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Page 10 of 15 Pintos-Morell et al. Rare Dis Orphan Drugs J 2024;3:12 https://dx.doi.org/10.20517/rdodj.2023.52

X-linked hypophosphatemic rickets PHEX Phosphate supplementation, active vit D, Burosumab
(monoclonal Ab)
Hypophosphatemic rickets with hypercalciuria SLC34A3 Phosphate supplement, active vit D
Hypophosphatasia ALPL Tissue-nonspecific alkaline phosphatase (TNSALP) ERT -
asfotase alfa, avoid bisphosphonates
Congenital serine biosynthesis defects PHGDH Serine, glycine
PSAT1
PSPH
Cerebral folate transport deficiency FOLR1 Folinic acid

This list is not intended to be a comprehensive list of treatable IMDs but just a useful indicator. The degree of evidence of the treatments is
variable and may be mutation- or patient-specific. ERT: Enzyme replacement therapy; SRT: substrate reduction therapy; PCT: pharmacological
chaperone therapy; BMT: bone marrow transplant; HSCT: hematopoietic stem cell transplantation; MCT: medium-chain triglycerides;
IV: intravenous; IM: intramuscular; IGF-I: insulin growth factor-I; GLP-I: glucagon-like peptide-1 receptor; mTOR: mammalian target of
#
rapamycin inhibitors. indicate list of lysosomal disorders that are presently best screened by MS/MS-based enzyme assay followed by genetic
confirmation; */** indicate the relationship of the disease or the gene with the correspondent treatment.

As illustrated in the first part of this review, the analytical and clinical validity, sensitivity, and specificity of
genome sequencing have not been extensively examined in a screening context. It is imperative to take into
account that the primary beneficiaries of NBS are healthy newborns, thus emphasizing the paramount
importance of ensuring the integrity and safety of screening methodologies to safeguard this vulnerable
[40]
population .

Table 3 highlights several practical hurdles that need to be considered and some possibilities to address
these challenges.

Two main paths can be envisioned for the evolution and progress of NBS for IMDs: the first could be a
progressive and prudent transition, including a consistent period of co-existence and thorough cross-
checking of metabolomics and NGS methodologies, from a biochemical profile to genomic confirmation up
to therapy, with progressive side-by-side support of conventional NBS and genomics. The traditional Bio-
NBS can yield false-positive or false-negative results and is affected by biochemical substrate-level
fluctuations. The genomic DNA extracted from dried blood spots can be used for NGS, generating reliable
sequencing results, and NGS may function as a second-tier diagnostic test for NBS in samples with
abnormal MS/MS results. Most centers use a multigene panel, comprising a library of genes related to the
IMDs, for NBS. Genetic testing as the second tier is more or less replacing the present clinical situation
toward the screening system. We would like to emphasize that using biochemical and genomic NBS in
parallel may increase the sensitivity of the screening and more newborns may be identified, decreasing the
number of false positives.

The second path could include genomics as the first-tier test and biochemistry/metabolomics as diagnostic
confirmation of the disease before starting treatment. However, gNBS is currently used as the first-tier test
only for those disorders not included in the Bio-NBS because of the lack of a reliable biomarker.

The primary objective of NBS is to diagnose pediatric diseases for which effective therapeutic interventions
exist, thereby mitigating symptom onset or progression and improving patient prognosis, quality of life, and
familial well-being. These interventions aim to avert irreversible damage, including severe physical and
cognitive impairments and, in extreme cases, mortality [41-43] .

Today, besides endocrine disorders (CH, CAH), hemoglobinopathies, SCID, and Cystic Fibrosis, most NBS
programs detect treatable IMDs that are identifiable in the first days of life, mainly with mass