Step 1) Is the Diagnoses Correct?
The recommended test for diagnosis of “Classical” Homocystinuria (HCU), i.e. homocystinuria caused by a deficiency in the enzyme cysteine beta synthetase (CBS), is a plasma total homocysteine level (tHcy). In some cases newborn screen is the test that brings a potential HCU patient to attention. The initial test (heel prick) looks for many things, but in the case of screening for HCU identifies elevated methionine levels. In some locations, the heel prick is then evaluated for elevated levels of tHcy . In other places, tHcy is measured as a confirmatory test by a separate blood test. The normal range for tHcy is 10-15 µmol/L, but untreated patients may be over 100 µmol/L. There are other tests that may be conducted, such as the plasma free homocystine, but this test is not as sensitive as the tHcy.
Clinicians may also measure methionine levels and cystathionine, sometimes as part of plasma amino acids. Methionine is often high in CBS deficient HCU patients, and cystathionine is often low.
Clinicians also can confirm the diagnosis of CBS deficient HCU through DNA analysis looking for changes in the CBS gene and occasionally by measuring enzyme activity in fibroblasts (skin cells).
Patients will also be tested for responsiveness to pyridoxine, Vitamin B6. Patients responsive to pyridoxine will likely achieve lower tHcy levels through pyridoxine supplementation, and may not need any other treatment.
To diagnose Methylene tetrahydrofolate reductase (MTHFR) deficiency, Cobalamin defects, or other remethylation cycle disorders, plasma total homocysteine (tHcy) is first assessed. Other tests that are then performed include plasma and/or urine tests for:
- Vitamin B12 (cobalamin)
- Methionine (Met)
- Methylmalonic Acid (MMA)
- Acylcarnitine profile
The diagnosis may be confirmed by DNA analysis and rarely enzyme activity assays.