OMIM ID:
Homocystinuria, Beta-Synthase Deficiency
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
More than half of patients have ectopia lentis by the age of 10 years and the dislocation is progressive. Ectopia lentis occurs in 90% of patients and 94% of these are noted by the age of 20 years. The lenses seem to be more mobile than those in Marfan syndrome with a significantly increased risk of lens migration into the anterior chamber (19%) or complete dislocation into the posterior chamber (14%). Lens surgery is required in homocystinuria about 7 years earlier than in Marfan syndrome with 62% of procedures necessitated by pupillary block glaucoma or displacement into the anterior chamber. Whereas nearly 70% of lenses dislocate superiorly in Marfan syndrome, only 9% of homocystinuria lenses do so.
Other ocular features include optic atrophy (23%), iris atrophy (21%), anterior staphylomas (13%) and corneal opacities (9%). Retinal detachments occur in 5-10%. The majority of patients both pre- and postoperatively have vision of 20/50 or worse.
Systemic Features
Arachnodactyly and tall stature in some patients may suggest Marfan syndrome. Mental deficiencies or behavioral problems are present in a majority of patients (50-60%) with mental functioning higher in the subset of patients who are B6-responsive. Thromboembolic events (strokes, myocardial infarctions) are a significant risk at any age, especially so after age 20 years, and this is responsible for considerable morbidity and mortality. The risk is especially high following general anesthesia unless hydration is strictly controlled. Osteoporosis and seizures are common. Hypopigmentation is often present but darkening of hair has been noted following pyridoxine treatment. Serum homocysteine is generally elevated and the urine contains elevated levels of methionine.
Genetics
Inheritance
Classic homocystinuria is an autosomal recessive disorder that results from mutations in the CBS (21q22.3) gene encoding cystathionine beta-synthase. It is the second most common error of amino acid metabolism. Numerous mutations have been identified but among the most common ones are I278T which causes a pyridoxine-responsive disorder, and the G3307S mutation which leads to a variant that is not responsive to pyridoxine treatment.
For another more aggressive form of homocystinuria caused by mutations in MTHFR (1p36.3) see Homosystinuria, MTHER Deficiency (236250).
Pedigree
Autosomal recessive
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.