Long-term functional correction of cystathionine ß-synthase deficiency in mice by adeno-associated viral gene therapy.

Cystathionine ß-synthase (CBS) deficiency is a recessive inborn error of sulfur metabolism characterized by elevated blood levels of total homocysteine (tHcy). Patients diagnosed with CBS deficiency are currently treated by a combination of vitamin supplementation and restriction of foods containing the homocysteine precursor methionine, but the effectiveness of this therapy is limited due to poor compliance. A mouse model for CBS deficiency (Tg-I278T Cbs-/- ) was used to evaluate a potential gene therapy approach to treat CBS deficiency utilizing an AAVrh.10-based vector containing the human CBS cDNA downstream of the constitutive, strong CAG promoter (AAVrh.10hCBS). Mice were administered a single dose of virus and followed for up to 1 year. The data demonstrated a dose-dependent increase in liver CBS activity and a dose-dependent decrease in serum tHcy. Liver CBS enzyme activity at 1 year was similar to Cbs+/- control mice. Mice given the highest dose (5.6 × 1011 genomes/mouse) had mean serum tHcy decrease of 97% 1 week after injection and an 81% reduction 1 year after injection. Treated mice had either full- or substantial correction of alopecia, bone loss, and fat mass phenotypes associated with Cbs deficiency in mice. Our findings show that AAVrh.10-based gene therapy is highly effective in treating CBS deficiency in mice and supports additional pre-clinical testing for eventual use human trials.

Liver transplant as a curative treatment in a pediatric patient with classic homocystinuria: A case report.

We report a patient with homocystinuria and hyperoxaluria who was cured of homocystinuria-related disease following liver transplant. The patient was diagnosed with homocystinuria as a newborn and was treated with dietary modifications and supplements. At 22 months, he passed a calcium oxalate stone and was found to have numerous bilateral kidney stones. Genetic testing confirmed primary hyperoxaluria, type 1. He underwent preemptive liver transplant at age four to treat primary hyperoxaluria. Following transplant, his serum methionine and homocysteine levels normalized, thus, demonstrating resolution of homocystinuria. Methionine and homocysteine levels remained normal 6 years later. Homocystinuria is associated with ophthalmologic, skeletal, neurologic, and thromboembolic complications. As cystathionine beta-synthase resides in the liver, transplant was hypothesized to be an effective treatment. Primary hyperoxaluria generally progresses to chronic kidney disease and is treated with combined kidney-liver transplant at the time of end stage kidney disease. Given this patient's dual diagnoses, we proceeded with preemptive liver transplantation. Three prior cases of patients with homocystinuria treated with liver transplantation have been reported. In all cases, transplant resolved metabolic effects. However, our case represents a pediatric patient without disease-related complications prior to transplant. This case supports liver-targeted gene therapies as an effective treatment for homocystinuria.

The Spectrum of Mutations of Homocystinuria in the MENA Region.

Homocystinuria is an inborn error of metabolism due to the deficiency in cystathionine beta-synthase (CBS) enzyme activity. It leads to the elevation of both homocysteine and methionine levels in the blood and urine. Consequently, this build-up could lead to several complications such as nearsightedness, dislocated eye lenses, a variety of psychiatric and behavioral disorders, as well as vascular system complications. The prevalence of homocystinuria is around 1/200,000 births worldwide. However, its prevalence in the Gulf region, notably Qatar, is exceptionally high and reached 1:1800. To date, more than 191 pathogenic CBS mutations have been documented. The majority of these mutations were identified in Caucasians of European ancestry, whereas only a few mutations from African-Americans or Asians were reported. Approximately 87% of all CBS mutations are missense and do not target the CBS catalytic site, but rather result in unstable misfolded proteins lacking the normal biological function, designating them for degradation. The early detection of homocystinuria along with low protein and methionine-restricted diet is the best treatment approach for all types of homocystinuria patients. Yet, less than 50% of affected individuals show a significant reduction in plasma homocysteine levels after treatment. Patients who fail to lower the elevated homocysteine levels, through high protein-restricted diet or by B6 and folic acid supplements, are at higher risk for cardiovascular diseases, neurodegenerative diseases, neural tube defects, and other severe clinical complications. This review aims to examine the mutations spectrum of the CBS gene, the disease management, as well as the current and potential treatment approaches with a greater emphasis on studies reported in the Middle East and North Africa (MENA) region.

Treatment of Cystathionine ß-Synthase Deficiency in Mice Using a Minicircle-Based Naked DNA Vector.

Cystathionine ß-synthase (CBS) deficiency is a recessive inborn error of metabolism characterized by extremely elevated total homocysteine (tHcy) in the blood. Patients diagnosed with CBS deficiency have a variety of clinical problems, including dislocated lenses, osteoporosis, cognitive and behavioral issues, and a significantly increased risk of thrombosis. Current treatment strategies involve a combination of vitamin supplementation and restriction of foods containing the homocysteine precursor methionine. Here, a mouse model for CBS deficiency (Tg-I278T Cbs-/-) was used to evaluate the potential of minicircle-based naked DNA gene therapy to treat CBS deficiency. A 2.3 kb DNA-minicircle containing the liver-specific P3 promoter driving the human CBS cDNA (MC.P3-hCBS) was delivered into Tg-I278T Cbs-/- mice via a single hydrodynamic tail vein injection. Mean serum tHcy decreased from 351 µM before injection to 176 µM 7 days after injection (p = 0.0005), and remained decreased for at least 42 days. Western blot analysis reveals significant minicircle-directed CBS expression in the liver tissue. Liver CBS activity increased 34-fold (12.8 vs. 432 units; p = 0.0004) in MC.P3-hCBS-injected animals. Injection of MC.P3-hCBS in young mice, subsequently followed for 202 days, showed that the vector can ameliorate the mouse homocystinuria alopecia phenotype. The present findings show that minicircle-based gene therapy can lower tHcy in a mouse model of CBS deficiency.

Enzyme Replacement Therapy Ameliorates Multiple Symptoms of Murine Homocystinuria.

Classical homocystinuria (HCU) is the most common inherited disorder of sulfur amino acid metabolism caused by deficiency in cystathionine beta-synthase (CBS) activity and characterized by severe elevation of homocysteine in blood and tissues. Treatment with dietary methionine restriction is not optimal, and poor compliance leads to serious complications. We developed an enzyme replacement therapy (ERT) and studied its efficacy in a severe form of HCU in mouse (the I278T model). Treatment was initiated before or after the onset of clinical symptoms in an effort to prevent or reverse the phenotype. ERT substantially reduced and sustained plasma homocysteine concentration at around 100 µM and normalized plasma cysteine for up to 9 months of treatment. Biochemical balance was also restored in the liver, kidney, and brain. Furthermore, ERT corrected liver glucose and lipid metabolism. The treatment prevented or reversed facial alopecia, fragile and lean phenotype, and low bone mass. In addition, structurally defective ciliary zonules in the eyes of I278T mice contained low density and/or broken fibers, while administration of ERT from birth partially rescued the ocular phenotype. In conclusion, ERT maintained an improved metabolic pattern and ameliorated many of the clinical complications in the I278T mouse model of HCU.

Adult classical homocystinuria requiring parenteral nutrition: Pitfalls and management.

BACKGROUND: Homocystinuria due to cystathionine beta synthase (CBS) deficiency presents with a wide clinical spectrum. Treatment by the enteral route aims at reducing homocysteine levels by using vitamin B6, possibly methionine-restricted diet, betaine and/or folate and vitamin B12 supplementation. Currently no nutritional guidelines exist regarding parenteral nutrition (PN) under acute conditions. METHODS: Exhaustive literature search was performed, in order to identify the relevant studies describing the pathogenesis and nutritional intervention of adult classical homocystinuria requiring PN. Description of an illustrative case of an adult female with CBS deficiency and intestinal perforation, who required total PN due to contraindication to enteral nutrition. RESULTS: Nutritional management of decompensated classical homocystinuria is complex and currently no recommendation exists regarding PN composition. Amino acid profile and monitoring of total homocysteine concentration are the main tools enabling a precise assessment of the severity of metabolic alterations. In case of contraindication to enteral nutrition, compounded PN will be required, as described in this paper, to ensure adequate low amounts of methionine and others essential amino acids and avoid potentially fatal toxic hypermethioninemia. CONCLUSIONS: By reviewing the literature and reporting successful nutritional management of a decompensated CBS deficiency using tailored PN with limited methionine intake and n-3 PUFA addition, we would like to underscore the fact that standard PN solutions are not adapted for CBS deficient critical ill patients: new solutions are required. High methionine levels (>800 µmol/L) being potentially neurotoxic, there is an urgent need to improve our knowledge of acute nutritional therapy.

Manifestations of neurological symptoms and thromboembolism in adults with MTHFR-deficiency.

BACKGROUND: Methylenetetrahydrofolate-reductase (MTHFR) deficiency is a rare autosomal recessive disorder affecting intracellular folate metabolism with affection of different organ systems and clinical manifestation usually in childhood. OBJECTIVE: We report on four adult members of a family with MTHFR deficiency presenting with neurological and thromboembolic complications in adulthood. METHODS: Extensive diagnostic work-up including genetic testing was performed in four adult members. RESULTS: The male siblings aged 42 and 32years presented with various neurological symptoms, and a recent history of deep vein thrombosis. Extensive diagnostic work-up revealed total homocysteine (tHcy) plasma concentrations of 135µmol/L and 231µmol/L. and compound heterozygosity for two novel MTHFR gene mutations in exon 2 (c.202C>G, p.Arg68Gly) and intron 10 (c.1632+2T>G), and the known polymorphic variant MTHFR c.665C>T (p.Ala222Val, MTHFR 677C>T). Their mother was heterozygous for MTHFR c.1632+2T>G and c.665C>T, and a paternal relative was heterozygous for MTHFR c.202.C>G and MTHFR c.665C>T mutation. Both brothers showed partial response to therapy with betaine and multivitamins with clinical improvement. MTHFR activity was determined in fibroblast extracts and was around 4% of the mean control. Cell culture analysis indicated a re-methylation defect due to MTHFR deficiency. CONCLUSION: Severe hyperhomocysteinemia due to two mutations of the MTHFR gene resulted in severe neurological symptoms in adulthood. Vitamin and methionine supplementation stabilize tHcy plasma levels. Severity of clinical manifestation varied greatly between the siblings. Damages to the nervous system may be present for years before becoming clinically manifest.

[Outcomes of patients with combined methylmalonic acidemia and homocystinuria after treatment].

OBJECTIVE: Combined methylmalonic acidemia with homocystinuria is a common form of methylmalonic acidemia in China. Patients with this disease can progress to death without timely and effective treatment. This study aimed to analyze the treatment outcomes of patients with combined methylmalonic acidemia and homocystinuria. METHOD: From September 2004 to April 2012, 58 patients with combined methylmalonic acidemia and homocystinuria (34 males and 24 females) were diagnosed and treated in our hospital. Fifty cases were from clinical patients including 42 early-onset cases and 8 late-onset cases. Their age when they were diagnosed ranged from 18 days to 30.8 years. The other 8 cases were from newborn screening. All the patients were treated with vitamin B12, betaine, folic acid, vitamin B6, and L-carnitine. The physical and neuropsychological development, general laboratory tests, the levels of amino acids, acylcarnitines, and homocysteine in blood, and organic acids in urine were followed up. RESULT: The follow-up period ranged from 1 month to 7.1 years. Three cases died (all were early-onset cases). In the other patients after treatment, the symptoms such as recurrent vomiting, seizures, lethargy, and poor feeding disappeared, muscle strength and muscle tension were improved, and general biochemical abnormalities such as anemia and metabolic acidosis were corrected. Among the surviving 55 cases, 49 had neurological impairments such as developmental delay and mental retardation. The median levels of blood propionylcarnitine and its ratio with acetylcarnitine, serum homocysteine, and urine methylmalonic acid were significantly decreased (P < 0.01), from 7.73 µmol/L (ranged from 1.5 to 18.61 µmol/L), 0.74 (ranged from 0.29 to 2.06), 97.3 µmol/L (ranged from 25.1 to 250 µmol/L) and 168.55 (ranged from 3.66 to 1032.82) before treatment to 2.74 µmol/L (ranged from 0.47 to 12.09 µmol/L), 0.16 (ranged from 0.03 to 0.62), 43.8 µmol/L (ranged from 17 to 97.8 µmol/L) and 6.81 (ranged from 0 to 95.43) after treatment, respectively. CONCLUSION: Patients with combined methylmalonic acidemia and homocystinuria respond to a combined treatment consisting of supplementation of hydroxycobalamin, betaine, folic acid, vitamin B6 and L-carnitine with clinical and biochemical improvement. But the long-term outcomes are unsatisfactory, with neurological sequelae in most patients.

Homocysteine alters glutamate uptake and Na+,K+-ATPase activity and oxidative status in rats hippocampus: protection by vitamin C.

In the present study we investigate the effect of homocysteine on glutamate uptake, Na+,K+-ATPase, enzymatic antioxidant defenses, as well as reactive species levels in hippocampus of rats. The influence of vitamin C, a classic antioxidant, on the effects elicited by homocysteine was also tested. Results showed that chronic hyperhomocysteinemia decreased glutamate uptake and the activities of Na+,K+-ATPase, catalase and superoxide dismutase in hippocampus of rats. Reactive species levels were increased by chronic homocysteine administration. Concomitant administration of vitamin C significantly prevented these alterations caused by homocysteine. According to our results, it seems possible to suggest that the reduction in glutamate uptake and Na+,K+-ATPase activity may be mediated by oxidative stress, since vitamin C prevented these effects. We suggest that the administration of antioxidants should be considered as an adjuvant therapy to specific diet in homocystinuria.

Isolated remethylation disorders: do our treatments benefit patients?

Deficiency of 5,10-methylenetetrahydrofolate reductase (MTHFR), the very rare methionine synthase reductase (CblE) and methionine synthase (CblG) defects, and the recently identified CblD-variant-1 defect are primary remethylation defects characterized by an isolated defect in methionine synthesis without methylmalonic aciduria. The clinical signs are mainly neurological, and hematological signs are seen in CblE, CblG, and CblD-variant-1 defects. Patients with neonatal or early-onset disease exhibit acute neurological distress. Infants and children have unspecific mental retardation, often with acquired microcephaly. Without appropriate therapy, they may experience acute or rapidly progressive neurological deterioration, which may be fatal. Adolescents and adults show normal development or mild developmental delay initially and then experience rapid neurological or behavioral deterioration. A few patients may have signs of subacute combined degeneration of the spinal cord. Adults may be asymptomatic or present with isolated thromboembolism. All patients with suspected remethylation disorders should receive emergency treatment with parenteral administration of hydroxocobalamin and folate supplements combined with betaine orally. The long-term treatment of CblE, CblG, and CblD-variant-1 defects consists of parenterally administered hydroxocobalamin and orally administered folate and betaine supplements, whereas patients with MTHFR deficiency require long-term oral folate and betaine supplements. Long-term oral methionine therapy should also be considered. Early treatment may lead to a favorable outcome with developmental recovery and prevention of further neurological deterioration. In contrast, most late-treated patients have severe and irreversible neuromotor impairments. Hematological abnormalities are easily corrected.

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.

Classical homocystinuria: vascular risk and its prevention.

Homocystinuria due to cystathionine beta-synthase deficiency is the second most treatable aminoacidopathy. The reported incidence varies from 1 in 344,000 worldwide to 1 in 65,000 in Ireland. Untreated patients with homocystinuria have severe hyperhomocysteinaemia. Amongst its pathological sequelae, which include mental retardation, ectopia lentis and osteoporosis, vascular events remain the major cause of morbidity and mortality in untreated patients. Recognized modalities of treatment include pyridoxine, in combination with folic acid and vitamin B12; methionine-restricted, cystine-supplemented diet; and betaine. The natural history of vascular events is such that half will have an event before age 30 years and there is a predicted one event per 25 years at the time of maximal risk. In 158 patients with 2822 patient-years of treatment, there would be a predicted 112 events if left untreated, but instead only 17 vascular events were recorded during treatment (relative risk 0.09, 95% CI 0.036 to 0.228; p < 0.0001). Appropriate chronic treatment to lower hyperhomocysteinaemia is effective in reducing the potentially life-threatening vascular risk in patients with homocystinuria. These findings may also have relevance to the significance of mild hyperhomocysteinaemia that is commonly found in patients with premature vascular disease.

Homocystinuria due to cystathionine beta-synthase deficiency: novel biochemical findings and treatment efficacy.

To explore the pathogenesis of cystathionine beta-synthase (CBS) deficiency and to test the efficacy of pharmacological therapy we examined a panel of metabolites in nine homocystinuric patients under treated and/or untreated conditions. Off pharmacological treatment, the biochemical phenotype was characterized by accumulation of plasma total homocysteine (median 135 micromol/L) and blood S -adenosylhomocysteine (median 246 nmol/L), and by normal levels of guanidinoacetate and creatine. In addition, enhanced remethylation was demonstrated by low serine level (median 81 micromol/L), and by increased concentration of methionine (median 76 micromol/L) and N -methylglycine (median 6.8 micromol/L). Despite the substantially blocked transsulphuration, which was evidenced by undetectable cystathionine and severely decreased total cysteine levels (median 102 micromol/L), blood glutathione was surprisingly not depleted (median 1155 micromol/L). In 5 patients in whom pharmacological treatment was withdrawn, the differences of median plasma total homocysteine levels (125 micromol/L after withdrawal versus 33 micromol/L under treatment conditions), total cysteine levels (139 versus 211 micromol/L) and plasma serine levels (53 versus 103 micromol/L) on and off treatment demonstrated the efficacy of long-term pyridoxine/betaine administration ( p <0.05). The treatment also decreased blood S -adenosylhomocysteine level (133 versus 59 nmol/L) with a borderline significance. In summary,our study shows that conventional treatment of CBS deficiency by diet and pyridoxine/betaine normalizes many but not all metabolic abnormalities associated with CBS deficiency. We propose that the finding of low plasma serine concentration in untreated CBS-deficient patients merits further exploration since supplementation with serine might be a novel and safe component of treatment of homocystinuria.

Aproximación al tratamiento nutricional de los errores innatos del metabolismo (III) / Approaches to the dietary treatment of inborn errors of metabolism (III)

No disponibe (AU)

Homocystinuria due to cystathionine beta-synthase deficiency in Ireland: 25 years' experience of a newborn screened and treated population with reference to clinical outcome and biochemical control.

Homocystinuria (HCU) due to cystathionine beta-synthase deficiency (Mudd et al 1964) was independently described by Gerritsen and colleagues (USA) and Carson and colleagues (Northern Ireland) in 1962. The worldwide frequency of HCU has been reported as 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 programme for HCU in Ireland was started in 1971 using the bacterial inhibition assay. A total of 1.58 million newborn infants have been screened over a 25-year period up to 1996. Twenty-five HCU cases were diagnosed, 21 of whom were identified on screening. The remaining four HCU cases were missed and presented clinically; three of these were breast-fed and one was pyridoxine responsive. Twenty-four HCU cases were pyridoxine nonresponsive. Once the status of pyridoxine responsiveness was identified, all pyridoxine nonresponsive cases, but one, were started on a low methionine, cystine-enhanced diet supplemented with pyridoxine, vitamin B12 and folate. Dietary treatment commenced within 6 weeks of birth (range 8-42 days) for those cases detected by screening, while for the late-detected cases treatment was started upon presentation and diagnosis. Biochemical control was monitored measuring deproteinized plasma methionine, free homocystine and cystine at least once a month. Review of the clinical outcome of the 25 HCU cases with 365.7 patient-years of treatment revealed no HCU-related complications in 18 screened, dietary-treated cases. Fifteen of these had lifetime medians of free homocystine < or = 11 mumol/L (range 4-11). The remaining three cases with higher lifetime medians of free homocystine (18, 18 and 48 mumol/L) have developed increasing myopia recently. Among the three screened non-dietary-compliant cases, two have ectopia lentis, one has osteoporosis and two have mental handicap. Of the four cases missed on screening, three presented with ectopia lentis after the age of 2 years. There were no thromboembolic events in any of the 25 HCU cases. The lifetime medians for methionine ranged from 47 to 134 mumol/L. The Irish HCU clinical outcome data suggest that newborn screening, early commencement of dietary treatment and a lifetime median of free homocystine of < or = 11 mumol/L had significantly reduced the probability of developing complications when it was compared to the untreated HCU data (Mudd et al 1985).

Strategies for the treatment of cystathionine beta-synthase deficiency: the experience of the Willink Biochemical Genetics Unit over the past 30 years.

Strategies for the treatment of cystathionine beta-synthase (CBS) deficiency include (1) increasing residual enzyme activity by giving pyridoxine in those patients with vitamin responsive variants, (2) reducing the load on the affected pathway with a low methionine diet and supplementing the diet with cysteine; and (3) giving betaine in order to utilise alternative pathways to remove homocyst(e)ine. In our experience of over 30 years in the diagnosis and management of patients with CBS deficiency, a normal outcome can only be achieved in patients diagnosed and treated from infancy. Pyridoxine combined with folic acid prevents further deterioration in pyridoxine responsive patients. Dietary treatment of patients with non-pyridoxine responsive CBS deficiency becomes more difficult outside childhood but since late complications are not uncommon must be continued for life. Betaine can be effective in this group but compliance is often poor.

Thiamine (vitamin B1) supplementation does not reduce fasting blood homocysteine concentration in most homozygotes for homocystinuria.

Homozygotes for homocystinuria due to cystathionine synthase (CS) deficiency accumulate homocysteine and methionine in their blood and tissues. High-dose pyridoxin, folic acid, vitamin B12, or betaine are therapeutical options to lower the elevated homocysteine concentration. These compounds stimulate the transsulfuration or remethylation of homocysteine. Despite such treatment, elevated blood homocysteine concentrations may persist in many homocystinurics. Therefore, it is warranted to study alternative regimen to reduce the blood homocysteine concentration in homocystinurics. Apart from entering the transsulfuration pathway, methionine can be catabolized via the transamination pathway, by conversion into 4-methylthio-2-oxobutyrate (MTOB), followed by oxidative decarboxylation of MTOB to 3-methylthiopropionate. Thiamine pyrophosphate, the active form of thiamine, is a cofactor of the supposed rate-limiting oxidative decarboxylation in the transamination of methionine. The effect of thiamine administered in 2 or 3 daily doses of 25 mg orally, was studied in nine homozygote CS deficient patients. Methionine levels decreased in 6 out of 9 patients. In 8 out of 9 patients, however, the levels of plasma homocysteine remained virtually unchanged, as did the serum transamination metabolites in all patients. We conclude that vitamin B1 cannot be used as an additional homocysteine-lowering treatment in most homozygotes for homocystinuria.

Homocysteine and coronary artery disease.

BACKGROUND: Homocystinuria is a rare autosomal recessive disease complicated by early and aggressive occlusive arterial disease. This may be related to the grossly increased homocysteine concentrations seen in this disease. More recently, milder hyperhomocysteinemia has been proposed as an independent risk factor for coronary artery disease. SUMMARY: Many patients with homozygous homocystinuria develop severe premature atherosclerosis and thromboembolism, probably caused by abnormally high concentrations of homocysteine. Homocysteine undergoes metabolism either by remethylation or transsulfuration, and deficiency or dysfunction of any of the substances that regulate these reactions may lead to hyperhomocysteinemia. Homocysteine may have adverse effects on platelets, clotting factors, and endothelial cells. Studies have demonstrated significantly higher plasma homocysteine levels in patients with occlusive arterial disease than in controls. The causes are not clearly understood but may include deficiency of vitamin B6, vitamin B12, and folic acid and heterozygosity for cystathionine synthase deficiency. Vitamin supplementation can lower plasma homocysteine levels. CONCLUSIONS: Whether measuring plasma homocysteine levels in patients with coronary artery disease should be routine and whether treating hyperhomocysteinemia in these patients may reduce the risk of coronary events remains to be determined.

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.