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MD Consult: Books: Goldman: Cecil Medicine: Chapter 228 – HOMOCYSTINURIA AND HYPERHOMOCYSTEINEMIA

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier


Bruce A. Barshop


Homocysteine is a nonprotein amino acid and an intermediate in methionine metabolism that arises when methionine (through S-adenosylmethionine) acts as a donor in methylation reactions ( Fig. 228-1 ). The fate of homocysteine is either remethylation to methionine or transsulfuration (through cystathionine) of serine to cysteine. Homocystinuria results from the accumulation of homocysteine because of a defect in either transsulfuration or remethylation. The classic finding of the disulfide homocystine in urine gives this class of disorders its common name. The free sulfhydryl form, homocysteine, is present in lower amounts in blood. The term total homocyst(e)ine is used to describe the mix of homocysteine and homocystine present as sulfhydryl and disulfide, although here the term total homocysteine is considered equivalent. The defining finding in blood is hyperhomocysteinemia, which is distributed about 10% as free homocysteine and 90% as protein-bound and soluble disulfides (e.g., homocystine, cysteine-SS-homocysteine).

FIGURE 228-1  Pathways of homocysteine metabolism. The systems of transmethylation, remethylation, and transsulfuration are marked. Steps discussed are numbered: (1) cystathionine β-synthase; (2) methylenetetrahydrofolate reductase; (3) methionine synthase and methyltransferase reductase; (4) systems of cobalamin absorption, distribution, and reduction. B6 = pyridoxine; B12 = cyanocobalamin/hydroxocobalamin; MeCbl = methylcobalamin; THF = tetrahydrofolate.



The classic form of homocystinuria is cystathionine β-synthase deficiency, which results in decreased transsulfuration and hypermethioninemic hyperhomocyst(e)inemia. Homocystinuria may also result from defective remethylation, as in a deficiency of methylenetetrahydrofolate reductase, or from a disorder in delivery, generation, or utilization of the methylcobalamin cofactor of methionine synthase. Defects of remethylation give rise to hyperhomocysteinemia with normal or low methionine. All of these disorders are inherited in an autosomal recessive manner ( Table 228-1 ).

TABLE 228-1   — 

Functional Defect Common Name Enzyme Defect Chromosome Locus
Transsulfuration “Classic” homocystinuria Cystathionine β-synthase 22q22.3
Remethylation Folate-dependent homocystinuria Methylenetetrahydrofolate reductase 1p36.3
Cbl G Methionine synthase (methyltransferase) 1q43
Cbl E Methyltransferase reductase 5p15.2-p15.3
Cobalamin transport TC-II Transcobalamin II 22q11-q13.1
Cbl F Lysosomal B12 translocase
Cobalamin reductase Cbl C Unknown 1p34.1
Cbl D Unknown
Incidence and Prevalence

Minimum estimates of the incidence of cystathionine β-synthase deficiency by newborn screening programs have ranged from 1 in 60,000 to 1 in 300,000 live births, varying with the population and method. Estimates of its incidence in Europe have been in the range of 1 in 40,000, which corresponds to a carrier (heterozygote) frequency of about 1%, but studies screening for known mutations suggest that the prevalence may be more than twice that rate. The incidence of severe homocysteine remethylation defects appears to be less than 1 in 500,000. In contrast, partial remethylation deficiencies seem to have a much greater incidence, which may be clinically relevant in predisposing individuals to thrombotic disorders, because evidence of deficiency has been reported in 15 to 30% in some series of patients with vaso-occlusive disease.


Homocysteine has effects on vascular endothelium, platelets, and coagulation factors that predispose to thrombosis. Endothelial dysfunction can be elicited in normal patients when hyperhomocysteinemia is induced transiently, and there is evidence of inflammatory mediator activation in experimental systems related to the pro-oxidant effects of homocysteine, but there remains some controversy about the relevance of these factors in humans. Modification of connective tissue proteins may cause the skeletal and ocular manifestations associated with homocystinuria. These effects are probably related to fibrillin, which is a component of the matrix of periosteum and perichondrium, the major component of the zonular fibers of the ocular lens, and a protein singularly rich in cysteine. Fibrillin structure is affected by linking of homocysteine to cysteine; as a result, some features of homocystinuria are also associated with fibrillin mutations (Marfan syndrome). The neurologic effects of homocysteine may be due predominantly to agonism of the N-methyl-d-aspartate receptor by homocysteic acid, although cerebral vascular effects may contribute as well.

Clinical Manifestations

Cystathionine β-synthase deficiency is pleiotropic, with effects in the eye, skeleton, and central nervous and vascular systems ( Table 228-2 ). The eye and skeletal system changes resemble those in Marfan syndrome. Nontraumatic dislocation of the ocular lens can be an initial finding. Some abnormality of the skeletal system develops in almost all untreated patients. Between a third and three fourths of untreated patients have mild or moderate mental retardation, and cerebrovascular thrombosis may play a role in the neurologic picture. Affected patients have a lifelong danger of thromboembolic phenomena, which are the major cause of mortality in those with untreated disease. Arterial and venous occlusion, in small or large vessels, may occur at any time in life, including infancy. Treatment with pyridoxine, the cofactor of the enzyme, may be effective in nearly half of these patients, particularly those with relatively high residual activity and spared amounts of immunologically detectable enzyme. Blood total homocysteine concentrations may be intermediately elevated in heterozygotes, especially after a methionine load, and heterozygotes are at some increased risk for vaso-occlusive events. Although increased vascular complications have not been formally demonstrated in outcome studies of obligate heterozygotes, a considerable number of studies show a highly disproportionate fraction of patients with various vaso-occlusive complications who manifest either total blood homocysteine concentrations or fibroblast cystathionine β-synthase activities that fall in the range observed for heterozygotes.

TABLE 228-2   — 

  Biochemical Features Clinical Features
Class Hcys met MMA System Signs
Cystathionine β-synthase deficiency Ocular Ectopia lentis, myopia, glaucoma, optic atrophy, retinal detachment
Skeletal Elongated and thinned bones, arachnodactyly, genu valgum, pectus malformation, scoliosis
Vascular Thromboembolic events (arterial or venous)
Neurologic Mental retardation often in untreated cases, cerebrovascular thromboses, seizures
  Psychiatric disorders, personality disorder
Methylenetetrahydrofolate reductase deficiency Ocular Ectopia lentis
Vascular Thromboses
Neurologic Variable—psychiatric to severe neurologic
Transcobalamin II deficiency -/↑ -/↓ +/- Hematologic Pancytopenia, macrocytosis
Pansystemic MMA, ketoacidosis, stomatitis
Cbl F -/↑ ? +/- Pansystemic MMA, macrocytosis, stomatitis
Cbl C, Cbl D -/↑ -/↓ + Hematologic Pancytopenia
Neurologic Mental retardation
Cbl E, Cbl G -/↓ Vascular Vaso-occlusive phenomena
        Neurologic Spasticity, dystonia

Cbl = cobalamin; Hcys = homocyst(e)inemia/homocystinuria; met = plasma methionine; MMA = methylmalonic acidemia.

Methylenetetrahydrofolate reductase deficiency has been described in a limited number of patients, and the spectrum of manifestations includes neurologic symptoms, thrombosis, and lens dislocation, but without conspicuous skeletal changes. Partial deficiencies and thermolabile variants have been observed in otherwise normal subjects who have premature vaso-occlusive disorders. Polymorphisms are also found in the methylenetetrahydrofolate reductase gene in association with spinal closure defects, a class of disease that has been known to be influenced by folate. Cobalamin metabolic disorders generally occur in early childhood and are characterized by neurologic symptoms, megaloblastic anemia, and in some cases, methylmalonic acidemia.


Qualitative detection using sodium nitroprusside led to the recognition of homocystinuria early in the history of biochemical genetics, but it is neither specific nor sensitive. Assay of plasma amino acids by routine methods may not reveal homocysteine as a result of the high degree of protein binding. Because of lower protein concentrations, routine amino acid analysis of urine is more successful, hence the common name homocystinuria. The preferred diagnostic method is total homocysteine, which is measured in plasma treated with a reducing agent to release bound homocysteine before deproteinization. Plasma amino acids will indicate a transsulfuration or remethylation defect, depending on the presence or absence of hypermethioninemia (see Table 228-2 ). The clinical diagnosis of remethylation defects is facilitated by detection of urine methylmalonate and blood vitamin B12 and folate. The normal range of total homocysteine in blood extends up to around 15 μmol/L and may be more than 50% higher 2 to 4 hours after an oral methionine load. A standard methionine load (100 mg/kg) may identify individuals with partial defects, which could increase the susceptibility to vascular disease.


Cystathionine β-synthase deficiency is responsive to administration of the cofactor pyridoxine in about 50% of cases. Doses of 100 to 500 mg/day have been used successfully. Higher doses of pyridoxine should be given cautiously because of the risk for peripheral neuropathy. Responsiveness is documented by the elimination of free homocysteine in blood and urine as pyridoxine is added, but measurement of total homocysteine demonstrates that the effect is generally far less than complete. Betaine (N,N,N-trimethylglycine, Cystadane) is effective in reducing homocysteine through an alternative remethylation step. It is particularly important in pyridoxine-unresponsive cases but may also be used as an adjunct in responsive patients. Betaine is generally given at 6 g/day in divided doses, but considerably higher doses have been used. The dose used in children is generally 100 to 250 mg/kg. There have been two reports of cerebral edema associated with betaine, presumably caused by unusually high levels of methionine or betaine. In the absence of pyridoxine responsiveness, special diets are adopted to restrict methionine and supplement cysteine. Folic acid may be effective in remethylation defects, and it is also generally used as a supplement (10 to 20 mg/day) in all forms of homocystinuria. Vitamin B12 preparations may be life-saving in disorders of cobalamin metabolism, although their effectiveness in the most common forms of cobalamin C or D defects is generally far from complete. Initial doses are usually 1000 μg/day, and hydroxocobalamin may be more effective than cyanocobalamin. It is prudent to adopt measures to decrease thrombosis, such as using low-dose aspirin or dipyridamole and avoiding smoking and birth control pills. Nitrous oxide may also be relatively contraindicated inasmuch as it can inhibit methionine synthase. Surgery poses serious risks but can be performed safely as long as attention is paid to hydration and coagulation status.


In cases of cystathionine β-synthase deficiency, pyridoxine responsiveness generally correlates with higher residual activity, and the prognosis is significantly better than that for unresponsive cases, with or without treatment. Skeletal, ocular, vascular, and neurologic risks are all reduced with successful treatment. Without early institution of treatment, the median IQ in a large outcome study was 57 for unresponsive patients and 78 for responsive patients. With early treatment, pyridoxine-unresponsive patients have a nearly normal median IQ. With treatment in responsive patients, the prognosis for intellectual development is very good, but significant increases in total homocysteine still generally persist, and some increased risk for vascular complications probably does remain.

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