Efficacy and Safety of Taliglucerase Alfa for the Treatment of Gaucher Disease: A 9-Year Experience

Abstract Gaucher disease (GD) is one of the most common lysosomal disorders, occurring in approximately 1 in 40,000 live births worldwide. Since 2014 enzyme replacement therapy (ERT) with taliglucerase alfa has been the treatment of choice for adult patients with GD in Brazil. The aim of this study was to evaluate the long-term efficacy and safety of taliglucerase alfa in a cohort of Brazilian patients treated at a referral center for inborn errors of metabolism. All patients who received at least one infusion of the enzyme at the study center were considered eligible to participate. Patients were followed for adverse reactions and events throughout the study period. Platelets, hemoglobin, chitotriosidase activity, bone marrow burden (BMB) score, bone mineral density, and the severity score index (SSI) were analyzed. For patients who were switched to taliglucerase alfa from imiglucerase, the same variables were compared before and after the switch. At 9-year follow-up, all parameters of interest had remained stable or improved. The overall rate of adverse events was lower than in other studies that evaluated long-term ERT with taliglucerase, and no serious adverse events were considered related to treatment. Based on our findings, ERT with taliglucerase alfa is an effective and safe approach for treatment of patients with GD.

Histomorphometric analysis of liver biopsies of treated patients with Gaucher disease type 1

Gaucher disease (GD) is an autosomal recessive lysosomal disorder caused by a disturbance in the metabolism of glucocerebroside in the macrophages. Most of its manifestations - hepatosplenomegaly, anemia, thrombocytopenia, and bone pain - are amenable to a macrophage-target therapy such as enzyme replacement. However, there is increasing evidence that abnormalities of the liver persist despite the specific GD treatment. In this work, we adapted histomorphometry techniques to the study of hepatocytes in GD using liver tissue of treated patients, developing the first morphometrical method for canalicular quantification in immunohistochemistry-stained liver biopsies, and exploring histomorphometric characteristics of GD. This is the first histomorphometric technique developed for canalicular analysis on histological liver biopsy samples.

Transferrin isoelectric focusing for the investigation of congenital disorders of glycosylation: analysis of a ten-year experience in a Brazilian center / Isoeletrofocalização da transferrina para investigação das doenças congênitasda glicosilação: análise de dez anos de experiência de um centro brasileiro

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.

Leigh Syndrome Due to mtDNA Pathogenic Variants

Abstract Leigh syndrome is a devastating neurodegenerative disease, typically manifesting in infancy or early childhood. Hallmarks of the disease are symmetrical lesions in the basal ganglia or brain stem on MRI, and a clinical course with rapid deterioration of cognitive and motor functions. It is genetically heterogeneous, causative mutations have been disclosed in mitochondrial DNA and nuclear genes involved in the process of energy production in the mitochondria .We investigated the whole mitochondrial DNA in three Brazilian patients with LS, based on their clinical and biochemical data, with the aim to identify the disease-causing mutations. In two of the patients, with complex I deficiency, a novel heteroplasmic variant m.4142G>T (p.R279L) in MT-ND1 and a recurrent homoplasmic mutation m.10197G>A (p.A47T) in MT-ND3 were identified. In the remaining patient, with complex IV deficiency, a de novo heteroplasmic variant in MT-CO1 m.6547T>C (p.L215P) was found. The molecular investigation in mitochondrial diseases have shifted their focus from mitochondrial DNA to nuclear DNA, however, mtDNA protein-coding genes are one of the important genetic causes of mitochondrial disorders for Leigh syndrome. This study expands the molecular and clinical spectrum associated with this disease.

Análise da densidade mineral óssea em pacientes com fenilcetonúria e sua correlação com parâmetros nutricionais / Bone mineral density assessment in patients with phenylketonuria and its correlation with nutritional parameters

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)

Nutritional Status and Body Composition in Patients With Hepatic Glycogen Storage Diseases Treated With Uncooked Cornstarch—A Controlled Study

Abstract Hepatic glycogen storage diseases (GSDs) are genetic diseases associated with fasting hypoglycemia. Periodic intake of uncooked cornstarch is one of the treatment strategies available for those disorders. For reasons that are still not clear, patients with hepatic GSDs may be overweight. Aims: To assess nutritional status and body composition in patients with hepatic GSDs receiving uncooked cornstarch. Methods: The sample included 25 patients with hepatic GSD (type Ia = 14; Ib = 6; III = 3; IX? = 1; IX? = 1), with a median age of 11.0 years (interquartile range [IQR] = 9.0-17.5), matched by age and gender with 25 healthy controls (median age = 12.0 years, IQR = 10.0-17.5). Clinical, biochemical, and treatment-related variables were obtained from medical records. Nutritional status and body composition were prospectively evaluated by bioelectrical impedance. Results: Patients and controls did not differ with regard to age and gender. Height was significantly reduced in patients (median = 1.43 m, IQR = 1.25-1.54) in comparison to controls (median = 1.54 m, IQR = 1.42-1.61; P = .04). Body mass index for age z-score and fat mass percentage were higher in patients (median = 1.84, IQR = 0.55-3.06; and 27.5%, IQR = 22.6-32.0, respectively) than in controls (median = 0.86, IQR = ?0.55 to 1.82; P = .04 and 21.1%, IQR = 13.0-28.3; P = .01, respectively). When patients were stratified by type, those with GSD Ia had significantly higher adiposity (median fat mass = 28.7%, IQR = 25.3-32.9) than those with GSD III and GSD IX?/? (median fat mass = 20.9%, IQR = 14.9-22.6; P = .02). Conclusions: Our findings suggest that patients with hepatic GSD on treatment with cornstarch, especially those with GSD Ia, exhibit abnormalities in nutritional status and body composition, such as short stature and a trend toward overweight and obesity.

Prevalence of thrombophilia and thrombotic events in patients with Fabry disease in a reference center for lysosomal disorders in Southern Brazil

Introduction: Venous thromboembolism (VTE) is a multifactorial genetic disorder that occurs in approximately one in a thousand adults per year. Because there is no laboratory test or clinical marker useful for predicting which patients with Fabry disease may develop thrombotic events, this study aimed to determine whether there is a hereditary predisposition to hypercoagulation in these patients. Methods: The prevalence of p.R506Q mutation in the factor V gene and of c.G20210A mutation in Factor II (prothrombin) gene was evaluated in 39 patients with Fabry disease from Southern Brazil and correlated with clinical findings. The DNA analysis was performed by real-time polymerase chain reaction on genomic DNA using TaqMan probes. Results: In this group of patients, the frequency of mutation in the prothrombin gene was 1.28%, whereas no patient showed mutation in the factor V gene; additionally, there was no correlation between these mutations and the incidence of thrombotic events. Conclusion: Hereditary thrombophilia due to mutations in factor V and prothrombin genes does not seem to be related to thrombotic events in Fabry patients in our cohort, although studies in larger cohorts and the inclusion of additional factors may be required to determine if a correlation exists.