Elevated homocysteine levels: What inborn errors of metabolism might we be missing?

Area of Science:

• Biochemistry
• Genetics
• Internal Medicine

Background:

• Elevated total plasma homocysteine (hyperhomocysteinemia) is linked to cardiovascular, thrombotic, and neuropsychological diseases.
• Common causes include vitamin B12 or folate deficiency, but rare, treatable inborn errors of metabolism (IEM) can be overlooked.
• Variable presentations and lack of awareness contribute to missed IEM diagnoses.

Purpose of the Study:

• To identify undiagnosed IEM in adults with significantly elevated homocysteine.
• To enable timely, IEM-specific treatment to improve patient outcomes.
• To propose a metabolic evaluation algorithm for elevated homocysteine.

Main Methods:

• Retrospective study involving data mining and chart review of patients with plasma total homocysteine >30 μmol/L over two years.
• Biochemical and genetic testing offered to patients with unexplained significant hyperhomocysteinemia.
• Diagnostic evaluation for suspected inborn errors of metabolism.

Main Results:

• Identified 22 subjects with significant hyperhomocysteinemia lacking a clear explanation.
• Genetic testing was offered to seven patients.
• One patient was diagnosed with classic homocystinuria due to cystathionine beta-synthase deficiency and showed health improvement with treatment.

Conclusions:

• Thorough investigation of hyperhomocysteinemia in adults is crucial for identifying rare but treatable IEM.
• Early diagnosis and treatment of IEM, such as homocystinuria, can significantly improve health.
• A proposed metabolic evaluation algorithm can aid in diagnosing IEM presenting with elevated homocysteine.