Carbamoyl Phosphate Synthetase (code 50470) Notice of Assessment

Transcription

1 Carbamoyl Phosphate Synthetase (code 50470) Notice of Assessment June 2013 DISCLAIMER: This document was originally drafted in French by the Institut national d'excellence en santé et en services sociaux (INESSS), and that version can be consulted at It was translated into English by the Canadian Agency for Drugs and Technologies in Health (CADTH) with INESSS s permission. INESSS assumes no responsibility with regard to the quality or accuracy of the translation. While CADTH has taken care in the translation of the document to ensure it accurately represents the content of the original document, CADTH does not make any guarantee to that effect. CADTH is not responsible for any errors or omissions or injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the information in this document, the original document, or in any of the source documentation.

2 1 GENERAL INFORMATION 1.1 Requestor: CHU Sainte-Justine. 1.2 Application Submitted: August 29, Notice Issued: April 12, Note: This notice is based on the scientific and commercial information (submitted by the requestor[s]) and on a complementary review of the literature according to the data available at the time that this test was assessed by INESSS. 2 TECHNOLOGY, COMPANY, AND LICENCE(S) 2.1 Name of the Technology Measurement of the enzymatic activity of carbamoyl phosphate synthetase by spectrophotometry (code 50470). 2.2 Brief Description of the Technology Manual enzyme assays using "in-house" reagents. Commercial kits are not available (information provided by the requestor). 2.3 Company or Developer: Not applicable. 2.4 Licence(s): Not applicable. 2.5 Patent, If Any: 2.6 Approval Status (Health Canada, FDA): Not applicable. 2.7 Weighted Value: according to the requestor (it is in the Index). 3 CLINICAL INDICATIONS, PRACTICE SETTINGS, AND TESTING PROCEDURES 3.1 Targeted Patients Patients with a strong clinical suspicion of carbamoyl phosphate synthetase deficiency, whose other test results, including those of molecular tests, are ambiguous or inconclusive (absence of mutations/genetic anomalies on the two alleles, or presence of variants of unknown significance) (information provided by the requestor). 1

3 3.2 Targeted Disease(s) Urea cycle disorders are caused by an inherited deficiency in one of the six enzymes involved in the urea cycle: carbamoyl phosphate synthetase 1 (CPS1); ornithine transcarbamoylase (OTC); argininosuccinate synthase (ASS1); argininosuccinate lyase (ASL); arginase (ARG), and N- acetylglutamate synthetase (NAGS). A severe deficiency in or total absence of CPS1, OTC, ASS1 (citrullinemia type I), and ASL (argininosuccinic aciduria) results in the accumulation of ammonia and other precursor metabolites during the first few days of life. Infants with a severe urea cycle disorder develop cerebral edema and the related signs of lethargy, anorexia, hyper- or hypoventilation, hypothermia, seizures, and coma (Lanpher et al., 2011). In recent years, early diagnosis and rapid treatment have dramatically improved survival rates for children with the disorder (Lanpher et al., 2011). 3.3 Number of Patients Targeted The requestor anticipates 0 to 1 clinical assays over the next three years. No assays have been carried out since Although demand is very low, assays are essential in certain circumstances to definitely confirm or rule out the diagnosis (information provided by the requestor). The incidence of urea cycle disorders is estimated to be 1 in 30,000 births (Lanpher et al., 2011). 3.4 Medical Specialties Involved (and Other Professions, If Any) Medical biochemistry, pediatrics, and medical genetics. 3.5 Testing Procedure Molecular genetic testing is used for diagnosis, carrier detection, and prenatal diagnosis for all six urea cycle disorders (Lanpher et al., 2011). When results are inconclusive, assays of enzyme activity are conducted in liver biopsy (CPS1, OTC, or NAGS), red blood cell (ARG), and fibroblast (ASS1 and ASL) samples (Häberle et al., 2012; Lanpher et al., 2011). 4 TECHNOLOGICAL BACKGROUND 4.1 Nature of the Diagnostic Technology: Complementary. 4.2 Brief Description of the Current Technological Context Assays measuring the enzymatic activity of carbamoyl phosphate synthetase in liver biopsies are already being conducted in Quebec. However, as these procedures are seldom performed, quality control is difficult. The option is to have these rarely occurring cases analyzed in laboratories outside Quebec (the test is available, for example, in the United States and in England.) These analyses are indicated when genetic testing is inconclusive and requires confirmation (Häberle et al., 2012). 4.3 Brief Description of the Advantages Cited for the New Technology Not applicable. 4.4 Cost of Technology and Options: Not assessed. 2

4 5 EVIDENCE 5.1 Clinical Relevance Other Tests Replaced: No Diagnostic or Prognostic Value Analysis is used to confirm the diagnosis when molecular genetic testing fails to identify a specific urea cycle disorder with certainty (Häberle et al., 2012). Scaglia et al. (2002) report the case of a child with a probable diagnosis of partial OTCD (ornithine transcarbamoylase deficiency). The level of urinary orotic acid was at 33.3 mmol/mol creatinine (normal: 0.1 mmol/mol creatine to 2.3 mmol/mol creatine). Urinary acylcarnitine and organic acid profiles were within normal limits. Following a liver biopsy, ornithine transcarbamoylase (OTC) (122 mol/h/g liver (control: 60 mol/h/g to 230 mol/h/g)) and carbamoyl phosphate synthetase (CPS) (770 mol/h/g liver (control: 1500 mol/h/g to 9000 mol/h/g)) activity were measured. These results, correlated with the physiological parameters, support the diagnosis of partial OTCD. No mutations of the OTC gene were identified by direct sequencing of a genomic DNA amplification product. The patient received a liver transplant (cadaveric) six months after the diagnosis, after which her biochemical phenotype returned to normal Therapeutic Value: Not applicable. 5.2 Clinical Validity The articles examined stated that enzyme assays provide an unambiguous diagnosis. 5.3 Analytical (or Technical) Validity No information is available in recent scientific literature. 5.4 Recommendations for Listing in Other Jurisdictions See aforementioned recommendations by Häberle et al. (2012). 6 ANTICIPATED OUTCOMES OF INTRODUCING THE TEST 6.1 Impact on Material and Human Resources: Not assessed. 6.2 Economic Consequences of Introduction Into Quebec's Health Care and Social Services System: Not assessed. 6.3 Main Organizational, Ethical, and Other (Social, Legal, Political) Issues: Not assessed. 3

5 7 INESSS NOTICE IN BRIEF Carbamoyl Phosphate Synthetase (Code 50470) Status of the Diagnostic Technology: Established Innovative Experimental (for research purposes only) Replacement for technology:, which becomes obsolete INESSS Recommendation: Keep test in the Index Remove test from the Index As this test is rarely performed, thus making it difficult to maintain a level of expertise and quality control, it may be conducted outside Quebec. Reassess test Additional Recommendation: Draw connection with listing of drugs, if companion test Production of an optimal use guide Production of indicators, when monitoring is required 4

6 REFERENCES Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 2012;7:32. Lanpher BC, Gropman A, Chapman KA, Lichter-Konecki U, Urea Cycle Disorders Consortium, Summar ML. Urea cycle disorders overview (updated on September 1, 2011). In : Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews. Seattle, WA : University of Washington; Available from : Scaglia F, Zheng Q, O Brien WE, Henry J, Rosenberger J, Reeds P, Lee B. An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency. Pediatrics 2002;109(1):