Newborn screening (NBS) began a revolution in the management of biochemical genetic diseases, greatly increasing the number of patients for whom dietary therapy would be beneficial in preventing complications in phenylketonuria as well as in a few similar disorders. The advent of next generation sequencing and expansion of NBS have markedly increased the number of biochemical genetic diseases as well as the number of patients identified each year. With the avalanche of new and proposed therapies, a second wave of options for the treatment of biochemical genetic disorders has emerged. These therapies range from simple substrate reduction to enzyme replacement, and now ex vivo gene therapy with autologous cell transplantation. In some instances, it may be optimal to introduce nucleic acid therapy during the prenatal period to avoid fetopathy. However, as with any new therapy, complications may occur. It is important for physicians and other caregivers, along with ethicists, to determine what new therapies might be beneficial to the patient, and which therapies have to be avoided for those individuals who have less severe problems and for which standard treatments are available. The purpose of this review is to discuss the \"Standard\" treatment plans that have been in place for many years and to identify the newest and upcoming therapies, to assist the physician and other healthcare workers in making the right decisions regarding the initiation of both the \"Standard\" and new therapies. We have utilized several diseases to illustrate the applications of these different modalities and discussed for which disorders they may be suitable. The future is bright, but optimal care of the patient, including and especially the newborn infant, requires a deep knowledge of the disease process and careful consideration of the necessary treatment plan, not just based on the different genetic defects but also with regards to different variants within a gene itself.

ADAGEN, a bovine-based enzyme replacement therapy (ERT), has been used to treat adenosine deaminase severe combined immunodeficiency (ADA-SCID). In 2018, ADAGEN was replaced by REVCOVI (elapegademase), a modified bovine recombinant protein.
To determine the real-life long-term benefits of REVCOVI in ADA-SCID.
Data on ERT, infectious and noninfectious complications, and metabolic and immune evaluations were collected from 17 patients with ADA-SCID treated for 6 months or more with REVCOVI.
Eleven patients had previously received ADAGEN for 16 to 324 months, whereas 6 patients were ERT-naive. REVCOVI was administered twice weekly at 0.4 mg/kg/wk in ERT-naive patients, whereas patients transitioning to REVCOVI from ADAGEN typically continued at the same frequency and equivalent dosing as ADAGEN, resulting in a significantly lower (P = .007) total REVCOVI dose in the transitioning group. REVCOVI treatment in the ERT-naive group led to the resolution of many clinical and laboratory complications of ADA deficiency, whereas there were no new adverse effects among the transitioning patients. REVCOVI treatment increased plasma ADA activity and decreased dAXP (which included deoxyadenosine mono-, di-, and tri phosphate) among most patients, effects that persisted throughout the 7- to 37-month treatment periods, except in 2 patients with incomplete adherence. Among some patients, after 0.5 to 6 months, injection frequency was reduced to once a week, while maintaining adequate metabolic profiles. All ERT-naive infants treated with REVCOVI demonstrated an increase in the number of CD4+ T and CD19+ B cells, although these counts remained stable but lower than normal in most transitioning patients.
REVCOVI is effective for the management of ADA-SCID.

Inherited defects in the adenosine deaminase (ADA) gene typically cause severe combined immunodeficiency. In addition to infections, ADA-deficient patients can present with neurodevelopmental, behavioral, hearing, skeletal, lung, heart, skin, kidney, urogenital, and liver abnormalities. Some patients also suffer from autoimmunity and malignancies. In recent years, there have been remarkable advances in the management of ADA deficiency. Most ADA-deficient patients can be identified by newborn screening for severe combined immunodeficiency, which facilitates early diagnosis and treatment of asymptomatic infants. Most patients benefit from enzyme replacement therapy (ERT). Allogeneic hematopoietic cell transplantation from an HLA-matched sibling donor or HLA-matched family member donor with no conditioning is currently the preferable treatment. When matched sibling donor or matched family member donor is not available, autologous ADA gene therapy with nonmyeloablative conditioning and ERT withdrawal, which is reported in recent studies to result in 100% overall survival and 90% to 95% engraftment, should be pursued. If gene therapy is not immediately available, ERT can be continued for a few years, although its excessive cost might be prohibitive. The recent improved outcome of hematopoietic cell transplantation using HLA-mismatched family-related donors or HLA-matched unrelated donors, after reduced-intensity conditioning, suggests that such procedures might also be considered rather than continuing ERT for prolonged periods. Long-term follow-up will further assist in determining the optimal treatment approach for ADA-deficient patients.

Itrducti Tta pacreatecty (TPE) ievitaby eads t absute excrie pacreatic isufficiecy (EPI) specific recedatis are avaiabe fr eye repaceet i such cases The ai f ur aaysis was t expre the actua EPI repaceet rates ag patiets fwig TPE after a certai perid f tie fr the surgeryethds This retrspective aaysis f ivig patiets wh had uderge TPE re tha 2 years ag was de usig a sipe questiaire t ivestigate the fwig BI prir t TPE 3 ths after TPE ad at the tie f data cecti (i 2022) tgether with the actua uber f daiy bwe veets ad the repaceet characteristics the daiy dse its schee ad subective satisfacti evauatiResuts I tta we btaied data fr 26 ivig patiets with the histry f TPE with their edia fw up f 56 ths (30157) aigat disease was cfired i 69% patiets based histgy a beig tur was preset i the rest athugh aigacy had bee suspected preperativey edia BI decreased fr preperative 274 (191411) t 241 (198337) 3 ths fwig TPE ad edia BI vaue f 255 (212345) was estabished at 30157 ths fr TPE The ea uber f daiy bwe veets was 22 (edia 2 rage 18) ad the ea daiy repaceet dse was 182000 uits f ipase (edia 175000 u rage 0250000 u) at the tie f ur ivestigati Subective satisfacti was reprted by 85% respders ad a ac f satisfacti despite axiu EPI repaceet was expressed by 15% respdersCcusi BI decreased shrty after TPE I the g ter up t 80% f the patiets achieved preperative BI vaues 10% after TPE Due t persistet steatrrhea ad re frequet bwe veets despite eye repaceet 15% f the patiets reaied subectivey dissatisfied after TPE but 85% f the patiets did t perceive eve re frequet bwe veets as upeasat ad were satisfied with their cditi The eed f idividuaied eye repaceet therapy f EPI fwig TPE is evidet.

This case reports concomitant use of enzyme and substrate reduction therapy to improve chemotherapy adherence in a pediatric patient diagnosed with Ewing sarcoma (ES) and type 1 Gaucher disease (GD). The 17-year-old female presented with 5 months of right knee pain with associated mass on exam. She was diagnosed with ES with pulmonary metastasis. The patient was treated with 17 alternating cycles of vincristine-doxorubicin-cyclophosphamide and ifosfamide and etoposide chemotherapy followed by tumor resection and radiation per standard protocol. As part of her staging work-up, bone marrow biopsy was performed, significant for Gaucher cells. After the second cycle of chemotherapy the patient began to experience severe delays averaging 30 days between cycles compared to 17.29 days observed in Children\'s Oncology Group data. Given her bone marrow biopsy findings and chemotherapy delays GD screening was obtained and the patient was diagnosed with GD following genetic confirmation. Due to delays in chemotherapy decreasing chance of remission, the patient was referred to Genetics for aggressive management with imiglucerase and eliglustat. After initiation of therapy the period between chemotherapy cycles decreased to 23 days on average, with a 21% increase in platelet count during therapy. The patient was able to complete ES therapy achieving remission. GD is associated with an increased risk of malignancy, as seen in our patient with ES. GD patients experience prolonged hematologic cytopenia during cancer treatment. Combining Enzyme and Substrate Reduction Therapies should be investigated as an option to improve chemotherapy adherence in GD patients.

The molecular understanding of the pathogenic mechanisms responsible for neurologic diseases of children has led to a remarkable period of research that addresses the root causes of diseases. The promise of this research has been realized with cures and treatments that correct underlying deficiencies. The breakneck rate at which new research is being proposed promises to usher in a transformation of child neurology from a diagnostic and supportive field into an interventional one. Training child neurology residents in clinical research and therapeutic intervention is increasingly important to assure the ongoing ability to support research discoveries and treatment.

OBJECTIVE: UK national guidelines recommend pancreatic enzyme replacement therapy (PERT) in pancreatic cancer. Over 80% of pancreatic cancers are unresectable and managed in non-surgical units. The aim was to assess variation in PERT prescribing, determine factors associated with its use and identify potential actions to improve prescription rates.
METHODS: RICOCHET was a national prospective audit of malignant pancreatic, peri-ampullary lesions or malignant biliary obstruction between April and August 2018. This analysis focuses on pancreatic cancer patients and is reported to STROBE guidelines. Multivariable regression analysis was undertaken to assess factors associated with PERT prescribing.
RESULTS: Rates of PERT prescribing varied among the 1350 patients included. 74.4% of patients with potentially resectable disease were prescribed PERT compared to 45.3% with unresectable disease. PERT prescription varied across surgical hospitals but high prescribing rates did not disseminate out to the respective referring network. PERT prescription appeared to be related to the treatment aim for the patient and the amount of clinician contact a patient has. PERT prescription in potentially resectable patients was positively associated with dietitian referral (p = 0.001) and management at hepaticopancreaticobiliary (p = 0.049) or pancreatic unit (p = 0.009). Prescription in unresectable patients also had a negative association with Charlson comorbidity score 5-7 (p = 0.045) or >7 (p = 0.010) and a positive association with clinical nurse specialist review (p = 0.028).
CONCLUSIONS: Despite national guidance, wide variation and under-treatment with PERT exists. Given that most patients with pancreatic cancer have unresectable disease and are treated in non-surgical hospitals, where prescribing is lowest, strategies to disseminate best practice and overcome barriers to prescribing are urgently required.

In orally fed preterm infants, poor weight gain may be linked to low fecal pancreatic elastase-1 (FPE-1) activity, indicative of exocrine pancreatic insufficiency. The objective of this study was the retrospective assessment of the effect of exogenous digestive enzyme replacement by gavage in preterm infants with growth failure and low FPE-1 (<200 μg/g). We analyzed weight gain relative to baseline and caloric intake during 14-day periods before and after institution of digestive enzyme replacement containing 6000 U lipase and 240 U protease kg-1 d-1. Among 46 of 132 preterm infants < 1250g birth weight surviving to at least 14 days in whom FPE-1 was determined, 38 infants had low FPE-1 (< 200 μg/g), and 33 infants received exogenous digestive enzyme replacement. Average daily weight gain significantly increased from 14.4 [range 2.6-22.4] g kg-1 d-1 to 17.4 [8.4-29.0] g kg-1 d-1 (P = 0.001), as did weight gain per kcal, from 0.08 [0.02-0.13] g kcal-1 d-1 to 0.11 [0.05-0.18] g kcal-1 d-1.Conclusion: In preterm infants with signs and symptoms of exocrine pancreatic insufficiency, exogenous digestive enzyme replacement is associated with improved growth. What is Known: • Very preterm infants on full enteral nutrition may display growth failure linked to transient poor exocrine pancreatic function. • Porcine pancreatic enzymes covered with an acid-resistant coating are too large to pass the internal diameter of most gavage tubes used in very preterm infants. What is New: • Administration of a liquid formulation of acid-resistant microbial digestive enzymes in preterm infants with growth failure and low fecal pancreatic elastase-1 values was associated with improved weight gain. • Response to exogenous digestive enzyme replacement was associated with the prior extent of growth failure.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory diagnostic tests are not routinely performed by most laboratories, accounting for common misdiagnosis. Factors predictive of progression and appropriate tests for monitoring are still undefined. Several treatment options showed promising results in restoring the biochemical imbalance of MNGIE. The lack of controlled studies with appropriate follow-up accounts for the limited evidence informing diagnostic and therapeutic choices. The International Consensus Conference (ICC) on MNGIE, held in Bologna, Italy, on 30 March to 31 March 2019, aimed at an evidence-based consensus on diagnosis, prognosis, and treatment of MNGIE among experts, patients, caregivers and other stakeholders involved in caring the condition. The conference was conducted according to the National Institute of Health Consensus Conference methodology. A consensus development panel formulated a set of statements and proposed a research agenda. Specifically, the ICC produced recommendations on: (a) diagnostic pathway; (b) prognosis and the main predictors of disease progression; (c) efficacy and safety of treatments; and (f) research priorities on diagnosis, prognosis, and treatment. The Bologna ICC on diagnosis, management and treatment of MNGIE provided evidence-based guidance for clinicians incorporating patients\' values and preferences.

Respiratory outcomes in Mucopolysaccharidosis Type I (MPS I), have mainly focused on upper airway obstruction, with the evolution of the restrictive lung disease being poorly documented. We report the long-term pulmonary function outcomes and examine the potential factors affecting these in 2 cohorts of MPS I patients, those who have undergone Haematopoietic Stem Cell Transplantation (HSCT) and those treated with Enzyme Replacement Therapy (ERT). The results were stratified using the American Thoracic Society (ATS) guidelines. 66 patients, capable of adequately performing testing, were identified by a retrospective case note review, 46 transplanted (45 Hurler, 1 Non-Hurler) and 20 having ERT (17 Non-Hurler and 3 Hurler diagnosed too late for HSCT). 5 patients died; 4 in the ERT group including the 3 Hurler patients. Overall 14% of patients required respiratory support (non-invasive ventilation (NIV) or supplemental oxygen)) at the end of follow up. Median length of follow-up was 12.2 (range = 4.9-32) years post HSCT and 14.34 (range = 3.89-20.4) years on ERT. All patients had restrictive lung disease. Cobb angle and male sex were significantly associated with more severe outcomes in the HSCT cohort, with 49% having severe to very severe disease. In the 17 Non-Hurler ERT treated patients there was no variable predictive of severity of disease with 59% having severe to very severe disease. During the course of follow up 67% of the HSCT cohort had no change or improved pulmonary function as did 52% of the ERT patients. However, direct comparison between therapeutic modalities was not possible. This initial evidence would suggest that a degree of restrictive lung disease is present in all treated paediatrically diagnosed MPS I and is still a significant cause of morbidity, though further stratification incorporating diffusing capacity for carbon monoxide (DLCO) is needed.