Diagnosis and Management of Classica Homocystinuria in Brazil: A Summary of 72 Late-Diagnosed Patients

Soraia Poloni Giovana W. Hoss Fernanda Sperb-Ludwig Taciane Borsatto Maria Juliana R. Doriqui Emília K.E.A Leão Ney Boa-Sorte Charles M. Lourenço Chong A. Kim Carolina F. M. de Souza Helio Rocha Marcia Ribeiro Carlos E. Steiner Carolina A. Moreno Pricila Bernardi Eugenia Valadares Osvaldo Artigalas Gerson Carvalho Hector Y. C. Wanderley Vânia D’Almeida Luiz C. Santana-da-Silva Henk J. Blom Ida V. D. Schwartz About the authors

Abstract

This study described a broad clinical characterization of classical homocystinuria (HCU) in Brazil. This was a cross-sectional, observational study including clinical and biochemical data from 72 patients (60 families) from Brazil (South, n = 13; Southeast, n = 37; Northeast, n = 8; North, n = 1; and Midwest, n = 1). Parental consanguinity was reported in 42% of families. Ocular manifestations were the earliest detected symptom (53% of cases), the main reason for diagnostic suspicion (63% of cases), and the most prevalent manifestation at diagnosis (67% of cases). Pyridoxine responsiveness was observed in 14% of patients. Only 22% of nonresponsive patients on treatment had total homocysteine levels <100 mmol/L. Most commonly used treatment strategies were pyridoxine (93% of patients), folic acid (90%), betaine (74%), vitamin B12 (27%), and low-methionine diet + metabolic formula (17%). Most patients diagnosed with HCU in Brazil are late diagnosed, express a severe phenotype, and poor metabolic control. Milder forms of HCU are likely underrepresented due to underdiagnosis.

Keywords
classical homocystinuria; CBS deficiency; homocysteine; pyridoxine responsiveness; diagnosis

Introduction

Classical homocystinuria (HCU; OMIM 236200) is an inborn error of methionine metabolism caused by deficient activity of cystathionine β-synthase (CβS; EC 4.2.1.22). Cystathionine β-synthase deficiency leads to massive accumulation of homocysteine and methionine and low levels of cysteine.11 Stipanuk MH, Ueki I. Dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur. J Inherit Metab Dis. 2011;34(1):17-32.,22 Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2011;34(1):75-81. Homocystinuria was first described in 196233 Carson NA, Neill DW. Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Arch Dis Child. 1962;37:505-513.; since then, many advances in treatment and early diagnosis, including newborn screening, have improved prognosis dramatically.44 Yap S, Rushe H, Howard PM, Naughten ER. The intellectual abilities of early-treated individuals with pyridoxinenonresponsive homocystinuria due to cystathionine betasynthase deficiency. J Inherit Metab Dis. 2001;24(4):437-447.

5 Naughten ER, Yap S, Mayne PD. Newborn screening for homocystinuria: Irish and world experience. Eur J Pediatr. 1998; 157(suppl 2):S84-S87.
-66 Skovby F, Gaustadnes M, Mudd SH. A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency. Mol Genet Metab. 2010;99(1):1-3. However, diagnosis and management of HCU is still a major challenge in developing countries, where newborn screening is unavailable and access to health-care services is often poor and unequal.77 Stopa SR, Malta DC, Monteiro CN, Szwarcwald CL, Goldbaum M, Cesar CLG. Use of and access to health services in Brazil, 2013 National Health Survey. Rev Saude Publica. 2017;51(suppl 1):3s.

From a clinical standpoint, the classic signs of HCU are lens dislocation, thromboembolism, mental retardation, psychiatric disorders, osteoporosis, and marfanoid features.88 Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985;37(1):1-31. Established treatment strategies include supplementation of pyridoxine (CβS cofactor), folic/folinic acid, betaine, and a methionine-restricted diet supplemented with an essential amino acids admixture free of methionine.99 Morris AA, Kozˇich V, Santra S, et al. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis. 2017;40(1):49-74. Novel therapies with chaperones and enzyme replacement are currently under development.1010 Singh LR, Chen X, Kozich V, Kruger WD. Chemical chaperone rescue of mutant human cystathionine beta-synthase. Mol Genet Metab. 2007;91(4):335-342.

11 Kopecka´ J, Krijt J, Rakova´ K, Kozˇich V. Restoring assembly and activity of cystathionine b-synthase mutants by ligands and chemical chaperones. J Inherit Metab Dis. 2011;34(1):39-48.
-1212 Majtan T, Hu˚lkova´ H, Park I, et al. Enzyme replacement prevents neonatal death, liver damage, and osteoporosis in murine homocystinuria. FASEB J. 2017;31(12):5495-5506. Usually, patients who respond to pyridoxine supplementation exhibit a milder phenotype and have a better prognosis.88 Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985;37(1):1-31.

The worldwide prevalence of HCU is estimated to be 1:100 000.1313 Moorthie S, Cameron L, Sagoo GS, Bonham JR, Burton H. Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases. J Inherit Metab Dis. 2014; 37(6):889-898. However, several mild and late presentation phenotypes have been described,1414 Magner M, Krupkova´ L, Honzı´k T, Zeman J, Hya´nek J, Kozˇich V. Vascular presentation of cystathionine beta-synthase deficiency in adulthood. J Inherit Metab Dis. 2011;34(1):33-37.

15 Quintas S, Dotor-Garcı´a Soto J, Alonso-Cerezo MC, Carreras MT. Late diagnosis of homocystinuria in an adult after extensive cerebral venous thrombosis. Pract Neurol. 2018;18(1):49-51.
-1616 Woods E, Dawson C, Senthil L, Geberhiwot T. Cerebral venous thrombosis as the first presentation of classical homocystinuria in an adult patient. BMJ Case Rep. 2017;2017. raising the issue of whether HCU is largely underdiagnosed. Newborn screening for HCU is performed in some countries with high incidence of the disease, such as Ireland and Qatar.55 Naughten ER, Yap S, Mayne PD. Newborn screening for homocystinuria: Irish and world experience. Eur J Pediatr. 1998; 157(suppl 2):S84-S87.,1717 Zschocke J, Kebbewar M, Gan-Schreier H, et al. Molecular neonatal screening for homocystinuria in the Qatari population. Hum Mutat. 2009;30(6):1021-1022. Usually, newborn screening is performed by the determination of methionine on filter paper. However, this method has a large percentage of false negatives (up to 50%), since pyridoxine-responsive HCU may not present with hypermethioninemia in the first days of life.1818 Yap S, Naughten E. Homocystinuria due to cystathionine betasynthase deficiency in Ireland: 25 years’ experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J Inherit Metab Dis. 1998;21(7): 738-747.,1919 Huemer M, Kozˇich V, Rinaldo P, et al. Newborn screening for homocystinurias and methylation disorders: systematic review and proposed guidelines. J Inherit Metab Dis. 2015;38(6): 1007-1019. In Brazil, the prevalence of HCU is unknown, and the disease is not included in the National Neonatal Screening Program.

Brazil is a very large country with over 200 million inhabitants, and the country is characterized by intense admixture.2020 Moura RR, Coelho AV, Balbino VeQ, Crovella S, Branda˜o LA. Meta-analysis of Brazilian genetic admixture and comparison with other Latin America countries. Am J Hum Biol. 2015; 27(5):674-680.,2121 Kehdy FS, Gouveia MH, Machado M, et al. Origin and dynamics of admixture in Brazilians and its effect on the pattern of deleterious mutations. Proc Natl Acad Sci U S A. 2015;112(28): 8696-8701. The country also has one of the world’s largest publicly funded health-care systems, the Unified Health System (Sistema Único de Saúde), which was established to provide equitable and comprehensive care to all users. However, betaine and the methionine-free amino acid formulation are not available through Unified Health System, and few centers across the country offer biochemical testing for diagnosis and management of this condition. Furthermore, several factors make diagnosis and management of HCU within the Brazilian health system a major challenge; hence, a substantial number of patients with this treatable condition are believed to remain undiagnosed and thus untreated. Within this context, the present study sought to establish a broad clinical characterization of HCU in Brazil through a survey on diagnosis and management of a representative patient population that is being followed at several centers nationwide.

Materials and Methods

The present study was approved by the local research ethics committee. Collection procedures for the study were conducted only after participants or their caregivers had agreed to take part in the investigation and provided written informed consent.

Patients

The study sample comprised 72 Brazilian patients with a diagnosis of HCU, from 60 different families. Diagnosis was in general made on clinical symptoms followed by clear elevations in homocysteine and methionine. Mutation analyses was performed in 35 of the 72 patients.2222 Poloni S, Sperb-Ludwig F, Borsatto T, et al. CBS mutations are good predictors for B6-responsiveness: a study based on the analysis of 35 Brazilian Classical Homocystinuria patients. Mol Genet Genomic Med. 2018;6(2):160-170. Families from all 5 regions of Brazil were represented: South (n = 13), Southeast (n = 37), Northeast (n = 8), North (n = 1), and Midwest (n = 1). Patients were recruited through contact with physicians involved in care and/or research activities at medical genetics centers across the country. A structured questionnaire containing queries regarding diagnosis, consanguinity, treatment strategies, metabolic control, and current health condition of patients with HCU was sent to 15 medical centers that had agreed to participate in the study. Clinical data regarding diagnosis were available only for 28 patients.

All 72 patients had delayed diagnoses: 62 patients had been diagnosed after clinical suspicion and biochemical findings consistent with HCU (hyperhomocysteinemia and hypermethioninemia), and the remaining 10 had been diagnosed on family screening. Each of the participating centers used a different protocol for determination of pyridoxine responsiveness. For the purposes of this study, patients were classified as responsive if they achieved homocysteine levels <50 µmol/L on pyridoxine alone or pyridoxine + folic acid (regardless of the number of weeks since testing). All other patients were classified as nonresponsive to pyridoxine.

Table 1
Classical Homocystinuria in Brazil: A Summary of Clinical Findings at Diagnosis.a

Target total homocysteine levels on treatment were set according HCU guidelines,99 Morris AA, Kozˇich V, Santra S, et al. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis. 2017;40(1):49-74. which were <50 µmol/L for pyridoxine-responsive patients and <100 µmol/L for nonresponsive patients. Treatment adherence was determined by the subjective impressions of the care team at each medical center.

Statistical Analysis

Statistical analysis was performed using SPSS for Windows, version 18.0 (SPSS Inc, Chicago, Illinois). Asymmetrically distributed variables were expressed as the median (range). The Mann-Whitney U test (continuous variables) or χ22 Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2011;34(1):75-81. test (categorical variables) was used to assess between-group differences. Values of P < .05 were considered significant.

Results

Of the 72 patients included, 55% were male. Two patients were already deceased at the time of inclusion in the study (presumably due to thromboembolic events). The patients belonged to 60 families; parental consanguinity was reported in 25 (42%) families. Median age at assessment was 19 years. The youngest patient was aged 5, and the oldest was 45. Regarding pyridoxine responsiveness, 61 (85%) patients were classified as nonresponsive and 10 (13.8%) as responsive. In 1 patient, pyridoxine responsiveness was not reported/determined.

Journey to Diagnosis

The very first symptom noticed by families and/or physicians was visual impairment (mainly due to ectopia lentis) in 53% of the cases, followed by developmental delay (22% of cases), seizures (11% of cases), and isolated thromboembolic episodes (9.5% of cases). Table 1 reports clinical features at diagnosis for the sample as a whole and stratified by pyridoxine responsiveness.

The median time elapsed between symptom onset and diagnosis was 5 years (maximum, 34 years). One-third of the patients had 3 or more systems already affected at the time of diagnosis. The main clinical findings leading to investigation of HCU are represented in Figure 1. Eye disease, the most prevalent symptom at diagnosis (67% of cases), accounted for 63% of referrals for HCU investigation.

Figure 1
Main reasons for clinical suspicion of classical homocystinuria in our sample (N = 72). *Including marfanoid habitus, **Other than ectopia lentis.

Management

Current clinical and biochemical data were available for 44 patients, of whom 7 were responsive and 37 were nonresponsive to pyridoxine. The median length of follow-up was 6 years (range, 0-27 years). Table 2 describes clinical manifestations and biochemical control in this group of patients. Ocular manifestations were more prevalent among pyridoxine-nonresponsive patients (71% vs 97%, P = .01). Ectopia lentis was the most common complication in our sample, affecting 91% of patients at the time of study inclusion.

Table 2
Classical Homocystinuria in Brazil: Clinical and Biochemical Profile of Patients on Treatment at the Time of Study Inclusion.a

Pyridoxine-responsive patients had significantly lower total homocysteine levels at study inclusion (P < .001). Only 22% of nonresponsive patients achieved target total homocysteine levels (<100 µmol/L) on treatment, while all responsive patients (n = 7) had total homocysteine <50 µmol/L. Treatment adherence was reported as appropriate in 44% of patients.

Regarding treatment strategies, 93% of patients were on pyridoxine supplementation, 90% on folic acid, 74% on betaine, 27% on vitamin B12, and only 17% on a low-methionine diet + metabolic formula.

Discussion

The present report provides the largest clinical profile of patients with HCU ever studied in Brazil to date. Clinical data of 72 patients (60 unrelated) from 15 medical genetics centers across Brazil were analyzed. Most families lived in the South and Southeast regions of the country. These regions are home to 57% of the country’s population (http://www.ibge.gov.br/) and, compared to other regions of Brazil, have higher rates of access to health-care services and procedures. The fact that patients from other regions, particularly the North (n = 1) and Midwest (n = 1), were underrepresented suggests high rates of HCU underdiagnosis and/or limited access to care in these regions.77 Stopa SR, Malta DC, Monteiro CN, Szwarcwald CL, Goldbaum M, Cesar CLG. Use of and access to health services in Brazil, 2013 National Health Survey. Rev Saude Publica. 2017;51(suppl 1):3s.

A high proportion of pyridoxine-nonresponsive patients with HCU was found in our study (85%). Nonresponsive patients usually present a more severe phenotype, have more complications, and younger ages .66 Skovby F, Gaustadnes M, Mudd SH. A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency. Mol Genet Metab. 2010;99(1):1-3.,88 Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985;37(1):1-31.,2323 Mudd SH, Levy HL, Kraus JP. Disorders of transulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw Hill; 2001. In our study, this proportion exceeded rates described worldwide of approximately 50%.88 Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985;37(1):1-31. In countries where the proportion of nonresponsive patients is disproportionately high, such as Qatar and Ireland, specific genotypes are highly prevalent and account for these discrepancies .2424 El-Said MF, Badii R, Bessisso MS, et al. A common mutation in the CBS gene explains a high incidence of homocystinuria in the Qatari population. Hum Mutat. 2006;27(7):719.,2525 Gallagher PM, Ward P, Tan S, et al. High frequency (71%)of cystathionine beta-synthase mutation G307 S in Irish homocystinuria patients. Hum Mutat. 1995;6(2):177-180. In a previous study of our group, we explored in more depth the genotype of 35 patients with HCU who are also included in the current study.2222 Poloni S, Sperb-Ludwig F, Borsatto T, et al. CBS mutations are good predictors for B6-responsiveness: a study based on the analysis of 35 Brazilian Classical Homocystinuria patients. Mol Genet Genomic Med. 2018;6(2):160-170.

Our results show there is no single molecular basis for the high prevalence of HCU nonresponsive phenotypes in Brazil. In fact, the most prevalent mutation in that study (p.Ile278Thr) is a pyridoxine-responsive mutation. Another genetic study of 14 Brazilian patients with HCU showed similar results.2626 Porto MP, Galdieri LC, Pereira VG, et al. Molecular analysis of homocystinuria in Brazilian patients. Clin Chim Acta. 2005; 362(1-2):71-78. These findings rather suggest underdiagnosis of pyridoxine-responsive patients in Brazil who express milder phenotypes with fewer symptoms and later onset of clinical presentation.66 Skovby F, Gaustadnes M, Mudd SH. A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency. Mol Genet Metab. 2010;99(1):1-3.,88 Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985;37(1):1-31. In our study, no significant differences in age at symptom onset or age at diagnosis were found between pyridoxine-responsive and nonresponsive patients; however, we believe our analysis was underpowered because of the low number of pyridoxine-responsive patients (n = 10 vs n = 61, respectively).

The high prevalence of ocular manifestations at diagnosis and their predominant contribution to diagnostic suspicion reinforce the importance of eye disease in HCU. Ectopia lentis is usually the earliest manifestation of HCU, occurring in half of all untreated patients by age 10 years and in over 90% by age 24 years.88 Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985;37(1):1-31. No significant difference in the prevalence of ocular manifestations at diagnosis was found between responsive and nonresponsive patients (75% vs 50%, P = .10), although the lack of significance could also be explained by the small sample size. However, this finding is consistent with previous reports in the literature.88 Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985;37(1):1-31.

Skeletal and neurologic manifestations were also highly prevalent at diagnosis, affecting more than half of patients of our cohort. The lower prevalence of vascular events at diagnosis is consistent with the natural history of HCU, in which such manifestations usually occur in general at a later age.88 Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985;37(1):1-31. However, vascular disease may have been underrepresented due to the high lethality of thromboembolic events. The relative large time gap between symptom onset to diagnosis (median, 5 years) and the presence of multiple clinical manifestations attest to the difficulty in establishing a definitive diagnosis in these patients.

The main strategies and goals of HCU treatment have been recently established in the first guidelines for the diagnosis and management of CβS deficiency.99 Morris AA, Kozˇich V, Santra S, et al. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis. 2017;40(1):49-74. Early diagnosis and early treatment are the key to prevent clinical manifestations and improve prognosis.44 Yap S, Rushe H, Howard PM, Naughten ER. The intellectual abilities of early-treated individuals with pyridoxinenonresponsive homocystinuria due to cystathionine betasynthase deficiency. J Inherit Metab Dis. 2001;24(4):437-447.,1818 Yap S, Naughten E. Homocystinuria due to cystathionine betasynthase deficiency in Ireland: 25 years’ experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J Inherit Metab Dis. 1998;21(7): 738-747. In the present study, current clinical and biochemical data were obtained from 44 patients in treatment. There was a clear difference in metabolic control between the groups: Responsive patients had low and even near-normal homocysteine and methionine levels, whereas most nonresponsive patients had persistently high homocysteine levels (>100 µmol/L) despite multiple treatment strategies. This difficulty in achieving metabolic control in pyridoxine-nonresponsive patients has been reported elsewhere.1818 Yap S, Naughten E. Homocystinuria due to cystathionine betasynthase deficiency in Ireland: 25 years’ experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J Inherit Metab Dis. 1998;21(7): 738-747.,2727 Yap S, Boers GH, Wilcken B, et al. Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol. 2001;21(12):2080-2085.,2828 Yap S, Naughten ER, Wilcken B, et al. Vascular complications of severe hyperhomocysteinemia in patients with homocystinuria due to cystathionine beta-synthase deficiency: effects of homocysteine-lowering therapy. Semin Thromb Hemost. 2000; 26(3):335-340.

The high rate of betaine supplementation and comparatively low use of methionine-restricted diet in the nonresponsive patients may be attributed to several factors: (1) difficulties in obtaining the metabolic formula, which is expensive and not provided by the Unified Health System in Brazil;2929 Chieffi AL, Barradas RCB, Golbaum M. Legal access to medications: a threat to Brazil’s public health system? BMC Health Serv Res. 2017;17(1):499. (2) low adherence to dietary methionine restriction, particularly in patients with a late diagnosis; and (3) limited training of health-care professionals in dietary prescription. In a European survey of 181 patients with pyridoxine-nonresponsive HCU, 66% were on dietary treatment, that is, twice as many as in the present study.3030 Adam S, Almeida MF, Carbasius Weber E, et al. Dietary practices in pyridoxine non-responsive homocystinuria: a European survey. Mol Genet Metab. 2013;110(4):454-459. Homocystinuria guidelines clearly state that betaine should not be considered a first-line treatment for HCU-nonresponsive patients but used as adjunct treatment in those who cannot achieve target levels of homocysteine by other means.99 Morris AA, Kozˇich V, Santra S, et al. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis. 2017;40(1):49-74. While dietary therapy dramatically reduces methionine and homocysteine and normalizes cysteine, betaine supplementation reduces homocysteine but increases methionine levels.3131 Lawson-Yuen A, Levy HL. The use of betaine in the treatment of elevated homocysteine. Mol Genet Metab. 2006;88(3):201-207.,3232 Komrower GM. Dietary treatment of homocystinuria. Am J Dis Child. 1967;113(1):98-100. In animal models, betaine is less effective at preventing clinical manifestations,3333 Gupta S, Wang L, Kruger WD. Betaine supplementation is less effective than methionine restriction in correcting phenotypes of CBS deficient mice. J Inherit Metab Dis. 2016;39(1):39-46. and its efficacy declines over time.3434 Maclean KN, Jiang H, Greiner LS, Allen RH, Stabler SP. Longterm betaine therapy in a murine model of cystathionine betasynthase deficient homocystinuria: decreased efficacy over time reveals a significant threshold effect between elevated homocysteine and thrombotic risk. Mol Genet Metab. 2012;105(3): 395-403. In humans, there are no studies of the long-term efficacy of betaine supplementation alone in HCU.

In conclusion, this study provides the first broad clinical characterization of HCU in Brazil. All patients described here were late diagnosed, and most expressed a severe phenotype associated with nonresponsiveness to pyridoxine, early and multisystem clinical manifestations, and poor metabolic control. Limitations of this study include the underrepresented number of patients responsive to pyridoxine, and the number of patients coming from some regions of the country. We believe that our findings will contribute to the development of protocols and guidelines to improve diagnosis and management of HCU in Brazil.

Acknowledgments

The authors thank Prof. Roberto Giugliani, Rede EIM Brasil, Simone Allan Arede, and Associação Brasileira de Homocistinúria for their assistance with patient diagnosis and follow-up.

Funding

  • The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Financial support for this study was provided by CNPq, CAPES, DAAD, and FIPE-HCPA.

References

  • 1
    Stipanuk MH, Ueki I. Dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur. J Inherit Metab Dis. 2011;34(1):17-32.
  • 2
    Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2011;34(1):75-81.
  • 3
    Carson NA, Neill DW. Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Arch Dis Child. 1962;37:505-513.
  • 4
    Yap S, Rushe H, Howard PM, Naughten ER. The intellectual abilities of early-treated individuals with pyridoxinenonresponsive homocystinuria due to cystathionine betasynthase deficiency. J Inherit Metab Dis. 2001;24(4):437-447.
  • 5
    Naughten ER, Yap S, Mayne PD. Newborn screening for homocystinuria: Irish and world experience. Eur J Pediatr. 1998; 157(suppl 2):S84-S87.
  • 6
    Skovby F, Gaustadnes M, Mudd SH. A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency. Mol Genet Metab. 2010;99(1):1-3.
  • 7
    Stopa SR, Malta DC, Monteiro CN, Szwarcwald CL, Goldbaum M, Cesar CLG. Use of and access to health services in Brazil, 2013 National Health Survey. Rev Saude Publica. 2017;51(suppl 1):3s.
  • 8
    Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 1985;37(1):1-31.
  • 9
    Morris AA, Kozˇich V, Santra S, et al. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis. 2017;40(1):49-74.
  • 10
    Singh LR, Chen X, Kozich V, Kruger WD. Chemical chaperone rescue of mutant human cystathionine beta-synthase. Mol Genet Metab. 2007;91(4):335-342.
  • 11
    Kopecka´ J, Krijt J, Rakova´ K, Kozˇich V. Restoring assembly and activity of cystathionine b-synthase mutants by ligands and chemical chaperones. J Inherit Metab Dis. 2011;34(1):39-48.
  • 12
    Majtan T, Hu˚lkova´ H, Park I, et al. Enzyme replacement prevents neonatal death, liver damage, and osteoporosis in murine homocystinuria. FASEB J. 2017;31(12):5495-5506.
  • 13
    Moorthie S, Cameron L, Sagoo GS, Bonham JR, Burton H. Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases. J Inherit Metab Dis 2014; 37(6):889-898.
  • 14
    Magner M, Krupkova´ L, Honzı´k T, Zeman J, Hya´nek J, Kozˇich V. Vascular presentation of cystathionine beta-synthase deficiency in adulthood. J Inherit Metab Dis. 2011;34(1):33-37.
  • 15
    Quintas S, Dotor-Garcı´a Soto J, Alonso-Cerezo MC, Carreras MT. Late diagnosis of homocystinuria in an adult after extensive cerebral venous thrombosis. Pract Neurol. 2018;18(1):49-51.
  • 16
    Woods E, Dawson C, Senthil L, Geberhiwot T. Cerebral venous thrombosis as the first presentation of classical homocystinuria in an adult patient. BMJ Case Rep. 2017;2017.
  • 17
    Zschocke J, Kebbewar M, Gan-Schreier H, et al. Molecular neonatal screening for homocystinuria in the Qatari population. Hum Mutat. 2009;30(6):1021-1022.
  • 18
    Yap S, Naughten E. Homocystinuria due to cystathionine betasynthase deficiency in Ireland: 25 years’ experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J Inherit Metab Dis. 1998;21(7): 738-747.
  • 19
    Huemer M, Kozˇich V, Rinaldo P, et al. Newborn screening for homocystinurias and methylation disorders: systematic review and proposed guidelines. J Inherit Metab Dis. 2015;38(6): 1007-1019.
  • 20
    Moura RR, Coelho AV, Balbino VeQ, Crovella S, Branda˜o LA. Meta-analysis of Brazilian genetic admixture and comparison with other Latin America countries. Am J Hum Biol. 2015; 27(5):674-680.
  • 21
    Kehdy FS, Gouveia MH, Machado M, et al. Origin and dynamics of admixture in Brazilians and its effect on the pattern of deleterious mutations. Proc Natl Acad Sci U S A. 2015;112(28): 8696-8701.
  • 22
    Poloni S, Sperb-Ludwig F, Borsatto T, et al. CBS mutations are good predictors for B6-responsiveness: a study based on the analysis of 35 Brazilian Classical Homocystinuria patients. Mol Genet Genomic Med. 2018;6(2):160-170.
  • 23
    Mudd SH, Levy HL, Kraus JP. Disorders of transulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease 8th ed. New York: McGraw Hill; 2001.
  • 24
    El-Said MF, Badii R, Bessisso MS, et al. A common mutation in the CBS gene explains a high incidence of homocystinuria in the Qatari population. Hum Mutat. 2006;27(7):719.
  • 25
    Gallagher PM, Ward P, Tan S, et al. High frequency (71%)of cystathionine beta-synthase mutation G307 S in Irish homocystinuria patients. Hum Mutat 1995;6(2):177-180.
  • 26
    Porto MP, Galdieri LC, Pereira VG, et al. Molecular analysis of homocystinuria in Brazilian patients. Clin Chim Acta 2005; 362(1-2):71-78.
  • 27
    Yap S, Boers GH, Wilcken B, et al. Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol. 2001;21(12):2080-2085.
  • 28
    Yap S, Naughten ER, Wilcken B, et al. Vascular complications of severe hyperhomocysteinemia in patients with homocystinuria due to cystathionine beta-synthase deficiency: effects of homocysteine-lowering therapy. Semin Thromb Hemost. 2000; 26(3):335-340.
  • 29
    Chieffi AL, Barradas RCB, Golbaum M. Legal access to medications: a threat to Brazil’s public health system? BMC Health Serv Res 2017;17(1):499.
  • 30
    Adam S, Almeida MF, Carbasius Weber E, et al. Dietary practices in pyridoxine non-responsive homocystinuria: a European survey. Mol Genet Metab. 2013;110(4):454-459.
  • 31
    Lawson-Yuen A, Levy HL. The use of betaine in the treatment of elevated homocysteine. Mol Genet Metab. 2006;88(3):201-207.
  • 32
    Komrower GM. Dietary treatment of homocystinuria. Am J Dis Child 1967;113(1):98-100.
  • 33
    Gupta S, Wang L, Kruger WD. Betaine supplementation is less effective than methionine restriction in correcting phenotypes of CBS deficient mice. J Inherit Metab Dis. 2016;39(1):39-46.
  • 34
    Maclean KN, Jiang H, Greiner LS, Allen RH, Stabler SP. Longterm betaine therapy in a murine model of cystathionine betasynthase deficient homocystinuria: decreased efficacy over time reveals a significant threshold effect between elevated homocysteine and thrombotic risk. Mol Genet Metab 2012;105(3): 395-403.

Publication Dates

  • Publication in this collection
    2018

History

  • Received
    16 Apr 2018
  • Reviewed
    07 June 2018
  • Accepted
    12 June 2018
Latin American Society Inborn Errors and Neonatal Screening (SLEIMPN); Instituto Genética para Todos (IGPT) Rua Ramiro Barcelos, 2350, CEP: 90035-903, Porto Alegre, RS - Brasil, Tel.: 55-51-3359-6338, Fax: 55-51-3359-8010 - Porto Alegre - RS - Brazil
E-mail: rgiugliani@hcpa.edu.br