At a Glance

Homocystinuria is most commonly due to a defect in sulfur-containing amino acid methylation cycle. This cycle includes methionine, homocysteine (HCY), and cysteine. Elevations of homocysteine are most frequently seen in cystathionine β-synthase (CBS) deficiency, but may also be seen in methylenetetrahydrofolate reductase (MTHFR) deficiency and disorders of cobalamin metabolism.

Homocystinuria due to CBS deficiency is inherited in an autosomal recessive manner, and affected individuals have inherited two abnormal copies of the CBS gene (each gene containing a mutation). Both parents of an individual with HCY are carriers and may have elevated homocysteine levels also, although not typically as highly elevated, and have not been found to manifest any symptoms of disease nor have risk for vascular disease.

Homocystinuria should be suspected in an individual with developmental delay, dislocated lenses (ectopia lentis), and skeletal abnormalities. Individuals also have an increased risk for thromboembolism of arteries and veins. Thromobphelbitis and pulmonary embolism from large-vessel thrombosis are major causes of mortality.

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Individuals have been described to have a “marfanoid” body habitus, as individuals are typically very tall and thin with long limbs with stiff joints or contractures. They may have pectus excavatum or pectus carinatum, genu valgus, flat feet, arachnodactyly, and scoliosis. Their lens dislocation is typically downward (in contrast to the upward dislocation in Marfan syndrome), and they may develop glaucoma and myopia progressing to retinal detachment and visual loss. In addition to intellectual disability, which may range from normal to profound, affected individuals may develop thrombotic strokes, seizures, and often have psychiatric disorders.

Newborns are now screened for Homocystinuria in all 50 states and in expanded newborn screening panels around the world. Initial screening is done through detection of elevated methionine levels.

MTHFR deficiency is an autosomal recessive disorder resulting in a block in remethylation of methionine and an increase in homocysteine and decrease in methionine. Affected individuals will have elevations of homocysteine as measured on serum total homocysteine quantification and very low levels of methionine on plasma amino acids. This disorder is typically severe, and infants present with progressive encephalopathy, seizures, and microcephaly, or later into the adult years with ataxia and psychiatric disorders. With treatment, however, many individuals may show significant improvement.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Plasma amino acid analysis and serum total homocysteine levels should be performed in all individuals.

Plasma amino acid analysis will reveal marked elevations of free homocysteine and methionine in homocystinuria. Cystine levels will typically be decreased. Total serum homocysteine may be well above 150 µM. Individuals suspected of having homocystinuria or infants with abnormal newborn screens with elevated methionine levels should have a quantitative serum methylmalonic acid level, urine organic acids, complete blood count (CBC) and mean corpuscular volume (MCV), folate and vitamin B12 level, and liver function tests, in addition to a clinical eye exam, skeletal survey, and developmental screening.

Cobalamin disorders have been subdivided into complementation classes A through G. Those with cobalamin disease type C, D3, and F may have elevations of homocysteine and methylmalonic acid with low methionine levels. Subtypes E, G, and D1 may only have elevations of homocysteine with low methionine levels. Subtypes A, B, and D2 may only have elevations of methylmalonic acid.

Individuals with MTHFR deficiency typically have elevations of total serum homocysteine greater than 100 µM with low methionine levels often below 10 µM (normal control ranges typically run between 15 and 35 µM).

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Individuals with vitamin B12 deficiency may have elevated homocysteine levels. Most commonly, this is seen in individuals with a vegetarian or vegan diet but may also be seen in other individuals with a low protein intake for other medical reasons. Dietary B12 malabsorption may occur from surgery or bacterial overgrowth of the stomach and small intestine, celiac disease, or other inflammatory intestinal disease, as well as from kidney and liver disease. Inherited defects in dietary B12 absorption may also be seen.

Inherited defects of hereditary intrinsic factor deficiency and of cobalamin transport (Imerslund-Gräsbeck syndrome), haptocorrin deficiency, or transcobalamin deficiency may occur but are rare. Disorders of intracellular cobalamin metabolism should be closely considered.

Drugs, such as methotrexate, trimethoprim, metformin, phenytoin, and niacin, may also cause Homocystinuria.

What Lab Results Are Absolutely Confirmatory?

Confirmation of CBS deficiency should be done with DNA sequencing of the CBS gene. Targeted mutation testing of two common mutations may pick up to 20-30% in Caucasian individuals, and the G207S mutation may be detected in up to 70% of individuals of Irish background. Enzyme analysis is also clinically available.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Early diagnosis of Homocystinuria is essential to ensuring early treatment and improving clinical outcome. Newborns are placed on methionine-restricted diets. Ongoing clinical management with close monitoring of dietary protein is important to ensure adequate growth and development. Betaine may be used to decrease homocysteine levels. Affected individuals are often started on supplementation with pyridoxine, folic acid, vitamin C, and, in some cases, vitamin B12. Antithromobotic agents, such as aspirin or dipyridamole, are often used, but their clinical efficacy has not yet been proven in CBS deficiency.

Complications from eye disease are often corrected surgically. Skeletal abnormalities, such as scoliosis, should be followed by an orthopedic surgeon. Oral hormone replacement should be carefully considered due increased risk for thrombosis. Surgical complications, such as thrombosis, are generally uncommon, and recommendations to maintain hydration with 1.5 times maintenance fluids should be closely monitored.

Women who become pregnant should be closely monitored, especially during the third trimester when there is an increased rise of thrombosis, although other adverse events have been reported in the first and second trimester. Supplementation with folic acid throughout pregnancy and anticoagulation in the third trimester should be considered.

Individuals with combined homocysteine-methylmalonic acidemia, most commonly Cobalamin C disease, have been found to have a good clinical response to early treatment with intramuscular vitamin B12 (hydroxocobalamin is recommended), folic or folinic acid, and betaine. Individuals with Cobalamin E or G disease are also treated intramuscular hydroxocobalamin and betaine but have not been found to have as significant a clinical response.

In MTHFR deficiency, early treatment with betaine, folic or folinic acid, pyridioxine, cobalamin, and L-carnitine may result in clinical improvement. This disorder should not be confused with MTHFR gene polymorphisms (677C > T and 1298A > C) that do not result in a similar clinical picture and have been associated with risk for cardiovascular disease, stroke, thromboembolism, pregnancy loss, and neural tube defects. Individuals with MTFHR polymorphisms may or may not have mild elevations of HCY.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Urine homocysteine measurement is not adequate for detection of Homocystinuria.

Plasma amino acids will only detect free homocysteine, not the protein-bound homocysteine. Serum total homocysteine measures all homocysteine present and is most suitable for accurate detection and regular monitoring.

Homocystine levels should be closely reviewed. Mildly elevated levels (typically <30 uM) are often consistent with vitamin B12 deficiency, and environmental, acquired, and inherited causes of B12 deficiency should be thoroughly completed.

New born screen positive infants suspected to have Homocystinuria typically only include detection high methionine levels. Some centers are able to perform second-tier homocysteine analysis to reduce false-positive screens with hypermethioninemia due to other causes, such as acquired and inherited liver disease, including galactosemia and tyrosinemia.