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PubMed1985

Homocystinuria and schizophrenia. Literature review and case report.

The autosomal recessive disorder homocystinuria involves, in all its subgroups, an abnormality of methionine metabolism. The metabolism of methionine has been a central focus of interest for those who propose the transmethylation hypothesis of schizophrenia. The "methionine effect," as described in the research literature, is thus a theoretical link between these two disorders. The authors review the literature and describe those cases where both have occurred in the same patient. They indicate that whereas many patients with homocystinuria have been psychotic, few have been actually labeled schizophrenic. A patient with homocystinuria, mental retardation, and episodic psychosis is described and this case is used to point to the difficulties in making a definite psychiatric diagnosis in these patients. A relationship between the two syndromes is suggested.

Adult↗
PubMed1964

HOMOCYSTINURIA DUE TO CYSTATHIONINE SYNTHETASE DEFICIENCY: THE MODE OF INHERITANCE.

Deficiency of cystathioninie synthetase activity results in the clinical syndrome of homocystinuria. In both parents of a patient with homocystinuria, the hepatic cystathionine synthetase activity was 40 percent of that in unrelated control patients. These findings demonstrate that the metabolic error is inherited and suggest that the parents, although clinically normal, represent the heterozygous. state. A second case of homocystinuria also is shown to be associated with cystathionine synthetase deficiency.

Amino Acid Metabolism, Inborn Errors↗
PubMed1980

Maternal homocystinuria: studies of an untreated mother and fetus.

A 20-year-old woman with untreated homocystinuria was examined when she was 18 weeks' pregnant. Amniocentesis was performed and raised levels of homocystine and methionine were present in the amniotic fluid. Assay of cystathionine synthetase activity in cultured amniotic fluid cells showed the carrier state for homocystinuria. An abortion was performed because of the possible adverse effects of continuing the pregnancy both for the mother and the fetus. No pathological abnormality was found in the aborted fetus. Further data are needed to assess the possible teratogenic effects of maternal homocystinuria and the adverse consequences of pregnancy in the affected mother.

Abortion, Induced↗
PubMed1989

Ocular complications in homocystinuria--early and late treated.

Homocystinuria due to cystathionine-beta-synthetase deficiency is an autosomal recessive disorder of methionine metabolism with an incidence in Ireland of 1 in 52,544 births. Ocular complications in untreated patients include ectopia lentis, secondary glaucoma, optic atrophy, and retinal detachment. There are no characteristic signs or symptoms in infancy, and early detection relies on screening of newborn babies. Nineteen patients with homocystinuria were studied; 14 received dietary treatment and vitamin supplementation starting in the newborn period. Of these, none developed ectopia lentis after a mean follow-up of 8.2 years, compared with a 70% dislocation rate in untreated patients with a similar follow-up period. Ectopia lentis developed and progressed in five patients diagnosed later in life, despite tight biochemical control. The risk of ocular complications in homocystinuria can be substantially reduced in patients started on treatment within six weeks of birth.

Adolescent↗
PubMed1989

Lowered antithrombin III activity and other clotting changes in homocystinuria: effects of a pyridoxine-folate regimen.

Few studies have dealt with blood-clotting changes in patients affected by homocystinuria. The aim of this contribution is to briefly review studies published so far on the topic and report the results of our investigation performed in 3 patients. At baseline we found reduced antithrombin III and factor VII levels in all the patients, in line with the results of other authors, and other slight and less constant changes such as lowered factor X activity and protein C antigen, and increased beta-thromboglobulin levels. During pyridoxine and folate treatment, antithrombin III activity rapidly returned to normal; factor VII increased and beta-thromboglobulin decreased. These blood-clotting abnormalities may play a role in the thrombotic tendency associated with homocystinuria. Their nature is still uncertain, but the improvement observed during active metabolic treatment suggests that the defect in amino acid transsulfuration of homocystinuria may directly affect synthesis or activity of some clotting factors.

Adolescent↗
PubMed2000

Relationship between homocysteine and superoxide dismutase in homocystinuria: possible relevance to cardiovascular risk.

A modest homocysteine elevation is associated with an increased cardiovascular risk. Marked circulating homocysteine elevations occur in homocystinuria due to cystathionine beta-synthase (CbetaS) deficiency, a disorder associated with a greatly enhanced cardiovascular risk. Lowering homocysteine levels reduces this risk significantly. Because homocysteine-induced oxidative damage may contribute to vascular changes and extracellular superoxide dismutase (EC-SOD) is an important antioxidant in vascular tissue, we assessed EC-SOD and homocysteine in patients with homocystinuria. We measured circulating EC-SOD, total homocysteine (free plus bound), and methionine levels during the treatment of 21 patients with homocystinuria, 18 due to CbetaS deficiency, aged 8 to 59 years, and 3 with remethylating defects. We measured total homocysteine by immunoassay, EC-SOD by ELISA, and methionine by amino acid analysis and assessed interindividual and intraindividual relationships. There was a significant, positive relationship between EC-SOD and total homocysteine. For the interindividual assessment, levels were highly correlated, r=0.746, N=21, P<0.0001. This relationship was maintained after taking into account intraindividual patient variation (r=0.607, N=62, P<0.0001). In 2 newly diagnosed CbetaS-deficient patients, treatment that lowered the markedly elevated pretreatment homocysteine level (from 337 to 72 and from 298 to 50 micromol/L) reduced the associated elevated EC-SOD in each by 50%. EC-SOD and methionine levels were unrelated (r=0.148, n=39, P=0.368). The positive relationship between circulating EC-SOD and homocysteine could represent a protective antioxidant response to homocysteine-induced oxidative damage and contribute to reducing cardiovascular risk in homocystinuric patients. EC-SOD levels may be relevant to the pathogenesis of vascular disease in other patient groups.

Adolescent↗
PubMed1998

Evidence of carotid artery wall hypertrophy in homozygous homocystinuria.

BACKGROUND: We aimed to determine whether intima-media thickness (IMT) was increased in the carotid artery of subjects with homocystinuria to better understand the in vivo contribution of homocysteine to early atherogenesis. METHODS AND RESULTS: We investigated ultrasonographically the right common carotid artery in 14 subjects with homozygous homocystinuria aged 3 to 34 years (mean, 13 years) and in 15 of their heterozygous parents aged 32 to 47 years (mean, 41 years) by comparison with 2 control groups of 15 healthy subjects of the same age. Far-wall IMT and lumen diameter were measured with a computerized program, and the cross-sectional area of the intima-media complex (CSA-IMC) was calculated from IMT and diameter. Comparison with their respective controls, adjusted for body surface area or height, showed that homozygotes had greater IMT (P<0.001) and CSA-IMC (P<0.05) and smaller diameter (P<0.05), whereas heterozygotes had values similar to their controls. Multivariate analysis of the arterial parameters with age, body surface area (or height), and plasma total homocysteine in the homozygous and heterozygous groups combined showed that IMT was related to age (P<0.05) and homocysteine (P<0.01), diameter was related to body surface area (P<0.001) or height (P<0.05), and CSA-IMC was related to age (P<0.05), body surface area (P<0.05) (but not height), and homocysteine (P<0.05). CONCLUSIONS: Homozygous homocystinuria was associated with common carotid wall hypertrophy, whereas heterozygous disease was not. Such hypertrophy may reflect a smooth muscle proliferation induced by hyperhomocysteinemia and represent a promising target for testing vascular effects of therapeutic measures to lower homocysteine.

Adolescent↗
PubMed1973

A collagen defect in homocystinuria.

The biochemical mechanism accounting for the connective tissue abnormalities in homocystinuria was explored by examining the effects of various amino acids known to accumulate in the plasma of patients with this disease on cross-link formation in collagen. Neutral salt solutions of purified, rat skin collagen, rich in cross-link precursor aldehydes, were polymerized to native type fibrils by incubating at 37 degrees C in the presence of homocysteine, homocystine, or methionine. After the polymerization was completed, each sample was examined for the formation of covalent intermolecular cross-links, assessed indirectly by solubility tests and directly by measuring the cross-link compounds after reduction with tritiated sodium borohydride and hydrolysis. Collagen solutions containing homocysteine (0.01 M-0.1 M) failed to form insoluble fibrils. Furthermore, much less of the reducible cross-links, Delta(6,7) dehydrohydroxylysinonorleucine, Delta(6,7) dehydrohydroxylysinohydroxynorleucine, and histidino-dehydrohydroxymerodesmosine were formed in the preparations containing homocysteine as compared with the control and the samples containing methionine or homocystine. The content of the precursor aldehydes, alpha-aminoadipic-delta-semialdehyde (allysine) and the aldol condensation product, was also markedly diminished in tropocollagen incubated with homocysteine. It is concluded that homocysteine interferes with the formation of intermolecular cross-links that help stabilize the collagen macromolecular network via its reversible binding to the aldehydic functional groups. Analysis of the collagen cross-links in skin biopsy samples obtained from three patients with documented homocystinuria showed that the cross-links were significantly decreased as compared with the age-matched controls, supporting the tentative conclusions reached from the in vitro model studies. In addition, the solubility of dermal collagen in non-denaturing solvents was significantly increased in the two patients examined, reflecting a functional defect in collagen cross-linking. Although the concentration of homocysteine used in this study to demonstrate these effects in vitro is clearly higher than that which is observed in homocystinuric's plasma, the data do suggest a possible pathogenetic mechanism of connective tissue defect in homocystinuria.

Adult↗
PubMed1993

Abnormally high thromboxane biosynthesis in homozygous homocystinuria. Evidence for platelet involvement and probucol-sensitive mechanism.

Homocystinuria due to homozygous cystathionine beta-synthase deficiency is an inborn error of metabolism characterized by a high incidence of thrombosis and premature atherosclerosis. We evaluated TXA2 biosynthesis in vivo and several in vitro tests of platelet function in 11 homocystinuric patients and 12 healthy controls. In vitro, patients' platelet aggregation was within control values as were TXB2 formation, fibrinogen binding, and ATP secretion in response to thrombin. In contrast, the urinary excretion of 11-dehydro-TXB2, a major enzymatic derivative of TXA2, was > 2 SD of controls in all patients (1,724 +/- 828 pg/mg creatinine, mean +/- SD, in patients vs. 345 +/- 136 in controls, P < 0.001). The administration to four patients of low-dose aspirin (50 mg/d for 1 wk) reduced metabolite excretion by > 80%. The recovery of 11-dehydro-TXB2 excretion over the 10 d that followed aspirin cessation occurred with a pattern consistent with the entry into the circulation of platelets with intact cyclooxygenase activity. Prolonged partial reduction in the abnormally high excretion of both 11-dehydro-TXB2 and 2,3-dinor-TXB2, was also observed in seven patients who ingested 500 mg daily for 3 wk of the antioxidant drug probucol. These results provide evidence for enhanced thromboxane biosynthesis in homocystinuria and for its partial dependence on probucol-sensitive mechanisms. Furthermore, the elevated TXA2 formation in homocystinuria is likely to reflect, at least in part, in vivo platelet activation.

Adolescent↗
PubMed2001

Homocystinuria with transverse sinus thrombosis.

A case of cerebral venous thrombosis caused by undiagnosed homocystinuria is reported. The pitfalls regarding the diagnosis of a potentially medically treatable condition are discussed. Cerebral venous thrombosis in children has a variable type of onset and a multiplicity of causes. This type of pathology, although not frequent, is more common than previously thought. Among the different etiologies, undiagnosed homocystinuria is not routinely considered. We report a case of venous thrombosis of the left transverse cerebral sinus in a girl with drug-resistant partial epilepsy and homocystinuria. This diagnosis was considered and confirmed after the appearance of acute cerebral symptoms caused by venous thrombosis.

Child↗
PubMed2001

[Cerebral venous thrombosis and homocystinuria: case report].

Homocystinuria presenting as cerebral venous thrombosis is not usual. We report on a 13-year-old boy who was admitted to the hospital due to severe headache, nausea, vomiting and fever (38 degrees C). The patient was Marfan like and presented left hemiparesis and meningeal irritation sings. He was mentally retarded, had severe myopia, and had right lens dislocation one month before. Cranial CT scan was suggestive of cerebral venous infarct. MRI and magnetic resonance angiography showed venous infarcts more prominent in the right thalamic projection with hemorrhagic transformation and multiple foci of cortical (occipital and parietal bilaterally) deep parietal and left capsular bleeding, secondary of thrombosis of the transverse and sigmoid venous sinuses. High levels of homocysteine were detected in the blood and urine. Homocystinuria is an autosomal recessive inborn error of methionine metabolism caused by cystathionine-beta-synthase defect in most cases. We discuss the clinical and radiological findings in this patient, analyzing the pathophysiology of the thrombotic events related to homocystinuria.

Adolescent↗
PubMed2004

Homocystinuria: a rare cause of megaloblastic anemia.

We present an eight-year-old boy who initially presented to us with megaloblastic anemia and subsequently developed dislocation of lens. The child had a positive sodium nitroprusside test and homocystinuria. He was diagnosed to have homocystinuria type 1. His anemia improved on oral pyridoxine and folic acid therapy. Homocystinuria should be remembered as a cause of megaloblastic anemia.

Anemia, Megaloblastic↗
PubMed2005

Homocystinuria in Thai patient--Phramongkutklao Hospital experience.

Homocystinuria is a rare autosomal recessive disorder of amino acid metabolism. Classic (type I) homocystinuria is the most common type and occurs as a consequence of a deficiency of cystathionine-b-synthase, producing increased blood and urine homocysteine. The authors report a 15-year-old Thai male who presented with generalized tonic-clonic seizures from superior sagittal sinus thrombosis, bilateral downward subluxation of ocular lenses (ectopia lentis), Marfanoid habitus, osteoporosis, attention deficit and hyperactivity disorder. Urine metabolic screening was positive for cyanide nitroprusside test. Levels of plasma homocysteine and methionine were elevated. The clinical and laboratory findings in this case are consistent with the diagnosis of "type I" or "classical homocystinuria". The treatment was started with a low methionine diet, vitamin B6 or pyridoxine, folic acid, anticonvulsants, antithrombotic treatment and calcium supplementation. Genetic counseling was provided to the family with the recurrent risk of 25%. Definite diagnosis by enzyme assay or mutation analysis and also prenatal diagnosis are not established in Thailand.

Adolescent↗
PubMedDate not supplied

Homocystinuria: pathogenetic mechanisms.

Homocystinuria with elevated plasma homocysteine and methionine levels is the result of deficient activity of cystathionine synthetase, the enzyme catalyzing conversion of homocysteine to cystathionine. It is inherited as an autosomal recessive trait with a worldwide distribution. The major clinical manifestations result from the elevated plasma homocysteine level. The excitotoxic effect of homocysteic acid accounts for mental retardation and seizures. Interference with collagen cross-linking by sulfhydryl groups of homocysteine causes ectopia lentis and skeletal deformities. Sulfation factor-like effects contribute to disruption of vascular endothelium, which is followed by platelet thrombosis and widespread arterial and venous occlusions. Low methionine homocystinuria, with deficient remethylation of homocysteine, results from deranged vitamin B(12) metabolism and from deficient 5,10-methylene-tetrahydrofolate reductase. Administration of azaribine produces homocystinuria by mechanism not yet elucidated.

Animals↗
PubMed1986

[Homocystinuria. A type with vascular thrombosis and factor VII deficiency].

In homocystinuria, thrombosis is frequent (50% of the cases). The authors report a case of cystathionine-synthetase deficiency-induced homocystinuria associated with thrombosis of a common iliac vein. This patient presented with a blood coagulation disorder which was related to severe factor VII deficiency and which was corrected by treatment. Homocystinuria was pyridoxine independent as witnessed by the fact that Brand's reaction remained positive with vitamin B6 therapy and cystathionine. Cystathionine-synthetase activity measured in cultured fibroblasts increased only slightly with pyridoxine therapy. Treatment (Betaine, folic acid, vitamin B 12) induced the disappearance of plasma methionine. Clinically, the patient whose treatment came late in the course of her disease, was only slightly improved. Hypotheses about etiopathogenic mechanisms of this disease are discussed. Difficulties of treatment and diet are reviewed. The relative inefficacy of therapy, even in case with early treatment, makes antenatal diagnosis preferable to neonatal diagnosis.

Child↗
PubMed1984

Homocystinuria and ectopia lentis.

Homocystinuria is a genetically determined error of metabolism of the amino acid, methionine, which results in increased levels of homocystine and methionine in the blood and urine. A variety of clinical manifestations may result, one of these being the dislocation of the crystalline lens(es). A patient presented in the residency clinic with bilateral ectopia lentis and upon subsequent consultation with her family physician, a diagnosis of homocystinuria was made. This paper discusses the ocular and systemic manifestations of homocystinuria, the differential diagnosis of ectopia lentis, and the management of the systemic disease and its ocular sequelae.

Adolescent↗
PubMed1982

Accumulation of pyroglutamic acid (5-oxoproline) in homocystinuria.

A 12-year-old boy with homocystinuria due to a cystathionine synthetase defect was shown to accumulate large amounts of pyroglutamic acid (pyroglu). In four different urine samples the concentration ranged between 4.1 and 9.7 mol/mol of creatinine. The pyroglu concentration in plasma was 1.6 mmol/l, and in erythrocytes 750 nmol/g cells. Normally only trace amounts are present. The pyroglu levels normalized during treatment with pyridoxine and folic acid. Accumulation of pyroglu has not previously been described in homocystinuria. Homocysteine can replace cysteine as a substrate for gamma-glutamylcysteine synthetase, an enzyme involved in the biosynthesis of glutathione, giving gamma-glutamylhomocysteine. This dipeptide is efficiently split by gamma-glutamylcyclotransferase to pyroglu and homocysteine. This reaction sequence most likely explains the accumulation of pyroglu in our patient. Ten other homocystinuria patients, who all had lower plasma levels of homocysteine, did not accumulate pyroglu. Our patient might either be a new variant, or more likely the pyroglu formation occurs only high levels of homocysteine.

Amino Acids↗
PubMed1981

A study of cardiovascular risk in heterozygotes for homocystinuria.

Early atherosclerotic-like lesions and thromboemobolic problems are prominent in homocystinuric patients. Recent evidence suggested that mild homocyst(e)inemia, such as is present in heterozygotes for homocystinuria due to cystathionine synthase deficiency, may cause a marked excess in early ischemic heart disease. To evaluate the risk due to mild homocyst(e)inemia, the frequencies of heart attacks and strokes in parents and grandparents of homocystinuric children were assessed in the present study. No statistically significant increases in the incidence of heart attacks or strokes were consistently detected. The data available are sufficient to virtually exclude an increase in the cardiovascular risk for homocystinuria heterozygotes of as much as fivefold compared to controls, and to make very improbable a relative risk of as much as threefold. Less than 5% of homocystinuria heterozygotes are likely to have a fatal or nonfatal heart attack by age 50. These results fail to suggest that mild homecyst(e)inemia is an important contributory factor in the overall incidence of cardiovascular disease.

Adult↗