The metabolism of Hcy is impaired in the homocystinurias, a group of disorders. These autosomal-recessive diseases are characterized by high levels of Hcy in the urine, high levels of Hcy and methionine in the plasma, and low levels of cysteine in the plasma. The primary cause of homocystinuria is a deficiency in the enzyme cystathionine β-synthase, which converts Hcy to cystathionine. Individuals with cystathionine β-synthase deficiency, who are homozygous for the defect, experience dislocation of the lens (ectopia lentis), skeletal abnormalities (long limbs and fingers), intellectual disability, and an increased risk of blood clots (thrombi). Thrombosis is the main cause of premature death in these individuals. Treatment involves limiting methionine intake and supplementing with vitamin B12 and folate. Some patients also respond to oral administration of pyridoxine (vitamin B6), which is converted to pyridoxal phosphate, the coenzyme of cystathionine β-synthase. These patients typically have milder symptoms that appear later compared to those who do not respond to B6. [Note: Elevated Hcy levels can also result from deficiencies in methylcobalamin or N5,N10-MTHF reductase (MTHFR).]

Alkaptonuria is an uncommon organic aciduria caused by a deficiency in homogentisic acid oxidase, leading to the accumulation of homogentisic acid (HA). HA is an intermediate in the breakdown of tyrosine. The condition is characterized by three main symptoms: elevated levels of HA in the urine (homogentisic aciduria), early onset of arthritis in the large joints, and deposition of black pigment (ochronosis) in cartilage and collagenous tissue. In infants, the disease may be indicated by dark staining of diapers, but symptoms typically do not manifest until around the age of 40. Treatment involves restricting dietary intake of phenylalanine and tyrosine to reduce HA levels. Although alkaptonuria is not life-threatening, the associated arthritis can be severely debilitating. [Note: Deficiencies in fumarylacetoacetate hydrolase, the final enzyme in tyrosine metabolism, lead to tyrosinemia type I and a distinct odor similar to cabbage in the urine.]
The homocystinurias are a group of disorders involving defects in the metabolism of Hcy. These autosomal-recessive diseases are characterized by high urinary levels of Hcy, high plasma levels of Hcy and methionine, and low plasma levels of cysteine. The most common cause of homocystinuria is a defect in the enzyme cystathionine β-synthase, which converts Hcy to cystathionine (Fig. 20.22). Individuals homozygous for cystathionine β-synthase deficiency exhibit dislocation of the lens (ectopia lentis), skeletal anomalies (long limbs and fingers), intellectual disability, and an increased risk for developing thrombi (blood clots). Thrombosis is the major cause of early death in these individuals. Treatment includes restriction of methionine and supplementation with vitamin B12 and folate. Additionally, some patients are responsive to oral administration of pyridoxine (vitamin B6), which is converted to pyridoxal phosphate, the coenzyme of cystathionine β-synthase. These patients usually have a milder and later onset of clinical symptoms compared with B6nonresponsive patients. [Note: Deficiencies in methylcobalamin (see Fig.
20.8) or N5,N10-MTHF reductase ([MTHFR]; see Fig. 20.12) also result in elevated Hcy.]
E. Alkaptonuria
Alkaptonuria is a rare organic aciduria involving a deficiency in homogentisic acid oxidase, resulting in the accumulation of homogentisic acid (HA), an intermediate in the degradative pathway of tyrosine (see Fig.
20.15 on p. 269). The condition has three characteristic symptoms: homogentisic aciduria (the urine contains elevated levels of HA, which is oxidized to a dark pigment on standing, as shown in Fig. 20.23A), early onset of arthritis in the large joints, and deposition of black pigment (ochronosis) in cartilage and collagenous tissue (see Fig. 20.23B). Dark staining of diapers can indicate the disease in infants, but usually no symptoms are present until about age 40 years. Treatment includes dietary restriction of phenylalanine and tyrosine to reduce HA levels. Although alkaptonuria is not life threatening, the associated arthritis may be severely crippling. [Note: Deficiencies in fumarylacetoacetate hydrolase, the terminal enzyme of tyrosine metabolism, result in tyrosinemia type I (see Fig. 20.15) and a characteristic cabbage-like odor to urine.]
VII. CHAPTER SUMMARY