Introduction
Background
Homocystinuria is an inherited autosomal recessive defect in methionine metabolism that is caused by a deficiency in cystathionine synthase. This defect leads to a multisystemic disorder of the connective tissue, muscles, CNS, and cardiovascular system. Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of homocysteine in the serum and an increased excretion of homocysteine in the urine.
In 1960, the first case of homocystinuria was reported from Northern Ireland. The patient was initially described as having an unusual case of Marfan syndrome with renal abnormalities at age 7 years. He had recovered from acute glomerulonephritis at age 6 years and was found to be hypertensive the following year. The patient was mentally slow and thin and had fair hair, pale skin, and flushed cheeks. He had arachnodactyly, dolichostenomelia, pes cavus, a high arched palate, and bilaterally dislocated lenses. At age 10 years, the patient's urine was found to contain a large quantity of homocysteine; urinalysis results for the nitroprusside cyanide test were positive. The boy's left eye was enucleated because of a staphylococcal infection that occurred after acute pupillary-block glaucoma developed. His right lens became dislocated into the anterior chamber and had to be removed.
The patient's blood pressure readings normalized after his left kidney was removed when he was aged 13 years. Thick-walled internal arteries were noted at histologic examination. When pyridoxine supplementation was initiated at age 18 years, the patient's plasma homocysteine levels decreased below the reference range. Daily folic acid supplementation was added 1 year later because his plasma folate level was low. At age 20 years, the patient had a perforated duodenal ulcer. Chest pain occurred at age 27 years and recurred at age 34 years. The chest pain was considered to be angina and was successfully treated. At age 50 years, the patient's plasma homocysteine levels still remained low. The patient developed acute gout, which responded to indomethacin therapy.
Pathophysiology
Homocysteine is metabolized by means of 2 pathways: remethylation and transsulfuration.The remethylation pathway comprises 2 intersecting biochemical pathways and results in the transfer of a methyl group (CH3) to homocysteine from methylcobalamin, which receives its methyl group from S-adenosylmethionine (SAM), from 5-methyltetrahydrofolate (an active form of folic acid), or from betaine (trimethylglycine). Methionine can then be used to produce SAM, the body's universal methyl donor, which participates in several other key metabolic pathways, including the methylation of DNA and myelin.
The transsulfuration pathway of methionine/homocysteine degradation produces the amino acids cysteine and taurine. This pathway is dependent on adequate intake of vitamin B-6 and the hepatic conversion of vitamin B-6 into its active form, pyridoxal-5'-phosphate (P5P). The amino acid serine, which is a downstream metabolite generated from betaine via the homocysteine remethylation pathway is another necessary step.
Folate and vitamin B-12 are required for the remethylation of homocysteine to methionine. Findings from experimental studies have indicated that thyroid hormones affect folate metabolism. The observation that methylenetetrahydrofolate reductase is increased in hyperthyroidism and decreased in hypothyroidism may be relevant to the relationship between plasma homocysteine levels and thyroid status.
Women tend to have lower basal levels of homocysteine than do men, and neither contraceptives nor hormone replacement therapy seems to significantly alter the levels. Homocysteine concentrations are higher in postmenopausal women than in premenopausal women.
On the basis of the type of homocystinuria, the following 3 nosologic units are distinguished:
- Homocystinuria can be caused by the deficiency of cystathionine synthase. This is the classic form. The gene for this deficiency is located on band 21q22.3. This unit includes the following forms: vitamin B-6 sensitivity (1.5% enzymatic activity), vitamin B-6 resistance (0% enzymatic activity), an intermediate variant, and a benign variant.
- Homocystinuria can be caused by insufficient vitamin B-12 synthesis resulting from a defect in the remethylation of homocysteine to methionine; methylmalonic aciduria is present.
- Homocystinuria can be caused by a deficiency in methylenetetrahydrofolate reductase. The methionine level is in the reference range.
Urine methionine and homocysteine levels are elevated because of deficient levels of cystathionine beta-synthase. In addition to this, at least 7 causes of homocystinuria are known: (1) defect in vitamin B-12 metabolism, (2) deficiency in N -5,10-methylenetetrahydrofolate reductase, (3) selective intestinal malabsorption of vitamin B-12, (4) homocystinuria responsive to vitamin B-12 (cobalamin [cbl] type E), (5) methylcobalamin deficiency with cbl type G, (6) type 2 vitamin B-12 metabolic defect, and (7) transcobalamin II deficiency.
The basis of the disease is a defect of the gene coding for L-serine dehydratase cystathionine synthase, which converts homocysteine and serine into cystathionine. Deficient activity of this enzyme has been demonstrated in liver extracts, in brain tissue, and in cultured skin fibroblasts and lymphocytes. The deficiency leads to an accumulation of homocysteine and methionine and to its conversion into homocysteine, which is excreted in the urine (Legal test results are positive). Alternatively, methionine is reformed and detectable in appreciable amounts in the urine and serum. The accumulation of homocysteine leads to damage of the collagen and elastic fibers. The binding of homocysteine to lysine residues results in the formation of thiazine bonds.
DL-homocysteine inhibits the production of tyrosinase, which is the major pigment enzyme. Increased concentrations of the methionine metabolite are toxic to the nervous system. Histologic analysis of brain tissue specimens from patients with homocystinuria reveals local foci of gliosis and necrosis.
In 1985, Mudd et al studied hybrid cells of human fibroblasts with normal cystathionine beta-synthase activity and hamster cells without enzyme activity and found that enzyme activity was co-segregated with chromosome 21.1 Two other enzymes involved in sulfur amino acid metabolism have been mapped: 5-methyltetrahydrofolate and L-homocysteine S-methyltransferase are mapped to chromosome 1, and cystathionase is mapped to chromosome 16.2
In cases of genetic deletion and partial trisomy, the levels of activity are consistent with the locus of cystathionine beta-synthase (CBS) between bands 21q22.1 and 21q21. As reported in the study of fibroblasts, 3 types of cystathionine synthetase deficiency exist; these include types with reduced activity and normal affinity for P5P and types with reduced activity and reduced affinity for the cofactor.
The human CBS gene spans more than 30 kilobases and contains 19 exons. Three different 5' untranslated regions exist in the gene.
Molecular analysis of the methionine synthase reductase (MTRR) gene in one patient reveals compound heterozygosity for a transition c.1459G>A (G487R) and a 2–base pair (bp) insertion (c.1623-1624insTA). Another patient was homozygous for a 140-bp insertion (c.903-904ins140). The insertion is caused by a T>C transition within intron 6 of the MTRR gene, which presumably leads to activation of an exon splicing enhancer. These findings support the concept that this disorder is caused by mutations in the MTRR gene.
Four different mutations were identified in patients in the United Kingdom (c.374G>A, R125Q; c.430G>A, E144K; c.833T>C, I278T; c.919G>A, G307S) and 8 mutations were identified in patients from the United States (c.341C>T, A114V; c.374G>A, R125Q; c.785C>T, T262M; c.797G>A, R266K; c.833T>C, I278T; c.919G>A, G307S; g.13217A>C (del ex 12); c.1330G>A, D444N).3 The I278T was the predominant mutation in both populations. The spectrum of mutations observed in patients from the United Kingdom and the United States is closer to that observed in Northern Europe and bears less resemblance to that observed in Ireland.
Severe deficiency of glycine N -methyltransferase (GNMT) activity due to apparent homozygosity for a novel mutation in the gene encoding this enzyme that changes asparagine-140 to serine can be another cause of hypermethioninemia.4
To date, 130 pathogenic mutations have been recognized in the CBS gene. In 2004, Orendae examined 10 independent alleles in Polish patients with cystathionine beta-synthase deficiency.5 They detected 4 already described mutations (c.1224-2A>C, c.684C>A, c.833T>C, and c.442G>A) and 2 novel mutations (c.429C>G and c.1039+1G>T). The pathogenicity of the novel mutations was demonstrated by expression in Escherichia coli. This is the first published communication on mutations leading to cystathionine beta-synthase deficiency in Poland.
Fibrillin-1 is a 350-kd calcium-binding protein that assembles to form 10- to 12-nm microfibrils in the extracellular matrix. The structure of fibrillin-1 is dominated by 2 types of disulfide-rich motifs, the calcium-binding epidermal growth factorlike and transforming growth factor beta binding proteinlike domains. Disruption of fibrillin-1 domain structure and function contributes to the pathogenic mechanisms of homocystinuria.6
Methylmalonic aciduria and homocystinuria, combined methylmalonic aciduria and homocystinuria (cblC) type, is the most frequent inborn error of vitamin B-12 metabolism. The gene responsible for cblC, MMACHC, has been identified. Several observations on ethnic origins were noted: the c.331C>T mutation is seen in Cajun and French-Canadian patients and the c.394C>T mutation is common in the Asiatic-Indian/Pakistani/Middle Eastern populations. The recognition of phenotype-genotype correlations and the association of mutations with specific ethnicities will be useful for identification of disease-causing mutations in cblC patients, for carrier detection, and for prenatal diagnosis in families in which mutations are known.7,8,9
The cblD gene is localized to 2q23.2, and a candidate gene, designated MMADHC (methylmalonic aciduria, cblD type, and homocystinuria), was identified in this region. Transfection of wild-type MMADHC rescued the cellular phenotype, and the functional importance of mutant alleles was shown by means of transfection with mutant constructs. The predicted MMADHC protein has sequence homology with a bacterial ATP-binding cassette transporter and contains a putative cobalamin-binding motif and a putative mitochondrial targeting sequence. Mutations in a gene designated MMADHC are responsible for the cblD defect in vitamin B-12 metabolism. Various mutations are associated with each of the 3 biochemical phenotypes of the disorder.10
Using data from 7038 Hordaland Homocysteine Study participants, tCys concentrations show a strong positive association with body mass index, mediated through fat mass. The link between cysteine and lipid metabolism deserves further investigation.11
The common polymorphism of the MTHFR gene, c.677C>T, a known risk factor for elevated plasma homocysteine levels, occurs frequently in the white persons. The sequence alteration c.677C>T combined with severe MTHFR mutations in a compound heterozygous state may lead to moderate biochemical and clinical abnormalities, exceeding those attributed to the c.677TT genotype, and might require, in addition to folate substitution, further therapy to normalize homocysteine levels.12,13
Jakubowski et al showed that plasma N -Hcy-protein levels are significantly elevated in CBS - and MTHFR -deficient patients and that CBS -deficient patients have significantly elevated plasma levels of prothrombotic N -Hcy-fibrinogen.14 These results provide a possible explanation for the increased atherothrombosis observed in CBS -deficient patients.
Frequency
United States
Homocystinuria is rare.
International
Homocystinuria rarely occurs. The worldwide frequency is reported to be 1 case per 344,000 population.
In Ireland, the frequency is higher, specifically 1 case per 65,000 population based on newborn screening and clinically detected cases. A surprisingly high prevalence of the CBS 833T-C mutation was detected among newborns who did not carry the 844ins68 variant, which is known to neutralize the 833T-CV mutation. This finding led some authors to suggest that the incidence of homocystinuria due to homozygosity for the mutation may be at least 1 case per 20,500 live births in Denmark.
Hypermethioninemia was reported in Korea in 2 compound heterozygous siblings with deficient activity of methionine adenosyltransferase (MAT) in their livers (MAT I/III deficiency). Molecular genetic studies demonstrate that each patient is a compound heterozygote for 2 mutations in MAT1A, the gene that encodes the catalytic subunit that composes MAT I and MAT III. These mutations include a previously known inactivating G378S point mutation and a novel W387X truncating mutation. W387X mutant protein, expressed in E coli and purified, has about 75% of wild-type activity.
Mortality/Morbidity
- The life expectancy of patients with homocystinuria is reduced.
- Almost one fourth of patients die as a result of thrombotic complications (eg, heart attack) before they are aged 30 years.
Sex
The disease is more common in males than in females.
Age
This condition is congenital.
Clinical
History
- Neurologic features
- An infant with homocystinuria is usually healthy, although thromboembolic complications of the CNS and psychomotor delay may occur during the first year of life.
- A developmental delay is noted when patients are aged 2-3 years.
- Psychiatric symptoms are also described in approximately one half of patients with homocystinuria.
- Pyramidal symptoms, including muscle weakness due to an insult to the innervation of the pyramidal motor tract neurons, are occasionally observed in areas such as the leg.
- Homocystinuria should be included in the differential diagnosis of children with acute/subacute neurological changes, particularly in the context of developmental delay.
- Skeletal and muscular features
- The characteristic long thin extremities and arachnodactyly may not appear until late in childhood or during adolescence.
- In contrast, osteoporosis, especially that of the spine, may have already been present for some time.
- Ophthalmologic features
- Severe myopia is the first sign of ectopia lentis and may precede lens dislocation by several months to a year or even longer.
- Once established, ectopia lentis progresses, even when good biochemical control is maintained.
- Vascular features
- Thromboembolic events, such as cerebrovascular occlusions or pulmonary emboli, usually do not occur until adulthood but are reported in childhood and infancy.
- Vascular occlusive disease is an important and serious feature.
- Other features
- Homocystinuria produces high concentrations of amino acids that are competitive inhibitors of tyrosinase.
- Accordingly, homocystinuria is associated with pale and pink skin. Occasionally, patients have malar rashes, fine fragile hair, and livedo reticularis.
Physical
Marfan syndrome is the primary differential diagnosis. Clinical features of homocystinuria, such as ectopia lentis, dolichocephalia, and chest and spinal deformities, are similar to the features found in patients with Marfan syndrome, although the cerebral symptoms, the changes in the hair, and the disorders of mental development are absent in patients with Marfan syndrome. Generalized osteoporosis, arterial and venous thrombosis, and mental retardation, which are features of homocystinuria, do not occur in patients with Marfan syndrome. In addition, homocysteine is not detectable in the urine of patients with Marfan syndrome.
Findings in homocystinuria include the following:
- Skin findings
- Buccal skin shows red macules in children, adolescents, and adults, especially those living in warm environments.
- Large pores are evident on the facial skin.
- A livedolike pattern of blood vessels and atrophic, small, cigarette paper–like scars may be observed on the arms and hands.
- Angiomata may develop in some patients.
- DL-homocysteine inhibits tyrosinase, the major pigment enzyme. Hypopigmentation may be reversible in patients with pyridoxine-responsive homocystinuria.
- Pigmentary dilution is observed in patients with homocystinuria. Therefore, an increase of local homocysteine may interfere with normal melanogenesis and may play a role in the pathogenesis of vitiligo. Vitamin B-12 and folic acid, levels of which are decreased in persons with vitiligo, are important cofactors in the metabolism of homocysteine. Shaker and El-Tahlawi found out that an elevated homocysteine level was higher in male patients than in female patients and higher in patients with progressive disease.15 No significant difference in homocysteine levels was found between either untreated vitiligo patients or patients receiving UV therapy. An elevated homocysteine level may be a precipitating factor for vitiligo in predisposed individuals.
- The hair can have a coarse texture. Hair stained with acridine orange produces orange-red fluorescence, whereas healthy hair produces green fluorescence.
- Hyperhidrosis, dry skin, and acrocyanosis may be present.
- Neurologic findings
- Patients may behave aggressively.
- Intelligence is slightly diminished, but in approximately one third of patients, intelligence is in the normal range.
- Patients' mental capabilities have been reported to be higher in conditions that respond to pyridoxine supplementation than others.
- Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency may manifest with variable neurologic manifestations. Radiologic features include white matter changes (leukoencephalopathy).16
- Muscular hypotonia is characteristic.
- Increased homocysteine levels have been detected in persons with neurological disorders such as Alzheimer disease, idiopathic Parkinson disease, Huntington disease, primary dystonia, and neural tube defects.
- Skeletal and muscular findings
- Signs of Marfan syndrome, such as thin and long extremities, arachnodactylia, kyphoscoliosis, and deformations of the thorax, may be present.
- Osteoporosis, genua valga, pectus carinatum (excavatum), and deformed teeth can be present.
- The homocysteine concentration is an important risk factor for hip fractures in Parkinson disease patients receiving levodopa.17
- Inguinal and umbilical hernias are observed.
- Muscular hypotonia is characteristic.
- Spasms may occur.
- Ophthalmologic findings
- Ophthalmologic findings are similar to those in patients with Marfan syndrome.
- Ectopia lentis is an almost universal feature in patients older than 10 years, and it can even be present in newborns.
- Other findings include myopia, iridopathy, cataracts, secondary glaucoma, and degeneratio (amotio) retinae.
- Atrophy of the optic nerve, strabismus, nystagmus, or diminished convergence can occur in some patients.
- Dislocation of the ocular lenses usually occurs in patients aged 4-10 years.
- Ocular phenotype in patients with cblC is variable.18 Ocular involvement seems to be correlated with age at onset. Patients with early-onset cblC developed generally progressive retinal disease ranging from subtle retinal nerve fiber layer loss to advanced macular and optic atrophy with bone-spicule pigmentation. Patients with late-onset disease showed no definite evidence of retinal degeneration.
- Retinal dysfunction in cblC disease may be more common than previously thought and can involve cones only or both rods and cones. Gaillard et al recommend a formal ocular examination with full-field electroretinography in patients with Cblc disease.19
- Vascular findings
- Vascular changes mainly affect the lower extremities. Fatal arterial and venous thromboses may occur.
- Hyperhomocysteinemia is an independent risk factor for atherosclerotic heart disease.
- Patients with homocystinuria resulting from a deficiency of cystathionine beta-synthase have an increased risk of thrombosis when they also have the Leiden mutation for factor V.
- Homocysteine induces tissue factor procoagulant activity in cultured human endothelial cells.
- Reduced survival and abnormally rapid turnover of platelets, fibrinogen, and plasminogen have been noted in patients with homocystinuria.
- Other findings
- A slightly foul odor of the urine is typical.
- Spontaneous pneumothorax is reported in some adolescents with homocystinuria.
- Pancreatitis is described as a complication of homocystinuria.
- Increased homocysteine levels are implicated in a variety of other clinical conditions, including neural tube defects, spontaneous abortion, placental abruption, renal failure, diabetic microangiopathy, and premenstrual syndrome.
- Children with autism might have lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of S-adenosylhomocysteine (SAH), adenosine, and oxidized glutathione. This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with autism. An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.20
- Cystathionine beta-synthase is encoded on chromosome 21, and deficiency in its activity causes homocystinuria. The most common genetic cause of mental retardation is trisomy 21 or Down syndrome. The levels of cystathionine beta-synthase in the brains of persons with Down syndrome are approximately 3 times greater than those in healthy individuals.21 The over-expression of cystathionine beta-synthase may cause the developmental abnormality in cognition in Down syndrome children and that may lead to Alzheimer-type disease in Down syndrome adults.
- Vascular disease is associated with increased plasma asymmetric dimethylarginine and homocysteine, and levels of both are increased in persons with renal failure. The relationship between hyperhomocysteinemia and increased plasma asymmetric dimethylarginine may not be direct, but could be secondary do reduced renal function.22
- Snyderman reports a case of a homocystinuric patient with development of paraparesis and increasing liver failure.23 A liver transplantation was successful in achieving metabolic control without the need for any dietary restrictions.
Causes
See Pathophysiology.
More on Homocystinuria |
 Overview: Homocystinuria |
| Differential Diagnoses & Workup: Homocystinuria |
| Treatment & Medication: Homocystinuria |
| Follow-up: Homocystinuria |
| References |
| Next Page » |
References
Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. Jan 1985;37(1):1-31. [Medline].
Finkelstein JD. Inborn errors of sulfur-containing amino acid metabolism. J Nutr. Jun 2006;136(6 Suppl):1750S-1754S. [Medline].
Vyletal P, Sokolova J, Cooper DN, et al. Diversity of cystathionine beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion. Hum Mutat. Mar 2007;28(3):255-64. [Medline].
Augoustides-Savvopoulou P, Luka Z, Karyda S, et al. Glycine N -methyltransferase deficiency: a new patient with a novel mutation. J Inherit Metab Dis. 2003;26(8):745-59. [Medline].
Orendae M, Pronicka E, Kubalska J, et al. Identification and functional analysis of two novel mutations in the CBS gene in Polish patients with homocystinuria. Hum Mutat. Jun 2004;23(6):631. [Medline].
Whiteman P, Hutchinson S, Handford PA. Fibrillin-1 misfolding and disease. Antioxid Redox Signal. Mar-Apr 2006;8(3-4):338-46. [Medline].
Morel CF, Lerner-Ellis JP, Rosenblatt DS. Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations. Mol Genet Metab. Aug 2006;88(4):315-21. [Medline].
Baumgartner ER, Wick H, Maurer R, et al. Congenital defect in intracellular cobalamin metabolism resulting in homocysteinuria and methylmalonic aciduria. I. Case report and histopathology. Helv Paediatr Acta. 1979;34(5):465-82. [Medline].
Zavadakova P, Fowler B, Zeman J, et al. CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families. J Inherit Metab Dis. Oct 2002;25(6):461-76. [Medline].
Coelho D, Suormala T, Stucki M, et al. Gene identification for the cblD defect of vitamin B12 metabolism. N Engl J Med. Apr 3 2008;358(14):1454-64. [Medline].
Elshorbagy AK, Nurk E, Gjesdal CG, et al. Homocysteine, cysteine, and body composition in the Hordaland Homocysteine Study: does cysteine link amino acid and lipid metabolism?. Am J Clin Nutr. Sep 2008;88(3):738-46. [Medline].
Rummel T, Suormala T, Haberle J, et al. Intermediate hyperhomocysteinaemia and compound heterozygosity for the common variant c.677C>T and a MTHFR gene mutation. J Inherit Metab Dis. Jun 2007;30(3):401. [Medline].
Bishop L, Kanoff R, Charnas L, Krenzel C, Berry SA, Schimmenti LA. Severe methylenetetrahydrofolate reductase (MTHFR) deficiency: a case report of nonclassical homocystinuria. J Child Neurol. Jul 2008;23(7):823-8. [Medline].
Jakubowski H, Boers GH, Strauss KA. Mutations in cystathionine beta-synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans. FASEB J. Dec 2008;22(12):4071-6. [Medline].
Shaker OG, El-Tahlawi SM. Is there a relationship between homocysteine and vitiligo? A pilot study. Br J Dermatol. Sep 2008;159(3):720-4. [Medline].
Tallur KK, Johnson DA, Kirk JM, et al. Folate-induced reversal of leukoencephalopathy and intellectual decline in methylene-tetrahydrofolate reductase deficiency: variable response in siblings. Dev Med Child Neurol. Jan 2005;47(1):53-6. [Medline].
Sato Y, Iwamoto J, Kanoko T, Satoh K. Homocysteine as a predictive factor for hip fracture in elderly women with Parkinson's disease. Am J Med. Nov 2005;118(11):1250-5. [Medline].
Gerth C, Morel CF, Feigenbaum A, Levin AV. Ocular phenotype in patients with methylmalonic aciduria and homocystinuria, cobalamin C type. J AAPOS. Dec 2008;12(6):591-6. [Medline].
Gaillard MC, Matthieu JM, Borruat FX. Retinal dysfunction in combined methylmalonic aciduria and homocystinuria (Cblc) disease: a spectrum of disorders. Klin Monatsbl Augenheilkd. May 2008;225(5):491-4. [Medline].
James SJ, Cutler P, Melnyk S, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. Dec 2004;80(6):1611-7. [Medline].
Ichinohe A, Kanaumi T, Takashima S, Enokido Y, Nagai Y, Kimura H. Cystathionine beta-synthase is enriched in the brains of Down's patients. Biochem Biophys Res Commun. Dec 23 2005;338(3):1547-50. [Medline].
Wilcken DE, Wang J, Sim AS, et al. Asymmetric dimethylarginine in homocystinuria due to cystathionine beta-synthase deficiency: relevance of renal function. J Inherit Metab Dis. Feb 2006;29(1):30-7. [Medline].
Snyderman SE. Liver failure and neurologic disease in a patient with homocystinuria. Mol Genet Metab. Mar 2006;87(3):210-2. [Medline].
Fowler B, Schutgens RB, Rosenblatt DS, et al. Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease). J Inherit Metab Dis. Nov 1997;20(6):731-41. [Medline].
Febriani AD, Sakamoto A, Ono H, et al. Determination of total homocysteine in dried blood spots using high performance liquid chromatography for homocystinuria newborn screening. Pediatr Int. Feb 2004;46(1):5-9. [Medline].
Refsum H, Fredriksen A, Meyer K, et al. Birth prevalence of homocystinuria. J Pediatr. Jun 2004;144(6):830-2. [Medline].
Navratil T, Petr M, Senholdova Z, et al. Diagnostic significance of urinary thiodiglycolic acid as a possible tool for studying the role of vitamins B12 and folates in the metabolism of thiolic substances. Physiol Res. Feb 23 2006;[Medline].
Sen S, Yu J, Yamanishi M, Schellhorn D, Banerjee R. Mapping peptides correlated with transmission of intrasteric inhibition and allosteric activation in human cystathionine beta-synthase. Biochemistry. Nov 1 2005;44(43):14210-6. [Medline].
Scherer EB, Stefanello FM, Mattos C, Netto CA, Wyse AT. Homocysteine reduces cholinesterase activity in rat and human serum. Int J Dev Neurosci. Jun 2007;25(4):201-5. [Medline].
Debray FG, Boulanger Y, Khiat A, et al. Reduced brain choline in homocystinuria due to remethylation defects. Neurology. Jul 1 2008;71(1):44-9. [Medline].
Longo D, Fariello G, Dionisi-Vici C, et al. MRI and 1H-MRS findings in early-onset cobalamin C/D defect. Neuropediatrics. Dec 2005;36(6):366-72. [Medline].
Gahl WA, Bernardini I, Chen S, et al. The effect of oral betaine on vertebral body bone density in pyridoxine-non-responsive homocystinuria. J Inherit Metab Dis. 1988;11(3):291-8. [Medline].
Lawson-Yuen A, Levy HL. The use of betaine in the treatment of elevated homocysteine. Mol Genet Metab. Jul 2006;88(3):201-7. [Medline].
Singh RH, Kruger WD, Wang L, et al. Cystathionine beta-synthase deficiency: effects of betaine supplementation after methionine restriction in B6-nonresponsive homocystinuria. Genet Med. Mar-Apr 2004;6(2):90-5. [Medline].
Sakamoto A, Sakura N. Limited effectiveness of betaine therapy for cystathionine beta synthase deficiency. Pediatr Int. Jun 2003;45(3):333-8. [Medline].
Yaghmai R, Kashani AH, Geraghty MT, et al. Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine beta-synthase (CBS) deficiency. Am J Med Genet. Feb 15 2002;108(1):57-63. [Medline].
Tada H, Takanashi J, Barkovich AJ, et al. Reversible white matter lesion in methionine adenosyltransferase I/III deficiency. AJNR Am J Neuroradiol. Nov-Dec 2004;25(10):1843-5. [Medline].
Alan L, Miller ND, Gregory S. Methionine and homocysteine metabolism and the nutritional prevention of certain birth defects and complications of pregnancy. Alt Med Rev. 1996;1:220-35.
Confalonieri M, Parigi P, Scartabellati A, et al. Heterozygosity for homocysteinuria: a detectable and reversible risk factor for pulmonary thromboembolism. Monaldi Arch Chest Dis. Apr 1995;50(2):114-5. [Medline].
Cruysberg JR, Boers GH, Trijbels JM, Deutman AF. Delay in diagnosis of homocystinuria: retrospective study of consecutive patients. BMJ. Oct 26 1996;313(7064):1037-40. [Medline].
Kim SZ, Santamaria E, Jeong TE, et al. Methionine adenosyltransferase I/III deficiency: two Korean compound heterozygous siblings with a novel mutation. J Inherit Metab Dis. Dec 2002;25(8):661-71. [Medline].
Kraus JP. Komrower Lecture. Molecular basis of phenotype expression in homocystinuria. J Inherit Metab Dis. 1994;17(4):383-90. [Medline].
Moat SJ, Bao L, Fowler B, et al. The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria. Hum Mutat. Feb 2004;23(2):206. [Medline].
Nugent A, Hadden DR, Carson NA. Long-term survival of homocystinuria: the first case. Lancet. Aug 22 1998;352(9128):624-5. [Medline].
Orendac M, Zeman J, Stabler SP, et al. Homocystinuria due to cystathionine beta-synthase deficiency: novel biochemical findings and treatment efficacy. J Inherit Metab Dis. 2003;26(8):761-73. [Medline].
Scriver CR, Beaudet AL, Sly WS. The Metabolic and Molecular Bases of Inherited Diseases. 7th ed. New York, NY: McGraw-Hill; 1995.
Further Reading
Keywords
homocystinuria, homocysteine, cystathionine synthase deficiency, cystathionine beta-synthase deficiency, CBS deficiency, metabolic disorder, methionine metabolism
