Phenylalanine hydroxylase deficiency

World Health Organization — For the first time, EU countries have more people over 65 years of age than under 15 years of age. Echoing the trend seen in Europe, much of the rest of the world is moving in a similar direction. Priority medicines for Europe and the world 2013 update calls for pharmaceutical researchers to adjust their research and development efforts to account for this shifting demography.

Priority medicines for Europe and the world

Objectives To determine the clinical effectiveness and cost utility of procedures alternative to TURP (transurethral resection of the prostate) for benign prostatic enlargement (BPE) unresponsive to expectant, non-surgical treatments. Data sources Electronic searches of 13 databases to identify relevant randomised controlled trials (RCTs). Review methods Two reviewers independently assessed study quality and extracted data. The International Prostate Symptom Score/American Urological Association (IPSS/AUA) symptom score was the primary outcome; others included quality of life, peak urine flow rate and adverse effects. Cost-effectiveness was assessed using a Markov model reflecting likely care pathways. Results 156 reports describing 88 RCTs were included. Most had fewer than 100 participants (range 12–234). TURP provided consistent, high-level, long-term symptomatic improvement. Minimally invasive procedures resulted in less marked improvement. Ablative procedures gave improvements equivalent to TURP. Holmium laser enucleation of the prostate (HoLEP) additionally resulted in greater improvement in flow rate. HoLEP is unique amongst the newer technologies in offering an advantage in urodynamic outcomes over TURP, although long-term follow-up data are lacking. Severe blood loss was more common following TURP. Rates of incontinence were similar across all interventions other than transurethral needle ablation (TUNA) and laser coagulation, for which lower rates were reported. Acute retention and reoperation were commoner with newer technologies, especially minimally invasive interventions. The economic model suggested that minimally invasive procedures were unlikely to be cost-effective compared with TURP. Transurethral vaporisation of the prostate (TUVP) was both less costly and less effective than TURP. HoLEP was estimated to be more cost-effective than a single TURP but less effective than a strategy involving repeat TURP if necessary. The base-case analysis suggested an 80% chance that TUVP, followed by HoLEP if required, would be cost-effective at a threshold of £20,000 per quality-adjusted life-year. At a £50,000 threshold, TUVP, followed by TURP as required, would be cost-effective, although considerable uncertainty surrounds this finding. The main limitations are the quantity and quality of the data available, in the context of multiple comparisons. Conclusions In the absence of strong evidence in favour of newer methods, the standard – TURP – remains both clinically effective and cost-effective. There is a need for further research to establish (i) how many years of medical treatment are necessary to offset the cost of treatment with a minimally invasive or ablative intervention; (ii) more cost-effective alternatives to TURP; and (iii) strategies to improve outcomes after TURP.

/pdf/systematic-review-and-economic-modelling-of-effectiveness-t9z6ifq698.pdf

Systematic review and economic modelling of effectiveness and cost utility of surgical treatments for men with benign prostatic enlargement

Background: Inherited metabolic disorders (IMDs) are a heterogeneous group of genetic conditions mostly occurring in childhood. They are individually rare but collectively numerous, causing substantial morbidity and mortality. Aims: To obtain up-to-date estimates of the birth prevalence of IMDs in an ethnically diverse British population and to compare these estimates with those of other published population-based studies. Methods: Retrospective data from the West Midlands Regional Diagnostic Laboratory for Inherited Metabolic Disorders (Birmingham, UK) for the 5 years (1999–2003) were examined. The West Midlands population of 5.2 million is approximately 10% of the UK population. Approximately 11% of the population of the region is from black and ethnic minority groups compared with approximately 8% for the the UK. Results: The overall birth prevalence was 1 in 784 live births (95% confidence interval (CI) 619 to 970), based on a total of 396 new cases. The most frequent diagnoses were mitochondrial disorders (1 in 4929; 95% CI 2776 to 8953), lysosomal storage disorders (1 in 5175; 95% CI 2874 to 9551), amino acid disorders excluding phenylketonuria (1 in 5354; 95% CI 2943 to 9990) and organic acid disorders (1 in 7962; 95% CI 3837 to 17 301). Most of the diagnoses (72%) were made by the age of 15 years and one-third by the age of 1 year. Conclusions: These results are similar to those of the comparison studies, although the overall birth prevalence is higher in this study. This is probably due to the effects of ethnicity and consanguinity and increasing ascertainment. This study provides useful epidemiological information for those planning and providing services for patients with IMDs, including newborn screening, in the UK and similar populations.

/pdf/the-incidence-of-inherited-metabolic-disorders-in-the-west-23duxeiov0.pdf

The incidence of inherited metabolic disorders in the West Midlands, UK

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most frequently diagnosed mitochondrial β-oxidation defect, and it is potentially fatal. Eighty percent of patients are homozygous for a common mutation, 985A→G, and a further 18% have this mutation in only one disease allele. In addition, a large number of rare disease-causing mutations have been identified and characterized. There is no clear genotype-phenotype correlation. High 985A→G carrier frequencies in populations of European descent and the usual avoidance of recurrent disease episodes by patients diagnosed with MCAD deficiency who comply with a simple dietary treatment suggest that MCAD deficiency is a candidate in prospective screening of newborns. Therefore, several such screening programs employing analysis of acylcarnitines in blood spots by tandem mass spectrometry (MS/MS) are currently used worldwide. No validation of this method by mutation analysis has yet been reported. We investigated for MCAD mutations in newborns from US populations who had been identified by prospective MS/MS-based screening of 930,078 blood spots. An MCAD-deficiency frequency of 1/15,001 was observed. Our mutation analysis shows that the MS/MS-based method is excellent for detection of MCAD deficiency but that the frequency of the 985A→G mutant allele in newborns with a positive acylcarnitine profile is much lower than that observed in clinically affected patients. Our identification of a new mutation, 199T→C, which has never been observed in patients with clinically manifested disease but was present in a large proportion of the acylcarnitine-positive samples, may explain this skewed ratio. Overexpression experiments showed that this is a mild folding mutation that exhibits decreased levels of enzyme activity only under stringent conditions. A carrier frequency of 1/500 in the general population makes the 199T→C mutation one of the three most prevalent mutations in the enzymes of fatty-acid oxidation.

Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms : Identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency

Objectives: To evaluate the evidence for the clinical effectiveness of neonatal screening for phenylketonuria (PKU) and medium-chain acyl-coA dehydrogenase (MCAD) deficiency using tandem mass spectrometry (tandem MS).

Study design: Systematic review of published research.

Data sources: Studies were identified by searching 12 electronic bibliographic databases; conference proceedings and experts consulted.

Results: Six studies were selected for inclusion in the review. The evidence of neonatal screening for PKU and MCAD deficiency using tandem MS was primarily from observational data of large-scale prospective newborn screening programmes and systematic screening studies from Australia, Germany and the USA. Tandem MS based newborn screening of dried blood spots for PKU and/or MCAD deficiency was shown to be highly sensitive (>93.220%) and highly specific (>99.971%). The false positive rate for PKU screening was less than 0.046% and for MCAD deficiency the false positive rate was less than 0.023%. The positive predictive values ranged from 20 to 32% and 19 to 100%, respectively.

Conclusions: This review suggests that neonatal screening of dried blood spots using a single analytical technique (tandem MS) is highly sensitive and specific for detecting cases of PKU and MCAD deficiency, and provides a basis for modelling of the clinical benefits and potential costeffectiveness.

Newborn screening using tandem mass spectrometry: A systematic review

Objectives: To evaluate the clinical and costeffectiveness
of tandem mass spectrometry (MS)-based
neonatal screening for inborn errors of metabolism
(IEM).

Data sources: 

Fourteen electronic bibliographic
databases covering biomedical, science, economic and
grey literature, the reference lists of relevant articles
and abstracts of conference proceedings and 18 health
services research-related resources.


Review methods: 

This review is an update of two
previous HTA reports of neonatal screening for IEM.
These reports have been updated by a systematic
review of published research (between 1995 and
January 2002) on neonatal screening of inherited
metabolic disorders using tandem MS. This was
supplemented by a search for economic literature and
the application of a modelling exercise to investigate
the economics of using tandem MS within a neonatal
screening programme in the UK.


Results: 

Evidence from the reviews of IEM found that
the UK screening programme for phenylketonuria
(PKU) was well established and there was universal
agreement that neonatal screening for PKU was
justified. Of the many other disorders that can be
detected by tandem MS, the best candidate condition
for a new screening programme was medium-chain
acyl-coenzyme A dehydrogenase (MCAD) deficiency.
For many other IEM that can be detected by tandem
MS, robust clinical evidence was limited. Costeffectiveness
analysis using economic modelling
indicated that substituting the use of tandem MS for
existing technologies for the screening of PKU alone
could not be justified. However, results from the
economic modelling indicate that the addition of
screening for MCAD deficiency as part of a neonatal
screening programme for PKU using tandem MS would
be economically attractive. Using an operational range
of 50,000–60,000 specimens per system per year, the
mean incremental cost for PKU and MCAD deficiency
screening combined using tandem MS from the model
was –£23,312 for each cohort of 100,000 neonates
screened. This cost saving is associated with a mean
incremental gain of 59 life-years. Additional economic
modelling using the available evidence does not support
including other inherited metabolic diseases within a
neonatal screening programme at present.


Conclusions: The evidence appears to support the
introduction of tandem MS into a UK neonatal
screening programme for PKU and MCAD deficiency
combined. Tandem MS has the potential for
simultaneous multi-disease screening using a single
analytical technique. Although the marginal cost of
extending the programme to include other conditions
may be relatively small, the application of this new
technology to PKU and MCAD deficiency screening
does not imply the wholesale inclusion of all disorders
detectable by tandem MS. It is suggested that the
primary focus of further research should be on the
long-term effectiveness of treatment strategies on
adverse outcomes (disabilities and impairments) under
conventional management and the potential impact of
early diagnosis using tandem MS.

/pdf/clinical-effectiveness-and-cost-effectiveness-of-neonatal-t59t1vly1f.pdf

Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review

Objectives: The clinical- and
 cost-effectiveness of tandem mass spectrometry (MS)-based neonatal
 screening for inborn errors of metabolism (IEM) were evaluated.

/pdf/clinical-effectiveness-and-cost-effectiveness-of-neonatal-uqh3eq5jrq.pdf

Clinical-effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: A systematic review

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Newborn screening using tandem mass spectrometry: A systematic review

Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review

Clinical-effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: A systematic review