Ectopia lentis

Homocystinuria Usually a failure of cystathionine synthase (Fig. 40-2 reaction 6). Rarely associated with aberrant vitamin B12 metabolism (Fig. 40-2) Thromboembolic diathesis, marfanoid habitus, ectopia lentis. Mental retardation is frequent. Diet low in methionine Vitamin B6 in pyridoxine-responsive syndromes Vitamin B12 in responsive syndromes Anticlotting agents... 

Accumulation of homocysteine and reduced transsulfation of various compounds leads to abnormalities in connective tissue structures that cause altered blood vessel wall structure, loss of skeletal bone density (osteoporosis), dislocated optic lens (ectopia lentis), and increased risk of blood clots. 

Ectopia lentis (with downward dislocation) is a characteristic finding of this disease, which may also lead to cardiovascular manifestations and mental retardation. 

The answer is A. The constellation of symptoms exhibited by this patient is characteristic of homocystinuria. The impairment of her cognitive function could be attributed to many conditions, but the key findings are ectopia lentis with downward lens dislocation and osteoporosis in a female of this age. Homocystinuria is produced by inherited deficiency of one of the enzymes in the pathway of Met conversion to Cys. The most common form is cystathionine P-synthase deficiency, which results in accumulation of all upstream components of the pathway, including homocysteine, which is responsible for the toxic effects, and Met, which becomes elevated in the blood. Cystathionine and cysteine, which are both downstream of the block in the pathway caused by cystathionine P Synthase deficiency, would be decreased. Metabolic pathways for lactate and urea are not involved in this disease mechanism. 

Characteristic ocuiar features of Marfan syndrome, such as ectopia lentis (upward iens disiocation instead of downward disiocation as in homocystinuria) and myopia, arise from the effects of defective fibriiiin in the eiastic fibers of the iens. 

The homocystinurias are a group of disorders involving defects in the metabolism of homocysteine. The diseases are inherited as autosomal recessive illnesses, characterized by high plasma and urinary levels of homocysteine and methionine and low levels of cysteine. The most common cause of homocystinuria is a defect in the enzyme cystathionine /3-synthase, which converts homocysteine to cystathionine (Figure 20.21). Individuals who are homozygous for cystathionine [3-synthase deficiency exhibit ectopia lentis (displace ment of the lens of the eye), skeletal abnormalities, premature arte rial disease, osteoporosis, and mental retardation. Patients can be responsive or non-responsive to oral administration of pyridoxine (vitamin B6)—a cofactor of cystathionine [3-synthase. Bg-responsive patients usually have a milder and later onset of clinical symptoms compared with B6-non-responsive patients. Treatment includes restriction of methionine intake and supplementation with vitamins Bg, B, and folate. 

Ectopia lentis may occur as part of the syndrome of homocystinuria and Marfen s syndrome. Dilate these patients with caution with a weak mydriatic due to the risk of angle closure. Place the patient in a supine position during the fundus assessment.After the examination, confirm that the crystalline lens remains behind the iris and then mydriasis can be reversed by using a miotic, such as 0.5% dapiprazole. 

Deficiencies of methionine adenosyltransferase, cystathionine 8-synthase, and cystathionine )/-lyase have been described. The first leads to hypermethioninemia but no other clinical abnormality. The second leads to hypermethioninemia, hyperhomocysteinemia, and homo-cystinuria. The disorder is transmitted as an autosomal recessive trait. Its clinical manifestations may include skeletal abnormalities, mental retardation, ectopia lentis (lens dislocation), malar flush, and susceptibility to arterial and venous thromboembolism. Some patients show reduction in plasma methionine and homocysteine concentrations and in urinary homocysteine excretion after large doses of pyridoxine. Homocystinuria can also result from a deficiency of cobalamin (vitamin B12) or folate metabolism. The third, an autosomal recessive trait, leads to cystathioninuria and no other characteristic clinical abnormality. 

Patients with this most common form of homocystinuria show evidence of involvement of the eye, the skeletal system, the vascular system, and the brain. It is important to note that individuals with cystathionine P-synthase deficiency do not manifest any abnormalities at birth and that the affected pregnancies are uneventful. Thus, this disorder, as opposed to the more rare remethylation defect variants of homocystinuria (described below), is not usually part of the differential diagnosis of the catastrophically ill newborn. Ectopia lentis does not usually appear before the age of 3 years, but most patients have some manifestations by the age of 10. The initial recognition of ocular abnormahties may be an observation by parent or physician that the iris shakes, when the head is moved rapidly. While a predilection for... 

Between 50 and 60% show mental retardation varying in degree from mild to profound [36]. Epileptic seizures are common in the more severely retarded. There is a generalized disorder of connective tissue causing ectopia lentis, arachno-dactyly, unduly tall stature (patients resemble those with Marfan s syndrome) and, probably, some abnorm2dity of the walls of blood vessels. There is also a marked tendency to develop thromboses and, by some tests, the platelets are unusually sticky. These thromboses may lead to pulmonary embolism, the commonest cause of death, or may occur in coronary or cerebral vessels many homocystinurics die in childhood from one of these causes. 

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