Introduction
Disorder, gene and chromosomal location | Mutations | Number of patients with laboratory data in R4S | Estimated number of patients/population frequency | ORPHA codes | MIM codes |
---|---|---|---|---|---|
Cystathionine-ß-synthase deficiency (classical homocystinuria); CBS; 21q22.3 | 187a
| 124 | >1000 1:344,000c
| 394 | 613381 |
Severe MTHFR deficiency; 1p36.22 | 101b
| 17 | >85 | 395 | 607093 |
Cobalamin E (CblE) defect MTRR; 5p15.31 | 26a
| ~50 | 2169 | 602568 | |
Cobalamin G (CblG) defect MTR; 1q43 | 22a
| ~50 | 2170 | 156570 | |
Cobalamin C (CblC) defect MMACHC; 1p34.1 | 77a
| 198 | >300 | 79282 | 609831 |
Cobalamin D (CblD) defect; MMADHC; 2q23.2 | 13a
| <20 | 79283 308380 308442 | 611935 | |
Cobalamin F (CblF) defect; LMBRD1; 6q13 | 9a
| 4 | <20 | 79284 | 612625 |
Cobalamin J (CblJ) defect; ABCD4; 14q24.3 | 5a
| 0 | <10 | 369955 | 603214 |
Methionine adenosyltransferase (MAT I/III) deficiency;
MAT1A; 10q23.1 | 48a
| 143 | 1:28,000d
| 168598 | 610550 |
Glycine-N-mMethyltransferase (GNMT) deficiency;
GNMT; 6p21.1 | 3a
| 0 | 3 | 289891 | 606664 |
S-adenosylhomocysteine hydrolase (SAHH) deficiency; AHCY; 20q11.22 | 10a
| 0 | 8 | 88618 | 613752 |
Adenosine kinase (ADK) deficiency; ADK; 10q22.2 | 5 a
| 0 | 6 | 289290 | 102750 |
Methods
Results
Classical homocystinuria or cystathionine-ß-synthase deficiency
Clinical findings
Methods for NBS in CBS deficiency
The combined remethylation defects cblC, cblF, cblJ, and cblD-MMA-Hcy
Clinical findings
Disease | Disease course | Response to treatment |
---|---|---|
CBS deficiency B6-non responsive | Severe | Early, strict treatment results in favorable physical and cognitive outcome. |
CBS deficiency B6-responsive | Mild to asymptomatic | Good response to pyridoxine |
cblC defect | Severe | Early-onset: Survival, hematological and microangiopathy symptoms responsive. Neurological, opthalmological and developmental problems often ongoing Late-onset: Predominantly responsive, residual myelopathy/neuropathy frequent in prolonged untreated courses |
cblD-Hcy defect cblD-MMA-Hcy defect | Severe | Variable, very limited data |
cblF defect | Severe | Variable, very limited data |
cblJ defect | Severe | Variable, very limited data |
Severe MTHFR deficiency | Severe | Early betaine treatment is beneficial |
cblE and cblG defect | Severe | Treatment seems beneficial in a majority of patients but response is variable. Individual case reports encourage early treatment |
MAT I/III deficiency, heterozygous individuals | Predominantly benign | Generally good without treatment |
MAT I/III deficiency, compound heterozygote and homozygote individuals | White matter disease, cognitive impairment observed | Methionine-lowering treatment may be beneficial but data is very limited |
GNMT deficiency | Predominantly benign | Generally good without treatment |
SAHH deficiency | Severe | Variable, very limited data |
ADK deficiency | Severe | Unknown |
Methods for NBS in the combined remethylation defects
Disease | Marker | Healthy newborns-concentration in DBS | Patients-concentration in DBS | Recommended range for cut-off value | Comment | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Number of laboratories with data | 1 % |
median
| 99 % | Number of patients | 1 % | 5 % |
median
| 90 % | 99 % | ||||
CBS deficiency | Met (μmol/L) | 154 | 10.65 |
20
| 39 | 124 | 26 | 51 |
103
| 540 | 964 | >39–50 | possibly poor sensitivity for pyridoxine-responsive form |
Met/Phe | 92 | 0.23 |
0.41
| 0.75 | 107 | 0.55 | 0.97 |
2.17
| 11.50 | 25 | >0.75–0.97 | ||
tHcy (μmol/L) | 3 | 4.12 |
6.00
| 10.70 | 31 | 12.46 | 14.2 |
40
| 80 | 158 | >0.7–12.4 | ||
Low Met/tHcy | 2 | 2.24 |
5.10
| 12.08 | 29 | 0.86 | 0.93 |
2.24
| 4.29 | 5.75 | <4.00–5.00 | ||
cblC/cblD | C3 acylcarnitine (μmol/L) | 151 | 0.58 |
1.68
| 4.3 | 198 | 2.65 | 3.46 |
8.40
| 13.3 | 19 | >4.3–5.4 | poor sensitivity |
C3/C2 acylcarnitine | 136 | 0.036 |
0.08
| 0.18 | 187 | 0.13 | 0.20 |
0.39
| 0.62 | 1.67 | >0.18–0.20 | ||
MMA (μmol/L) | 3 | 0.010 |
0.20
| 1.52 | 28 | 7.13 | 10.94 |
28
| 114 | 437 | >3.0–7.0 | ||
Methylcitrate (μmol/L) | 2 | 0.036 |
0.21
| 12.4 | 10 | 0.37 | 0.38 |
0.63
| 6.13 | 10.42 | >0.7–1.2 | ||
Met (μmol/L) | 154 | 10.65 |
20
| 39 | 3.62 | 4.90 |
10.2
| 26 | 47 | <10.2–10.6 | poor sensitivity | ||
Low Met/Phe | 92 | 0.23 |
0.41
| 0.75 | 178 | 0.050 | 0.081 |
0.18
| 0.47 | 0.70 | <0.17–0.23 | poor sensitivity | |
tHcy (μmol/L) | 3 | 4.12 |
6.00
| 10.70 | 23 | 14.66 | 20 |
52.00
| 172 | 241 | >10.7–12.4 | ||
cblF | C3 acylcarnitine (μmol/L) | 151 | 0.58 |
1.68
| 4.3 | 4 | 8.75 | 8.88 |
10.18
| 12.87 | 13.76 | >4.3–5.4 | |
cbE/cblG/ MTHFR | Low Met (μmol/L) | 154 | 10.65 |
20
| 39 | 17 | 2.52 | 3.78 |
5.91
| 9.76 | 10.22 | <10.2–10.6 | |
Low Met/Phe | 92 | 0.23 |
0.41
| 0.75 | 17 | 0.038 | 0.068 |
0.10
| 0.16 | 0.17 | <0.17–0.23 | ||
tHcy (μmol/L) | 3 | 4.12 |
6.00
| 10.70 | 8 | 42 | 48 |
70
| 132 | 154 | >10.7–12.4 | ||
Low Met/tHcy | 2 | 2.24 |
5.10
| 12.08 | 8 | 0.034 | 0.048 |
0.083
| 0.17 | 0.25 | <4.00–5.00 | ||
MATI/III | Met (μmol/L) | 154 | 10.65 |
20
| 39 | 143 | 44 | 50 |
103
| 173 | 582 | >39–50 | |
Met/Phe | 92 | 0.23 |
0.41
| 0.75 | 137 | 0.84 | 1.1 |
1.77
| 3.72 | 6.32 | >0.75–0.97 | ||
Met/tHcy | 2 | 2.24 |
5.10
| 12.08 | 2 | 10.87 | 12.53 |
31
| 48 | 52 | >14.00–15.00 |