Tatiéle Nalin

Maple syrup urine disease in Brazil: a panorama of the last two decades

OBJECTIVE To characterize a sample of Brazilian patients with maple syrup urine disease (MSUD) diagnosed between 1992 and 2011. METHODS In this retrospective study, patients were identified through a national reference laboratory for the diagnosis of MSUD and through contact with other medical genetics services across Brazil. Data were collected by means of a chart review. RESULTS Eighty-three patients from 75 families were enrolled in the study (median age, 3 years; interquartile range [IQR], 0.57-7). Median age at onset of symptoms was 10 days (IQR 5-30), whereas median age at diagnosis was 60 days (IQR 29-240, p=0.001). Only three (3.6%) patients were diagnosed before the onset of clinical manifestations. A comparison between patients with (n=12) and without (n=71) an early diagnosis shows that early diagnosis is associated with the presence of positive family history and decreased prevalence of clinical manifestations at the time of diagnosis, but not with a better outcome. Overall, 98.8% of patients have some psychomotor or neurodevelopmental delay. CONCLUSION In Brazil, patients with MSUD are usually diagnosed late and exhibit neurological involvement and poor survival even with early diagnosis. We suggest that specific public policies for diagnosis and treatment of MSUD should be developed and implemented in the country.

Glycogen storage disease type I: clinical and laboratory profile

OBJECTIVES To characterize the clinical, laboratory, and anthropometric profile of a sample of Brazilian patients with glycogen storage disease type I managed at an outpatient referral clinic for inborn errors of metabolism. METHODS This was a cross-sectional outpatient study based on a convenience sampling strategy. Data on diagnosis, management, anthropometric parameters, and follow-up were assessed. RESULTS Twenty-one patients were included (median age 10 years, range 1-25 years), all using uncooked cornstarch therapy. Median age at diagnosis was 7 months (range, 1-132 months), and 19 patients underwent liver biopsy for diagnostic confirmation. Overweight, short stature, hepatomegaly, and liver nodules were present in 16 of 21, four of 21, nine of 14, and three of 14 patients, respectively. A correlation was found between height-for-age and BMI-for-age Z-scores (r=0.561; p=0.008). CONCLUSIONS Diagnosis of glycogen storage disease type I is delayed in Brazil. Most patients undergo liver biopsy for diagnostic confirmation, even though the combination of a characteristic clinical presentation and molecular methods can provide a definitive diagnosis in a less invasive manner. Obesity is a side effect of cornstarch therapy, and appears to be associated with growth in these patients.Objectives To characterize the clinical, laboratory, and anthropometric profile of a sample of Brazilian patients with glycogen storage disease type I managed at an outpatient referral clinic for inborn errors of metabolism.

Body composition in patients with classical homocystinuria: body mass relates to homocysteine and choline metabolism

INTRODUCTION Classical homocystinuria is a rare genetic disease caused by cystathionine β-synthase deficiency, resulting in homocysteine accumulation. Growing evidence suggests that reduced fat mass in patients with classical homocystinuria may be associated with alterations in choline and homocysteine pathways. This study aimed to evaluate the body composition of patients with classical homocystinuria, identifying changes in body fat percentage and correlating findings with biochemical markers of homocysteine and choline pathways, lipoprotein levels and bone mineral density (BMD) T-scores. METHODS Nine patients with classical homocystinuria were included in the study. Levels of homocysteine, methionine, cysteine, choline, betaine, dimethylglycine and ethanolamine were determined. Body composition was assessed by bioelectrical impedance analysis (BIA) in patients and in 18 controls. Data on the last BMD measurement and lipoprotein profile were obtained from medical records. RESULTS Of 9 patients, 4 (44%) had a low body fat percentage, but no statistically significant differences were found between patients and controls. Homocysteine and methionine levels were negatively correlated with body mass index (BMI), while cysteine showed a positive correlation with BMI (p<0.05). There was a trend between total choline levels and body fat percentage (r=0.439, p=0.07). HDL cholesterol correlated with choline and ethanolamine levels (r=0.757, p=0.049; r=0.847, p=0.016, respectively), and total cholesterol also correlated with choline levels (r=0.775, p=0.041). There was no association between BMD T-scores and body composition. CONCLUSIONS These results suggest that reduced fat mass is common in patients with classical homocystinuria, and that alterations in homocysteine and choline pathways affect body mass and lipid metabolism.

Original articleGlycogen storage disease type I: clinical and laboratory profileDoença de depósito de glicogênio tipo I: perfil clínico e laboratorial☆☆☆

OBJECTIVES To characterize the clinical, laboratory, and anthropometric profile of a sample of Brazilian patients with glycogen storage disease type I managed at an outpatient referral clinic for inborn errors of metabolism. METHODS This was a cross-sectional outpatient study based on a convenience sampling strategy. Data on diagnosis, management, anthropometric parameters, and follow-up were assessed. RESULTS Twenty-one patients were included (median age 10 years, range 1-25 years), all using uncooked cornstarch therapy. Median age at diagnosis was 7 months (range, 1-132 months), and 19 patients underwent liver biopsy for diagnostic confirmation. Overweight, short stature, hepatomegaly, and liver nodules were present in 16 of 21, four of 21, nine of 14, and three of 14 patients, respectively. A correlation was found between height-for-age and BMI-for-age Z-scores (r=0.561; p=0.008). CONCLUSIONS Diagnosis of glycogen storage disease type I is delayed in Brazil. Most patients undergo liver biopsy for diagnostic confirmation, even though the combination of a characteristic clinical presentation and molecular methods can provide a definitive diagnosis in a less invasive manner. Obesity is a side effect of cornstarch therapy, and appears to be associated with growth in these patients.Objectives To characterize the clinical, laboratory, and anthropometric profile of a sample of Brazilian patients with glycogen storage disease type I managed at an outpatient referral clinic for inborn errors of metabolism.

Enzyme Replacement Therapy in a Patient with Gaucher Disease Type III: A Paradigmatic Case Showing Severe Adverse Reactions Started a Long Time After the Beginning of Treatment.

INTRODUCTION There are three recombinant enzymes available for the treatment of Gaucher disease (GD): imiglucerase, velaglucerase alfa, and taliglucerase alfa. CASE REPORT A male GD type III patient, 14 years old, genotype p.L444P/L444, diagnosed at 2 years old. He had been treated with imiglucerase for 9 years since the diagnosis. In 2008, however, he presented a severe adverse reaction to imiglucerase, characterized by cough, laryngeal stridor, and periorbital edema. The infusions were suspended for 3 months when imiglucerase was restarted with premedication and a slower infusion rate. After 5 months, he presented a new adverse reaction with vomiting, tachypnea, cough, and periorbital edema. Intradermal testing confirmed IgE-mediated reaction but serological tests were negative. After 2 years and 10 months with no specific treatment and a significant worsening of the clinical picture, taliglucerase alfa was prescribed, with premedication and a slower infusion rate. At the first infusion, he presented moderate adverse reaction and the infusions were suspended. After 2 months, velaglucerase alfa was initiated uneventfully. He maintains day-hospital infusions without premedication and shows improvement of clinical and laboratory parameters. CONCLUSION This is the first report of the use of velaglucerase alfa in patients with GD type III. The use of recombinant enzymes is safe for the majority of GD patients, but severe reactions may occur even many years after the beginning of the treatment. Premedication and slower infusion rate reduce the incidence of adverse reactions but may not solve the problem. This case report further demonstrates the different safety profile among all the recombinant enzymes available for the treatment of GD.

Access to treatment for phenylketonuria by judicial means in Rio Grande do Sul, Brazil.

Treatment of phenylketonuria (PKU) includes the use of a metabolic formula which should be provided free of charge by the Unified Health System (SUS). This retrospective, observational study sought to characterize judicial channels to obtain PKU treatment in Rio Grande do Sul (RS), Brazil. Lawsuits filed between 2001- 2010 and having as beneficiaries PKU patients requesting treatment for the disease were included. Of 20 lawsuits filed, corresponding to 16.8% of RS patients with PKU, 19 were retrieved for analysis. Of these, only two sought to obtain therapies other than metabolic formula. In all the other 17 cases, prior treatment requests had been granted by the State Department of Health. Defendants included the State (n = 19), the Union (n = 1), and municipalities (n = 4). In 18/19 cases, the courts ruled in favor of the plaintiffs. Violation of the right to health and discontinuation of State-provided treatment were the main reasons for judicial recourse. Unlike other genetic diseases, patients with PKU seek legal remedy to obtain a product already covered by the national pharmaceutical assistance policy, suggesting that management failures are a driving factor for judicialization in Brazil.

Optimized loading test to evaluate responsiveness to tetrahydrobiopterin (BH4) in Brazilian patients with phenylalanine hydroxylase deficiency

INTRODUCTION Recent studies showed that phenylalanine (Phe) plasma concentrations may decrease in some patients with hyperphenylalaninemia (HPA) due to phenylalanine hydroxylase (PAH) deficiency, after the administration of tetrahydrobiopterin (BH(4)). OBJECTIVE To determine responsiveness to a single dose of BH(4) administered according to an innovative protocol using a combined Phe and BH(4) loading test in Brazilian phenylketonuria (PKU) patients. METHODS Patient age should be ≥ 4 years, and median Phe plasma concentration ≤ 600 μmol/L when following dietary restrictions. Participants received a simple Phe loading test using 100mg/kg L-Phe (Test 1) and a combined Phe+BH(4) loading test using 100mg/kg L-Phe and 20mg/kg/BH(4) (Test 2). Blood samples were collected at baseline and 3, 11 and 27 h after Phe ingestion (T0, T1, T2 and T3). Responsiveness was defined as: criterion A: plasma Phe reduction of ≥ 30% at T1 and T2 for Tests 1 and 2; criterion B: plasma Phe reduction of ≥ 30% at T1 and T3 for Tests 1 and 2; and criterion C: at least 30% difference of the areas under the Phe curve for Tests 1 and 2. RESULTS Eighteen patients (median age 12 yrs; 8 classical PKU; 10 mild PKU) participated in the study. Six patients (2 classical PKU; 4 mild PKU) were classified as responsive according to at least one of the criteria. Responsiveness was concordant when criteria A + B we compared with criterion C (kappa = 0.557; p = 0.017). Of the patients whose genotype was available (n = 16), six had data about BH(4)-responsiveness genotypes described in the literature, which were in agreement with our findings. CONCLUSION The comparison of simple Phe loading and combined Phe + BH(4) loading seems to be an optimal method to evaluate responsiveness to BH(4) in patients with good metabolic control.

Determination of amylose/amylopectin ratio of starches

Dear editor, Nalin et al 2014, in a paper recently published in the JIMD, tested in vitro digestion of seven different starches in a dynamic gastro-small intestine model (TIM-1), and did not find large differences between different brands of uncooked cornstarches (UCCS) and of a modified starch (Glycosade®) (Correia et al 2008). However, the authors found that sweet polvilho, and the mixture of sweet polvilho and UCCS, seem to have a slower and extended release of glucose, which looks promising as an option for the treatment of diseases associated with fasting intolerance, such as hepatic glycogen storage diseases. We would like to report herein the experiment we performed to determine the percentage of amylose and amylopectin in the same starch samples analyzed by Nalin et al 2014. Starch consists of a mixture of amylose (linear chain) and amylopectin (branched chain) (Tester et al 2004). The amylose/amylopectin ratio has an important influence on the rate and extent of starch digestion (Bjorck et al 1994), which may, in turn, influence the treatment of patients with fasting intolerance. The amylose/amylopectin ratio was measured using a commercial kit (Megazyme Co., Wicklow, Ireland), according to the manufacturer’s recommendations. For a better characterization of the sweet polvilho, we also analyzed two different batches of this product and, in addition, two samples of the same batch but with different expiration dates (Table 1). The different brands of UCCS did not differ regarding the amylose/amylopectin ratio. As expected, the Glycosade® presented the highest amylopectin content. The sweet polvilho was found to present a slightly higher value of amylopectin compared to the UCCS. Furthermore, little variation was found between different batches or within the same batch of sweet polvilho, demonstrating the stability of the composition of this product (Table 1). Although the data presented herein supports some of the findings described by Nalin et al 2014, e.g., different brands of UCCS present small differences among themselves, they did not explain the slower and lower digestibility found for sweet polvilho in the TIM-1 model. This is not a surprising finding since many other factors, besides the amylose/amylopectin ratio, may be responsible for the differences in the glucose and insulin responses, such as the solubility of the starch. Additional studies using the TIM-2, which includes the large intestine Communicated by: Bruce A Barshop

Adherence to Treatment of Phenylketonuria: A Study in Southern Brazilian Patients

Introduction:Phenylketonuria (PKU) is caused by the deficient activity of phenylalanine hydroxylase.Aim:To identify the factors associated with treatment adherence among patients with PKU seen at a southern Brazil reference center.Methodology:A cross-sectional, outpatient-based study including 56 patients with PKU (median age, 12 years) for whom a Phe-restrict diet plus specific metabolic formula have been prescribed. Patients were considered adherent or nonadherent depending on the median phenylalanine concentration for the 12 months prior to study and target levels of phenylalanine for each age range (<13 years = ≤360 µmol/L; ≥13 years = ≤900 µmol/L). Data were collected through a review of patient’s medical records and a set of interviews with patients and their relatives.Results:Eighteen patients (32.1%; ≥13 years, 11) were classified as treatment adherent. Among all factors analyzed, only mental retardation, living with parents, and level of maternal education were associated with adherence to treatm...

Assessment of newborn screening in the public health system of a municipality in northern Rio Grande do Sul

Introduction: Newborn screening allows the screening of diseases that are still in the asymptomatic period and whose early diagnosis and treatment are associated with reduced infant morbidity and mortality. The aim of this study was to evaluate the public National Newborn Screening Program in the municipality of Carazinho, state of Rio Grande do Sul (RS), Brazil. Methods: This was a population-based, retrospective, descriptive study. We collected and transcribed data from a database of the Carazinho municipal laboratory, which is affiliated with the referral center for newborn screening in RS. The records of all individuals undergoing newborn screening from 2005 to 2010 were reviewed, and information was collected on the program coverage, time elapsed between birth and screening (first collection), and test results. Results: The program had a coverage of 75.5%. One suspected case of phenylketonuria, three suspected cases of congenital hypothyroidism and no suspected cases of hemoglobinopathy were identified. In addition, there were 18 positive results for hemoglobin S heterozygosity, five for hemoglobin D heterozygosity, two for hemoglobin C heterozygosity, and one for a rare variant hemoglobin. When analyzing the newborn’s age at the time of blood collection, it was observed that 63.1% were within the recommended age range. Conclusion: Our findings suggest the need for optimization of public newborn screening in the evaluated municipality. The strategies to be adopted should include education of the population and especially of managers and health professionals about the importance of newborn screening. Keywords: Newborn screening; public health; mass screening