INTRODUCTION

Background: Homocystinuria is an inherited autosomal recessive defect in methionine metabolism that is caused by a deficiency in cystathionine synthase. This defect leads to a multisystemic disorder of the connective tissue, muscles, CNS, and cardiovascular system. Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of homocysteine in the serum and an increased excretion of homocysteine in the urine.

In 1960, the first case of homocystinuria was reported from Northern Ireland. The patient was initially described as an unusual case of Marfan syndrome with renal abnormalities at the age of 7 years. He had recovered from acute glomerulonephritis at age 6 years and was found to be hypertensive the following year. The patient was mentally slow and thin and had fair hair, pale skin, and flushed cheeks. He had arachnodactyly, dolichostenomelia, pes cavus, a high arched palate, and bilaterally dislocated lenses. At age 10 years, the patient's urine was found to contain a large quantity of homocysteine; urinalysis results for the nitroprusside cyanide test were positive. The boy's left eye was enucleated because of a staphylococcal infection that occurred after acute pupillary-block glaucoma developed. His right lens became dislocated into the anterior chamber and had to be removed.

The patient's blood pressure readings normalized after his left kidney was removed when he was aged 13 years. Thick-walled internal arteries were noted at histologic examination. When pyridoxine supplementation was initiated at age 18 years, the patient's plasma homocysteine levels decreased below the reference range. Daily folic acid supplementation was added 1 year later because his plasma folate level was low. At the age of 20 years, the patient had a perforated duodenal ulcer. Chest pain occurred at age 27 years and recurred at age 34 years. The chest pain was considered to be angina and was successfully treated. At the age of 50 years, the patient's plasma homocysteine levels still remained low. The patient developed acute gout, which responded to indomethacin therapy.

Pathophysiology: Homocysteine is metabolized by means of 2 pathways: remethylation and transsulfuration.

The remethylation pathway comprises 2 intersecting biochemical pathways and results in the transfer of a methyl group (CH₃) to homocysteine from methylcobalamin, which receives its methyl group from S-adenosylmethionine (SAM); from 5-methyltetrahydrofolate, an active form of folic acid; or from betaine (trimethylglycine). Methionine can then be used to produce SAM, the body's universal methyl donor, which participates in several other key metabolic pathways, including the methylation of DNA and myelin.

The transsulfuration pathway of methionine/homocysteine degradation produces the amino acids cysteine and taurine. This pathway is dependent on the adequate intake of vitamin B-6 and the hepatic conversion of vitamin B-6 into its active form, pyridoxal-5'-phosphate (P5P). The amino acid serine, which is a downline metabolite generated from betaine via the homocysteine remethylation pathway is another necessary step.

Folate and vitamin B-12 are required for the remethylation of homocysteine to methionine. Findings from experimental studies have indicated that thyroid hormones affect folate metabolism. The observation that methylenetetrahydrofolate reductase is increased in hyperthyroidism and decreased in hypothyroidism may be relevant to the relationship between plasma homocysteine levels and the patient's thyroid status.

Women tend to have lower basal levels of homocysteine than do men, and neither contraceptives nor hormone replacement therapy seems to significantly alter the levels. Homocysteine concentrations are higher in postmenopausal women than in premenopausal women.

On the basis of the type of homocystinuria, the following 3 nosologic units are distinguished: (1) Homocystinuria can be caused by the deficiency of cystathionine synthase. This is the classic form. The gene for this deficiency is located on chromosomal band 21q22.3. This unit includes the following forms: vitamin B-6 sensitivity (1.5% enzymatic activity), vitamin B-6 resistance (0% enzymatic activity), an intermediate variant, and a benign variant. (2) Homocystinuria can be caused by insufficient vitamin B-12 synthesis resulting from a defect in the remethylation of homocysteine to methionine: Methylmalonic aciduria is present. (3) Homocystinuria can be caused by a deficiency in methylenetetrahydrofolate reductase. The methionine level is in the reference range.

Urine methionine and homocysteine levels are elevated because of deficient levels of cystathionine-beta-synthase. In addition to this, at least 7 causes of homocystinuria are known. (1) defect in vitamin B-12 metabolism, (2) deficiency in N-5,10-methylenetetrahydrofolate reductase, (3) selective intestinal malabsorption of vitamin B-12, (4) homocystinuria responsive to vitamin B-12 responsive homocystinuria with chronic blood loss (cbl) type E, (5) methylcobalamin deficiency with cbl type G, (6) type 2 vitamin B-12 metabolic defect, and (7) transcobalamin II deficiency.

The basis of the disease is a defect of the gene coding for L-serine dehydratase cystathionine synthase, which converts homocysteine and serine into cystathionine. Deficient activity of this enzyme has been demonstrated in liver extracts, in brain tissue, and in cultured skin fibroblasts and lymphocytes. The deficiency leads to an accumulation of homocysteine and methionine and to its conversion into homocysteine, which is excreted in the urine (Legal test results are positive). Alternatively, methionine is reformed and detectable in appreciable amounts in the urine and serum. The accumulation of homocysteine leads to damage of the collagen and elastic fibers. The binding of homocysteine to lysine residues results in the formation of thiazine bonds.

DL-homocysteine inhibits the production of tyrosinase, which is the major pigment enzyme. Increased concentrations of the methionine metabolite are toxic to the nervous system. Histologic analysis of brain tissue specimens from patients with homocystinuria reveals local foci of gliosis and necrosis.

Mudd et al studied hybrid cells of human fibroblasts with normal cystathionine beta-synthase activity and hamster cells without enzyme activity and found that enzyme activity was cosegregated with chromosome 21. Two other enzymes involved in sulfur amino acid metabolism have been mapped: 5-methyltetrahydrofolate and L-homocysteine S-methyltransferase are mapped to chromosome 1 and cystathionase is mapped to chromosome 16. In cases of genetic deletion and partial trisomy, the levels of activity are consistent with the locus of cystathionine-beta-synthase (CBS) between chromosomal bands 21q22.1 and 21q21. As reported in the study of fibroblasts, 3 types of cystathionine synthetase deficiency exist; these include a type with reduced activity and normal affinity for P5P and a type with reduced activity and reduced affinity for the cofactor.

The human CBS gene spans more than 30 kilobases and contains 19 exons. Three different 5' untranslated regions exist in the gene.

Frequency:

• In the US: Homocystinuria is rare.

• Internationally: Homocystinuria rarely occurs. The worldwide frequency is reported to be 1 case per 344,000 population.

  In Ireland, the frequency is higher, specifically 1 case per 65,000 population based on newborn screening and clinically detected cases. A surprisingly high prevalence of the CBS 833T-C mutation was detected among newborns who did not carry the 844ins68 variant, which is known to neutralize the 833T-CV mutation. This finding led some authors to suggest that the incidence of homocystinuria due to homozygosity for the mutation may be at least 1 case per 20,500 live births in Denmark.

Mortality/Morbidity:

• The life expectancy of patients with homocystinuria is reduced.

• Almost one fourth of patients die as a result of thrombotic complications (eg, heart attack) before they are aged 30 years.

Sex: The disease is more common in males than in females.

Age: This condition is congenital.

CLINICAL

History:

• Neurologic features

• An infant with homocystinuria is usually healthy, although thromboembolic complications of the CNS and psychomotor delay may occur during the first year of life.

• A developmental delay is noted when patients are aged 2-3 years.

• Psychiatric symptoms are also described in approximately one half of the patients with homocystinuria.

• Pyramidal symptoms, including muscle weakness due to an insult to the innervation of the pyramidal motor tract neurons, are occasionally observed in areas such as the leg.

• Skeletal and muscular features

• The characteristic long thin extremities and arachnodactyly may not appear until late in childhood or during adolescence.

• In contrast, osteoporosis, especially that of the spine, may have already been present for some time.

• Ophthalmologic features

• Severe myopia is the first sign of ectopia lentis and may precede lens dislocation by several months to a year or even longer.

• Once established, ectopia lentis progresses, even when good biochemical control is maintained.

• Vascular features

• Thromboembolic events, such as cerebrovascular occlusions or pulmonary emboli, usually do not occur until adulthood but are reported in childhood and infancy.

• Vascular occlusive disease is an important and serious feature.

• Other features

• Homocystinuria produces high concentrations of amino acids that are competitive inhibitors of tyrosinase.

• Accordingly, homocystinuria is associated with pale and pink skin. Occasionally, patients have malar rashes, fine fragile hair, and livedo reticularis.

Physical: Marfan syndrome is the primary differential diagnosis. Clinical features of homocystinuria, such as ectopia lentis, dolichocephalia, and chest and spinal deformities, are similar to the features found in patients with Marfan syndrome, although the cerebral symptoms, the changes in the hair, and the disorders of mental development are absent in patients with Marfan syndrome. Generalized osteoporosis, arterial and venous thrombosis, and mental retardation, which are features of homocystinuria, do not occur in patients with Marfan syndrome. In addition, homocysteine is not detectable in the urine of patients with Marfan syndrome.

Findings in homocystinuria include the following:

• Skin findings

• Buccal skin shows red macules in children, adolescents, and adults, especially those living in warm environments.

• Large pores are evident on the facial skin.

• A livedolike pattern of blood vessels and atrophic, small, cigarette paper–like scars may be observed on the arms and hands.

• Angiomata may develop in some patients.

• DL-homocysteine inhibits tyrosinase, the major pigment enzyme. Hypopigmentation may be reversible in patients with pyridoxine-responsive homocystinuria.

• The hair can have a coarse texture. Hair stained with acridine orange produces orange-red fluorescence, whereas healthy hair produces green fluorescence.

• Hyperhidrosis, dry skin, and acrocyanosis may be present.

• Neurologic findings

• Patients may behave aggressively.

• Intelligence is slightly diminished, but in approximately one third of patients, intelligence is in the normal range.

• Patients' mental capabilities have been reported to be higher in conditions that respond to pyridoxine supplementation than others.

• Muscular hypotonia is characteristic.

• Skeletal and muscular findings

• Signs of Marfan syndrome, such as thin and long extremities, arachnodactylia, kyphoscoliosis, and deformations of the thorax, may be present.

• Osteoporosis, genua valga, pectus carinatum (excavatum), and deformed teeth can be present.

• Inguinal and umbilical hernias are observed.

• Muscular hypotonia is characteristic.

• Spasms may occur.

• Ophthalmologic findings

• Ophthalmologic findings are similar to those in patients with Marfan syndrome.

• Ectopia lentis is an almost universal feature in patients older than 10 years, and it can even be present in newborns.

• Other findings include myopia, iridopathy, cataracts, secondary glaucoma, and degeneratio (amotio) retinae.

• Atrophy of the optic nerve, strabismus, nystagmus, or diminished convergence can occur in some patients.

• Dislocation of the ocular lenses usually occurs in patients aged 4-10 years.

• Vascular findings
  • Vascular changes mainly affect the lower extremities. Fatal arterial and venous thromboses may occur.

  • Hyperhomocystinemia is an independent risk factor for atherosclerotic heart disease.

  • Patients with homocystinuria resulting from a deficiency of cystathionine-beta-synthase have an increased risk of thrombosis when they also have the Leiden mutation for factor V.

  • Homocysteine induces tissue factor procoagulant activity in cultured human endothelial cells.

  • Reduced survival and abnormally rapid turnover of platelets, fibrinogen, and plasminogen have been noted in patients with homocystinuria.

• Other findings
  • A slightly foul odor of the urine is typical.

  • Spontaneous pneumothorax is reported in some adolescents with homocystinuria.

  • Pancreatitis is described as a complication of homocystinuria.

  • Increased homocysteine levels are implicated in a variety of other clinical conditions, including neural tube defects, spontaneous abortion, placental abruption, renal failure, diabetic microangiopathy, and premenstrual syndrome.

DIFFERENTIALS

Thrombophlebitis

Other Problems to be Considered:

Marfan syndrome