The cost-effectiveness of expanding newborn screening for up to 21 inherited metabolic disorders using tandem mass spectrometry: results from a decision-analytic model.

OBJECTIVES: In 2005, in Ontario, Canada, newborns were only screened for phenylketonuria (PKU) and hypothyroidism. Tandem mass spectrometry (MS/MS) has since been implemented as a new screening technology because it can screen for PKU and many other diseases simultaneously. We estimated the cost-effectiveness of using this technology to expand the Ontario newborn screening program to screen for each disease independently and for hypothetical bundles of up to 21 metabolic diseases. METHODS: We constructed a decision-analytic model to estimate the incremental costs and life-years of survival that can be gained by screening or changing screening technologies. Costs and health benefits were estimated for a cohort of babies born in Ontario in 1 year. Secondary sources and expert opinion were used to estimate the test characteristics, disease prevalence, treatment effectiveness, disease progression rates, and mortality. The London Health Sciences Centre Case Costing Initiative, the Ontario Health Insurance Plan Schedule, and the Ontario Drug Benefits plan formulary were used to estimate costs. RESULTS: Changing screening technologies, from the Guthrie test to MS/MS, for PKU detection had an incremental cost of $5,500,000 per life-year (LY) gained. We identified no diseases for which the incremental cost of screening for just that disease was less than $100,000 per LY gained. The incremental costs of screening ranged from $222,000 (HMG-CoA lyase deficiency) to $142,500,000 (glutaric acidemia type II) per LY gained. Screening for a bundle of diseases including PKU and the 14 most cost-effective diseases to screen for cost less than $70,000 per LY gained, and the incremental cost-effectiveness of adding each of the 14 diseases to the bundle was less than $100,000 per LY gained. The incremental cost of adding the 15th most cost-effective disease was $309,400 per LY gained. CONCLUSIONS: Early diagnosis and treatment of metabolic disease is important to reduce disease severity and delay or prevent the onset of the disease. Screening at birth reduces the morbidity, mortality, and social burden associated with the irreversible effects of disease on the population. Our analysis suggests that the cost-efficiencies gained by using MS/MS to screen for bundles of diseases rather than just one disease are sufficient to warrant consideration of an expanded screening program. It is, however, not cost-effective to screen for all diseases that can be screened for using this technology.

Five novel mutations in the lysosomal sialidase gene (NEU1) in type II sialidosis patients and assessment of their impact on enzyme activity and intracellular targeting using adenovirus-mediated expression.

Sialidosis is an autosomal recessive disease resulting from a deficiency of lysosomal sialidase. Type II sialidosis is a rare disease characterized clinically by hydrops fetalis, hepatosplenomegaly, and severe psychomotor retardation. Genomic DNA from four unrelated sialidosis patients was screened for mutations within the sialidase gene NEU1. Five novel mutations were identified. Four are missense and one is nonsense: c.674G>C (p.R225P), c.893C>T (p.A298V), c.3G>A (p.M1?), c.941C>G (p.R341G), and c.69G>A (p.W23X). We have used our findings and diagnostic tools to confirm the presence of a homozygous null allele in a neonate sibling. Recombinant adenoviruses expressing the mutant sialidase alleles in primary cell cultures were utilized to assess the impact of each mutation on enzyme activity and intracellular localization. None of the mutant alleles expressed significant enzymatic activity. The p.R341G mutation exerts its pathological effect by perturbing substrate binding, while the p.A298V and p.R225P mutations appear to impair the folding of the sialidase enzyme. Our findings point to mutation-sensitive amino acids involved in catalytic function or structural stability and indicate the potential utility of these mutations for molecular diagnosis of this rare disease.