HOMOCYSTINURIA

Alternative titles; symbols

CYSTATHIONINE BETA-SYNTHASE DEFICIENCY
CBS DEFICIENCY
CYSTATHIONINE BETA-SYNTHASE, INCLUDED; CBS, INCLUDED
HOMOCYSTINURIA, PYRIDOXINE-RESPONSIVE, INCLUDED
Gene map locus 21q22.3

TEXT

DESCRIPTION

Homocystinuria is a metabolic disorder due to cystathionine beta-synthase (EC 4.2.1.22) deficiency producing increased urinary homocystine and methionine. Major clinical manifestations involve the eyes and the central nervous, skeletal, and vascular systems.


CLINICAL FEATURES

Mudd et al. (1985) compiled data on 629 patients with homocystinuria collected from all parts of the world. Among patients not discovered by newborn screening, mental capabilities were higher in B6-responsive patients (mean IQ, 79) than in B6-nonresponsive patients (mean IQ, 57). Time-to-event curves for other major clinical abnormalities were presented as well. For untreated B6-responsive and B6-nonresponsive patients, these were, respectively: chance of dislocation of lenses by age 10, 55% and 82%; chance of having clinically detected thromboembolic event by age 15, 12% and 27%; chance of radiologic detection of spinal osteoporosis by age 15, 36% and 64% and chance of not surviving to age 30, 4% and 23%. When initiated neonatally, methionine restriction prevented mental retardation, reduced the rate of lens dislocation, and may have reduced the incidence of seizures. Pyridoxine treatment of late-detected B6-responsive patients reduced the rate of occurrence of initial thromboembolic events. Following 586 surgical procedures, 25 postoperative thromboembolic complications occurred, of which 6 were fatal. Few abnormalities were found in the offspring of either male or female patients and the evidence was inconclusive concerning the rate of fetal loss from mothers with untreated homocystinuria. Among patients detected neonatally, only 13% were B6-responsive as compared with 47% among late-detected B6-responders.

In a sibship of 6, Visy et al. (1991) found 3 sibs with homocystinemia and homocystinuria due to this enzyme deficiency. All 3 came to medical attention because of severe recurrent strokes in adulthood, at ages 23, 24, and 20 years. All 3 had mild mental retardation with IQs in the 80s. Although marfanoid habitus, with long limbs and pectus excavatum, was described, there was no ectopia lentis. Two of the sibs died within a year of clinical onset.

(See sulfocysteinuria (272300), another disorder of sulfur metabolism associated with neurologic defect and ectopia lentis.)


Central Nervous System
Homocystinuria was discovered independently by Gerritsen et al. (1962) in Madison, Wisconsin, and by Carson and Neill in Belfast, Northern Ireland. The patients of both groups were studied because of mental retardation.

Abbott et al. (1987) evaluated 63 patients with homocystinuria for psychiatric disturbance, intelligence, evidence of other CNS problems, and responsiveness to vitamin B6. Clinically significant psychiatric disorders were found in 51%. The average IQ was 80; IQ was lower among vitamin B6-nonresponsive patients.

About one-third of homocystinuric subjects have normal intelligence.

Yap et al. (2001) studied mental capabilities of 23 pyridoxine-nonresponsive individuals with cystathionine beta-synthase deficiency with over 339 patient-years of treatment and compared these individuals to those of 10 unaffected sibs (controls). Of the 23 individuals, 19 were diagnosed through newborn screening with early treatment, 2 were late-detected, and 2 were untreated at the time of assessment. Thirteen of the newborn-screened group who were compliant with treatment had no complications, while the remaining 6, who were poorly compliant, developed complications. Good compliance was defined by a lifetime plasma free homocystine median of less than 11 micromole per liter. The newborn-screened good-compliance group (n = 13) with a mean age of 14.4 years (range 4.4-24.9) had a full-scale IQ of 105.8 (range 84-120), while the poorly compliant group (n = 6) with a mean age of 19.9 years (range 13.8 to 25.5) had a mean full-scale IQ of 80.8 (range 40-103). The control group had a mean age of 19.4 years and a mean IQ of 102. The 2 late-detected patients had IQs of 80 and 102 at the age of almost 19 years, while the 2 untreated patients had IQs in the mid-fifties at the age of 22 and 11 years.


Eyes
Ectopia lentis is a nearly constant feature in patients over age 10 years but because of its progressive nature may be absent in younger patients.


Skeleton
Skeletal features suggest Marfan syndrome, but with limitation of joint mobility, and generalized osteoporosis occurs.


Vascular System
Thrombotic lesions of arteries and veins are major features. The observations of Ratnoff (1968) may have a bearing on the mechanism of the thrombotic accidents.

In a study of 203 families, Mudd et al. (1981) could find no evidence of increased frequency of heart attacks or strokes in parents or grandparents of homocystinuric children. The data available were sufficient to exclude a 5-fold increase in cardiovascular risk for homocystinuria heterozygotes and to make very improbable a relative risk of as much as 3-fold.

Mandel et al. (1996) concluded that patients with concurrent homocystinuria due to deficiency of cystathionine beta-synthase have an increased risk of thrombosis when they also have the factor V Leiden mutation (612309.0001). They studied 7 unrelated consanguineous kindreds in which at least 1 member was homozygous for homocystinuria. Thrombosis (venous, arterial, or both) occurred in 6 of 11 patients with homocystinuria (aged 0.2 to 8 years). All 6 also had the factor V Leiden mutation. One patient with prenatally diagnosed homocystinuria who was also heterozygous for factor V Leiden received warfarin therapy from birth and by the age of 18 months had not had thrombosis. Of 4 patients with homocystinuria who did not have factor V Leiden, none had thrombosis (aged 1 to 17 years). Three women who were heterozygous for both homocystinuria and factor V Leiden had recurrent fetal loss and placental infarctions.


Other Features
Cochran et al. (1990) described an unusual presentation of pyridoxine-unresponsive homocystinuria: an intelligent teenaged boy had had asthma from infancy and at age 14 was hospitalized for recurrent left pneumothoraces requiring chest tubes. Soon thereafter he developed a right pneumothorax and subsequently a superior sagittal sinus thrombosis with papilledema and transient right hemiparesis as well as deep venous thromboses. He was found to have a very low level of cystathionine beta-synthase despite normal eye examination, including repeated slit lamp examinations. The homocystinuria did not respond to pyridoxine or folate administration but was reduced by methionine restriction and betaine supplementation. Bass et al. (1997) noted that spontaneous pneumothorax had been reported previously in 2 homocystinuric patients, both with the pyridoxine-refractory form. They described an adolescent boy with the pyridoxine-responsive form who experienced 2 episodes of spontaneous pneumothorax.

Hypopigmentation is a feature of homocystinuria and can be shown to be reversible in patients with pyridoxine-responsive homocystinuria. Instances have been observed in which darkening of newly growing hair is observed after initiation of pyridoxine therapy, creating a clear demarcation between the old, blond and the new, dark hair (Reish et al., 1995). The consistency of the hair also changed from a coarse to a softer texture.

Collins and Brenton (1990) described 2 children in whom pancreatitis was a complication of homocystinuria. One patient presented at age 6 with acute pancreatitis complicated by a pseudocyst requiring drainage on 2 occasions. The second patient presented at 15.5 years of age with severe colicky abdominal pain and a history of recurring abdominal pain for 6 years. Surgery was required for drainage of a large pseudocyst of the lesser sac in which necrotic portions of the body and tail of the pancreas were free floating.


BIOCHEMICAL FEATURES

Methionine as well as homocystine is elevated in the urine due to defective cystathionine beta-synthase. In addition to cystathionine beta-synthase deficiency, at least 7 'causes' of homocystinuria are known. These are (1) defect in vitamin B12 metabolism (277400); (2) deficiency of N(5,10)-methylenetetrahydrofolate reductase (607093); (3) selective intestinal malabsorption of vitamin B12 (261100); (4) vitamin B12-responsive homocystinuria, cbl E type (236270); (5) methylcobalamin deficiency, cbl G type (250940); (6) vitamin B12 metabolic defect, type 2 (277410); and (7) transcobalamin II deficiency (275350).

Spaeth and Barber (1967) described a silver-nitroprusside test which is almost completely specific for homocystine. Wadman et al. (1983) referred to the cyanide-nitroprusside reaction used in the detection of cystinuria and homocystinuria as the Brand reaction.

Uhlendorf and Mudd (1968) found that cultured fibroblasts derived from normal skin, as well as cells in amniotic fluid, have cystathionine synthase activity, although the enzyme is not detectable in intact normal skin. Fibroblasts grown from the skin of homocystinuric persons are deficient in the enzyme.

Harker et al. (1974) showed endothelial desquamation in baboons chronically perfused with homocystine. In human cases of homocystinuria, they demonstrated reduced survival and abnormally rapid turnover of platelets, fibrinogen, and plasminogen. These abnormalities were corrected by clearing the plasma of homocystine with pyridoxine (in B6-responsive cases) or by administration of dipyridamole (in B6-unresponsive cases), but not by heparin anticoagulation. Platelet function was normal in patients and in the animal model.

Di Minno et al. (1993) found evidence for enhanced thromboxane biosynthesis in homocystinuria and concluded from the response to administration of the antioxidant drug probucol that the enhanced thromboxane biosynthesis was dependent in part on probucol-sensitive mechanisms. High urinary excretion of 11-dehydro-TXB2, a major enzymatic derivative of TXA2, was observed in all 11 homocystinuric patients. The elevated thromboxane biosynthesis was thought to reflect, at least in part, in vivo platelet activation.

Fryer et al. (1993) demonstrated that homocysteine can induce tissue factor procoagulant activity in cultured human endothelial cells.

Reish et al. (1995) demonstrated that DL-homocysteine inhibits tyrosinase (TYR; see 606933), the major pigment enzyme. The activity of tyrosinase extracted from pigmented human melanoma cells that were grown in the presence of homocysteine was reduced in comparison to that extracted from cells grown without homocysteine. Copper sulfate restored homocyst(e)ine-inhibited tyrosinase activity when added to the culture cell medium. The results suggested that the probable mechanism of the inhibition is the interaction of homocyst(e)ine with copper at the active site of tyrosinase.


PATHOGENESIS

Reviewing the nature of the ocular zonule, Streeten (1982) pointed out that the zonular fibers are composed of glycoprotein with a high concentration of cysteine, which undoubtedly explains their susceptibility to abnormal formation in diseases of sulfur metabolism.

McKusick (1966) suggested that excess homocysteine may interfere with the normal synthesis of collagen crosslinks, thus accounting for the development of osteoporosis. Lubec et al. (1996) studied collagen synthesis and crosslinking by noninvasive tests in 10 patients with homocystinuria. Synthesis of collagen type I and type III was not different from age-matched healthy controls as reflected by comparable plasma levels of C-terminal propeptide of type I procollagen and of plasma levels of N-terminal propeptide of procollagen type III. Collagen type I crosslinks expressed by serum C-terminal telopeptide of collagen type I in the patient group were, however, only about one-third of the values found in the control group. This significant reduction of crosslinks in the patients with homocystinuria did not correlate with serum homocysteine or homocystic acid concentrations. The data supported the disturbed crosslinking hypothesis and indicated that the bone manifestations of homocystinuria are not due to deficient collagen synthesis.

Malinow and Stampfer (1994) reviewed the role of plasma homocysteine in arterial occlusive diseases. (Homocysteine is the sum of the thio-containing amino acid homocysteine and the homocystinyl moiety of the disulfides cysteine-homocysteine, whether free or bound to proteins.) Malinow and Stampfer (1994) used the term hyperhomocysteinemia for above-normal concentrations of plasma/serum homocysteine.

Levy et al. (2002) reported the results of 15 pregnancies in 11 women, 5 of whom were pyridoxine-nonresponsive and 6 of whom were pyridoxine-responsive. Complications of pregnancy included preeclampsia at term in 2 pregnancies and superficial venous thrombosis of the leg in a third pregnancy. One pregnancy was terminated and 2 pregnancies resulted in first-trimester spontaneous abortions. The remaining 12 pregnancies produced liveborn infants with normal or above-normal birth measurements. One offspring had multiple congenital anomalies that included colobomas of the iris and choroids, neural tube defect, and undescended testes. He was also mentally retarded and autistic. A second offspring had Beckwith-Wiedemann syndrome. The remaining 10 offspring were normal at birth and remained normal. There was no relationship between the severity of the biochemical abnormalities or the therapies during pregnancy to either the pregnancy complications or the offspring outcomes. The infrequent occurrences of pregnancy complications, offspring abnormalities, and maternal thromboembolic events in this series suggested that pregnancy and outcome in maternal homocystinuria are usually normal. Nevertheless, Levy et al. (2002) suggested a cautious approach, which would include careful monitoring of these pregnancies with attention to metabolic therapy and possibly anticoagulation.


CBS Deficiency Heterozygotes
See homocysteinemia (603174).

Saudubray (1997) pointed out that heterozygotes for homocystinuria show a dominant-negative effect. Enzyme levels in heterozygotes tend to be 25 to 30% of normal, rather than the expected 50%. This finding may be related to the fact that the enzyme molecule is a homodimer. However, it is likely that enzyme levels have no effect on homocysteine levels since the pathway through cystathionine is not the main pathway for disposition of homocysteine.

Wilcken and Wilcken (1976) studied methionine loading in males under age 50 with angiographic evidence of ischemic heart disease but free of known risk factor. Of 25 such persons, 7 had peak postmethionine concentrations of homocysteine-cysteine elevated in the heterozygous range, whereas only 1 of 22 controls had such an elevation.

Boers et al. (1985) tested for heterozygosity for homocystinuria by pathologic homocysteinemia after methionine loading and cystathionine synthase deficiency in cultured fibroblasts. Heterozygosity was established by these means in 7 of 25 patients with occlusive peripheral vascular disease manifest before age 50 and in 7 of 25 patients with occlusive cerebrovascular disease manifest before age 50 but in none of 25 patients with myocardial infarction manifest before age 50. Testing for heterozygosity, especially in families of homocystinuria patients, may be very valuable as a guide to reduced methionine intake and B6 supplementation as preventive measures (Mudd, 1985).

Falcon et al. (1994) determined the prevalence of hyperhomocysteinemia before and 4 hours after methionine load in 80 patients who had had at least one verified episode of venous thromboembolism before the age of 40 years and in 51 healthy control subjects. According to their criteria, hyperhomocysteinemia was found in 15 patients (18.8%) and in 1 control subject (1.9%). Family history for venous thromboembolism was positive in 7 of the 15 patients. Family studies, performed for 8 kindreds, showed that for more than half of the studied probands the abnormality was inherited.

Kozich et al. (1995) investigated the possibility that the approximately 30% of patients with premature occlusive arterial disease (POAD) with hyperhomocysteinemia are heterozygotes. To test the possibility, they studied cDNA derived from 4 well-characterized patients with POAD, who exhibited hyperhomocysteinemia and reduced CBS activities and compared the results with those in 4 normal controls and 4 obligatory heterozygotes for CBS deficiency. The cDNA from at least 7 of the 8 possible independent POAD alleles encoded catalytically active, stable CBS that exhibited normal response to both S-adenosylmethionine and pyridoxal 5-prime-phosphate. The sequences of the 3-prime untranslated regions of all 7 isolated POAD alleles were identical to the normal, wildtype CBS sequences. The results of the expression studies were confirmed for 1 POAD patient by determining the full-length cDNA sequences for both alleles; these were entirely normal over the length of the cDNA. In contrast, the screening method correctly distinguished mutant from normal alleles in all 4 obligatory heterozygotes studied. Kozich et al. (1995) concluded that CBS mRNAs from POAD patients are free from inactivating mutations, including all 33 previously identified in heterozygous carriers and homocystinuric patients.

Franken et al. (1996) studied homocysteine levels after fasting as well as after methionine load among 96 family members of 21 post-load hyperhomocysteinemic vascular index patients: 6 parents, 27 offspring, 38 sibs, 19 uncles and aunts, and 6 cousins. In 15 of 21 screened families, post-load mild hyperhomocysteinemia was established in at least 1 family member. Fasting and post-load hyperhomocysteinemia were observed in 21% of screened family members and 32% of screened family members, respectively. Franken et al. (1996) concluded that both fasting and post-load hyperhomocysteinemia is inherited in the majority of instances.

Heme may be necessary for binding of pyridoxal 5-prime phosphate to CBS and for correct CBS folding (Kery et al., 1999). Janosik et al. (2001) reported observations suggesting that inability to bind heme may prevent correct folding and subsequent tetramer formation of mutant and, to a lesser extent, normal CBS subunits. They postulated that, as with other genetic defects (Bross et al., 1999), mutant CBS misfolding and aggregation may be the primary defect in a significant proportion of patients with homocystinuria.


POPULATION GENETICS

Homocystinuria has been observed in Japan (Tada et al., 1967) and in persons of many different ethnic extractions living in the United States (Schimke et al., 1965).

Carey et al. (1968) pointed out that 27 cases had been found in Ireland. Kraus (1994) reported that the G307S mutation (236200.0001) in the CBS gene is the most common cause of homocystinuria in patients of Celtic origin. Gallagher et al. (1995) estimated that the G307S mutation accounted for 71% of alleles in Irish homocystinuria patients. Gallagher et al. (1998) identified 3 new CBS mutations in Irish patients. They estimated that more than 40 CBS mutations in homocystinuria in various ethnic groups had been identified. Most of these were missense mutations; however, 7 deletions had been documented, 2 of which were total deletions of exons 11 and 12.

The worldwide frequency of homocystinuria has been reported to be 1 in 344,000, while that in Ireland is much higher at 1 in 65,000, based on newborn screening and cases detected clinically. The national newborn screening program for homocystinuria in Ireland was started in 1971 using the bacterial inhibition assay. Yap and Naughten (1998) reported that a total of 1.58 million newborn infants had been screened over a 25-year period up to 1996. Twenty-five homocystinuria cases were diagnosed, 21 of whom were identified on screening. The remaining 4 cases were missed and presented clinically; 3 of these were breastfed and 1 was pyridoxine responsive. Twenty-four of the 25 patients were nonresponsive to pyridoxine. All but one of the pyridoxine nonresponsive cases were started on a low methionine, cystine-enhanced diet supplemented with pyridoxine, vitamin B12, and folate. The data suggested that ectopia lentis, osteoporosis, mental handicap, and thromboembolic events could be prevented by this regimen. Three patients with relatively high lifetime medians of free homocystine developed increasing myopia, an ocular feature that often precedes ectopia lentis (Burke et al., 1989).

Mudd et al. (1995) found estimates of the frequency of homocystinuria ranging from 1 in 58,000 to 1 in 1,000,000 in countries that systematically screen newborns. Gaustadnes et al. (1999) stated that the I278T mutation (236200.0004), which results from an 833T-C insertion, is geographically widespread. They determined the frequency of this mutation among Danish newborns by screening 500 consecutive Guthrie cards (specimens of infants' blood collected on filter paper). The frequent genetic insertion variant, 844ins68 (see 236200.0004), was simultaneously sought. A surprisingly high prevalence of the 833T-C mutation was detected among newborns who did not carry the 844ins68 variant, which is known to neutralize the 833T-C mutation. This led the authors to suggest that the incidence of homocystinuria due to homozygosity for this mutation may be at least 1 per 20,500 live births in Denmark. The 844ins68 variant was present in 10% of the Danish newborns. This neutral variant was thought to be deleted from mRNA during splicing.

Janosik et al. (2001) reported that during the previous 20 years, CBS deficiency had been detected in the former Czechoslovakia with a calculated frequency of 1 in 349,000. About half of 21 Czech and Slovak patients they studied were not responsive to pyridoxine. Twelve distinct mutations were detected in 30 independent homocystinuric alleles. One-half of the mutated alleles carried either the 833T-C or the IVS11-2A-C mutation (236000.0012); the remaining alleles contained private mutations. The high prevalence of the 833T-C allele, which confers pyridoxine-responsiveness, was not surprising because it is one of the most prevalent pathogenic CBS mutation in whites (Kraus et al., 1999).

Urreizti et al. (2006) reported a high frequency of the T191M mutation (236200.0016) among patients with homocystinuria from the Iberian peninsula and several South American countries. Combined with previously reported studies, the prevalence of T191M among mutant CBS alleles in different countries was 0.75 in Colombia, 0.52 in Spain, 0.33 in Portugal, 0.25 in Venezuela, 0.20 in Argentina, and 0.14 in Brazil. Haplotype analysis suggested a double origin for this mutation. The phenotype was B6-nonresponsive.


DIAGNOSIS


Screening
Peterschmitt et al. (1999) reviewed the results of neonatal screening for homocystinuria over a period of 32 years in New England. For the first 23.5 years of the review, the blood methionine cutoff value was 2 mg per deciliter (134 micromole per liter). Among the 2.2 million infants screened during that period, 8 with homocystinuria were identified, giving a frequency of 1 in 275,000. In 1990, the cutoff value was reduced to 1 mg per deciliter (67 micromole per liter). Among the 1.1 million infants screened in the subsequent 8.5 years, 7 with the disorder were identified, giving a frequency of 1 in 157,000. During the latter period, the specimens were collected from 6 of the 7 infants when they were 2 days of age or less; 5 of the 6 had blood methionine concentrations below 2 mg per deciliter. Use of the reduced cutoff level increased the false-positive rate from 0.006% to 0.03%. Peterschmitt et al. (1999) concluded that a cutoff level for blood methionine of 1 mg per deciliter in neonatal screening tests for homocystinuria should identify affected infants who have only slightly elevated concentrations of methionine and reduce the frequency of false-negative results. They commented, furthermore, that the increased false-positive rate would not represent an undue burden in terms of requests for repeat analysis. Indeed, the false-positive rates were considerably lower than those associated with neonatal screening for other disorders such as congenital adrenal hyperplasia, congenital hypothyroidism, and phenylketonuria.

Guttormsen et al. (2001) concluded that abnormal response of total urinary homocysteine after methionine loading was the most sensitive test and a satisfactory way for studying mild disturbances in homocysteine metabolism.


CLINICAL MANAGEMENT

Carey et al. (1968) suggested that folic acid in pharmacologic doses is therapeutically valuable in this disease. Decrease in urinary excretion of homocystine and increase in methionine was noted during treatment.

Wilcken et al. (1985) concluded that additional benefit can be realized from betaine in B6-responsive patients. Homocysteine that is not metabolized to cystine is remethylated to methionine in reactions that use either N5-methyltetrahydrofolate or betaine (trimethylglycine) as methyl donors.

Harrison et al. (1998) reviewed the management of ophthalmic complications of homocystinuria on the basis of an extraordinarily large experience with 45 patients reviewed retrospectively in Saudi Arabia. Eighty-four surgical procedures were performed on 40 patients; 82 procedures were done under general anesthesia and 2 under local anesthesia. Five patients had only medical treatment. All patients had lens subluxation or dislocation. Mental retardation was present in 29 (64%). Harrison et al. (1998) suggested that surgical treatment should be considered, especially for cases of repeated lens dislocation into the anterior chamber or pupillary block glaucoma.

Gerding (1998) reviewed the ocular manifestations of homocystinuria and described a surgical approach to lens dislocation that allowed minimally invasive removal of the lens, complete preservation of the anterior vitreous cortex, and stable fixation of an artificial intraocular lens.

Several reports indicated a likely role for homocysteine in the pathogenesis of atherosclerosis, including those of Wilcken et al. (1983), Kang et al. (1986), Tsai et al. (1996), and Chao et al. (1999). Schnyder et al. (2001) found that treatment with a combination of folic acid, vitamin B12, and pyridoxine significantly reduced homocysteine levels and decreased the rate of restenosis and the need for revascularization of the target lesion after coronary angioplasty. They proposed that this inexpensive treatment, which has minimal side effects, should be considered as adjunctive therapy for patients undergoing coronary angioplasty. The benefit in relation to the vascular disease of homocystinuria would be dependent on the responsiveness of the particular mutation to this form of therapy.

Treatment of B6-nonresponsive patients centers on lowering homocysteine and its disulfide derivatives by adherence to a methionine-restricted diet. However, lifelong dietary control is difficult. Betaine supplementation is used extensively in CBS-deficient patients to lower plasma disulfide derivatives. With betaine therapy, methionine levels increase over baseline, but usually remain at levels that are not associated with adverse affects. Yaghmai et al. (2002) reported the case of a child with B6-nonresponsive CBS deficiency and dietary noncompliance whose methionine reached very high levels on betaine and who subsequently developed massive cerebral edema without evidence of thrombosis. They concluded that the cerebral edema was most likely precipitated by the betaine therapy, although the exact mechanism was uncertain. This case cautioned that methionine levels should be monitored in CBS-deficient patients on betaine and that betaine should be considered as an adjunct, not an alternative, to dietary control.

Pullin et al. (2002) investigated the endothelial effect of acute (2 g single dose) and chronic (1 g/day for 6 months) administration of oral vitamin C in 5 patients with homocystinuria (mean age 26 years, 1 male) and 5 age- and sex-matched controls. Brachial artery endothelium-dependent flow-mediated dilatation and endothelium-independent responses to nitroglycerin were measured using high-resolution ultrasonic vessel wall-tracking. At baseline, plasma total homocysteine was 100.8 plus or minus 61.6 and 9.2 plus or minus 1.9 micromol/L in the patient and control groups, respectively. Flow-mediated dilatation responses were impaired in the patient group (20 plus or minus 40 micro m) compared with the controls (116 plus or minus 30 micro m). With vitamin C administration, flow-mediated dilatation responses in the patient group improved both acutely and chronically at 2 weeks and at 6 months. Flow-mediated dilatation responses in the control group were unaltered. Within both groups, neither the vascular response to nitroglycerin nor plasma homocysteine was altered. Pullin et al. (2002) concluded that vitamin C ameliorates endothelial dysfunction in patients with homocystinuria, independent of changes in homocysteine concentration, and should therefore be considered as an additional adjunct to therapy to reduce the potential long-term risk of atherothrombotic disease.


GENE FUNCTION

The CBS gene on chromosome 21 is overexpressed in patients with trisomy 21 (190685). Pogribna et al. (2001) evaluated homocysteine metabolism in Down syndrome and sought to determine whether the supplementation of trisomy 21 lymphoblasts in vitro with selected nutrients would shift the genetically induced metabolic imbalance. They found that the increased activity of CBS in Down syndrome significantly alters homocysteine metabolism as such that the folate-dependent resynthesis of methionine is compromised. The decreased availability of homocysteine promotes the well-established 'folate trap' creating a functional folate deficiency that may contribute to the metabolic pathology of this complex genetic disorder.


MAPPING

Studying somatic cell hybrids between human fibroblasts with normal cystathionine beta-synthase activity and hamster cells without this enzyme activity, Skovby et al. (1984) found that enzyme activity cosegregated with chromosome 21. In a useful control study using homocystinuric fibroblasts in the creation of the hybrids, no enzyme activity was found. Two other enzymes of sulfur amino acid metabolism have been mapped: 5-methyltetrahydrofolate:L-homocysteine S-methyltransferase (156570) to chromosome 1 and cystathionase (219500) to chromosome 16. Chadefaux et al. (1985) demonstrated a dosage effect for CBS enzymatic activity in fibroblasts from patients trisomic for chromosome 21, and in cases of deletion and partial trisomy found levels of activity consistent with location of the CBS locus between 21q22.1 and 21q21. By in situ hybridization, Munke et al. (1985) assigned the CBS locus to 21q22. Using a rat cDNA probe for in situ hybridization to structurally rearranged chromosomes 21, Munke et al. (1988) assigned CBS to the subtelomeric region of band 21q22.3. The homologous locus in the mouse was mapped to the proximal half of chromosome 17 by Southern analysis of hamster-mouse somatic cell hybrid DNA.

Stubbs et al. (1990) demonstrated that the murine equivalents of the CBS and CRYA1 (123580) genes are very closely situated on mouse chromosome 17 in a segment not larger than 130 kb. Most of the genes concentrated in band 21q22, which may be relevant to the phenotype of Down syndrome, are located on mouse chromosome 16 or mouse chromosome 10. The close physical linkage of the mouse equivalents of CBS and CRYA1, combined with data that localize closely flanking mouse markers to human chromosome 6, suggest that the human 21q22/mouse chromosome 17 conserved segment is of limited physical size and contains a small number of Down syndrome-related genes. Avramopoulos et al. (1993) used single-strand conformation polymorphism (SSCP) to detect DNA polymorphisms in the 3-prime untranslated region of the CBS gene. Using one of these for linkage studies in CEPH families, they placed the CBS gene on human chromosome 21.


MOLECULAR GENETICS

Chasse et al. (1997) reported that the human CBS gene spans over 30 kb and consists of 19 exons. There are 3 different 5-prime untranslated regions, including 3 different exons 1: exon 1a, 1b, and 1c. Exons 1a and 1b are 390 bp apart and are linked to exon 2 in cDNAs reported by the authors. Exon 1c, which is linked to exon 5 in another cDNA, is 7 kb from exon 1b. All splice sites conform to the GT/AG rule, including those from exon 1a or 1b to exon 2 and from exon 1c to exon 5. Their results suggested that the mRNAs containing the different exons 1 are under the control of different promoters.

By genomic sequence analysis, Kraus et al. (1998) determined that the CBS gene contains 23 exons, ranging in size from 42 to 299 bp. The 5-prime UTR is formed by 1 of 5 alternatively used exons and 1 invariably present exon. The 3-prime UTR is encoded by exons 16 and 17. Kraus et al. (1998) also described 2 alternatively used GC-rich promoter regions. The authors noted that the CBS locus contains an unusually high number of Alu repeats and suggested that these may predispose the gene to deleterious rearrangements.

From study of fibroblast lines, Fowler et al. (1978) found 3 types of cystathionine synthetase deficiency: one with no residual activity; one with reduced activity and normal affinity for pyridoxal-phosphate; and one with reduced activity and reduced affinity for the cofactor. Chrzanowska et al. (1979) could find no evidence that homocysteic acid has growth hormone-like activity, as previously suggested by others. Skovby et al. (1982) studied fibroblast extracts from 20 patients for immunoreactive cystathionine beta-synthase antigen. Each of 14 mutant extracts with detectable synthase activity had CRM ranging from 5 to 100% of controls; the lower limit of sensitivity for detection of CRM was 1.5% of controls. No correlation was observed between the percent residual activity and the percent CRM. Of 6 mutant extracts without detectable catalytic activity, 3 had no CRM, while 3 had 13%, 17%, and 26% CRM. Great heterogeneity is displayed by these results. With a rabbit antiserum against human hepatic CBS, Skovby et al. (1984) studied the enzyme in cultured fibroblasts derived from 17 homocystinuric patients. In 15 of the 17 lines, the enzyme had subunits indistinguishable in size from the normal (Mr = 63,000). Material from one homocystinuric patient showed 2 mRNA species coding for equal amounts of 2 immunoprecipitable polypeptides: one of normal size and one smaller (Mr = 56,000). The father had 2 mRNAs also; the mother had only normal mRNA. Thus, the patient is a compound heterozygote; one of his mutant alleles codes for a synthase polypeptide missing about 60 amino acids.

Kruger and Cox (1994) showed that the human CBS protein can substitute for the endogenous yeast CBS protein in Saccharomyces cerevisiae. Kruger and Cox (1995) showed that expression of 3 different CBS mutants known to be associated with reduced enzyme activity in humans failed to complement growth in the yeast assay. In addition, they used the yeast CBS assay to identify 8 mutant CBS alleles in cell lines from patients with CBS deficiency. These mutant alleles included 2 previously identified and 5 novel CBS mutations. The results also demonstrated that the yeast CBS assay can detect a large percentage of individuals heterozygous for mutations in CBS. Using the Kruger-Cox yeast system for studying human CBS gene function, Shan and Kruger (1998) reported that a mutation that deletes the carboxy-terminal 145 amino acids of CBS can functionally suppress the phenotype of several CBS mutant alleles found in homocystinurics when expressed in yeast. This C-terminal domain of CBS acts to inhibit enzymatic activity and is in turn regulated by S-adenosylmethionine (AdoMet), a positive effector of CBS.

Shan and Kruger (1998) suggested that most mutations in patients with homocystinuria do not cause dysfunction of the catalytic domain, but rather interfere with the activation of the enzyme. These findings suggested a new drug target to treat homocystinuria and homocysteine-related vascular disease.

Kraus (1994) tabulated 14 mutations that he and his colleagues had demonstrated in homocystinuria. The G307S mutation (236200.0001) is the most common cause of homocystinuria in patients of Celtic origin. Kraus (1994) indicated that even though patients have no measurable CBS activity in their fibroblasts and despite the fact that CBS subunits are undetectable in fibroblast extracts of some of these individuals, many of them are pyridoxine responsive. Examples were cited in which the identical genotype resulted in a different phenotype within the family. In general, G307S is a pyridoxine nonresponsive mutation, while individuals homozygous for the I278T (236200.0004) replacement are responsive to pyridoxine (Hu et al., 1993).

Tsai et al. (1996) stated that at least 17 mutations in the CBS gene had been identified on the basis of clinical homocystinuria. The most prevalent mutations are the G307S (236200.0001) and I278T mutations. Most of these mutations were found by use of RT-PCR of mRNA coding for the CBS enzyme in cultured fibroblasts. The need for cell culture made this method laborious and not suitable for screening large numbers of individuals.

Tsai et al. (1996) used genomic DNA isolated from peripheral blood and primers complementary to intronic sequences to screen for mutations in the CBS gene by simple PCR-based methods. In a group of patients with premature coronary artery disease, they found an unexpectedly high prevalence of a mutation involving a 68-bp insertion in the coding region of exon 8. The mutation did not seem to affect the activity of the CBS enzyme. Screening of controls showed that the mutation also was prevalent in that population. The prevalence was somewhat greater in patients with premature coronary artery disease, although the difference did not reach statistical significance. The mutation had previously been reported by Sebastio et al. (1995). In their control population, Tsai et al. (1996) found that 11.7% of controls were heterozygous carriers. In contrast to the report by Sebastio et al. (1995), which assumed that the 68-bp insertion introduced a premature termination codon and resulted in a nonfunctional CBS enzyme, Tsai et al. (1996) found that the insertion created an alternate splicing site, which eliminated not only the inserted intronic sequences but also the T-to-C mutation of nucleotide 833 (ile278 to thr) associated with this insertion. The net result was the generation of both quantitatively and qualitatively normal mRNA and CBS enzyme. Although the CBS insertion apparently does not result in impairment of enzyme activity or in hyperhomocysteinemia, mRNA data provided evidence that the allele carrying the insertion is fully transcribed (Sperandeo et al., 1996).

Kraus et al. (1999) stated that 92 different disease-associated mutations of the CBS gene had been identified in 310 examined homocystinuric alleles in more than a dozen laboratories around the world. Most of these mutations were missense, and the vast majority of these were private mutations occurring in only 1 or a very small number of families. The 2 most frequently encountered mutations were the pyridoxine-responsive I278T (236200.0004) and the pyridoxine-nonresponsive G307S (236200.0001). Mutations due to deaminations of methylcytosines represented 53% of all point substitutions in the coding region of the CBS gene.

Kluijtmans et al. (1999) investigated the molecular basis of CBS deficiency in 29 Dutch patients from 21 unrelated pedigrees and studied the possibility of a genotype-phenotype relationship with regard to biochemical and clinical expression and response to homocysteine-lowering treatment. Of 10 different mutations detected in the CBS gene, 833T-C (I278T; 236200.0004) was predominant, being present in 23 (55%) of 42 independent alleles. At diagnosis, all 12 homozygotes for this mutation tended to have higher homocysteine levels than the 17 patients with other genotypes, but similar clinical manifestations. During follow-up, I278T homozygotes responded more efficiently to homocysteine-lowering treatment. After 378 patient-years of treatment, only 2 vascular events were recorded; without treatment, at least 30 would have been expected (P less than 0.01).

Shan et al. (2001) used a yeast genetic screen to identify missense mutations in the C-terminal region of CBS that could suppress the most common patient mutation, I278T. Seven suppressor mutations were identified, 4 of which mapped to the CBS domain. When combined in cis with another pathogenic mutation, val168 to met (V168M; 236200.0011), 6 of 7 of the suppressor mutations rescued the yeast phenotype. Enzyme activity analyses indicated that the suppressors restored activity from less than 2% to 17 to 64% of the wildtype levels. Analysis of the suppressor mutations in the absence of the pathogenic mutation showed that 6 of the 7 suppressor alleles had lost enzymatic responsiveness to S-adenosylmethionine. Using homology modeling, the suppressor mutations appeared to map on one face of the CBS domain. The authors concluded that subtle changes to the C-terminus of CBS may restore activity to mutant proteins and provide a rationale for screening for compounds that could activate mutant CBS alleles.

Maclean et al. (2002) described a novel class of 3 missense mutations, including P422L (236200.0013) and S466L (236200.0014), that are located in the noncatalytic C-terminal region of CBS and yield enzymes that are catalytically active but deficient in their response to S-adenosylmethionine (AdoMet). The P422L and S466L mutations were found in patients suffering premature thrombosis and homocystinuric levels of homocysteine but lacking any of the connective tissue disorders typical of homocystinuria due to CBS deficiency. These 2 mutants demonstrated a level of CBS activity comparable to that of the AdoMet-stimulated wildtype CBS but could not be further induced by the addition of AdoMet. In terms of temperature stability, oligomeric organization, and Heme saturation the 3 mutants were indistinguishable from wildtype CBS. The findings illustrated the importance of AdoMet for the regulation of homocysteine metabolism and were consistent with the possibility that the characteristic connective tissue disturbances observed in homocystinuria due to CBS deficiency may not be due to elevated homocysteine.

Gaustadnes et al. (2002) determined the molecular basis of CBS deficiency in 36 Australian patients from 28 unrelated families, using direct sequencing of the entire coding region of the CBS gene. Seven novel and 20 known mutations were detected. The G307S and I278T mutations were the most common and were present in 19% and 18% of independent alleles, respectively. Expression studies of 2 novel mutations (C109R and G347S), as well as 2 known mutations (L101P and N228K), showed complete lack of catalytic activity by the mutant proteins. Gaustadnes et al. (2002) studied the correlation between genotype and biochemical response to pyridoxine treatment in 13 pyridoxine-responsive, 21 nonresponsive, and 2 partially responsive patients. The G307S mutation always resulted in a severe nonresponsive phenotype, whereas I278T resulted in a milder B6-responsive phenotype. From their results, Gaustadnes et al. (2002) were also able to establish 3 other mild mutations: P49L, R369C, and V371M.

Kruger et al. (2003) examined the relationship of the clinical and biochemical phenotypes with the genotypes of 12 CBS-deficient patients from 11 families in the state of Georgia, USA. By DNA sequencing of all of the coding exons, they identified mutations in the CBS genes in 21 of the 22 possible mutant alleles. Ten different missense mutations were identified and 1 novel splice site mutation was found. Five of the missense mutations were previously described, while 5 were novel. Each missense mutation was tested for function by expression in S. cerevisiae and all were found to cause decreased growth rate and to have significantly decreased levels of CBS enzyme activity. The I278T (236200.0004) and T353M (236200.0015) mutations accounted for 45% of the mutant alleles in this patient cohort.

CBS domains were originally identified as sequence motifs of approximately 60 amino acids that occur in cystathionine beta-synthase and several other proteins, in all organisms from archaea to humans (Bateman, 1997). Their functional importance was emphasized by findings that point mutations within them cause several hereditary diseases in humans, including homocystinuria. Scott et al. (2004) showed that tandem pairs of CBS domains from AMP-activated protein kinase, IMP dehydrogenase-2 (IMPDH2; 146691), the chloride channel CLC2 (600570), and cystathionine beta-synthase bind AMP, ATP, or S-adenosylmethionine, whereas mutations that cause hereditary diseases impair this binding. This showed that tandem pairs of CBS domains act, in most cases, as sensors of cellular energy status and, as such, represent a class of binding domain for adenosine derivatives.

In 6 patients from 5 Korean families with homocystinuria, Lee et al. (2005) identified 8 different mutations in the CBS gene, including 4 novel mutations. In vitro functional expression studies showed that the mutant enzymes had significantly decreased activities.


ANIMAL MODEL

Nishinaga et al. (1993) presented results from experiments in cultured porcine aortic endothelial cells suggesting that inhibited expression of anticoagulant heparan sulfate may contribute to the thrombogenic property resulting from the homocysteine-induced endothelial cell perturbation.

To determine whether elevated plasma homocysteine concentrations are directly causative of cardiovascular diseases, Watanabe et al. (1995) generated mice that were moderately and severely homocysteinemic, using homologous recombination in mouse embryonic stem cells to inactivate the Cbs gene. Homozygous mutants completely lacking cystathionine beta-synthase were born at the expected frequency from matings of heterozygotes, but they suffered from severe growth retardation and most of them died within 5 weeks after birth. Histologic examination showed that the hepatocytes of homozygotes were enlarged, multinucleated, and filled with microvesicular lipid droplets (resembling the finding in some severe homocystinuric patients). Plasma homocysteine levels of the homozygotes were approximately 40 times normal. Heterozygous mutants had approximately 50% reduction in CBS mRNA and enzyme activity in the liver and had twice normal plasma homocysteine levels. Thus, Watanabe et al. (1995) concluded that homozygotes are a useful model for the clinical disorder homocystinuria and the heterozygotes should be useful for studying the role of elevated levels of homocysteine in the causation of cardiovascular disease. They noted that most of the homozygous mutant mice had eyes with delayed and narrow eye openings but without obvious histologic abnormalities. Seemingly, the homozygotes did not survive long enough to develop osteoporosis and vascular occlusions.

To investigate the mechanism whereby folate supplementation protects against heart and neural tube defects, Rosenquist et al. (1996) tested the effects of homocysteine on chick embryos and the effect of added folate. The hypothesis was that homocysteine may be the teratogenic agent, since serum homocysteine increases in folate depletion. Of embryos treated with homocysteine or homocysteine thiolactone, 27% showed neural tube defects. A high frequency of ventricular septal defects and neural tube defects was observed. Also, a ventral closure defect was found in a high percentage of day 9 embryos. The teratogenic dose was shown to raise serum homocysteine to over 150 nmol/ml, compared with a normal level of about 10 nmol/ml. F1late supplementation kept the rise in serum homocysteine to approximately 45 nmol/ml and prevented the teratogenic effect. Rosenquist et al. (1996) concluded that homocysteine per se causes dysmorphogenesis of the heart and neural tube, as well as of the ventral wall.

Wang et al. (2005) engineered mice that expressed the common human mutant I278T and I278T/T424N CBS proteins. These transgene-containing mice were then bred to Cbs +/- mice to generate Cbs -/- mice that expressed only the I278T or I278T/T424N human transgenes. Both the I278T and the I278T/T424N transgenes were able to entirely rescue the neonatal mortality phenotype of Cbs -/- mice (see Watanabe et al., 1995) despite these mice having a mean homocysteine level of 250 micromols. The transgenic Cbs -/- animals exhibited facial alopecia, had moderate liver steatosis, and were slightly smaller than heterozygous littermates. In contrast to human CBS deficiency, these mice did not exhibit hypermethioninemia. The mutant proteins were stable in several tissues, although liver extracts had only 2 to 3% of the Cbs enzyme activity found in wildtype mice. The I278T/T424N enzyme had exactly the same activity as the I278T enzyme, indicating that T424N was unable to suppress I278T in mice. Wang et al. (2005) concluded that elevated homocysteine levels per se were not responsible for the neonatal lethality observed in Cbs -/- animals and suggested that CBS protein may have other functions in addition to its role in homocysteine catabolism.


HISTORY

Nugent et al. (1998) gave follow-up information on 'the first case' of homocystinuria. This was a patient who was identified during a survey of a group of mentally retarded children in Northern Ireland in 1960 by Carson and Neill (1962). He was followed at the Royal Belfast Hospital for Sick Children until age 39 years when he was transferred to the Adult Metabolic Clinic at the Royal Victoria Hospital, Belfast. Despite early difficulties and the late start in treatment to lower his serum homocysteine, the patient had remained in reasonable health. He was initially reported at age 7 years as an unusual case of Marfan syndrome with renal abnormalities, case 4 of Loughridge (1959). He had recovered from acute glomerulonephritis at the age of 6 years and was found to be hypertensive the next year. He was mentally slow and thin, with fair hair, pale skin, and flushed cheeks. He had arachnodactyly, dolichostenomelia, pes cavus, high-arched palate, and bilateral dislocated lenses. At age 10 years, during a survey of urinary amino acid chromatography of mentally retarded people in Northern Ireland, his urine was found to contain a large quantity of homocysteine accompanied by a positive nitroprusside cyanide test (Carson and Neill, 1962). His left eye was enucleated because of staphylococcal infection after acute pupillary-block glaucoma; his right lens dislocated into the anterior chamber and had to be removed. His hypertension disappeared after removal of his left kidney at the age of 13 years; thick-walled medial hypertrophic intrarenal arteries and pads of intimal fibrous tissue were found histologically. When supplementation with pyridoxine was initiated at the age of 18 years, his plasma homocysteine fell to low normal values. Daily folic acid supplementation was added 1 year later since his plasma folate concentration was low. At age 20 years he had a perforated duodenal ulcer. Chest pain occurred at age 27 years and recurred at age 34 years; it was considered to be angina and was successfully treated. At age 50 years, his plasma homocysteine remained low. He developed acute gout which responded to indomethacin.


ALLELIC VARIANTS
(selected examples)


.0001 HOMOCYSTINURIA [CBS, GLY307SER]
In 2 unrelated patients, patients with homocystinuria, Gu et al. (1991) found a G-to-A transition in the CBS gene, resulting in substitution of serine for glycine at residue 307 of the protein. When this allele was expressed in E. coli, a peptide of normal mobility on Western blot analysis was synthesized but the peptide lacked CBS activity. Hu et al. (1993) found the G307S mutation in one allele of a patient of French/Scottish ancestry and in both alleles of a patient of Irish ancestry. Both parents of the second patient were heterozygotes for G307S. The mutant protein was apparently stable in expression studies in E. coli but lacked catalytic activity. Sequencing of exon 8 revealed the G307S mutation in 5 additional families. All had pyridoxine-nonresponsive homocystinuria. Hu et al. (1993) observed this mutation in 9 of 52 apparently unrelated alleles of varied ethnic backgrounds. All 9 were from patients with Celtic (Irish/English/Scottish/French) ancestry in either one or both parents. Indeed, the G307S mutation was detected in 9 of 18 Celtic alleles in their series. A second mutation found in exon 8 is the ile278-to-thr mutation (236200.0004), which appears to be associated with pyridoxine responsiveness.

Gallagher et al. (1995) analyzed 17 Irish unrelated persons with homocystinuria for the G307S mutation. Homozygosity for the mutation was found in 8 of the 17. A further 8 patients were compound heterozygotes, with the G307S mutation present on 1 allele. A single patient did not have G307S. Thus, of the 34 alleles, 24 (71%) were G307S. Screening of newborns for homocystinuria has been routine in Ireland since 1971. Newly diagnosed infants are also assessed for responsiveness to pyridoxine; all patients analyzed by Gallagher et al. (1995) were unresponsive.

.0002 HOMOCYSTINURIA [CBS, PRO145LEU]
In an adult female patient of Irish and German ancestry with relatively mild and late-onset signs of homocystinuria and with response to pyridoxine, Kozich et al. (1993) found compound heterozygosity for two different mutations of the CBS gene, one of which was a C-to-T transition at nucleotide 434 resulting in substitution of proline at position 145 with leucine (P145L).

.0003 HOMOCYSTINURIA [CBS, ALA114VAL]
A second mutation in the patient with pyridoxine-responsive homocystinuria reported by Kozich et al. (1993) was a C-to-T transition at nucleotide 341 leading to substitution of alanine at position 114 by valine (A114V).

.0004 HOMOCYSTINURIA, PYRIDOXINE-RESPONSIVE [CBS, ILE278THR]
In one allele of a pyridoxine-nonresponsive patient with homocystinuria and in both alleles of a pyridoxine-responsive patient, Hu et al. (1993) found a missense mutation in exon 8 of the CBS gene, resulting in substitution of threonine for isoleucine-278. Kozich and Kraus (1992) observed this mutation in a mildly affected pyridoxine-responsive patient of Ashkenazi Jewish origin. The 2 patients in whom the I278T mutation was identified by Hu et al. (1993) were both of Polish ancestry. By PCR amplification and sequencing of exon 8 from genomic DNA, Shih et al. (1995) detected the I278T mutation in 7 of 11 patients with in vivo pyridoxine-responsiveness and in none of 27 pyridoxine-nonresponsive patients; 2 pyridoxine-responsive patients were homozygous and 5 were heterozygous for I278T. They further observed the I278T mutation in 9 of 22 (41%) independent alleles in pyridoxine-responsive patients of various ethnic backgrounds. In 2 of the compound heterozygotes, they identified novel mutations (G139R, 236200.0005 and E114K, 236200.0006) in the other allele. The 2 patients who were homozygous for I278T had only ectopia lentis and mild bone demineralization. They concluded that compound heterozygous patients who have one copy of the I278T mutation are likely to retain some degree of pyridoxine responsiveness.

Although this mutation (833T-to-C) is found in 50% of the CBS alleles in Dutch homozygous CBS-deficient patients, Kluijtmans et al. (1996) found it in none of 60 patients with premature cardiovascular disease. This led them to conclude that heterozygosity for CBS deficiency is not involved in premature cardiovascular disease. In a study of 21 unrelated Dutch pedigrees, Kluijtmans et al. (1999) found that of 10 different mutations detected in the CBS gene, I278T was predominant, being present in 23 (55%) of 42 independent alleles. Homozygotes for this mutation tended to have higher homocysteine levels than those in patients with other genotypes, but similar clinical manifestations. I278T homozygotes responded more efficiently to homocysteine-lowering treatment. After 378 patient-years of treatment, only 2 vascular events were recorded; without treatment at least 30 would have been expected.

The I278T mutation is the most frequent mutation in homocystinuria in Italy, where most cases are B6-responsive and the disorder has a total frequency of approximately 1 in 55,000 as compared with a frequency of 1 in 58,000 in the United States and 1 in 889,000 in Japan (Sebastio, 1997).

In a study of a group of patients with premature coronary artery disease, Tsai et al. (1996) found an unexpectedly high prevalence of a mutation involving a 68-bp insertion in the coding region of exon 8. The mutation did not seem to affect the activity of the CBS enzyme. Screening of controls showed that the mutation also was prevalent in that population. The prevalence was somewhat greater in patients with premature coronary artery disease, although the difference did not reach statistical significance. The mutation had previously been reported by Sebastio et al. (1995). In their control population, Tsai et al. (1996) found that 11.7% of controls were heterozygous carriers. In contrast to the report by Sebastio et al. (1995), which assumed that the 68-bp insertion introduced a premature termination codon and resulted in a nonfunctional CBS enzyme, Tsai et al. (1996) found that the insertion created an alternate splicing site that eliminated not only the inserted intronic sequences but also the T-to-C mutation at nucleotide 833 (ile278thr) associated with this insertion. The net result was the generation of both quantitatively and qualitatively normal mRNA and CBS enzyme.

Franco et al. (1998), who referred to the 68-bp insertion in the coding region of exon 8 of the CBS gene as 844ins68, investigated its prevalence in 405 persons belonging to 4 different ethnic groups. The insertion was found in heterozygous state in 14 of 104 whites (13.5%), was absent among Asians, and was found in only 1 of 220 Amerindian chromosomes analyzed, whereas a much higher prevalence was observed among blacks (37.7% of heterozygotes and 4% of mutant homozygotes). In all carriers of the insertion, the 833T-C CBS mutation cosegregated in cis with 844ins68. The finding of the double mutant among blacks and Caucasians suggested that it antedated the divergence between Africans and non-Africans, and provided evidence for a partly or completely neutralizing effect conferred by the 68-bp insertion, since it allows the skipping of the 833T-C mutation.

In a mildly affected pyridoxine-responsive patient of Ashkenazi Jewish origin, Kozich and Kraus (1992) identified compound heterozygosity for a maternal I278T mutation and a paternal IVS11-2A-C mutation (236200.0012).

In a study of 11 families in the state of Georgia, USA, Kruger et al. (2003) found that I278T and T353M (236200.0015) mutations accounted for 45% of the mutant alleles. The T353M mutation, found exclusively in 4 African American patients, was associated with a B6-nonresponsive phenotype and detection by neonatal screening for hypermethioninemia. The I278T mutation was found exclusively in Caucasian patients and was associated with a B6-responsive phenotype.

.0005 HOMOCYSTINURIA [CBS, GLY139ARG]
See 236200.0004.

.0006 HOMOCYSTINURIA [CBS, GLU144LYS]
See 236200.0004.

.0007 HOMOCYSTINURIA, PYRIDOXINE-RESPONSIVE [CBS, LYS384GLU]
In 2 unrelated French vitamin B6-responsive homocystinuria patients with no Celtic origin, Aral et al. (1997) demonstrated novel mutations in the CBS gene. One patient had unilateral lens subluxation and deep vein thrombosis at age 6, and a Marfan-like appearance with thinning of long bones and digits, together with osteoporosis of the lower limbs. This patient was found to have an A-to-G transition of nucleotide 1150, resulting in substitution of lysine-384 with glutamic acid (K384E) in the CBS protein. See also 236200.0008.

.0008 HOMOCYSTINURIA, PYRIDOXINE-RESPONSIVE [CBS, LEU539SER ]
In the second patient studied by Aral et al. (1997) with pyridoxine-responsive homocystinuria, they demonstrated homozygosity for a leu539-to-ser (L539S) mutation in the CBS gene.

.0009 HOMOCYSTINURIA, PYRIDOXINE-RESPONSIVE [CBS, ARG266LYS ]
Kim et al. (1997) stated that more than 20 different point mutations had been identified in patients with CBS deficiency. Studies of the CBS gene had provided a good example of the problems inherent in distinguishing disease-causing mutations from polymorphisms. A case in point is the 68-bp duplication of the region containing the intron 7-exon 8 junction which was initially reported as a mutation in an Italian CBS deficient patient (Sebastio et al., 1995). Later this was shown to be a benign polymorphism found in 3 to 6% of all CBS-containing chromosomes (Tsai et al., 1996; Sperandeo et al., 1996), as discussed earlier. Kim et al. (1997) studied the mutations in 10 Norwegian CBS-deficiency families and identified 18 of the 20 mutant alleles. In 9 of the 20 CBS alleles (45%), they found the 68-bp duplication allele. This frequency was much higher than the 6% reported by Tsai et al. (1996) in a study population from the upper midwest of the US. In unaffected Norwegian chromosomes, Kim et al. (1997) found the frequency of the duplication to be approximately 5.5% (2 in 36). Five of the 7 patients classified as pyridoxine-responsive contained a newly identified point mutation, arg266lys or R266K (797G-A). This point mutation was tightly linked with the previously identified 'benign' 68-bp duplication of the intron 7-exon 8 boundary within the CBS gene. Kim et al. (1997) tested the effect of all the mutations identified on human CBS function utilizing a yeast system. Five of the 6 mutations had a distinguishable phenotype in yeast, indicating that they were, in fact, pathogenic. The 797G-A had no phenotype when the yeast were grown in high concentrations of pyridoxine, but a severe phenotype when grown in low concentrations, thus mirroring the behavior in humans. The yeast functional assay was suggested as a guide to therapy.

It should be noted that Kim et al. (1997) found a different distribution of CBS alleles in Norwegian cystinurics. The gly307-to-ser mutation (263200.0001), which was found in 71% of mutant alleles in Ireland, accounted for only 20% in the Norwegian group and in Italian patients was not observed at all (Sperandeo et al., 1995).

.0010 HOMOCYSTINURIA, PYRIDOXINE-RESPONSIVE [CBS, ASP444ASN ]
Kluijtmans et al. (1996) studied a 20-year-old woman who had been admitted to the hospital at the age of 9 years because of psychomotor retardation and marfanoid features. Treatment was instituted with pyridoxine, folic acid, and betaine. Eleven years later she was in very good physical condition and her intellectual development had reached an average level. Her height was 182 cm. Ectopia lentis, osteoporosis, and vascular complications had not occurred. She was found to be homozygous for a 1330G-A missense mutation in the CBS gene. The mutation was predicted to cause a asp444-to-asn amino acid substitution, a negatively charged amino acid replacing a neutral one. Both parents and an unaffected sister were heterozygous for the mutation. Despite the homozygous mutation, CBS activities in extracts of cultured fibroblasts of this patient were not in the homozygous but in the heterozygous range. Furthermore, Kluijtmans et al. (1996) observed no stimulation of CBS activity by S-adenosylmethionine, contrary to a 3-fold stimulation in control fibroblast extract. The mutation was introduced into an E. coli expression system, and CBS activities were measured after addition of different S-adenosylmethionine concentrations. Again, defective stimulation of CBS activity by S-adenosylmethionine was observed in the mutated construct, whereas the normal construct showed a 3-fold stimulation in activity. These data suggested that the D444N mutation interfered with S-adenosylmethionine regulation of CBS. Furthermore, it indicated the importance of S-adenosylmethionine regulation of the transsulfuration pathway in homocysteine homeostasis in humans.

CBS domains are defined as sequence motifs that occur in several different proteins in all kingdoms of life. Their functional importance is underlined by the finding that mutations in conserved residues within them cause a variety of human hereditary diseases, including homocystinuria. Scott et al. (2004) showed that tandem pairs of CBS domains from cystathionine beta-synthase, as well as the CBS domains from at least 3 other proteins that are the sites of mutations causing hereditary diseases, bind AMP, ATP, or S-adenosylmethionine, whereas mutations that cause hereditary diseases impair this binding. An interesting feature of the pathogenic mutations in CBS domains is that they tend to occur in equivalent positions. Thus, 3 mutations in the PRKAG2 gene that cause disease--R302Q (602743.0001), H383R, and R531G (602743.0006)--all align (plus or minus 1 residue) with the D444N mutation in the CBS gene.

.0011 HOMOCYSTINURIA, PYRIDOXINE-RESPONSIVE [CBS, VAL168MET]
Shan et al. (2001) identified 7 mutations that could suppress the most common CBS patient mutation, I278T (236200.0004), 4 of which mapped to the CBS domain. The suppressors, in combination with the val168-to-met mutation, expressed full-length CBS.

.0012 HOMOCYSTINURIA, PYRIDOXINE-RESPONSIVE [CBS, IVS11AS, A-C, -2]
In a mildly affected pyridoxine-responsive patient of Ashkenazi Jewish origin, Kozich and Kraus (1992) identified compound heterozygosity for a maternal I278T mutation (236000.0004) and a paternal A-to-C transversion in the intron 11 splice acceptor. The latter mutation led to an in-frame deletion of exon 12.

.0013 THROMBOSIS, HYPERHOMOCYSTEINEMIC [CBS, PRO422LEU]
In a group of unrelated patients that were screened for elevated homocysteine after an idiopathic thrombotic event (Gaustadnes et al., 2000), one patient was found to be a compound heterozygote for a pro422-to-leu missense mutation and an asp444-to-asn mutation (236200.0010). The diagnosis of elevated homocysteine had been made after an episodic transient ischemic attack at the age of 22 years. The patient was found to be unresponsive to therapy with either pyridoxine or betaine. The patient did not carry the 677C-T transition in the MTHFR gene (607093.0003). The usual manifestations of classic homocystinuria such as ectopia lentis, marfanoid skeletal features, and mental retardation were lacking.

.0014 THROMBOSIS, HYPERHOMOCYSTEINEMIC [CBS, SER466LEU]
In a patient found to have high homocysteine levels when screened after an episodic transient ischemic attack at the age of 36 years (Gaustadnes et al., 2000), Maclean et al. (2002) found a ser466-to-leu missense mutation in the CBS gene. The patient had no ectopia lentis, mental retardation, marfanoid skeletal features, or other characteristic features of classic homocystinuria.

.0015 HOMOCYSTINURIA [CBS, THR353MET]
In the state of Georgia, USA, Kruger et al. (2003) studied 11 families with CBS deficiency. The thr353-to-met (T53M) mutation, found exclusively in 4 African American patients, was associated with a B6-nonresponsive phenotype and with detection by newborn screening for hypermethioninemia. The I278T (236200.0004) and T353M mutations accounted for 45% of the mutant alleles in the affected members of the 11 families. The I278T mutation was found exclusively in Caucasian patients and was associated with a B6-responsive phenotype.

.0016 HOMOCYSTINURIA [CBS, THR191MET ]
Among 35 patients from 30 pedigrees with homocystinuria from the Iberian peninsula and several South American countries, Urreizti et al. (2006) found a high frequency of a 572C-T transition in the CBS gene, resulting in a thr191-to-met (T191M) substitution. The patients were from Spain, Portugal, Colombia, and Argentina. Combined with previously reported studies, the prevalence of T191M among mutant CBS alleles in different countries was 0.75 in Colombia, 0.52 in Spain, 0.33 in Portugal, 0.25 in Venezuela, 0.20 in Argentina, and 0.14 in Brazil. Haplotype analysis suggested a double origin for this mutation. The phenotype was B6-nonresponsive.



SEE ALSO

Almgren et al. (1978); Barber and Spaeth (1967); Boers et al. (1985); Carey et al. (1968); Carson and Carre (1969); Carson et al. (1963); Field et al. (1962); Frimpter (1969); Goldstein et al. (1972); Goldstein et al. (1973); Harker et al. (1976); Hooft et al. (1967); Kaeser et al. (1969); Kim and Rosenberg (1974); Komrower (1967); Kraus et al. (1978); Kurczynski et al. (1980); McCully and Ragsdale (1970); Milan et al. (2000); Mudd et al. (1970); Mudd et al. (1964); Mudd and Levy (1978); Mudd et al. (1969); Munnich et al. (1983); Perry et al. (1968); Shelley et al. (1972); Shih and Efron (1970); Shipman et al. (1969); Skovby (1985); Skovby et al. (1984); Skovby et al. (1984); Uhlemann et al. (1976); Wong et al. (1968)


REFERENCES

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97. Rosenquist, T. H.; Ratashak, S. A.; Selhub, J. :
Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc. Nat. Acad. Sci. 93: 15227-15232, 1996.
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98. Saudubray, J. M. :
Personal Communication. Paris, France, 5/20/1997.

99. Schimke, R. N.; McKusick, V. A.; Huang, T.; Pollack, A. D. :
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100. Schnyder, G.; Roffi, M.; Pin, R.; Flammer, Y.; Lange, H.; Eberli, F. R.; Meier, B.; Turi, Z. G.; Hess, O. M. :
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101. Scott, J. W.; Hawley, S. A.; Green, K. A.; Anis, M.; Stewart, G.; Scullion, G. A.; Norman, D. G.; Hardie, D. G. :
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102. Sebastio, G. :
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105. Shan, X.; Kruger, W. D. :
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PubMed ID : 9590298

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PubMed ID : 5472941

108. Shih, V. E.; Fringer, J. M.; Mandell, R.; Kraus, J. P.; Berry, G. T.; Heidenreich, R. A.; Korson, M. S.; Levy, H. L.; Ramesh, V. :
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112. Skovby, F.; Krassikoff, N.; Francke, U. :
Assignment of the gene for cystathionine beta-synthase (CBS) to human chromosome 21 in somatic cell hybrids. (Abstract) Cytogenet. Cell Genet. 37: 585 only, 1984.

113. Skovby, F.; Kraus, J.; Redlich, C.; Rosenberg, L. E. :
Immunochemical studies on cultured fibroblasts from patients with homocystinuria due to cystathionine beta-synthase deficiency. Am. J. Hum. Genet. 34: 73-83, 1982.
PubMed ID : 7081217

114. Skovby, F.; Kraus, J. P.; Rosenberg, L. E. :
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PubMed ID : 6711564

115. Spaeth, G. L.; Barber, G. W. :
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PubMed ID : 6051058

116. Sperandeo, M. P.; de Franchis, R.; Andria, G.; Sebastio, G. :
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PubMed ID : 8940285

117. Sperandeo, M. P.; Panico, M.; Pepe, A.; Candito, M.; de Franchis, R.; Kraus, J. P.; Andria, G.; Sebastio, G. :
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PubMed ID : 7564249

118. Streeten, B. W. :
The nature of the ocular zonule. Trans. Am. Ophthal. Soc. 80: 823-854, 1982.
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119. Stubbs, L.; Kraus, J.; Lehrach, H. :
The alpha-A-crystallin and cystathionine beta-synthase genes are physically very closely linked in proximal mouse chromosome 17. Genomics 7: 284-288, 1990.
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120. Tada, K.; Yoshida, T.; Hirono, H.; Arakawa, T. :
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PubMed ID : 6081779

121. Tsai, M. Y.; Bignell, M.; Schwichtenberg, K.; Hanson, N. Q. :
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PubMed ID : 8940271

122. Uhlemann, E. R.; TenPas, J. H.; Lucky, A. W.; Schulman, J. D.; Mudd, S. H.; Shulman, N. R. :
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123. Uhlendorf, B. W.; Mudd, S. H. :
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CONTRIBUTORS

George E. Tiller - updated : 11/20/2008
Cassandra L. Kniffin - updated : 5/24/2006
Cassandra L. Kniffin - updated : 2/17/2006
Victor A. McKusick - updated : 2/10/2004
Victor A. McKusick - updated : 1/12/2004
Ada Hamosh - updated : 10/8/2003
Ada Hamosh - updated : 10/6/2003
Victor A. McKusick - updated : 8/20/2002
Victor A. McKusick - updated : 6/14/2002
Victor A. McKusick - updated : 2/8/2002
Ada Hamosh - updated : 1/16/2002
Victor A. McKusick - updated : 1/10/2002
Victor A. McKusick - updated : 9/7/2001
Victor A. McKusick - updated : 6/27/2001
Carol A. Bocchini - updated : 6/27/2001
George E. Tiller - updated : 5/29/2001
Victor A. McKusick - updated : 5/15/2001
Paul J. Converse - updated : 6/8/2000
Victor A. McKusick - updated : 12/21/1999
Victor A. McKusick - updated : 6/30/1999
Victor A. McKusick - updated : 6/18/1999
Victor A. McKusick - updated : 6/7/1999
Victor A. McKusick - updated : 5/14/1999
Ada Hamosh - updated : 4/21/1999
Victor A. McKusick - updated : 2/25/1999
Victor A. McKusick - updated : 2/3/1999
Victor A. McKusick - updated : 12/2/1998
Ada Hamosh - updated : 10/26/1998
Victor A. McKusick - updated : 9/17/1998
John F. Jackson - reorganized : 9/2/1998
Victor A. McKusick - updated : 4/28/1998
Victor A. McKusick - updated : 4/15/1998
Victor A. McKusick - updated : 2/25/1998
Victor A. McKusick - updated : 2/17/1998
Victor A. McKusick - updated : 2/12/1998
Victor A. McKusick - updated : 1/29/1998
Victor A. McKusick - updated : 12/19/1997
Victor A. McKusick - updated : 6/5/1997
Victor A. McKusick - updated : 4/24/1997
Victor A. McKusick - updated : 4/4/1997
Victor A. McKusick - updated : 2/28/1997
Moyra Smith - updated : 5/21/1996



CREATION DATE

Victor A. McKusick : 6/3/1986



EDIT HISTORY

terry : 2/26/2009
wwang : 11/20/2008
carol : 10/8/2008
ckniffin : 5/15/2007
terry : 11/15/2006
wwang : 5/31/2006
ckniffin : 5/24/2006
wwang : 3/14/2006
ckniffin : 2/17/2006
carol : 3/17/2004
tkritzer : 2/17/2004
terry : 2/10/2004
cwells : 1/14/2004
terry : 1/12/2004
cwells : 10/8/2003
cwells : 10/6/2003
tkritzer : 8/26/2002
tkritzer : 8/23/2002
terry : 8/20/2002
ckniffin : 7/9/2002
cwells : 6/19/2002
terry : 6/14/2002
ckniffin : 5/15/2002
terry : 3/5/2002
alopez : 2/18/2002
terry : 2/8/2002
alopez : 1/18/2002
terry : 1/16/2002
carol : 1/10/2002
terry : 1/10/2002
mcapotos : 12/27/2001
cwells : 10/31/2001
carol : 10/1/2001
carol : 9/10/2001
alopez : 9/7/2001
mcapotos : 6/27/2001
mcapotos : 6/27/2001
cwells : 6/22/2001
cwells : 6/4/2001
cwells : 5/29/2001
cwells : 5/25/2001
terry : 5/15/2001
alopez : 3/8/2001
joanna : 11/9/2000
carol : 6/8/2000
carol : 4/24/2000
mcapotos : 1/19/2000
mcapotos : 1/13/2000
terry : 12/21/1999
mgross : 7/16/1999
carol : 7/15/1999
jlewis : 7/14/1999
terry : 6/30/1999
jlewis : 6/30/1999
terry : 6/18/1999
mgross : 6/16/1999
terry : 6/7/1999
mgross : 6/3/1999
mgross : 5/28/1999
terry : 5/14/1999
alopez : 4/21/1999
carol : 3/9/1999
terry : 2/25/1999
carol : 2/12/1999
terry : 2/3/1999
dkim : 12/14/1998
carol : 12/8/1998
terry : 12/2/1998
carol : 10/26/1998
carol : 10/23/1998
dkim : 10/21/1998
carol : 10/21/1998
carol : 10/21/1998
carol : 9/24/1998
terry : 9/17/1998
carol : 9/3/1998
carol : 9/2/1998
alopez : 4/29/1998
terry : 4/28/1998
carol : 4/17/1998
terry : 4/15/1998
alopez : 3/16/1998
alopez : 3/16/1998
alopez : 3/16/1998
terry : 2/25/1998
terry : 2/12/1998
mark : 2/2/1998
terry : 1/29/1998
dholmes : 1/12/1998
mark : 1/2/1998
terry : 12/19/1997
mark : 6/14/1997
terry : 6/5/1997
terry : 4/24/1997
terry : 4/21/1997
jenny : 4/4/1997
terry : 3/31/1997
mark : 2/28/1997
terry : 2/26/1997
jamie : 1/15/1997
terry : 1/10/1997
terry : 1/7/1997
terry : 12/10/1996
terry : 11/13/1996
mark : 10/21/1996
terry : 7/9/1996
terry : 7/9/1996
mark : 5/21/1996
mark : 5/21/1996
terry : 5/21/1996
mark : 4/12/1996
terry : 4/5/1996
mark : 3/6/1996
terry : 3/4/1996
mark : 1/25/1996
terry : 1/23/1996
mark : 11/6/1995
terry : 4/19/1995
carol : 2/9/1995
davew : 8/19/1994
jason : 6/17/1994
mimadm : 4/18/1994