From the Guidelines
Homocystinuria can be recognized through a combination of clinical features and laboratory testing, with a focus on measuring total homocysteine in plasma or urine, which will be significantly elevated (typically >100 μmol/L in plasma) 1. The classic signs of homocystinuria include:
- Tall, thin body habitus
- Lens dislocation (ectopia lentis)
- Skeletal abnormalities like scoliosis and chest deformities
- Intellectual disability
- Thromboembolism at a young age Early diagnosis often involves newborn screening that detects elevated methionine levels. Confirmatory testing includes measuring total homocysteine in plasma or urine, which will be significantly elevated (typically >100 μmol/L in plasma) 1. Genetic testing for mutations in the CBS gene (most common form) or other genes involved in homocysteine metabolism can provide definitive diagnosis. Additional clinical manifestations may include fair skin and hair, malar flush, and osteoporosis. The condition results from defective metabolism of the amino acid methionine, most commonly due to cystathionine beta-synthase deficiency, leading to toxic accumulation of homocysteine that damages connective tissue, blood vessels, and the central nervous system 1. Treatment with pyridoxine (vitamin B6, 50–250 mg/day), betaine (6-9 g daily), folate, vitamin B12, and a methionine-restricted diet can prevent complications, with the specific treatment modality depending on the underlying cause of homocystinuria, such as CBS deficiency or MTHFR deficiency 1.
From the Research
Recognizing Homocystinuria
To recognize homocystinuria, several key factors and tests should be considered:
- Biochemical abnormalities: Characteristic biochemical abnormalities in the blood and urine include abnormal accumulation of methionine, abnormal presence of homocystine, and low values of cystathionine, cysteine, or cystine (disulfide of the cysteine) 2.
- Clinical signs: The most frequent clinical signs are subluxation of the lenses, mental retardation of different degrees, long bones excessively lengthened, scoliosis, and susceptibility to arterial and venous thromboembolism 2.
- Laboratory investigations: Additional laboratory investigations, including a complete blood count and quantitation of methionine and methylmalonic acid, can help infer the correct diagnosis 3.
- Urine organic acid analysis: Urine organic acid analysis using gas chromatography-mass spectrometry can identify intermediate metabolites and help diagnose inherited metabolic diseases, including homocystinuria 4.
- Distinguishing from other disorders: Homocystinuria must be differentiated from other disorders, such as Marfan's syndrome, through laboratory tests 2 and from remethylation disorders, which can be distinguished by the presence or absence of methylmalonic acid in urine or plasma 3.
Diagnostic Considerations
When diagnosing homocystinuria, consider the following:
- Vitamin B12 or folate deficiency: Underlying vitamin B12 or folate deficiency must be excluded first, as these can cause high blood homocysteine levels 3.
- Inherited metabolic conditions: If vitamin B12 or folate deficiency is excluded, an inherited metabolic condition, such as classical homocystinuria or remethylation disorders, can be considered 3.
- Genetic analysis: Comprehensive genetic analyses can provide new insights into inherited metabolic diseases and help identify the underlying genetic cause 5.