Table 1. Follow-up from sample collection to the result of the Metabolic Laboratory
|
Years 2003–2020
|
Years 2021–2022
|
|
P50
|
P95
|
P50
|
P95
|
Time 1. Age at first NBS sample collection
|
3 days
|
5 days
|
2 days
|
4 days
|
Time 2. Age at sample receipt at laboratory
|
7 days
|
15 days
|
4 days
|
11 days
|
Time 3. Age at first NBS report (suspected diagnosis)
|
9 days
|
18 days
|
5 days unless organic acid evaluation was required, in which case the P50 was 7 days
|
15 days
|
NBS, newborn screening; P, percentile
Table 2. Characteristics of 326 cases diagnosed by NBS (total newborns screened: 440,723)
Disorders
|
No.
Subjects
|
Prevalence
(live births)
|
Abnormal biochemical markers in the screening test (median [range])
|
Dietary/
Pharmacologic treatment
|
Dialysis therapy
|
Mean follow-up (months)
|
MD EO
|
MD LO
|
Mean
PDI/IQ
|
Current
status
|
Amino acid disorders
|
|
|
|
|
|
|
|
|
|
|
|
|
Phenylketonuria
|
40
|
1/11,018
|
Phe (b) 602 µM (188–1418)
Phe/Tyr: 10.5 (3.6–29.5)
|
Yes
|
No
|
12 y 5 m
|
0
|
0
|
104
|
Normal life with
treatment.
Appropriate LE
|
Mild HPA
|
78
|
1/5650
|
Phe (b): 170 µM (102–393)
Phe/Tyr: 2.7 (1.2–7.2)
|
No
|
No
|
11 y 8 m
|
0
|
0
|
110
|
Normal life
Appropriate LE
|
Classic HCY
|
1
|
1/440,723
|
Met (b): 59 µM
Hcy (u): 22 mmol/mol crea
|
Yes
|
No
|
18 y 4 m
|
0
|
0
|
133
|
Normal life with
treatment.
Appropriate LE
|
TYR I
|
3
|
1/146,908
|
Tyr (b): 662 µM (101–729)
Suac (b): 15.4 µM
|
Yes
|
No
|
13 y 6 m
|
1 case
|
0
|
86
|
Normal life with
treatment. Appropriate LE ADHD (1 case)
|
MSUD
|
10
|
1/44,072
|
XLeu (Leu+Ile) (b): 1368 µM (514–3367)
Val (b): 644 µM (244–925)
|
Yes
|
4 cases
|
12 y 9 m
|
6 cases
|
6 times/4 cases
|
113
|
2 exitus not related
with their metabolic
disease. Appropriate LE
|
Citrullinaemia type 1
|
3
|
1/146,908
|
Cit (b): 904 µM (139–1096)
Orotic acid (u): 80 mmol/mol crea (4.2–1153)
|
Yes
|
2 cases
|
12 y 9 m
|
2 cases
|
1
|
79
|
1 exitus due to sepsis
during neonatal onset.
Appropriate LE
|
Argininosuccinic aciduria
|
2
|
1/220,362
|
Cit (b): 19.5–62 µM
ASA (u): 186–1785 mmol/mol crea
|
Yes
|
No
|
9 y 8 m
|
0
|
0
|
95
|
Normal life with treatment.
ADHD(1 case)
|
Argininaemia
|
1
|
1/440,723
|
Arg (b): 35 µM
Orotic acid (u): 639 mmol/mol crea
|
Yes
|
No
|
16 y 2 m
|
0
|
0
|
90
|
Normal life with
treatment. Appropriate LE
|
Secondary conditions:
|
|
MAT I/III deficiency
|
15
|
1/29,381
|
Met (b): 82 µM (45.1–147)
|
Partial
|
No
|
15 y 5 m
|
0
|
0
|
>95
|
Normal life. Appropriate LE
|
Alcaptonuria
|
4
|
1/110,181
|
Homogentisic acid (u): 245 mmol/mol crea (190–7000)
|
Yes
|
No
|
12 y 7 m
|
0
|
0
|
>95
|
Normal life with
treatment. Appropriate LE
|
TYR III
|
1
|
1/440,723
|
Tyr (b): 392 µM; Suac (b): 0.58 µM (normal)
|
Yes-
|
No
|
9 y
|
0
|
0
|
124
|
Normal life with
treatment. Appropriate LE
|
Organic acid disorders
|
|
|
|
|
|
|
|
PA
|
3
|
1/146,908
|
C3 (b): 8.42 µM (8.2–14.6)
C3/C2: 1.08 µM (0.51–1.7)
C3/C16: 3.24 µM (2.8–7.4)
|
Yes
|
2 cases
|
7 m
|
3 cases
|
2
|
NA
|
Exitus at 2m, 4m and 12m of life
|
MMA
|
3
|
1/146,908
|
C3 (b): 5.2–5.8 µM
C3/C2: 0.49–0.68 µM
MMA (u): 241–874 mmol/mol crea
|
Yes
|
1 case
|
8 y 11 m
|
1 case
|
0
|
113
|
Normal life with
treatment. Appropriate LE
|
IVA
|
1
|
1/230,998
|
C5 (b): 3.43 µM; C5/C2 (b): 0.26
|
Yes
|
No
|
9 y 8 m
|
0
|
0
|
110
|
Normal life with
treatment. Appropriate LE
|
MMA CblC, CblD
|
4
|
1/110,181
|
C3 (b): 7.73 µM (2.83–152)
MMA (u): 887 mmol/mol crea (89–2274)
Hcy (u): 30 mmol/mol crea (ND–86.9)
|
Yes
|
No
|
10 y 8 m
|
0
|
0
|
78
|
Normal life with treatment (2)
Retinopathy and
developmental delay: 2 cases.
2 cases with special needs
in school
|
GA-1
|
7
|
1/62,960
|
Glutarylcarnitine (b): 1.62 µM (0.27–4.23)
Glutarylcarnitine (u): 52.9 mmol/mol crea (6.5–132)
|
Yes
|
No
|
16 y 8 m
|
0
|
1
|
95
|
Normal life with treatment: 5/6
Slight cognitive delay: 1/6
1 with special needs in school +
speech therapy
|
HMG
|
2
|
1/220,362
|
C5OH (b): 0.93–1.88 µM
3-methylglutarylcarnitine (b): 0.54–0.57 µM
|
Yes
|
No
|
13 y 5 m
|
0
|
1
|
98
|
Normal life with treatment.
Appropriate LE
|
3-MCCD
|
10
|
1/44,072
|
C5OH (b): 1.35 (0.74–5.3)
3-OH isovaleric acid (u): 318 mmol/mol crea (60–3521)
|
Yes
|
No
|
12 y 10 m
|
0
|
0
|
110
|
Normal life with treatment
Appropriate LE
|
Secondary conditions:
|
|
|
|
|
|
|
|
|
|
|
Combined malonic and methylmalonic aciduria
|
4
|
1/110,181
|
C3 (b): 1.16 µM (0.96–3.1)
MMA (u): 845 mmol/mol crea (772–948)
|
No
|
No
|
5 y 11 m
|
0
|
0
|
97
|
Normal life. Appropriate LE
|
Disorders of glutathione metabolism: GSSD
|
1
|
1/440,723
|
|
Yes
|
No
|
19 y
|
1
|
42
|
55
|
Developmental delay, severe
hypoacusis and frequent
hemolytic crisis. Special needs
in school
|
Fatty acid β-oxidation disorders
|
|
|
|
|
|
|
|
|
|
|
|
|
MCADD
|
26
|
1/16,951
|
C8 (b): 9.5 µM (0.42–15.8)
C8/C10 (b): 5.3 µM (0.09–13.71)
|
Yes
|
No
|
10 y 7 m
|
0
|
1
|
>95
|
Exitus (1) during respiratory infection
Normal life with treatment (25/26)
|
LCHADD
|
2
|
1/220,362
|
C16OH (b): 0.79–0.68 µM; C18: 1OH(b): 0.97–0.51 µM; C18OH (b): 1.4–0.7 µM
|
Yes
|
No
|
18 y 3 m
|
0
|
8
|
>95
|
Normal life with treatment
Retinopathy: 1 case
Appropriate LE
|
VLCADD
|
3
|
1/146,908
|
C14 (b): 0.98 µM; C14: 1 (b): 0.58 µM
|
Yes
|
No
|
9 y 3 m
|
0
|
0
|
>95
|
Normal life with treatment
Appropriate LE
|
CACTD
|
1
|
1/440.723
|
C16 (b): 16.4 µM; C18 (b): 2.83 µM; C18: 1 (b): 4.0 µM
|
Yes
|
No
|
9 m
|
1
|
1
|
85
|
Exitus due to a arrhythmia at 9m
during infection
|
CTD
|
2
|
1/220,362
|
C0 (b): 2.3–9.8 µM
|
Yes
|
No
|
13 y 1 m
|
0
|
0
|
>95
|
Normal life with treatment
Appropriate LE
|
MADD
|
1
|
1/440,723
|
C8 (b): 0.44 µM; C10 (b): 0.806 µM; C5DC (b): 0.22 µM
|
Yes
|
No
|
1 y 11 m
|
1
|
0
|
>95
|
Normal life with treatment
Appropriate LE
|
CPT2 deficiency
|
1
|
1/440,723
|
C16 (b): 12.52 µM; C16: 1 (b): 1.02 µM; C18 (b): 5.53 µM
|
Yes
|
No
|
3 y 2 m
|
0
|
0
|
>95
|
Normal life with treatment
Appropriate LE
|
SCADD
|
12
|
1/36,726
|
C4 (b): 1.21 µM (0.35–2.16)
EMA (u): 31.7mmo/mol crea (16.5–102)
|
only recommendation to avoid fasting
|
No
|
11 y 6 m
|
0
|
0
|
>95
|
Normal life.
Appropriate LE
|
Galactosaemias
|
|
|
|
|
|
|
|
|
|
|
|
|
GALT deficiency
|
13
|
1/34,024
|
Gal-1-P (b): 1.61 mM (0.41–3.99)
|
Yes
|
No
|
10 y
|
1 case
|
0
|
90
|
Normal life with treatment: 11 cases
Developmental delay: 2 cases with
special needs in school
Ovarian insufficiency: 2 cases.
|
GALK deficiency
|
7
|
1/62,960
|
Gal-1-P (b): Normal, Gal (u) elevated
|
Yes
|
No
|
10 y 4 m
|
0
|
0
|
>95
|
Normal life with treatment
Appropriate LE
|
Secondary conditions:
|
|
|
|
|
|
|
|
|
|
|
GALE deficiency
|
7
|
1/62,960
|
Gal-1-P (b): 2.59 mM (0.95–4)
|
No
|
No
|
13 y 4 m
|
0
|
0
|
> 95
|
Normal life. Appropriate LE
|
GALM deficiency
|
2
|
1/220,362
|
Gal-1-P (b): Normal, Gal (u) elevated
|
Yes
|
No
|
8 y 2 m
|
0
|
0
|
>95
|
Normal life with treatment
Appropriate LE
|
Disorders of biotin metabolism
|
|
|
|
|
|
|
|
|
|
|
|
|
BTD partial deficiency
|
9
|
1/48,969
|
BTD activity (b): 21.5% (13.6–25)
|
Yes
|
No
|
13 y
|
0
|
0
|
>100
|
Normal life with treatment
Appropriate LE
|
BTD total deficiency
|
4
|
1/110,181
|
BTD activity (b): 1.3% (0–3.1)
|
Yes
|
No
|
13 y 10 m
|
0
|
0
|
>100
|
Normal life with treatment
Appropriate LE
|
Amino acid transport defects
|
|
|
|
|
|
|
|
|
|
|
|
|
Cystinuria
|
43
|
1/10,249
|
Cys (u): 383 mg/g crea (173–1614)
|
Yes
|
No
|
14 y 5 m
|
0
|
0
|
>100
|
Normal life with treatment
Urolithiasis: 1 case
|
ADHD: Attention Deficit Hyperactivity Disorder; Arg, arginine; ASA, argininosuccinic acid; b, blood; BTD, biotinidase ; C0, free carnitine; C2, acetyl carnitine; C3, propionyl carnitine; C4, butyryl-carnitine; C5, isovaleryl carnitine; C5OH, 3-hydroxyisovalerilcarnitine; C5DC, glutarylcarnitine; C8, octanoylcarnitine; C10, decanoylcarnitine ; C16, palmitoylcarnitine; CACTD, carnitine-acylcarnitine translocase deficiency; CblC, cobalamine C; CblD, cobalamine D; Cit, citrulline; CPT2, carnitine palmitoyltransferase II deficiency; crea:creatinine; CTD, carnitine transporter deficiency; Cys, cysteine; EMA, ethylmalonic acid; EO, early onset; GA-1, glutaric aciduria type 1; Gal, galactose; Gal-1-P, galactose-1-phosphate; GALE, galactose epimerase; GALK, galactokinase; GALM, galactose mutarotase; GALT, galactose-1-phospahte uridyltransferase; GSSD, glutathione synthetase deficiency; Hcy, homocysteine; classic HCY, classic homocystinuria; HMG, 3-hydroxy-3-methylglutaric aciduria; HPA, hyperphenylalaninaemia; Ile, isoleucine; IVA, isovaleric acidaemia; LCHADD, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency; Leu, leucine; LO, late onset (after the neonatal period); MADD, multiple acyl-CoA dehydrogenase deficiency; MAT I/III deficiency, methionine adenosyltransferase I/III deficiency; MCADD, medium-chain acyl-CoA dehydrogenase deficiency; 3-MCCD, 3-methylcrotonyl-CoA carboxylase deficiency; MD, metabolic decompensation; Met, methionine; MMA, methylmalonic acidaemia; m, months; MSUD, maple syrup urine disease; ND, not detectable; PA, propionic acidemia; PDI/IQ, psychomotor developmental index/ intelligence quotient; Phe, phenylalanine; SCADD, short-chain acyl-CoA dehydrogenase deficiency; Suac, succinylacetone; Tyr, tyrosine; TYR I, tyrosinaemia type I; TYR III, tyrosinaemia type III; u, urine; Val, valine; VLCADD, very long-chain acyl-CoA dehydrogenase deficiency; y, years.
Table 3. Cases with clinical onset prior to NBS results (period 2000–2022)
Case
|
Age at detection by NBS
(days)
|
Age at clinical onset
(days)
|
1. Citrullinaemia type 1
|
9
|
2
|
2. Citrullinaemia type 1
|
8
|
3
|
3. MSUD
|
5
|
4
|
4. MSUD
|
7
|
5
|
5. MSUD
|
8
|
4
|
6. MSUD
|
10
|
3
|
7. MSUD
|
6
|
3
|
8. MSUD
|
9
|
4
|
9. Propionic acidaemia
|
8
|
2
|
10. Propionic acidaemia
|
7
|
3
|
11. Propionic acidaemia
|
7
|
3
|
12. MMA mutase deficiency
|
8
|
3
|
13. CACTD
|
6
|
1
|
CACTD, carnitine acylcarnitine translocase deficiency; MMA, Methylmalonic acidaemia; MSUD: maple syrup urine disease; NBS: newborn screening.
Table 4. Characteristics of the 61 false positive cases and 18 maternal defects (period 2000–2022)
No. of cases
|
Possible unconfirmed entity
|
Abnormal biochemical marker
|
Level
|
Cut-off ª
|
3
|
Mild HPA
|
Phe (b)
Phe/Tyr (b)
|
150.8 µM [143–155]
1.62 [1.63–1.96]
|
120 µM
1.96
|
4
|
IVA
|
C5 (b)
|
2.57 μM [0.81–7.39]
|
0.46µM
|
3
|
GALT deficiency
|
Gal-1-P (b)
with galactose (u) normal
|
1.49 mM [0.81-2.4]
|
0.7 mM
|
6
|
GALK deficiency
|
Galactose (u)
with Gal-1-P(b) normal
|
elevated
|
Qualitative findings
|
20
|
Citrullinaemia
|
Cit (b)
|
106 μM [36–265]
|
31µM
|
5
|
MCADD
(3 of them carriers)
|
C8 (b)
|
0.62 µM [0.34-0.75]
|
0.26 µM
|
1
|
VLCADD
|
C14 (b)
C14:1 (b)
|
0.87 µM
0.53 µM
|
0.52 µM
0.47 µM
|
6
|
CPT1
|
C0 (b)
C16 (b)
C18 (b)
|
73.1 µM [56.9–91.1]
0.83 µM [0.45–1.5]
0.58 µM [0.4–0.84]
|
9.5–75 µM
0.41–7.1 µM
0.24–2 µM
|
2
|
SCADD
|
C4 (b)
|
1.11 μM [0.94–1.29]
|
0.94µM
|
11
|
BTD deficiency
|
Biotinidase activity (b)
|
0.12 Aus [0.09–0.16]
|
0.20 Aus
|
Transitory alterations due to undiagnosed maternal IEM or vitamin deficiencies
|
4
|
CTD
|
C0 (b)
|
5.3 μM [4.9–5.6]
|
9.5 µM
|
4
|
3-MCCD
|
C5OH (b)
|
3.3 µM [2.94–3.69]
|
0.35 µM
|
10
|
MMA
|
Methylmalonic acid (u)
|
113 mmol/mol crea
|
13 mmol/mol crea
|
ª As of June 2010, cut-offs were re-evaluated every 6 months; Aus, absorbance units; BTD, biotinidase deficiency; C0, free carnitine; C2, acetylcarnitine; C3, propionylcarnitine; C4, butyrylcarnitine; C5, isovalerylcarnitine; C5OH, 3-hidroxyisovalerilcarnitine; C8, octanoylcarnitine; C10, decanoylcarnitine ; C16, hexadecanoyl-L-carnitine; Cit, citrulline; CPT1, carnitine palmitoyltransferase I deficiency; CTD, carnitine transporter deficiency; Gal-1-P, galactose-1-phosphate; GALK, galactokinase; GALT, galactose-1-P uridyltransferase; HPA, hyperphenylalaninaemia; IVA, isovaleric aciduria; MCADD, medium chain acyl-CoA dehydrogenase deficiency; 3-MCCD, 3-methylcrotonyl-CoA carboxylase deficiency; MMA, methylmalonic acidaemia; Phe, phenylalanine; SCADD, short-chain acyl-CoA dehydrogenase deficiency; Tyr, tyrosine; U, urine; VLCADD, very long-chain acyl-CoA dehydrogenase deficiency.