thromboembolism

Homocystinuria, MTHFR Deficiency

Clinical Characteristics
Ocular Features: 

The ocular signs in MTHFR deficiency are likely similar to those found in beta-synthase deficiency (236200) but no comparative study has been reported.  Ectopia lentis is common and the high mobility of the lens carries a significant risk of pupillary block glaucoma and migration into the anterior chamber.

Systemic Features: 

There is a wide range in clinical disease in MTHFR deficiency but the neurological signs and the progressive of disease seem to be more aggressive than in beta-synthase deficiency (236200) . Neonates may have seizures and failure to thrive but other affected patients may live to adulthood without symptoms.  Early death from neurological complications is more common and the mental retardation is apparently more severe.  There is a serious risk for thromboembolic events which may be life-threatening.  Hyperhomocyteinemia and low plasma methionine are present as is increased homocystine in urine.

Genetics

Mutations in MTHFR (1p36.3) are responsible for this form of homocystinuria.  Another form, beta-synthase deficiency (236200), is caused by a mutation in the CBS  gene (21q22.3).  This is an autosomal recessive disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Administration of betaine has been reported to reduce the neurological disease but it must be started early before brain damage occurs.  It does not correct hyperhomocysteinemia nor does it correct CNS MTHFR deficiency.  It has also been reported that betaine in combination with folic acid and cobalamin can prevent symptoms.

References
Article Title: 

Mutation Update and Review of Severe MTHFR

Froese DS, Huemer M, Suormala T, Burda P, Coelho D, Gueant JL, Landolt MA,
Kozich V, Fowler B, Baumgartner MR. Mutation Update and Review of Severe MTHFR
Deficiency. Hum Mutat. 2016 Feb 13.

PubMed ID: 
2687264

Homocystinuria, Beta-Synthase Deficiency

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

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
Treatment
Treatment Options: 

Patients with this disorder form two groups: those who respond to pyridoxine (vitamin B6) and those who do not.  Those who do not respond to B6 tend to have more severe disease.  Methionine restriction administered neonatally has been reported to prevent mental retardation and reduce the rate of lens dislocation.  Neonates should be treated with B6 therapy, protein and methionine restriction, betaine, and folate with vitamin B12 supplementation.  Surgical removal of lenses may be required but the rate of vitreous loss is high.

References
Article Title: 
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