Considering Proximal Urea Cycle Disorders in Expanded Newborn Screening

Proximal urea cycle disorders (PUCDs) have adverse outcomes such as intellectual disability and death, which may benefit from newborn screening (NBS) through early detection and prevention with early treatment. Ornithine transcarbamylase deficiency (OTCD) and carbamoyl phosphate synthetase 1 deficiency (CPS1D) are screened in six and eight states in the United States. We analyzed current evidence to see if it supports inclusion of PUCDs in the NBS panels based upon prevention potential, medical, diagnostic, treatment, and public health rationales. A literature review was performed in PubMed using MESH terms for OTCD, CPS1D, and NAGSD. A systematic review was performed in the hallmark of NBS inclusion criteria. We reviewed 31 articles. Molecular and biochemical diagnosis is available to provide diagnostic evidence. Untreated PUCDs have a significant burden with considerable developmental delay and mortality that may improve with early treatment. Tandem mass spectrometry can be used for NBS for PUCDs; however, citrulline and glutamine alone are not specific. Medical treatments currently available for PUCDs meet existing medical, diagnostic, treatment, and public health rationales. Improvement in NBS algorithms to increase sensitivity and specificity will allow earlier diagnosis and treatment to potentially improve disability and mortality rates.


Rationale
3 Describe the rationale for the review in the context of what is already known.
2 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

Protocol and registration
5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
NA Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.
2 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
2 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
2 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).
2 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
2 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in NA any data synthesis.

Summary measures
13 State the principal summary measures (e.g., risk ratio, difference in means).

Synthesis of results
14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2 ) for each meta-analysis. Over 25 years, 299 patients with UCDs were treated with sodium phenylacetate and benzoate. Overall survival was 84% (250 of 299 patients). 96% of the patients survived episodes of hyperammonemia (1132 of 1181 episodes). Patients over 30 days of age were more likely than neonates to survive an episode (98% vs. 73%, P<0.001). Patients 12 or more years of age, who had 437 episodes, were more likely than all younger patients to survive. 81% of patients who were comatose at admission survived. Patients less than 30 days of age with a peak ammonium level >1000 μmol/L were least likely to survive a hyperammonemic episode. Among those patients with EO OTCD (n=43), 60.5% (n=26) survived the first episode and 53% (n=23) survived all known episodes. Mortality for all known episodes was 47%. There was a 79% decrease from baseline after treatment with sodium benzoate and arginine. Ammonia change in subgroups: decreased EO: from 334 to 364 µmol/L; survivors EO, from 374 to 24 µmol/L.

Summar et al 2008, (USA) [8]
A large longitudinal interventional study of patients with a urea cycle disorder (UCD) in hyperammonemic crisis . For patients with AS or CPS-I deficiencies and males with OTC deficiency, approximately 70% of episodes. Occurred between the age of 31 days and 12 years. For females with OTC deficiency, 92% of episodes occurred at age >2 years. The treatment for hyperammonemic crises caused by UCDs was an intravenous combination of nitrogen scavenging drugs. 34% out of 260 patients presented within the first 30 days of life and the mortality rate was 32%. Survival was better among patients with CPS1D and females with OTCD. Cumulative percentiles of amino acids and acylcarnitines in dried blood spots of approximately 25-30 million normal newborns and 10,742 deidentified true positive cases are compared to assign clinical significance. The cutoff target ranges of analytes and ratios are then defined as the interval between selected percentiles (either 1 st or 99 th percentiles) of the two populations. When overlaps occur, adjustments are made to maximize. Sensitivity and specificity taking all available factors into consideration. The overall proportion of cutoff values within the respective target range was 42%. For CPS1D and OTCD, they used markers such as citrulline to arginine, citrulline to phenylalanine, glutamine/citrulline, glutamic acid/citrulline, and methionine/citrulline ratios. Kido et al 2012, (Japan) [29] In Japan, the prevalence of UCDs is 1/50,000 and 177 patients with UCDs between 1999-2009 (OTCD 116/177). Among OTCD (n= 116), EO=24% (28/116), LO 68% (80/116), unknown n=8. Among OTCD males (n=57): 37% had neonatal onset, 53% late onset, and unknown 10%. Among OTCD females (n=59): 12% had neonatal onset, 85% had late onset and 3% were unknown. The 5-year survival rate of patients with OTCD was 86% (21/28) for those with neonatal-onset, and 92% (74/80) for those with LO. The 10-year survival rate for the three types of OTCD, except for female neonate-onset OTCD, was more than 80%. The survival rate at 20 years of age for patients with LO OTCD was 89.4% in males and 83.8% in females. 23% (27/116)  This is a longitudinal study that uses US and European data to find out prevalence of UCDS: NAGS <1:2,000,000; CPS1D 1:1,300,000; OTCD 1:56,500. Kim et al 2013, (USA) [28] This study reports 23 children affected with UCDs who underwent liver transplant. Fifteen (65%) patients received a whole-liver graft, seven patients (30%) received a reduced size graft, and one patient received a living donor graft. Mean 74% (17/23) had an EO UCD[15], 5 had CPSD, 8 had OTCD (4 females). For the EO PUCDs, age of transplant varied (CPSD 6-203 weeks, OTCD males 3-6 weeks, and OTCD females 50-119 weeks). Patient survival at one and 5 years were 100% each time. After transplant ammonia levels (28 µmol/L) decreased compared to before transplant levels (772 µmol/L, range: 178-2969 µmol/L). There were no episodes of hyperammonemia post-transplant. Lim et al 2014, (Singapore) [36] This study shares the experience of 8 years of tandem mass spectrometry in Singapore. The incidence rate of OTCD was 1:177,000 and the PPV was 20%.

Husson et al 2016 (France) [27]
This is a 10-year retrospective cohort study reporting the efficacy and safety of sodium benzoate among 61 patients with UCDs. This study shows that sodium benzoate was effective in decreasing ammonium levels ≤100 μmol/L in 92.8% of the episodes.