1/130. Fatal haemorrhagic infarct in an infant with homocystinuria. Thrombotic and thromboembolic complications are the main causes of morbidity and mortality in patients with homocystinuria. However, it is unusual for thrombosis and infarction to be the presenting feature leading to investigation for homocystinuria and cerebrovascular lesions in the first year of life. We describe a previously healthy 6-month-old infant who presented with a large middle-cerebral-artery territory infarction and died of massive brain swelling. homocystinuria due to cystathionine beta-synthase (CBS) deficiency was diagnosed by metabolite analysis and confirmed by enzymatic activity measurement in a postmortem liver biopsy. homocystinuria should be considered in the differential diagnosis of venous or arterial thrombosis, regardless of age, even in the absence of other common features of the disease. We recommend systematic metabolic screening for hyperhomocysteinemia in any child presenting with vascular lesions or premature thromboembolism. ( info) |
2/130. Mutational analysis of the cystathionine beta-synthase gene: a splicing mutation, two missense mutations and an insertion in patients with homocystinuria. Mutations in brief no. 120. Online. RT-PCR and direct sequence analyses were used to define mutations in the cystathionine beta-synthase (CBS) gene in two unrelated male patients with vitamin B6 nonresponsive homocystinuria. Both patients were compound heterozygotes for CBS alleles containing point mutations. One patient had a maternally derived G->A transition in the splice-donor site of intron 1, resulting in aberrant splicing of CBS mRNA. The other allele contained a missense mutation resulting in the previously reported E144K mutant CBS protein. The second patient had a maternally derived 4 bp insertion in exon 17, predicted to cause a CBS peptide of altered amino acid sequence. A 494G->A transition was found in exon 4 of the other allele, predicting a C165Y substitution. Expression of recombinant CBS protein, containing the C165Y mutation, had no detectable catalytic activity. Each mutation was confirmed in genomic dna. ( info) |
3/130. homocystinuria and psychiatric disorder: a case report. Deficiency of cystathionine beta-synthase (CBS) is the commonest cause of primary homocystinuria. Homocysteine metabolism is intimately linked with the metabolism of folate, vitamin B12 (cobalamin) and pyridoxine. It is hypothesised that the pathogenesis of neuropsychiatric manifestations in homocystinuria, folate and cobalamin deficiencies are related to imbalance neurotransmitters in the CNS through disturbances in the pathways linking the metabolism of homocysteine and these vitamins. Although neuropsychiatric disorders are relatively common among patients with homocystinuria, it is not well recognised as the causative factor among patients presenting with neuropsychiatric disorders. A 31 year old woman presented with a three week history of delirium and inappropriate and labile affect. There was no history suggestive of drug or alcohol abuse, nutritional deficiency or organic disorders. EEG, cerebral CT, MRI and microbiological investigations did not reveal any organic causes. Because of a diagnosis of pyridoxine-responsive homocystinuria seven years previously, the possibility of homocystinuria was considered and investigated. Laboratory tests revealed macrocytosis and a high concentration of urinary total homocystine. Commencement of pyridoxine at 400 mg/day resulted in disappearance of homocystine in urine within four days with remarkable clinical improvement. homocystinuria should be considered in the differential diagnosis of unexplained neuropsychiatric disorders in patients who have past or family history of homocystinuria, mental retardation, thromboembolic episodes, vascular diseases or clinical and laboratory features resembling folate and/or vitamin B12 deficiencies. homocystinuria-associated neuropsychiatric disturbances can easily be treated with pyridoxine in 50% of cases. ( info) |
| The first case in the dental literature of congenital contractural arachnodactyly (C.C.A. syndrome) is presented. This newly delineated syndrome is an autosomal dominant heritable disorder of connective tissue. Its similarities to Marfan's syndrome and homocystinuria, as well as other syndromes, are discussed. The lack of cardiovascular disease, specific ocular anomalies, and mental retardation are presented in the differential diagnosis of the C.C.A syndrome with Marfan's syndrome and homocystinuria. ( info) |
| PURPOSE: To determine the successful treatment of unilateral phacolytic glaucoma by vitrectomy and trabeculectomy in a patient with homocystinuria whose lens had dislocated into the vitreous at least 15 years earlier. methods: In a 32-year-old woman with homocystinuria, bilateral dislocation of the lens into the vitreous, and phacolytic glaucoma in her left eye a three-port pars plana vitrectomy was performed with the patient under general anesthesia. The lens was removed and a trabeculectomy fashioned. Special precautions for general anesthesia included preoperative aspirin and compression stockings for thromboembolic prophylaxis and intraoperative dextrose infusion, 5%, to maintain intravascular volume and prevent hypoglycemia. RESULTS: The intraocular pressure and uveitis resolved postoperatively with improvement in the visual acuity and intraocular pressure, which returned to normal without further treatment. CONCLUSIONS: Phacolytic glaucoma is best resolved by removal of the exciting lens material. Pars plana vitrectomy with the patient under general anesthesia can be carried out safely despite the risks traditionally associated with homocystinuria. ( info) |
6/130. Molecular genetic analysis of pyridoxine-nonresponsive homocystinuric siblings with different blood methionine levels during the neonatal period. Two mutations in the cystathionine beta-synthase (CBS) gene were found in two Japanese siblings with pyridoxine non-responsive homocystinuria who had different methionine levels in their blood during the neonatal period. Both patients were compound heterozygotes of two mutant alleles: one had an A-to-G transition at nucleotide 194 (A194 G) that caused a histidine-to-arginine substitution at position 65 of the protein (H65R), while the other had a G-to-A transition at nucleotide 346 (G346A) which resulted in a glycine-to-arginine substitution at position 116 of the protein (G116R). The two mutant proteins were separately expressed in escherichia coli, and they completely lacked catalytic activity. Despite their identical genotypes and almost equal protein intake, these siblings showed different levels of blood methionine during the neonatal period, suggesting that the level of methionine in blood is determined not only by the defect in the CBS gene and protein intake, but also by the activity of other enzymes involved in methionine and homocysteine metabolism, especially during the neonatal period. Therefore, high-risk newborns who have siblings with homocystinuria, even if the level of methionine in their blood is normal in a neonatal mass screening, should be followed up and diagnosed by an assay of enzyme activity or a gene analysis so that treatment can be begun as soon as possible to prevent the development of clinical symptoms. In addition, a new, more sensitive method for the mass screening of CBS deficiency in neonates should be developed. ( info) |
7/130. Vasospasmus: a rare manifestation of homocystinuria. We report about a patient suffering from multiple spastic stenoses of varying degree of both iliac arteries and from occlusion of the left tibiofibular trunc. Laboratory investigations revealed increased levels of homocysteine and the diagnosis of homocystinuria was confirmed by fibroblast cell culture. The spasms responded well to vasodilative therapy with nitroglycerine, molsidomine (cGMP mediated) and prostaglandine E1 but not with nifedipine (Ca influx blocker). Our review of literature demonstrated that this arterial spastic abnormality is a very rare complication in patients suffering from homocystinuria. ( info) |
| homocystinuria types I, II and III are characterized by different etiologies, biochemical abnormalities and therapeutic measures. For this reason, differential diagnosis is critical for effective treatment. We describe here a rapid and simple procedure for establishing a differential diagnosis of the three types of homocystinuria by analyzing the urine of patients. This procedure, which consists of urease treatment, stable isotope dilution and GC-MS, enables a simultaneous quantification of methionine, homocystine, cystine, methylmalonate, orotate, uracil and creatinine. Analysis with this procedure showed that a case of homocystinuria type I, who progressed into transient megaloblastic anemia, secondarily excreted an increased concentration of orotate, which normalized after treatment with folate and vitamin B12. Therefore, the present diagnostic procedure not only enables rapid differential diagnosis of homocystinuria, but also should prove useful for monitoring the disease state and understanding the nutritional condition and therapeutic state of patients, which in turn can be used to evaluate the efficacy of treatment. ( info) |
9/130. Methylenetetrahydrofolate reductase deficiency: importance of early diagnosis. Methylenetetrahydrofolate reductase deficiency is the most common inborn error of folate metabolism and should be suspected when homocystinuria is combined with hypomethioninemia. The main clinical findings are neurologic signs such as severe developmental delay, marked hypotonia, seizures, microcephaly, apnea, and coma. Most patients present in early life. The infantile form is severe, with rapid deterioration leading to death usually within 1 year. Treatment with betaine has been shown to be efficient in lowering homocysteine concentrations and returning methionine to normal, but the clinical response is variable. We report two brothers with methylenetetrahydrofolate reductase deficiency: the first was undiagnosed and died at 8 months of age from neurologic deterioration and apnea, while his brother, who was treated with betaine from the age of 4 months, is now 3 years old and has developmental delay. ( info) |
| PURPOSE: To report the association of optic atrophy with cobalamin C (cblC) disease. methods: Descriptive case reports on three patients, two of whom were siblings. RESULTS: All three patients with cblC disease exhibited bilateral optic atrophy with decreased visual acuity. Of the two siblings, the younger sister had received cobalamin supplements from birth and the mother had been given cobalamin supplements prenatally. CONCLUSION: These three cases confirm the association of optic atrophy with cblC disease. Early treatment with cobalamin supplements does not appear to prevent the development of optic atrophy. ( info) |