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Mucopolysaccharidosis type IIIB (MPS IIIB) is caused by deficiency of alpha-N-acetylglucosaminidase, leading to storage of heparan sulphate. The disease is characterized by intellectual disability and hyperactivity, among other neurological and somatic features. Here we studied retrospective data from a total of 19 MPS IIIB patients from Brazil, aiming to evaluate disease progression. Mean age at diagnosis was 7.2 years. Speech delay was one of the first symptoms to be identified, around 2-3 years of age. Behavioral alterations include hyperactivity and aggressiveness, starting around age four. By the end of the first decade, patients lost acquired abilities such as speech and ability to walk. Furthermore, as disease progresses, respiratory, cardiovascular and joint abnormalities were found in more than 50% of the patients, along with organomegaly. Most common cause of death was respiratory problems. The disease progression was characterized in multiple systems, and hopefully these data will help the design of appropriate clinical trials and clinical management guidelines.

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Abstract Data on Mucopolysaccharidosis type II (MPS II) in Latin America are scarce. This retrospective database study, using data from the Informatics Department of the Brazilian Health System (DATASUS), aimed to estimate the prevalence of MPSII in Brazil from 2008 to 2020 and to describe demographic and clinical profiles from patients under treatment. The study population was derived from DATASUS records of MPS II (ICD-10 E76.1) diagnosed in Brazil. Initially 455 patients were found, but only 181 patients who were receiving idursulfase treatment were included in this study. Among these cases, as expected in a X-linked disease, all were males and 40% of the cases were recorded in the Southeast region, and another 34% in the Northeast region. The biggest proportion of patients (39%) were diagnosed when they were 10-19 years old. There are 212 clinical conditions associated with MPS II, although the main comorbidities related to MPSII include: abdominal/inguinal hernia, respiratory complications, and carpal tunnel syndrome. Respiratory disorders were the fifth most frequent comorbidity recorded in these patients. The healthcare professionals in Brazil more involved in the diagnosis of MPS II were radiologists, followed by geneticists and cardiologists. Despite some limitations, DATASUS is a relevant database to provide information on rare diseases such as MPS II. Most cases were reported in southeast and northeast regions, respectively. This information is crucial to help design targeted public policies.

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Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare inborn error of fructose metabolism caused by pathogenic variants in the FBP1 gene. As gluconeogenesis is affected, catabolic episodes can induce ketotic hypoglycemia in patients. FBP1 analysis is the most commonly used approach for the diagnosis of this disorder. Herein, a Brazilian patient is reported. The proband, a girl born to a consanguineous couple, presented with severe hypoglycemia crisis in the neonatal period. At the age 17 months, presented a new crisis accompanied by metabolic acidosis associated with a feverish episode. Genetic analysis was performed by next-generation sequencing (NGS), identifying the NM_000507.3:c.611_614del variant in homozygosis in the FBP1 gene. In silico analysis and 3D modeling were performed, suggesting that this variant is associated with a loss of sites for substrate and Mg2+ binding and for posttranslational modifications of FBPase. The c.611_614del variant is located in a repetitive region of the FBP1 gene that appears to be a hotspot for mutational events. This frameshift creates a premature termination codon in the last coding exon which escapes the nonsense-mediated decay mechanism, according to in silico analysis. This variant results in an intrinsically disordered protein with loss of substrate recognition and post-translational modification sites.

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Abstract Objectives: To characterize cases of suspected congenital disorders of glycosylation (CDG) investigated in a laboratory in southern Brazil using the transferrin isoelectric focusing TfIEF test from 2008 to 2017. Method: Observational, cross-sectional, retrospective study. The laboratory records of 1,546 individuals (median age = 36 months, 25-75 IQR = 10-108; males = 810) submitted to the TfIEF test during the period were reviewed. Results: Fifty-one individuals (3%) had an altered TfIEF pattern (5 ± 2.8 cases/year; median age = 24 months, 25-75 IQR = 11-57 months; males = 27, 53%). For 14 of them, data on diagnosis conclusion were available (classic galactosemia = 4; hereditary fructose intolerance = 4; peroxisomal diseases = 2; PMM2-CDG = 2; MPDU1-CDG = 1; SLC35A2-CDG = 1).Comparing the cases with the normal and altered TfIEF patterns, there was a higher prevalence of altered cases in the age group from 11 months to 3 years. There was an increase in the likelihood of change in TfIEF, especially in the presence of inverted nipples or liver disease. Conclusions: The data suggest that the investigation of a case with suspected CDG is a complex problem, being aggravated by the existence of other IEMs (inborn errors of metabolism) associated with altered TfIEF pattern and lack of access to confirmatory tests. The presence of inverted nipples and liver disease, especially in individuals aged 11 months to 3 years, should suggest the need for TfIEF investigation.

Resumo Objetivos: Caracterizar os casos com suspeita de CDG investigados em laboratório do sul do Brasil pelo exame de IEFTF de 2008 a 2017. Metodologia: Estudo observacional, transversal, retrospectivo. Foram revisadas as fichas laboratoriais de 1.546 indivíduos (mediana de idade = 36 meses, IQ 25-75 = 10-108; sexo masculino = 810) que fizeram o exame de IEFTF no período. Resultados: Cinquenta e um indivíduos (3%) apresentaram padrão alterado na IEFTF (5 ± 2,8 casos/ano; mediana de idade = 24 meses, IQ 25-75 = 11-57 meses; sexo masculino = 27, 53%). Para 14 deles, estavam disponíveis dados sobre a conclusão do diagnóstico (galactosemia clássica = 4; intolerância hereditária à frutose = 4; doenças peroxissomais = 2; PMM2-CDG = 2; MPDU1-CDG = 1; SLC35A2-CDG = 1). Comparando os casos com padrão normal e alterado na IEFTF, houve maior prevalência de casos alterados na faixa etária de 11 meses a 3 anos. Verificou-se um aumento na probabilidade de alteração na IEFTF principalmente na presença de mamilos invertidos ou de hepatopatia. Conclusões: Os nossos dados sugerem que a investigação de um caso com suspeita de CDG é complexa, é agravada pela existência de outros EIM associados a padrão alterado na IEFTF e pela falta de acesso a exames confirmatórios. A presença principalmente de mamilos invertidos e de hepatopatia em indivíduos na faixa etária de 11 meses a 3 anos deve sugerir a necessidade de investigação por IEFTF.

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RESUMO

OBJECTIVES: To characterize cases of suspected congenital disorders of glycosylation (CDG) investigated in a laboratory in southern Brazil using the transferrin isoelectric focusing TfIEF test from 2008 to 2017. METHOD: Observational, cross-sectional, retrospective study. The laboratory records of 1,546 individuals (median age=36 months, 25-75 IQR=10-108; males=810) submitted to the TfIEF test during the period were reviewed. RESULTS: Fifty-one individuals (3%) had an altered TfIEF pattern (5±2.8 cases/year; median age=24 months, 25-75 IQR=11-57 months; males=27, 53%). For 14 of them, data on diagnosis conclusion were available (classic galactosemia=4; hereditary fructose intolerance=4; peroxisomal diseases=2; PMM2-CDG=2; MPDU1-CDG=1; SLC35A2-CDG=1).Comparing the cases with the normal and altered TfIEF patterns, there was a higher prevalence of altered cases in the age group from 11 months to 3 years. There was an increase in the likelihood of change in TfIEF, especially in the presence of inverted nipples or liver disease. CONCLUSIONS: The data suggest that the investigation of a case with suspected CDG is a complex problem, being aggravated by the existence of other IEMs (inborn errors of metabolism) associated with altered TfIEF pattern and lack of access to confirmatory tests. The presence of inverted nipples and liver disease, especially in individuals aged 11 months to 3 years, should suggest the need for TfIEF investigation.

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Brazil is a country of continental dimensions and most genetic services are concentrated in the Southeast and South, including the Medical Genetics Service of the Hospital de Clínicas de Porto Alegre (MGS/HCPA). As many areas on the country do not have adequate medical genetics support, networks were designed to extend the service of the MGS/HCPA reference center. This paper presents the information and diagnosis networks that have their headquarters at MGS/HCPA: SIAT (National Information System on Teratogenic Agents), SIEM (Information Service on Inborn Errors of Metabolism), Alô Genética (Hello Genetics - Medical Genetics Information Service for Primary Health Care Professionals); Rede MPS Brasil (MPS-Mucopolysaccharidosis Brazil Network); Rede EIM Brasil (IEM-Inborn Errors of Metabolism Brazil Network), Rede NPC Brasil (Niemann-Pick C - NPC Brazil Network), Rede DLD Brasil (LSD-Lysosomal Storage Disorders Brazil Network), Rede DXB (MSUD-Maple Syrup Urine Disease Network), RedeBRIM (Brazilian Network of Reference and Information in Microdeletion Syndromes Project), Rede Neurogenética (Neurogenetics Network), and Rede Brasileira de Câncer Hereditário (Brazilian Hereditary Cancer Network). These tools are very useful to provide access to a qualified information and/or diagnostic service for specialized and non-specialized health services, bypassing difficulties that preclude patients to access reference centers.

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Lysosomal diseases (LDs), also known as lysosomal storage diseases (LSDs), are a heterogeneous group of conditions caused by defects in lysosomal function. LDs may result from deficiency of lysosomal hydrolases, membrane-associated transporters or other non-enzymatic proteins. Interest in the LD field is growing each year, as more conditions are, or will soon be treatable. In this article, we review the diagnosis of LDs, from clinical suspicion and screening tests to the identification of enzyme or protein deficiencies and molecular genetic diagnosis. We also cover the treatment approaches that are currently available or in development, including hematopoietic stem cell transplantation, enzyme replacement therapy, small molecules, and gene therapy.

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Introdução: Redução da densidade mineral óssea (DMO) está associada à Fenilcetonúria (PKU), mas a causa desta associação não é completamente entendida. O objetivo desse estudo foi avaliar a ingestão de nutrientes relacionados ao metabolismo ósseo (cálcio, fósforo, magnésio, potássio), e sua associação com a DMO em pacientes com PKU. Métodos: Estudo transversal, observacional. Foram incluídos 15 pacientes (PKU Clássica=8; Leve=7; mediana de idade=16 anos, IQ=15-20), todos em tratamento com dieta restrita em fenilalanina (Phe) e 13 em uso de fórmula metabólica. Foi realizado recordatório alimentar de 24 horas de um dia e demais dados (histórico de fraturas, parâmetros antropométricos, DMO e níveis plasmáticos de Phe, Tyr, cálcio) foram obtidos por revisão de prontuário. Resultados: Nenhum paciente apresentou histórico de fraturas e seis realizavam suplementação de cálcio (alteração prévia da DMO=5; baixa ingestão=1). A mediana dos níveis de Phe foi 11,6 mg/dL (IQ=9,3-13,3). Em relação ao recordatório alimentar, dez indivíduos apresentaram inadequado consumo de carboidratos; 14, de lipídeos; 9, de cálcio; 11, de magnésio; 13, de fósforo; e todos de potássio. A mediana da DMO foi de 0,989 g/cm2 (IQ=0,903-1,069), sendo duas classificadas como reduzidas para idade, ambas de pacientes com PKU Leve que recebiam suplementação de cálcio. Não foi observada correlação entre níveis de Phe, DMO e demais variáveis analisadas. Conclusão: Redução da DMO não foi frequente na amostra, embora ingestão inadequada de cálcio assim o seja. Estudos adicionais são necessários para esclarecer o efeito da Phe e da ingestão dietética sobre o metabolismo ósseo na PKU. (AU)

Introduction: Reduced bone mineral density (BMD) is associated with phenylketonuria (PKU), but this association is not completely understood. This research aimed to evaluate intake of nutrients related to bone metabolism (calcium, phosphorus, magnesium, potassium) and its association with BMD in patients with PKU. Methods: In this cross-sectional, observational study, 15 patients with PKU (Classical=8, Mild=7; median age=16 years, IQ=15-20 years) were included, all of them on phenylalanine (Phe) restricted diet and 13 being supplemented with a metabolic formula. A 24-hour dietary recall was performed and remaining data (history of fractures, anthropometric parameters, BMD and plasma Phe, tyrosine and calcium levels) were obtained through medical chart review. Results: No patient had any fractures and six received calcium supplements, five due to previous change in BMD and one due to inadequate nutritional intake. Median Phe level was 11.6 mg/dL (IQ=9.3-13.3). In relation to dietary recall, all individuals had inadequate intake of some nutrient (carbohydrate=10; lipids=14; calcium=9; magnesium=11; phosphorus=13; potassium=15). The median BMD was 0.989 g/cm2 (IQ=0.903-1.069). Two cases were classified as low BMD for age, both in patients with mild PKU receiving calcium supplements. Conclusion: Reduced BMD was not common in this sample, although inadequate calcium intake was frequently reported. Additional studies are needed to clarify the effect of Phe and dietary intake on bone metabolism in patients with PKU.(AU)

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