(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] |
high methionine; |
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]. |
|
low or normal methionine; |
- | - | ↑ | ↓ |
low or normal methionine; |
- | - | ↑ |
↓ |
low or normal methionine; |
261000 | ↑ | often ↓ | |
low or normal methionine; |
261100 | ↑ | often ↓ | |
low or normal methionine; |
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]. |
|
low or normal methionine; |
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; |
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; |
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; |
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]. |
|
low or normal methionine; |
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; |
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; |
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; |
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]. |