An adult with cystathionine beta-synthase deficiency, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, and deafness: A case report.

Massive sequencing platforms allow the identification of complex clinical phenotypes involving more than one autosomal recessive disorder. In this study, we report on an adult patient, born to a related couple (third degree cousins), referred for genetic evaluation due to ectopia lentis, deafness and previous diagnosis of juvenile idiopathic arthritis. He was biochemically diagnosed as having Classic Homocystinuria (HCU); Sanger sequencing of the CBS gene showed the genotype NM_000071.2(CBS):c.[833T>C];[833T>C], compatible with the diagnosis of pyridoxine-responsive HCU. As he also had symptoms not usually associated with HCU, exome sequencing was performed. In addition to the variants found in the Sanger sequencing, the following variants were identified: NM_001256317.1(TMPRSS3):c.[413C>A];[413C>A]; and the NM_005807.6(PRG4):c.[3756dup]:[3756dup], confirming the diagnosis of autosomal recessive nonsyndromic deafness and Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome (CACP), respectively. Genomic analysis allowed the refinement of the diagnosis of a complex case and improvement of the patient's treatment.

Homocysteine and methylmalonic acid in Phenylketonuria patients.

Hyperhomocysteinemia and vitamin B12 deficiency have been reported in patients with phenylketonuria. In this study, total homocysteine (tHcy) and methylmalonic acid (MMA) levels were analyzed in samples from 25 phenylketonuria (PKU) patients. Comparisons were made between pre- and post-treatment values (n= 3); on treatment values, between periods with high and normal/low phenylalanine (Phe) levels (n= 20); and in women before, during and after pregnancy (n= 3). THcy levels decreased after treating PKU with metabolic formula (p=0.014). Except for a pregnant woman before pregnancy, none of the patients had tHcy values above the normal range. In fact, tHcy was < 5 µmol/L in 34% of the samples. We observed a decrease in Phe, tHcy, and tyrosine levels during pregnancy. MMA levels did not differ significantly, with values remaining in the normal range. These data indicate that there was no B12 deficiency in patients who adhere to the diet. In conclusion, in PKU patients treated with metabolic formula, tHcy is frequently not elevated, remaining even in the lower normal range in some patients. Thus, clinical follow-up and adherence to dietary treatment are crucial to prevent B12 deficiency.

Adequacy of Fatty Acids Consumption Among Individuals in Secondary Cardiovascular Prevention. / Adequação do Consumo de Ácidos Graxos entre Pacientes em Prevenção Cardiovascular Secundária.

BACKGROUND: Adhering to a diet adequate in macronutrients is crucial for the secondary prevention of cardiovascular diseases. OBJECTIVE: To assess the prevalence of adherence to recommendations for the consumption of dietary fatty acids for the prevention and treatment of cardiovascular diseases and to estimate whether the presence of certain cardiovascular risk factors would be associated with adherence. METHODS: Cross-sectional study using baseline data from 2,358 participants included in the "Brazilian Cardioprotective Nutritional Program Trial". Dietary intake and cardiovascular risk factors were assessed. Adequate intake of polyunsaturated fatty acids (PUFA) was considered as ≥10% of total daily energy intake; for monounsaturated fatty acids (MUFA), 20%; and for saturated fatty acids (SFA), <7% according to the Brazilian Society of Cardiology. A significance level of 5% was considered in the statistical analysis. RESULTS: No participant adhered to all recommendations simultaneously, and more than half (1,482 [62.9%]) did not adhere to any recommendation. Adherence exclusively to the SFA recommendation was the most prevalent, fulfilled by 659 (28%) participants, followed by adherence exclusively to the PUFA (178 [7.6%]) and MUFA (5 [0.2%]) recommendations. There was no association between the number of comorbidities and adherence to nutritional recommendations (p = 0.269). Participants from the Brazilian Northeast region showed a higher proportion of adherence to SFA consumption recommendations (38.42%) and lower adherence to PUFA intake (3.52%) (p <0.001) compared to other regions. CONCLUSIONS: Among the evaluated sample, there was low adherence to nutritional recommendations for dietary fatty acid consumption.

FUNDAMENTO: A adesão à uma alimentação adequada em macronutrientes é fundamental para a prevenção secundária de doenças cardiovasculares. OBJETIVO: Avaliar a prevalência de adesão às recomendações de consumo de ácidos graxos para prevenção e tratamento de doenças cardiovasculares, e estimar se a presença de determinados fatores de risco cardiovascular estaria associada à adesão. MÉTODOS: Estudo transversal com os dados de linha de base de 2358 participantes do estudo "Brazilian Cardioprotective Nutritional Program Trial". Dados de consumo alimentar, e fatores de risco cardiovascular foram avaliados. Foi considerada, de acordo com a Sociedade Brasileira de Cardiologia, uma ingestão adequada de ácidos graxos poli-insaturados (AGPI) ≥10% do consumo total de energia diária, para ácidos graxos monoinsaturados (AGM), 20% e para ácidos graxos saturados (AGS), <7%. Na análise estatística foi considerando nível de significância de 5%. RESULTADOS: Nenhum participante aderiu a todas as recomendações de forma simultânea e mais da metade (1482 [62,9%]) não aderiu a nenhuma recomendação. A adesão exclusivamente à recomendação de AGS foi a mais prevalente, sendo cumprida por 659 (28%) dos participantes, seguida da adesão exclusivamente à recomendação de AGP (178 [7,6%]) e de AGM (5 [0,2%]). Não houve associação entre o número de comorbidades e a adesão às recomendações nutricionais (p =0,269). Os participantes da região Nordeste do país apresentaram maior proporção de adesão às recomendações para consumo de AGS (38,42%), e menor para ingestão de AGPI (3,52%) (p <0,001) em comparação às demais. CONCLUSÕES: Na amostra avaliada, evidenciou-se baixa adesão às recomendações nutricionais para consumo de ácidos graxos.

Adequação do consumo de ácidos graxos entre pacientes em prevenção cardiovascular secundária / Adequacy of Fatty Acids Consumption Among Individuals in Secondary Cardiovascular Prevention

FUNDAMENTO: A adesão à uma alimentação adequada em macronutrientes é fundamental para a prevenção secundária de doenças cardiovasculares. OBJETIVO: Avaliar a prevalência de adesão às recomendações de consumo de ácidos graxos para prevenção e tratamento de doenças cardiovasculares, e estimar se a presença de determinados fatores de risco cardiovascular estaria associada à adesão. MÉTODOS: Estudo transversal com os dados de linha de base de 2358 participantes do estudo "Brazilian Cardioprotective Nutritional Program Trial". Dados de consumo alimentar, e fatores de risco cardiovascular foram avaliados. Foi considerada, de acordo com a Sociedade Brasileira de Cardiologia, uma ingestão adequada de ácidos graxos poli-insaturados (AGPI) ≥10% do consumo total de energia diária, para ácidos graxos monoinsaturados (AGM), 20% e para ácidos graxos saturados (AGS), <7%. Na análise estatística foi considerando nível de significância de 5%. RESULTADOS: Nenhum participante aderiu a todas as recomendações de forma simultânea e mais da metade (1482 [62,9%]) não aderiu a nenhuma recomendação. A adesão exclusivamente à recomendação de AGS foi a mais prevalente, sendo cumprida por 659 (28%) dos participantes, seguida da adesão exclusivamente à recomendação de AGP (178 [7,6%]) e de AGM (5 [0,2%]). Não houve associação entre o número de comorbidades e a adesão às recomendações nutricionais (p =0,269). Os participantes da região Nordeste do país apresentaram maior proporção de adesão às recomendações para consumo de AGS (38,42%), e menor para ingestão de AGPI (3,52%) (p <0,001) em comparação às demais. CONCLUSÕES: Na amostra avaliada, evidenciou-se baixa adesão às recomendações nutricionais para consumo de ácidos graxos.

Factors associated with diet quality among Brazilian individuals with cardiovascular diseases.

BACKGROUND: An individual's dietary pattern contributes in different ways to the prevention and control of recurrent cardiovascular events. However, the quality of the diet is influenced by several factors. The present study aimed to evaluate the quality of the diet of individuals with cardiovascular diseases and determine whether there is an association between sociodemographic and lifestyle factors. METHODS: This is a cross-sectional study carried out with individuals with atherosclerosis (coronary artery disease, cerebrovascular disease or peripheral arterial disease) recruited from 35 reference centres for the treatment of cardiovascular disease in Brazil. Diet quality was assessed according to the Modified Alternative Healthy Eating Index (mAHEI) and stratified into tertiles. For comparing two groups, the Mann-Whitney or Pearson's chi-squared tests were used. However, for comparing three or more groups, analysis of variance or Kruskal-Wallis was used. For the confounding analysis, a multinomial regression model was used. p < 0.05 was considered statistically significant. RESULTS: In total, 2360 individuals were evaluated: 58.5% male and 64.2% elderly. The median (interquartile range [IQR]) of the mAHEI was 24.0 (20.0-30.0), ranging from 0.4 to 56.0 points. When comparing the odds ratios (ORs) for the low (first tertile) and medium (second tertile) diet quality groups with the high-quality group (third tertile), it was observed that there was an association between diet quality with a family income of 1.885 (95% confidence intervals [CI] = 1.302-2.729) and 1.566 (95% CI = 1.097-2.235), as well as physical activity of 1.391 (95% CI = 1.107-1.749) and 1.346 (95% CI = 1.086-1.667), respectively. In addition, associations were observed between diet quality and region of residence. CONCLUSIONS: A low-quality diet was associated with family income, sedentarism and geographical area. These data are extremely relevant to assist in coping with cardiovascular disease because they enable an assessment of the distribution of these factors in different regions of the country.

Factors associated with diet quality among Brazilian individuals with cardiovascular diseases

BACKGROUND: An individual's dietary pattern contributes in different ways to the prevention and control of recurrent cardiovascular events. However, the quality of the diet is influenced by several factors. The present study aimed to evaluate the quality of the diet of individuals with cardiovascular diseases and determine whether there is an association between sociodemographic and lifestyle factors. METHODS: This is a cross-sectional study carried out with individuals with atherosclerosis (coronary artery disease, cerebrovascular disease or peripheral arterial disease) recruited from 35 reference centres for the treatment of cardiovascular disease in Brazil. Diet quality was assessed according to the Modified Alternative Healthy Eating Index (mAHEI) and stratified into tertiles. For comparing two groups, the Mann-Whitney or Pearson's chi-squared tests were used. However, for comparing three or more groups, analysis of variance or Kruskal-Wallis was used. For the confounding analysis, a multinomial regression model was used. p < 0.05 was considered statistically significant. RESULTS: In total, 2360 individuals were evaluated: 58.5% male and 64.2% elderly. The median (interquartile range [IQR]) of the mAHEI was 24.0 (20.0-30.0), ranging from 0.4 to 56.0 points. When comparing the odds ratios (ORs) for the low (first tertile) and medium (second tertile) diet quality groups with the high-quality group (third tertile), it was observed that there was an association between diet quality with a family income of 1.885 (95% confidence intervals [CI] = 1.302-2.729) and 1.566 (95% CI = 1.097-2.235), as well as physical activity of 1.391 (95% CI = 1.107-1.749) and 1.346 (95% CI = 1.086-1.667), respectively. In addition, associations were observed between diet quality and region of residence. CONCLUSIONS: A low-quality diet was associated with family income, sedentarism and geographical area. These data are extremely relevant to assist in coping with cardiovascular disease because they enable an assessment of the distribution of these factors in different regions of the country.

Cytokine profiling in patients with hepatic glycogen storage disease: Are there clues for unsolved aspects?

INTRODUCTION: Hepatic Glycogen Storage Diseases (GSD) are rare genetic disorders in which the gluconeogenesis pathway is impaired. Cytokines control virtually every aspect of physiology and may help to elucidate some unsolved questions about phenotypes presented by GSD patients. METHODS: This was an exploratory study in which 27 GSD patients on treatment (Ia = 16, Ib = 06, III = 02, IXα = 03) and 24 healthy age- and sex-matched subjects had plasma samples tested for a panel of 20 cytokines (G-CSF,GM-CSF, IL-1α,IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-13, IL-17A, GRO, IP-10/CXCL10, MCP-1/CCL2, MIP-1α/CCL3, MIP-1ß/CCL4, MDC/CCL22, IFN-γ, TNF-α, TNF-ß, VEGF) through a multiplex kit and analyzed in comparison to controls and among patients, regarding to clinical features as anemia, hepatic adenocarcinoma and triglyceride levels. RESULTS: Patients (GSD-Ia/III/IX) presented reduced levels of IL-4 (p = 0.040), MIP-1α/CCL3 (p = 0.003), MDC/CCL22 (p < 0.001), TNF-ß (p = 0.045) and VEGF (p = 0.043) compared to controls. When different types of GSD were compared, G-CSF was higher in GSD-Ib than -Ia (p < 0.001) and than -III/IX (p = 0.033) patients; IL-10 was higher in GSD-Ib than in GSD-Ia patients (p = 0.019); and GSD-III/IX patients had increased levels of IP-10/CXCL10 than GSD-Ib patients (p = 0.019). When GSD-I patients were gathered into the same group and compared with GSD-III/IX patients, IP10/CXCL10 and MCP-1 were higher in the latter group (p = 0.005 and p = 0.013, respectively). GSD-I patients with anemia presented higher levels of IL-4 and MIP-1α in comparison with patients who had not. Triglyceride level was correlated with neutrophil count and MDC levels on GSD-Ia patients without HCA. CONCLUSION: Altogether, altered levels of cytokines in GSD-I patients reflect an imbalance in immunoregulation process. This study also indicates that neutrophils and some cytokines are affected by triglyceride levels, and future studies on the theme should consider this variable.

Brazilian Food Reference Guide for Phenylalanine Content: A Study Based on the Perception of PKU Patients and Health Providers

Abstract The mainstay of management of phenylketonuria (PKU) is restriction of dietary phenylalanine (Phe) intake. The present study sought to assess the perception and understanding of health care providers and lay users (patients/family members/caregivers) regarding the national reference database for checking the Phe content of foods, provided by the Brazilian Health Regulatory Agency (Anvisa), whose data are presented in the Table of Phenylalanine Content of Foods (TCFA-Anvisa) and recently in the Phenylalanine Content of Foods Dashboard (PCCFA-Anvisa); and to identify factors which interfere with the usability of these resources. Two online questionnaires, one for providers (n=33) and another for lay users (n=194), were used to collect sociodemographic information, knowledge about dietary management of PKU, sources of information about the Phe content of foods, and perception and understanding of the Anvisa tools. TCFA-Anvisa and PCCFA-Anvisa were not used as main sources of information by either group. Among the participants who had used these tools (15 providers;35 lay users), most considered the PCCFA-Anvisa to be superior or partially superior to the TCFA-Anvisa. The main limitations reported were related to layout and limited variety of foods. We suggest that the limitations identified in this study be considered for future improvement of these resources.

Bone Mineral Density in Patients with Hepatic Glycogen Storage Diseases.

The association between bone mineral density (BMD) and hepatic glycogen storage diseases (GSDs) is still unclear. To evaluate the BMD of patients with GSD I, IIIa and IXα, a cross-sectional study was performed, including 23 patients (GSD Ia = 13, Ib = 5, IIIa = 2 and IXα = 3; median age = 11.9 years; IQ = 10.9-20.1) who underwent a dual-energy X-ray absorptiometry (DXA). Osteocalcin (OC, n = 18), procollagen type 1 N-terminal propeptide (P1NP, n = 19), collagen type 1 C-terminal telopeptide (CTX, n = 18) and 25-OH Vitamin D (n = 23) were also measured. The participants completed a 3-day food diary (n = 20). Low BMD was defined as a Z-score ≤ -2.0. All participants were receiving uncooked cornstarch (median dosage = 6.3 g/kg/day) at inclusion, and 11 (47.8%) presented good metabolic control. Three (13%) patients (GSD Ia = 1, with poor metabolic control; IIIa = 2, both with high CPK levels) had a BMD ≤ -2.0. CTX, OC and P1NP correlated negatively with body weight and age. 25-OH Vitamin D concentration was decreased in seven (30.4%) patients. Our data suggest that patients with hepatic GSDs may have low BMD, especially in the presence of muscular involvement and poor metabolic control. Systematic nutritional monitoring of these patients is essential.

Current Practices and Challenges in the Diagnosis and Management of PKU in Latin America: A Multicenter Survey.

This study aimed to describe the current practices in the diagnosis and dietary management of phenylketonuria (PKU) in Latin America, as well as the main barriers to treatment. We developed a 44-item online survey aimed at health professionals. After a pilot test, the final version was sent to 25 practitioners working with inborn errors of metabolism (IEM) in 14 countries. Our results include 22 centers in 13 countries. Most countries (12/13) screened newborns for PKU. Phenylalanine (Phe) targets at different ages were very heterogeneous among centers, with greater consistency at the 0-1 year age group (14/22 sought 120-240 µmol/L) and the lowest at >12 years (10 targets reported). Most countries had only unflavored powdered amino acid substitutes (10/13) and did not have low-protein foods (8/13). Only 3/13 countries had regional databases of the Phe content of foods, and only 4/22 centers had nutrient analysis software. The perceived obstacles to treatment were: low purchasing power (62%), limited/insufficient availability of low-protein foods (60%), poor adherence, and lack of technical resources to manage the diet (50% each). We observed a heterogeneous scenario in the dietary management of PKU, and most countries experienced a lack of dietary resources for both patients and health professionals.

Prevalence of breastfeeding in children with congenital heart diseases and down syndrome.

BACKGROUND: According to the World Health Organization, the worldwide incidence of Down syndrome is one in a thousand live births a year. Of these, it is estimated that 20-60% have congenital heart disease, a factor that hinders breastfeeding. Considering the numerous benefits of breastfeeding, a study verifying this prevalence in children with Down syndrome and congenital heart disease is indispensable, and this is not yet evidenced in the literature. The aim of this study is to verify the prevalence of breastfeeding in children with Down syndrome and congenital heart disease admitted to a referral hospital in cardiology. METHODS: Cross-sectional study with 62 patients, aged between 0 and 5 years. Anthropometric variables (weight, height) and data related to breastfeeding were collected. Statistical analysis was performed using the SPSS® version 26.0 statistical software. RESULTS: The prevalence of breastfeeding was of 80.6%, but the median of exclusive breastfeeding was of only 3 days. Only 38.7% received breastfeeding for more than 6 months. The main reasons for interruption were difficulty in sucking and tiredness to breastfeed. Statistical significance was evidenced when comparing the time of exclusive breastfeeding and maintenance with the mother's education, with p = 0.006 and p = 0.041, respectively. No relationship was found between nutritional status and breastfeeding. CONCLUSIONS: Despite the high prevalence of breastfeeding, the maintenance time is well below the recommendations. Therefore, further monitoring and promotion of breastfeeding is necessary for this population, given the countless benefits of breast milk.

Is the gut microbiota dysbiotic in patients with classical homocystinuria?

Classical homocystinuria (HCU) is characterized by increased plasma levels of total homocysteine (tHcy) and methionine (Met). Treatment may involve supplementation of B vitamins and essential amino acids, as well as restricted Met intake. Dysbiosis has been described in some inborn errors of metabolism, but has not been investigated in HCU. The aim of this study was to investigate the gut microbiota of HCU patients on treatment. Six unrelated HCU patients (males = 5, median age = 25.5 years) and six age-and-sex-matched healthy controls (males = 5, median age = 24.5 years) had their fecal microbiota characterized through partial 16S rRNA gene sequencing. Fecal pH, a 3-day dietary record, medical history, and current medications were recorded for both groups. All patients were nonresponsive to pyridoxine and were on a Met-restricted diet and presented with high tHcy. Oral supplementation of folate (n = 6) and pyridoxine (n = 5), oral intake of betaine (n = 4), and IM vitamin B12 supplementation (n = 4), were reported only in the HCU group. Patients had decreased daily intake of fat, cholesterol, vitamin D, and selenium compared to controls (p < 0.05). There was no difference in alpha and beta diversity between the groups. HCU patients had overrepresentation of the Eubacterium coprostanoligenes group and underrepresentation of the Alistipes, Family XIII UCG-001, and Parabacteroidetes genera. HCU patients and controls had similar gut microbiota diversity, despite differential abundance of some bacterial genera. Diet, betaine, vitamin B supplementation, and host genetics may contribute to these differences in microbial ecology.

Implementation of a Brazilian Cardioprotective Nutritional (BALANCE) Program for improvement on quality of diet and secondary prevention of cardiovascular events: A randomized, multicenter trial

Background Complex percutaneous coronary intervention (PCI) is associated with higher ischemic risk, which can be mitigated by long-term dual antiplatelet therapy (DAPT). However, concomitant high bleeding risk (HBR) may be present, making it unclear whether short- or long-term DAPT should be prioritized. Objectives This study investigated the effects of ischemic (by PCI complexity) and bleeding (by PRECISE-DAPT [PRE dicting bleeding Complications in patients undergoing stent Implantation and Sub sequent Dual Anti Platelet Therapy] score) risks on clinical outcomes and on the impact of DAPT duration after coronary stenting. Methods Complex PCI was defined as ≥3 stents implanted and/or ≥3 lesions treated, bifurcation stenting and/or stent length >60 mm, and/or chronic total occlusion revascularization. Ischemic and bleeding outcomes in high (≥25) or non-high (<25) PRECISE-DAPT strata were evaluated based on randomly allocated duration of DAPT. Results Among 14,963 patients from 8 randomized trials, 3,118 underwent complex PCI and experienced a higher rate of ischemic, but not bleeding, events. Long-term DAPT in non-HBR patients reduced ischemic events in both complex (absolute risk difference: −3.86%; 95% confidence interval: −7.71 to +0.06) and noncomplex PCI strata (absolute risk difference: −1.14%; 95% confidence interval: −2.26 to −0.02), but not among HBR patients, regardless of complex PCI features. The bleeding risk according to the Thrombolysis In Myocardial Infarction scale was increased by long-term DAPT only in HBR patients, regardless of PCI complexity. Conclusions Patients who underwent complex PCI had a higher risk of ischemic events, but benefitted from long-term DAPT only if HBR features were not present. These data suggested that when concordant, bleeding, more than ischemic risk, should inform decision-making on the duration of DAPT. (AU)

Contribution of ultra-processed foods consumption in sodium ingestion of atherosclerotic disease patients, residents in the southern region of Brazil.

BACKGROUND AND OBJECTIVE: Recent studies have related the consumption of ultra-processed foods with the development of cardiovascular diseases and have considered this relation with excessive sodium intake. While Brazilian studies have analysed that this consumption may have no direct relationship with the processing, but rather with the addition of salt. The purpose of this study is to investigate the contribution of the consumption of processed products in the daily intake of sodium ingestion by atherosclerotic disease patients. METHODS: A sub study, conducted with data from 630 cardiopathic patients who take part in "Effect of Brazilian Cardioprotective Food Program study on the reduction of events and risk factors in secondary prevention of cardiovascular disease part". Food was classified as: unprocessed or minimally processed foods, processed culinary ingredients, processed foods, ultra-processed food and beverages. Twenty-four-hour food recall (R24h) was collected from patients, and the estimation of total calories and sodium intake were calculated, as well as the percentage of sodium contribution according to the categories already mentioned. For the adequacy ratio analysis, the daily values of sodium intake were used to compared to the recommendations of the World Health Organization (<2000 mg / day). RESULTS: The average sodium intake was 1970.87 mg for women and 2642.86 mg for men, being higher for males' patients aged 60-79. It was observed that 64% of the studied population demonstrated sodium intake > 2000 mg. When considered levels > 3001 mg, a higher incidence of consumption was observed in the male group. Only 21.1% were intaking sodium within the recommended amount. Industrialized foods contributed to 33% of the mineral intake. CONCLUSION: These findings have demonstrated that the majority of the studied patients exceeded the dietary sodium recommendation. It has also indicated that patient's male, have presented increased consumption of the mineral. Consequently, warning for the necessity of greater investments in the nutritional re-education of these patients.

Three Main Causes of Homocystinuria: CBS, cblC and MTHFR Deficiency. What do they Have in Common?

Abstract Genetic homocystinurias are a group of inborn errors of metabolism that result in the massive excretion of homocysteine (Hcy) in the urine due to Hcy accumulation in the body, usually causing neurological and cardiovascular complications. The three most frequent causes are classical homocystinuria [deficiency of cystathionine beta-synthase (CBS)], methylmalonic aciduria with homocystinuria, cblC type (cblC deficiency) and severe methylenetetrahydrofolate reductase (MTHFR) deficiency. In this review, we highlight the similarities and differences among these disorders. Briefly, their joint manifestation is the accumulation of tHcy, however, the other sulfur amino acids show various and even invers profiles. Vascular disease, developmental delay and seizures are found in all homocystinurias, nevertheless, the complications of CNS differ in a wide variety of presentations and severities and are apparently less pronounced in CBS deficiency. Moreover, patients with remethylation defects typically do not present ectopia lentis and bone disturbances, tall stature and osteoporosis. Whereas hematological alterations, such as megaloblastic anemia, thrombocytopenia neutropenia and life-threatening microangiopathy, are specific findings of cblC deficiency.

CBS mutations are good predictors for B6-responsiveness: A study based on the analysis of 35 Brazilian Classical Homocystinuria patients.

BACKGROUND: Classical homocystinuria (HCU) is a monogenic disease caused by the deficient activity of cystathionine ß-synthase (CßS). The objective of this study was to identify the CBS mutations in Brazilian patients with HCU. METHODS: gDNA samples were obtained for 35 patients (30 families) with biochemically confirmed diagnosis of HCU. All exons and exon-intron boundaries of CBS gene were sequenced. Gene expression analysis by qRT-PCR was performed in six patients. Novel missense point mutations were expressed in E. coli by site-directed mutagenesis. RESULTS: Parental consanguinity was reported in 16 families, and pyridoxine responsiveness in five (15%) patients. Among individuals from the same family, all presented the same phenotype. Both pathogenic mutations were identified in 29/30 patients. Twenty-one different mutations were detected in nine exons and three introns; being six common mutations. Most prevalent were p.Ile278Thr (18.2%), p.Trp323Ter (11.3%), p.Thr191Met (11.3%), and c.828+1G>A (11.3%). Eight novel mutations were found [c.2T>C, c.209+1delG, c.284T>C, c.329A>T, c.444delG, c.864_868delGAG c.989_991delAGG, and c.1223+5G>T]. Enzyme activity in E. coli-expressed mutations was 1.5% for c.329A>T and 17.5% for c.284T>C. qRT-PCR analysis revealed reduced gene expression in all evaluated genotypes: [c.209+1delG; c.572C>T]; [c.2T>C; c.828+1G>A]; [c.828+1G>A; c.1126G>A]; [c.833T>C; c.989_991delAGG]; [c.1058C>T; c.146C>T]; and [c.444delG; c.444delG]. The expected phenotype according to the genotype (pyridoxine responsiveness) matched in all cases. CONCLUSIONS: Most patients studied were pyridoxine nonresponsive and presented early manifestations, suggesting severe phenotypes. Many private mutations were observed, but the four most prevalent mutations together accounted for over 50% of mutated alleles. A good genotype-phenotype relationship was observed within families and for the four most common mutations.

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

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.

Leptin concentrations and SCD-1 indices in classical homocystinuria: Evidence for the role of sulfur amino acids in the regulation of lipid metabolism.

BACKGROUND: We describe body composition, lipid metabolism and Stearoyl-CoA desaturase-1 (SCD-1) indices in patients with classical homocystinuria (HCU). METHODS: Eleven treated HCU patients and 16 healthy controls were included. Body composition and bone mineral density were assessed by dual X-ray absorptiometry. Sulfur amino acids (SAA) and their derivatives (total homocysteine, cysteine, methionine, S-adenosylmethionine, S-adenosylhomocysteine, and glutathione), lipids (free fatty acids, acylcarnitines, triglycerides and lipoproteins), glucose, insulin, leptin, adiponectin, and isoprostanes were measured in plasma. Insulin resistance was evaluated by HOMA-IR. To estimate liver SCD-1 activity, SCD-16 [16:1(n-7)/16:0] and SCD-18 [18:1(n-9)/18:0] desaturation indices were determined. RESULTS: In HCU patients, SCD-16 index was significantly reduced (p=0.03). A trend of an association of SCD-16 index with cysteine was observed (r=0.624, p=0.054). HCU patients displayed lower lean mass (p<0.05), with no differences in fat mass percentage. Leptin and low-density lipoprotein concentrations were lower in HCU patients (p<0.05). Femur bone mineral density Z-scores were correlated with plasma cysteine (r=0.829; p=0.04) and total homocysteine (r=-0.829; p=0.04) in HCU patients. CONCLUSIONS: We report alterations in leptin and SCD-1 in HCU patients. These results agree with previous findings from epidemiologic and animal studies, and support a role for SAA on lipid homeostasis.

Stearoyl-CoA Desaturase-1: Is It the Link between Sulfur Amino Acids and Lipid Metabolism?

An association between sulfur amino acids (methionine, cysteine, homocysteine and taurine) and lipid metabolism has been described in several experimental and population-based studies. Changes in the metabolism of these amino acids influence serum lipoprotein concentrations, although the underlying mechanisms are still poorly understood. However, recent evidence has suggested that the enzyme stearoyl-CoA desaturase-1 (SCD-1) may be the link between these two metabolic pathways. SCD-1 is a key enzyme for the synthesis of monounsaturated fatty acids. Its main substrates C16:0 and C18:0 and products palmitoleic acid (C16:1) and oleic acid (C18:1) are the most abundant fatty acids in triglycerides, cholesterol esters and membrane phospholipids. A significant suppression of SCD-1 has been observed in several animal models with disrupted sulfur amino acid metabolism, and the activity of SCD-1 is also associated with the levels of these amino acids in humans. This enzyme also appears to be involved in the etiology of metabolic syndromes because its suppression results in decreased fat deposits (regardless of food intake), improved insulin sensitivity and higher basal energy expenditure. Interestingly, this anti-obesogenic phenotype has also been described in humans and animals with sulfur amino acid disorders, which is consistent with the hypothesis that SCD-1 activity is influenced by these amino acids, in particularly cysteine, which is a strong and independent predictor of SCD-1 activity and fat storage. In this narrative review, we discuss the evidence linking sulfur amino acids, SCD-1 and lipid metabolism.