There is little question that as we become more proficient

There is little question that as we become more proficient in the diagnosis of arginase 1 deficiency individuals with intermediary elevations in arginine on newborn screening and partial defects in enzymatic activity will be found. There are no reliable data to determine a safe level of arginine and indeed this may differ from patient to patient and vary with age. With any disorder, time and experience help with these decisions and they may be slow in coming with a disorder so relatively rare. In the meantime, NBS offers a means of early detection and treatment, and programs should consider using available resources such as R4S as a means to harmonizing screening algorithms. Because all relevant metabolites are already captured in routine MS/MS screening, adjustment of the interpretive algorithm is all that is needed to immediately implement one of the suggested approaches. As with any new and rare newborn screening condition, it will be critical to maintain a national (or international) database of relevant screening data (screening algorithm, time of screening, demographics of detected patients, etc.) that can be periodically analyzed in order to refine the screening algorithms being used [16], [19].
Acknowledgments
This work was supported in part by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, U54HD-087101 to the Intellectual and Developmental Disabilities Research Center at UCLA (SDC) and some economic support was provided by Aeglea BioTherapeutics, but the company played no role in assembling the data or in the writing of the paper.
Introduction Engineered sequence-specific nucleases, such as zinc finger nucleases (ZFNs), transcription activator-like D-Pantothenic acid sale nucleases (TALENs), and CRISPRs have been exploited for modeling diseases and developing novel therapeutic applications. These programmable nucleases can be broadly classified into two categories based on their mode of DNA recognition: ZFNs and TALENs achieve specific DNA binding via protein-DNA interactions, whereas CRISPR/Cas9 is directed to specific target sites by a single guide RNA that base-pairs directly with the target DNA sequence, as well as by protein-DNA interactions between Cas9 protein and the protospacer-adjacent motif (PAM).1, 2, 3, 4 Among these gene-editing technologies, TALENs exhibit a high degree of targeting specificity and flexibility. They recognize and cleave nearly any given DNA sequence with high efficiency in a broad range of organisms, including human cells, rodents, zebrafish, and plants.6, 7, 8, 9, 10, 11, 12, 13, 14, 15 Moreover, the low off-target effects and reduced nuclease-associated cytotoxicities make TALENs great tools for gene engineering in cells.10, 16 These site-specific nucleases are engineered fusion proteins of the catalytic domain of the endonuclease FokI with the TALE DNA-binding domain specifically designed to target a desired genomic site for gene modifications.3, 5 TALEs bind specifically to DNA targets via a central repeat domain and activate transcription of their targets by means of a C-terminal transcriptional activation domain. The binding domain is a series of customized 34-residue TALE repeat arrays in “two amino acids for one base” (“repeat variable di-residue”; RVD) recognition code, providing DNA-binding specificity.18, 19 Double-strand breaks (DSBs) occur when two independent TALENs, working in heteromeric pairs, bind to opposite strands of the target site separated by a 12- to 20-bp spacer region, thereby allowing dimerization of FokI and cleavage of the target locus.3, 5 This cleavage can then be resolved by cellular DNA repair, either by error-prone non-homologous end joining (NHEJ), which has the potential to introduce mutations at the site of the DSB, or by template-dependent homologous recombination (also termed homology-directed repair [HDR]) for precise genetic modification. Depending on the donor DNA template design, the repair mechanism can be initiated for gene replacement, single-nucleotide substitutions, or large-scale deletions.