caused by deficiency of arginase 1 (ARG1, NP_000036.2), is a scarce autosomal recessive genetic disease. The patients who suffered with argininemia often showed spastic paraplegia, epileptic seizures, severe mental retardation, and even the hyperammonemia. In neonatal screening, we found a healthy baby with mild elevated arginine levels. We have demonstrated the genetic etiology of the patient. The patient's clinical characteristic and family history were collected. The technologies including Next Generation Sequencing (NGS), Sanger sequencing, Bioinformatics Analysis, RNA extraction, cDNA obtained, Sanger sequencing, Minigene splicing assay, Real-time PCR, Single-molecule real-time (SMRT) sequencing were applied. One homozygous variant, c.57G > A (p.Q19=), was identified in the proband, which was inherited from the parents. Through different detection methods, we found that the c.57G > A variant causes three different transcriptional versions: normal mRNA (mRNA from blood), mRNA with the exon2 deletion (73bp, mRNA from blood and minigene assay), and mRNA sequence from the SMRT sequencing (parts of exons and introns were detected, including exon 1-4, intron 1 and 4, and part of intron 2, 3, and 5). The expression of ARG1 mRNA and protein also decreased in the blood. The related genes of NMD (Nonsense-mediated mRNA decay), SMG1, UPF1, and UPF3b, were expressed higher than the controls in the blood, which hints the NMD could play a role in the mRNA decay regarding the cDNA with 73bp deletion by c.57G > A variant. The study is the first study considering a synonymous variant of the ARG1 gene influencing alternative splicing(AS). Otherwise, the variant c.57G > A is relatively frequent in the general population( MAF = 0.0146). Our discovery revealed the variant possesses partial pathogenic potential, which would contribute to the deeper understanding and gold model for the intricate relationship between genetic mutations, arginine metabolism, and physical function.

Argininemia is a rare autosomal recessive metabolic disorder characterized by a deficiency of arginase, a vital enzyme in the urea cycle. This metabolic defect results in the accumulation of arginine and its metabolites, leading to hyperammonemia and associated neurological symptoms. We present a case detailing the perioperative management of an 11-year-old male child diagnosed with argininemia undergoing circumcision. The perioperative management of patients with argininemia presents unique challenges due to the risk of hyperammonemia and neurological decompensation triggered by physiological stress, fasting, and the catabolic state associated with surgery. This case report highlights the importance of individualized anesthetic strategies for patients with rare metabolic disorders like argininemia. A multidisciplinary approach involving collaboration among anesthesiologists, endocrinologists, dietitians, and surgeons is essential to ensuring a safe perioperative experience for these patients. Further research is essential to refine perioperative protocols and optimal anesthetic interventions for individuals with argininemia undergoing surgical procedures. Arginase deficiency (argininemia) is an autosomal recessive metabolic disorder characterized by hyperammonemia secondary to arginine accumulation. Ammonia levels can vary according to the patient’s current age and status, presenting initially with slow growth, followed by developmental delay and cognitive problems. When improperly treated, it may lead to regression.  Often diagnosed at birth through newborn screening (NBS), affected newborns are found to have elevated levels (up to 4 times) of arginine. Its management is similar to other classic urea cycle disorders, although with mild or absent hyperammonemia. If hyperammonemia is present, it responds adequately to ammonia-reducing interventions. Chronic treatment consists of protein restriction along with nitrogen-scavenging medications.

Arginase deficiency is considered a masquerader of diplegic cerebral palsy. The rarity of hyperammonemic crisis and the slowly progressive course has made it a unique entity among the urea cycle defects. The aim of our study is to describe the varied phenotypic spectrum of children with arginase deficiency. This retrospective study included children and adolescents aged <18 years with a biochemical or genetic diagnosis of arginase deficiency from May 2011 to May 2022. Data were collected from the hospital's electronic database. The clinical presentation, laboratory parameters at baseline and during metabolic decompensation, neuroimaging, electroencephalography findings, and molecular studies were analyzed. About 11 children from nine families with biochemically or genetically proven arginase deficiency were analyzed. The male: female ratio was 2.7:1. Consanguineous parentage was observed in all children. The median age at presentation was 36 months (Range: 5 months-18 years). All children with onset of symptoms in early childhood had a predominant delay in motor milestones of varying severity. Metabolic decompensation with encephalopathy occurred in all except two children (n = 9, 81.8%). Pyramidal signs were present in all patients and additional extrapyramidal signs in two children. Positive family history was present in four probands. Seizures occurred in all children. Epilepsy with electrical status in slow wave sleep and West syndrome was noted in three children. All children had elevated ammonia and arginine at the time of metabolic crisis. The spectrum of neuroimaging findings includes periventricular, subcortical, and deep white matter signal changes and diffusion restriction. The mean duration of follow-up was 38.6 ± 34.08 months. All patients were managed with an arginine-restricted diet and sodium benzoate with or without ornithine supplementation. Spastic diparesis, recurrent encephalopathy, presence of family history, and elevated serum arginine levels must alert the clinician to suspect arginase deficiency. Atypical presentations in our cohort include frequent metabolic crises and epileptic encephalopathy. Early identification and management will ensure a better neurodevelopmental outcome.