Figure 1
Figure 2
Figure 3
Symptoms at disease presentation by age in remethylation disorders (a) and CBS deficiency (b) in estimated order of frequency_ There is wide range of ages at presentation and spectrum of severity, from asymptomatic individuals to severely affected patients with multi-system disease_
| (a) Remethylation disorders |
| Feeding difficulties / failure to thrive |
| Muscular hypotonia |
| Developmental / cognitive impairment |
| Seizures |
| Eye disease (nystagmus, visual impairment) The typical eye disease observed in Cbl-related remethylation disorders is generally limited to early onset forms and not present in MTHFR deficiency. |
| Acute metabolic decompensation |
| Cardiac disease (cardiac malformation; cardiomyopathy |
| Atypical haemolytic uraemic syndrome |
| Behavioural problems |
| Movement disorders |
| Stroke / thromboembolic event |
| Anaemia/thrombocytopenia or pancytopenia, megaloblastosis |
| Chronic renal failure |
| Pulmonary hypertension |
| Failure to thrive / weight loss / feeding problems |
| Developmental / cognitive impairment |
| Seizures |
| Muscular hypotonia / muscle weakness |
| Thromboembolism / stroke / pulmonary embolism |
| Psychiatric disease |
| Movement disorder |
| Myelopathy |
| Atypical haemolytic uraemic syndrome |
| Acute metabolic decompensation |
| Chronic renal failure |
| Cardiac disease |
| [5, 9, 10, 14] |
| (b) CBS deficiency (classical homocystinuria) Clinical manifestations are generally more severe in pyridoxine non-responsive disease. |
| Ectopia lentis and/or severe myopia |
| Developmental delay/intellectual disability |
| Thromboembolic events |
| Excessive height and length of the limbs (‘marfanoid’ habitus) |
| Osteoporosis and bone deformities (pectus excavatum or carinatum, genu |
| valgum, scoliosis) |
| Seizures, psychiatric and behavioural problems and extrapyramidal signs |
| [3,4, 15,32] |
Inborn errors and acquired conditions associated with elevated tHcy in blood
| Gene | MIM code | MMA | Cbl | |
|---|---|---|---|---|
high methionine; | CBS 21q22.3 | 236200 | n | Cbl is expected to be normal (but may be affected by acquired conditions such as decreased su pply). In haptocorrin deficiency, transcobalamin receptor deficiency, MTHFD1 deficiency, and the X-chromosomally inherited HCFC1 defect, tHcy may be but is not consistently elevated. In hypermethioninemias caused by MAT I/III, GNMT, SAHH or ADK deficiencies, tHcy is usually normal or only mildly elevated (usually below 50 μmol/L ) [6, 19, 20]. |
| Acquired conditions resulting in decreased cobalamin supply / absorption | ||||
low or normal methionine; | - | - | ↑ | ↓ |
low or normal methionine; | - | - | ↑ | ↓ |
low or normal methionine; | GIF 11q12.1 | 261000 | ↑ | often ↓ |
| Inborn errors of cobalamin absorption | ||||
low or normal methionine; | AMN 14q32.32 CUBN 10p13 | 261100 | ↑ | often ↓ |
low or normal methionine; | TCN2 22q12.2 | 275350 | ↑ | Cbl is expected to be normal (but may be affected by acquired conditions such as decreased su pply). In haptocorrin deficiency, transcobalamin receptor deficiency, MTHFD1 deficiency, and the X-chromosomally inherited HCFC1 defect, tHcy may be but is not consistently elevated. In hypermethioninemias caused by MAT I/III, GNMT, SAHH or ADK deficiencies, tHcy is usually normal or only mildly elevated (usually below 50 μmol/L ) [6, 19, 20]. |
| Combined inborn errors of remethylation | ||||
low or normal methionine; | LMBRD1 6q13 | 277380 | ↑ | Cbl is expected to be normal (but may be affected by acquired conditions such as decreased su pply). In haptocorrin deficiency, transcobalamin receptor deficiency, MTHFD1 deficiency, and the X-chromosomally inherited HCFC1 defect, tHcy may be but is not consistently elevated. In hypermethioninemias caused by MAT I/III, GNMT, SAHH or ADK deficiencies, tHcy is usually normal or only mildly elevated (usually below 50 μmol/L ) [6, 19, 20]. |
low or normal methionine; | ABCD4 14q24.3 | 614857 | ↑ | Cbl is expected to be normal (but may be affected by acquired conditions such as decreased su pply). In haptocorrin deficiency, transcobalamin receptor deficiency, MTHFD1 deficiency, and the X-chromosomally inherited HCFC1 defect, tHcy may be but is not consistently elevated. In hypermethioninemias caused by MAT I/III, GNMT, SAHH or ADK deficiencies, tHcy is usually normal or only mildly elevated (usually below 50 μmol/L ) [6, 19, 20]. |
low or normal methionine; | MMACHC 1p34.1 | 277400 | ↑ | Cbl is expected to be normal (but may be affected by acquired conditions such as decreased su pply). In haptocorrin deficiency, transcobalamin receptor deficiency, MTHFD1 deficiency, and the X-chromosomally inherited HCFC1 defect, tHcy may be but is not consistently elevated. In hypermethioninemias caused by MAT I/III, GNMT, SAHH or ADK deficiencies, tHcy is usually normal or only mildly elevated (usually below 50 μmol/L ) [6, 19, 20]. |
low or normal methionine; | MMADHC 2q23.2 | 277410 | ↑ | Cbl is expected to be normal (but may be affected by acquired conditions such as decreased su pply). In haptocorrin deficiency, transcobalamin receptor deficiency, MTHFD1 deficiency, and the X-chromosomally inherited HCFC1 defect, tHcy may be but is not consistently elevated. In hypermethioninemias caused by MAT I/III, GNMT, SAHH or ADK deficiencies, tHcy is usually normal or only mildly elevated (usually below 50 μmol/L ) [6, 19, 20]. |
| Isolated inborn errors of remethylation | ||||
low or normal methionine; | MMADHC 2q23.2 | 277410 | n | Cbl is expected to be normal (but may be affected by acquired conditions such as decreased su pply). In haptocorrin deficiency, transcobalamin receptor deficiency, MTHFD1 deficiency, and the X-chromosomally inherited HCFC1 defect, tHcy may be but is not consistently elevated. In hypermethioninemias caused by MAT I/III, GNMT, SAHH or ADK deficiencies, tHcy is usually normal or only mildly elevated (usually below 50 μmol/L ) [6, 19, 20]. |
low or normal methionine; | MTRR 5p15.31 | 236270 | n | Cbl is expected to be normal (but may be affected by acquired conditions such as decreased su pply). In haptocorrin deficiency, transcobalamin receptor deficiency, MTHFD1 deficiency, and the X-chromosomally inherited HCFC1 defect, tHcy may be but is not consistently elevated. In hypermethioninemias caused by MAT I/III, GNMT, SAHH or ADK deficiencies, tHcy is usually normal or only mildly elevated (usually below 50 μmol/L ) [6, 19, 20]. |
low or normal methionine; | MTR 1q43 | 250940 | n | Cbl is expected to be normal (but may be affected by acquired conditions such as decreased su pply). In haptocorrin deficiency, transcobalamin receptor deficiency, MTHFD1 deficiency, and the X-chromosomally inherited HCFC1 defect, tHcy may be but is not consistently elevated. In hypermethioninemias caused by MAT I/III, GNMT, SAHH or ADK deficiencies, tHcy is usually normal or only mildly elevated (usually below 50 μmol/L ) [6, 19, 20]. |
low or normal methionine; | MTHFR 1p36.22 | 236250 | n | Cbl is expected to be normal (but may be affected by acquired conditions such as decreased su pply). In haptocorrin deficiency, transcobalamin receptor deficiency, MTHFD1 deficiency, and the X-chromosomally inherited HCFC1 defect, tHcy may be but is not consistently elevated. In hypermethioninemias caused by MAT I/III, GNMT, SAHH or ADK deficiencies, tHcy is usually normal or only mildly elevated (usually below 50 μmol/L ) [6, 19, 20]. |