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Clinical and molecular basis of
NAGS and CPS1 deficiencies
Johannes Häberle University Children‘s Hospital Zurich
27 March 2015 Salt Lake City
CME Satellite Symposium «Age Is No Barrier: Time to Consider Late-onset UCDs»
Disclosure
• Nothing to disclose
1. Characteristics of both disorders
Rare, autosomal recessive Panethnic Often emergency situation Presentation identical: neonatal or late-onset Lab identical: high NH3, low citrulline, no orotic acid
2. Methods for diagnosis
3. General, typical and unusual findings
Enzymatic, DNA, RNA
Overview
Requires liver biopsy
Tissue needs to be immediately frozen
Offered only by few labs
Intermediate results are difficult to interpret
General recommendation: maybe helpful in selected cases
enzymatics not first line test
Enzyme testing for NAGS or CPS1 deficiency
Häberle et al, Orphanet J Rare Dis, 2012
Tuchman et al, Mol Genet Metab, 2008
Summar et al, Acta Pediatr, 2008
Time of presentation: data from literature
NAGS CPS1
small gene (7 exons) large gene (38 exons)
short introns long introns
single recurrent mutation few recurrent mutations
frequent splice mutations
DNA preferred RNA preferred
Genetic testing for NAGS or CPS1 deficiency
Mutation analysis first choice
Material required: 1 ml EDTA blood and 1 ml heparin blood
Inform lab in urgent cases (TAT < 1 week is possible!)
Practical summary regarding diagnostics
1. General findings from literature and own lab
2. Typical findings
3. Unusual findings
Genetic basis of NAGS or CPS1 deficiency
0
50
100
150
200
250
300
positive
negative
Data from 2004 - 2014
NAGS CPS1
total
13% 51%
Total: > 30% late-onset
0
5
10
15
20
25
30
35
40
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
CPS1 gene requests, n=218
0
5
10
15
20
25
30
35
NAGS gene requests, n=248
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
total samples positive tests
1. France 88 30%
2. Turkey 67 32%
3. Germany 41 21%
4. Great Britain 38 19%
5. Italy 23 29%
Country-specific statistics
Data from 2004 - 2014
~ 240 mutations known
44 are characterised
Häberle et al, Hum Mutat, 2011
Pekkala et al, Hum Mutat, 2010 Diez et al, Hum Mutat, 2013; Diez et al, Mol Genet Metab, 2014
CPS1 mutation database
48 patients
26 neonatal onset (plus few siblings treated prospectively)
15 late onset („safe guess“)
33 different mutations known (including 12 unpublished)
24 missense mutations
5 are characterised by expression studies
Schmidt et al, BBA, 2005
NAGS mutation database
unpublished data
conserved in all vertebrate conserved in vertebrate and fungal NAGS mutations
Caldovic et al, Hum Mutat, 2005
conserved in all vertebrate conserved in vertebrate and fungal NAGS mutations
kinase domain
acetyltransferase domain: binding of - acetyl-CoA - glutamate
Caldovic et al, Hum Mutat, 2005 Sancho-Vaello et al, FEBS Letters, 2008
conserved in all vertebrate conserved in vertebrate and fungal NAGS mutations
mutations in late-onset
kinase domain
acetyltransferase domain: binding of - acetyl-CoA - glutamate
conserved in all vertebrate conserved in vertebrate and fungal NAGS mutations
mutations in neonatal-onset
kinase domain
acetyltransferase domain: binding of - acetyl-CoA - glutamate
Recurrent mutation in Turkish CPS1D: p.Val1013del
Recurrent mutation in Turkish NAGSD: p.Trp484Arg
> 90% of CPS1 mutations are private
Only 5 (of 33) NAGS mutations are recurrent
Genetic basis: typical findings
Hu et al, Mol Genet Metab, 2014
„CPS1D patients“ turn out to be NAGSD patients
CPS1 mutations may be missed on DNA analysis
Only 2 neonatal NAGSD patients in US
Enhancer mutation in NAGS deficiency
Genetic basis: unusual findings
Kuchler et al, JIMD, 1996
Heibel et al, Hum Mutat, 2011
Conclusion & summary
NAGS deficiency Rare but more frequent than often assumed
CPS1 deficiency More frequent than NAGS deficiency High detection rate despite difficult preanalytical situation
For both Patients are identified in centers that actively seek diagnosis About 30% of cases are late-onset Mutation analysis 1st choice for diagnostics
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