This metabolic disorder is characterised by an increased blood and urine concentration of homocysteine - a sulphur-containing amino acid.
There are seven distinct types:

1. Cystathionine β-synthase (CBS) deficiency
2. 5,10-Methylenetetrahydrofolate reductase deficiency
3. Deficiency of cobalam in coenzyme synthesis - consists of five subtypes (cblC, -D, -E, -F and -G)

Cystathionine β-synthase deficiency

Pathophysiology

Results from reduced activity of the enzyme cystathionine β-synthase which is involved in the conversion of methionine to cysteine. The enzyme is mapped to gene locus 21q22.¹ Homocysteine and methionine accumulate in tissues and interfere with the cross-linking of collagen fibres.

Epidemiology

The G307 S mutation is the most common cause of homocystinuria in patients of Celtic origin. Guthrie testing has shown the incidence to be 1 in 344,000 worldwide but it is much higher in Ireland (1 in 65,000). All cases are inherited as autosomal recessive. 50% are responsive to pyridoxine (vitamin B6) and tend to have milder disease.¹

Clinical findings

• Raised plasma homocysteine that results in homocystinuria and raised plasma methionine levels.²
• 80% of homozygous patients will develop ocular abnormalities and half of these will have mental retardation.
• Abnormalities manifest themselves by age 3-4 years.

Heterozygous carriers (1 in 70 of general population) have hyperhomocystinaemia - raised plasma homocysteine levels with no homocystinuria. Their risk of premature cardiovascular disease is increased.

Presentation

• Skeletal features: Marfanoid habitus with normal to tall stature (occasionally failure to thrive in infancy), fine, brittle hair, hypopigmentation, high arched palate, crowded teeth, arachnodactyly, limited joint mobility, pectus excavatum/carinatum, kyphoscoliosis
• Eyes: dislocation of lens usually downward and medially (ectopia lentis), myopia, glaucoma
• CNS: mental retardation (average IQ = 80; 30% have normal IQ), seizures, cerebrovascular events, psychiatric disorders³

Investigations

• The cyanide-nitroprusside test is an easy way to detect increased excretion of sulfhydryl-containing compounds in the urine.
• Urine amino acids - elevated homocysteine and methionine levels.
• Plasma levels of free methionine and homocysteine (methionine is raised in CBS deficiency and low or normal in those with other causes of homocystinuria).
• Ophthalmology tests to detect myopia and dislocated lens.
• Diagnosis depends on measurement of CBS activity in tissues, e.g. liver biopsy, skin biopsy.
• Imaging e.g. X-rays or DEXA scan to detect osteoporosis.

Complications

• Thromboembolism
• Coronary artery disease e.g. myocardial infarction
• Mitral valve prolapse
• Osteoporosis - in two thirds of patients by age 15
• Fatty infiltration of liver
• Pancreatitis

Management

• Effective treatment requires early diagnosis and initiation of therapy.
• Try pyridoxine in all - increases CBS activity.
• Methionine-restricted, cystine-supplemented diet for those who do not respond to pyridoxine (betaine may also be useful).
• Methionine restriction has been shown to prevent mental retardation and reduce the rate of lens dislocation and seizure activity.
• Pyridoxine supplementation for responders (usually 50% of affected patients).
• Pyridoxine treatment of those who are detected late reduces the rate of thromboembolic events.
• Avoid folate deficiency.
• Consider primary prevention of cardiovascular disease, e.g. aspirin, statin.
• Referral to specialists as indicated by clinical picture e.g. ophthalmologist, psychiatrist.

Prognosis

25% of patients will die by the age of 30 years from vascular related diseases. Increased homocysteine levels is an independent risk factor for coronary, cerebrovascular and peripheral vascular disease and deep vein thrombosis.⁴

Differential diagnosis

Marfan's syndrome is the main differential diagnosis to consider.

The following conditions also elevate urinary cysteine levels:

• Elderly
• Post-menopausal
• Renal failure
• Hypothyroidism
• Leukaemia
• Psoriasis
• Drugs, e.g. methotrexate, isoniazid

Other causes of homocystinuria

All other forms of homocystinuria result from enzyme abnormalities involved in the conversion of homocysteine to methionine. This is catalysed by homocysteine:methyltetrahydrofolate methyltransferase (also called methionine synthase) and its two cofactors - methyltetrahydrofolate and methylcobalamin (methyl-vitamin B12).

These cases are severe and rarely reported; thus experience with treatments and other data are limited.

Document references

1. Homocystinuria, Online Mendalian Inheritance in Man (OMIM).
2. Finkelstein JD; Inborn errors of sulfur-containing amino acid metabolism. J Nutr. 2006 Jun;136(6 Suppl):1750S-1754S. [abstract]
3. Gomber S, Dewan P, Dua T; Homocystinuria: a rare cause of megaloblastic anemia. Indian Pediatr. 2004 Sep;41(9):941-3. [abstract]
4. Brattstrom L, Wilcken DE; Homocysteine and cardiovascular disease: cause or effect? Am J Clin Nutr. 2000 Aug;72(2):315-23. [abstract]
5. Summers KM, West JA, Peterson MM, et al; Challenges in the diagnosis of Marfan syndrome. Med J Aust. 2006 Jun 19;184(12):627-31. [abstract]

Acknowledgements