Introduction
Patients and methods
Panel of screened disorders
Disorder | N | Group 1 NBS | Group 2 symptomatic | Group 3 high risk | Treatment | Confirmation of diagnosis Minimal criteria to accept diagnosis as confirmed | ||
---|---|---|---|---|---|---|---|---|
Yes | No | Un-known | ||||||
Amino acid disorders/ Urea cycle disorders
| ||||||||
PKUa,f | 85 | 84 | 1b | 79 | 0 | 6 | Blood phenylalanine ≥ 600 μmol/L, normal urinary pterins and DBS dihydropteridine reductase activity | |
MHPa,f | 88 | 88 | 2 | 61 | 25 | First and control phenylalanine levels < 600 μmol/L, phenylalanine/tyrosine < 3, normal urinary pterins and DBS dihydropteridine reductase activity | ||
PTPSDe | 1 | 1 | 1 | Characteristic pterin profile in urine | ||||
MSUDa, e | 7 | 4 | 1 | 2 | 7 | Elevated branched-chain amino acids including alloisoleucine | ||
TYR Ie | 2 | 2 | 2 | Elevated succinylacetone in urine | ||||
TYR IIIf | 1 | 1 | 1 | Tyrosine persistently > 500 μM, succinylacetone in urine normal, no clinical indication for tyrosinaemia type II or liver dysfunction | ||||
Homocystinuriaf | 0 | Characteristic profile of homocysteine, methionine, cysteine in plasma | ||||||
NKHc,f | 1 | 1 | 1 | Elevated glycine in plasma and CSF and pathological ratio plasma/CSF glycine | ||||
CIT I classice | 4 | 1 | 3 | 3 | 1 | Characteristic amino acid profile in plasma and ammonia in blood | ||
CIT I mildf | 6 | 6 | 1 | 5 | Characteristic amino acid profile in plasma and ammonia in blood, molecular genetic analysis | |||
ASLDe | 1 | 1 | 1 | Characteristic amino acid profile in plasma and urine | ||||
Arginase deficiencyf | 0 | Enzyme deficiency in erythrocytes | ||||||
Fatty acid oxidation disorders
| ||||||||
CPT IDa,e | 1 | 1 | 1 | Enzyme deficiency in fibroblasts | ||||
CPT IIDa,e | 1 | 1 | 1 | Enzyme deficiency in fibroblasts | ||||
CACTDa,e | 0 | Enzyme deficiency in fibroblasts | ||||||
CTDe | 3 | 3 | 3 | Pathological tubular carnitine reabsorption, fibroblast transport studies | ||||
MCADDa,e | 81 | 77 | 2 | 2 | 70 | 1 | 10 | Characteristic acylcarnitine profile in plasma/DBS and/or hexanoylglycine in urine and/or informative genotype |
LCHADD/ mTFPa,c,e | 6 | 5 | 1 | 5 | 1 | Characteristic acylcarnitine profile in plasma/DBS and/or informative genotype and/or enzyme activity | ||
VLCADDa,e | 6 | 6 | 6 | Characteristic acylcarnitine profile in plasma/DBS and/or enzyme activity in lymphocytes or fibroblasts and/or informative genotype | ||||
SCADDf | 9 | 9 | 3 | 6 | Characteristic acylcarnitine profile in plasma/DBS and ethylmalonic acid in urine and enzyme activity | |||
MADDe | 3 | 3 | 2 | 1 | Characteristic profiles of acylcarnitines in plasma and organic acids in urine | |||
Organic acid disorders
| ||||||||
GA Ia,e | 6 | 6 | 6 | Characteristic urinary organic acid profile, informative genotype | ||||
IVA classica,e | 5 | 4 | 1 | 5 | Characteristic urinary organic acid profile | |||
IVA milda,f | 10 | 9 | 1 | 10 | Characteristic urinary organic acid profile, informative genotype | |||
MBDf | 0 | Characteristic urinary organic acid profile | ||||||
MMA/Cble | 4 | 3 | 1 | 4 | Characteristic urinary organic acid profile +/- abnormal concentrations of plasma homocysteine and methionine (complementation studies in fibroblasts in all patients) | |||
PAe | 4 | 3 | 1 | 4 | Characteristic urinary organic acid profile | |||
3-MCCDf | 8 | 8 | 5 | 2 | 1 | Characteristic urinary organic acid profile | ||
MHBDe | 0 | Characteristic urinary organic acid profile, informative genotype | ||||||
MGAe | 0 | Characteristic urinary organic acid profile, informative genotype | ||||||
HCSDe | 0 | Characteristic urinary organic acid profile, enzyme deficiency | ||||||
BIODa,e | 9 | 9 | 7 | 2 | Enzyme deficiency in DBS and/or serum | |||
KTDe | 0 | Characteristic profiles of acylcarnitines in plasma and organic acids in urine | ||||||
HMG-CoA LDe | 1 | 1 | 1 | Characteristic profiles of acylcarnitines in plasma and organic acids in urine | ||||
Other disorders
| ||||||||
Galactosaemiaa,e | 14 | 9 | 2 | 3 | 12 | 2 | Enzyme deficiency and elevated galactose-1-phosphate in DBS and erythrocytes | |
Others conditions
| ||||||||
Maternal 3-MCCDf | 6 | 6 | 6 | Characteristic acylcarnitine profile in plasma/DBS of mother and clearing of the pathological profile in the newborn | ||||
Not confirmedd | 4 | 4 | 3 | 1 | ||||
Total
| 377 | 355 | 11 | 11 | 239 | 82 | 56 |
Population
Cases with confirmed diagnosis of a metabolic disorder
Process evaluation
Outcome evaluation
Data management and statistics
Results
Part 1: Process analysis
Diagnosis | Age at decom-pensation (days) | Age at blood samp-ling 1st screening card (days) | Age at 1st screening result (days) | Age at con-firmed diagnosis (days) | Age at start of treatment (days) |
---|---|---|---|---|---|
MCADD | 0.0 | 4.0 | 11.0 | 12.0 | 14.0 |
MCADD | 3 | 1.7 |
6.8
| 6.0 | 3.0 |
CIT I classic | 1.0 | 3.0 |
12.0
| 2.0 | 2.0 |
CIT I classic | 1.0 | 3.0 |
10.0
| 5.0 | Not available |
CIT I classic | 2.0 | 2.7 |
8.6
| 2.0 | 2.0 |
IVA classic | 3.0 | 4.4 |
10.7
| 8.0 | 8.0 |
PA | 3.0 | 3.0 |
16.0
| 3.0 | 3.0 |
Cobalamin C/D defect | 3.0 | 5.0 |
15.0
| 5.0 | 5.0 |
Galactosaemia | 4.0 | 3.5 | 7.0 | 8.0 | 7.0 |
Galactosaemia | 8.0 | 4.2 |
11.1
| 9.0 | 9.0 |
MSUD | 4.0 | 3.4 |
9.3
| 5.0 | 5.0 |
Part 2: Outcome analysis
Metabolic decompensations
Clinical signs, cognitive outcome and school placement
Subsample | Positive clinical status score*; number (%) | Cognitive outcome IQ <85; number (%) |
---|---|---|
Symptomatic group | 3/6 (50) | 4/6 (66.7) |
High risk group | 1/7 (14.3) | 3/7 (42.9) |
NBS without MCADD and PKU | 12/30 (40.0) | 2/26 (7.7) |
NBS: MCADD | 3/32 (9.4) | 1/32 (3.1) |
NBS: PKU | 7/50 (14.0) | 4/49 (8.2) |
Total | 26/125 (20.8) | 14/120 (11.7) |
Disorders of screening panel 2005 without PKU and BIOD$ | 8/61 (13.1) | 5/60 (8.3) |
Additional disorders screened until 2005# | 11/14 (78.6) | 5/11 (45.5) |
Discussion
Wilcken et al., 2009[13] Screened cohort born 1998-2002 N = 461,500 | This study Screened cohort born 1999-2009 N = 1,084,195 | OR; 95% CI | |
---|---|---|---|
Prevalence group 1: MSUD, BIOD, GA I, IVA, MCADD, CACTD, CPT ID, CPT IID; LCHADD, VLCADD | n = 37 8.0:100,000 | n = 122 11.25: 100,000 | 1.40; [0.97;2.02] |
Prevalence group 2: Group 1 without MCADD | n = 13 2.8: 100,000 | n = 41 3.8: 100,000 | 1.34; [0.72;2.51] |
MCADD
| |||
Prevalence | n = 24 5.2: 100,000 | n = 81 7.5: 100,000 | 1.44; [0.91;2.27] |
Clinical presentation by day 5 | N = 2 | N = 2 | |
Asymptomatic or clinical presentation after day 5 | N = 22 | N = 79 | |
Metabolic decompensation during follow-up | Not reported | 6/69 | |
Physical score nil significant at 6 (Australia)/3 (Heidelberg) years | 22/22 | 31*/32 | |
No intellectual handicap at 6 (Australia)/3 (Heidelberg) years (IQ or intellectual development in normal range (IQ≥85)) | 22/22 | 31*/32 | |
Normal school at ~6 yrs | 15/15 | 9/9 |