Revisão sistemática e metanálise sobre terapia de reposição enzimática para doença de Pompe

Base teórica: A Doença de Pompe (DP) (ou glicogenose tipo II) é uma glicogenose muscular, causada pela atividade deficiente da alfa glicosidase ácida que leva ao acúmulo de glicogênio dentro dos lisossomos e do citoplasma das células da musculatura lisa, esquelética e cardíaca, danificando o funcionamento celular e destruindo as células, com acometimento neuromuscular progressivo. A prevenção das manifestações clínicas e o tratamento das manifestações já estabelecidas são realizados com a terapia de reposição enzimática (TRE) com maltase ácida recombinante humana (alfa-alglicosidase). Objetivo: Avaliar eficácia e segurança da TRE endovenosa com alfa-alglicosidase para DP. Métodos: Revisão sistemática da literatura com buscas conduzidas nas bases: Clinical Trials, MEDLINE / PubMed, EMBASE e Cochrane Library. A pesquisa foi limitada aos ensaios clínicos publicados até 30 de maio de 2021 para DP Tardia (DPT) (artigo já publicado) e até 25 de abril de 2022 para DP Precoce (DPP). Para a avaliação de eficácia da TRE considerou-se elegíveis: ensaios clínicos randomizados (ECR) comparando alfa-alglicosidase a placebo/história natural da doença. Estudos de intervenção não randomizados poderiam ser considerados na ausência de ECR elegíveis. A revisão sistemática considerou as recomendações do Handbook da Cochrane, e o relato seguiu o Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Desfechos primários para DPP foram qualidade de vida (QV), sobrevida, tempo para início de ventilação (TSV), deglutição, segurança, massa de ventrículo esquerdo (VE), função miocárdica [medida por fração de ejeção (FE)], atraso de marcos do desenvolvimento e hipotonia; para DPT: QV, capacidade funcional, sobrevida, horas em ventilação (TOV), força em membros superiores, qualidade do sono e deglutição. Quando aplicável, para cada desfecho, meta-análises para a comparação por pares foram realizadas, considerando o padrão de heterogeneidade presente e utilizando medidas sumárias apropriadas. A certeza da evidência para cada desfecho foi avaliada pelo Grading of Recommendation, Assessment, Development and Evaluation (GRADE). 7 Resultado: Dos 1.722 artigos identificados, 37 foram incluídos (15 artigos avaliavam os desfechos para DPP e 22 para DPT). Os estudos eram heterogêneos e com muito baixa certeza de evidência para a maioria dos resultados. Com relação à DPP, TRE com alfa-alglicosidase apresentou melhora significativa para: massa de VE [média de variação de 131,3 g/m² (intervalo de confiança de 95% [IC95%] 81,02 a 181,59)], TSV [HR 0,21 (IC95% 0,12 a 0,36)] e sobrevivência [HR 0,10 (IC95% 0,05 a 0,19)]. Com relação à DPT, TRE com alfa-alglicosidase apresentou melhora significativa para: distância percorrida no teste de caminhada de 6 minutos (TC6M) [média de variação de 35,7m (IC95% 7,78 a 63,75)], domínio físico da QV por SF-36 [média de variação de 1,96 (IC95% 0,33 a 3,59)] e TOV [média de variação de -2,64 h (IC95% -5,28 a 0,00)]. Os eventos adversos (EAs) após TRE foram leves na maioria dos casos para DPP e DPT. Conclusão: Nossos dados sugerem que TRE com alfa-alglicosidase potencialmente melhora massa de VE, TSV e sobrevida em pacientes com DPP, e melhora TC6M, QV física e TOV em pacientes com DPT, sendo segura em ambas as formas da doença.Theoretical basis: Pompe disease (PD) (or type II glycogenosis) is a muscle glycogenosis, caused by deficient activity of acid alpha glucosidase that leads to the accumulation of glycogen within lysosomes and cytoplasm of smooth, skeletal and cardiac muscle cells, damaging cellular functioning and destroying cells, with progressive neuromuscular involvement. Prevention of clinical manifestations and treatment of established manifestations are performed with enzyme replacement therapy (ERT) with human recombinant acid maltase (alglucosidase alfa). Objective: To evaluate the efficacy and safety of intravenous ERT with alglucosidase alfa for PD. Methods: Systematic literature review with searches conducted in the following databases: Clinical Trials, MEDLINE / PubMed, EMBASE and Cochrane Library. The search was limited to clinical trials published up to 30 May 2021 for Late PD (LOPD) (article already published) and up to 25 April 2022 for Early PD (EOPD). For the evaluation of the effectiveness of ERT the following were considered eligible: randomized controlled trials (RCTs) comparing alglucosidase alfa to placebo/natural history of the disease. Nonrandomized intervention studies could be considered in the absence of eligible RCTs. The systematic review considered the recommendations of the Cochrane Handbook, and the report followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Primary outcomes for EOPD were quality of life (QOL), survival, time to ventilation (TSV), swallowing, safety, left ventricular (LV) mass, myocardial function [measured by LV ejection fraction (EF)], delayed developmental milestones, and hypotonia; for LOPD: QOL, functional capacity, survival, hours on ventilation (TOV), strength in upper limbs, quality of sleep and swallowing. When applicable, for each outcome, meta-analyses for pairwise comparison were performed, considering the pattern of heterogeneity present and using appropriate summary measures. The certainty of evidence for each outcome was assessed by the Grading of Recommendation, Assessment, Development and Evaluation (GRADE). 9 Result: Of the 1,722 articles identified, 37 were included (15 articles evaluated outcomes for DPP and 22 for DPT). The studies were heterogeneous and with very low certainty of evidence for most outcomes. Regarding EOPD, ERT with alglucosidase alfa showed significant improvement for: LV mass [mean change 131.3 g/m² (95% confidence interval [CI] 81.02 to 181.59)], TSV [HR 0.21 (95% CI 0.12 to 0.36)] and survival [HR 0.10 (95% CI 0.05 to 0.19)]. Regarding LOPD, ERT with alglucosidase alfa showed significant improvement for: distance covered in the 6-minute walk test (6MWT) [mean variation of 35.7m (95% CI 7.78 to 63.75)], physical domain of QOL by SF-36 [mean change 1.96 (95% CI 0.33 to 3.59)] and TOV [mean change -2.64 h (95% CI -5.28 to 0.00)]. Adverse events (AEs) after ERT were mild in most cases for EOPD and LOPD. Conclusion: Our data suggest that ERT with alglucosidase alfa potentially improves LV mass, TSV and survival in patients with EOPD, and potentially improves 6MWT, physical QOL and TOV in patients with LOPD, being safe in both forms of the disease

Treatment of hypernatremia in breastfeeding neonates : a systematic review

Background/Aims: Hypernatremic dehydration in term neonates is associated with inadequate fluid intake, usually related to insufficient lactation. The use of hypotonic fluids is appropriate to dilute serum sodium (SNa), but cerebral edema may develop when it happens abruptly. Our objective was to clarify how to correct hypernatremic dehydration properly. Methods: The following databases were searched, limited to studies published until January 31st, 2016: Clinical Trials, MEDLINE/PubMed, EMBASE, LILACS, and the Cochrane Library. We included open-label trials, nonrandomized controlled trials, or prospective and retrospective case series evaluating relevant outcomes. Information regarding the way of administering the treatment, type of fluid used, rates of complications and outcomes, as well as the rate of SNa reduction were collected. Results: Searches yielded 771 articles: 64 had the full text reviewed and 9 were included. No randomized clinical trials or systematic reviews focusing on treatment of hypernatremic dehydration and its outcomes were found. We found a scarcity of high quality studies and great methodology heterogeneity. Conclusions: More severe hypernatremia is at greater risk of causing severe adverse effects of treatment. There is no consensus about the optimal rate of SNa drop in this population, but a slower correction appears to be safer. Questions as when parenteral fluids are indicated remain unanswered

Case report of acquired pyroglutamic acidemia in a pediatric patient

Pyroglutamic acid (also known as 5-oxoproline) is an organic acid intermediate of the gamma-glutamyl cycle. Accumulation of pyroglutamic acid is a rare cause of high anion gap metabolic acidosis. In the pediatric population, the congenital form of pyroglutamic acidemia has been extensively described. However, there are scarce reports of the acquired form of this condition in children. The urine test for organic acids confirms the diagnosis of pyroglutamic acidemia. We report the case of a 16-month-old girl who developed transient 5-oxoprolinemia associated with malnutrition and the use of acetaminophen and ampicillin for the treatment of acute otitis media and abdominal pain. The patient received 21-hour course of n-acetylcysteine with improvement of metabolic acidosis. This report highligts the need of considering pyroglutamic acidemia in the differencial diagnosis for high anion gap metabolic acidosis in pediatric patients with malnutrition and other risk factors

Case report of acquired pyroglutamic acidemia in a pediatric patient

Pyroglutamic acid (also known as 5-oxoproline) is an organic acid intermediate of the gamma-glutamyl cycle. Accumulation of pyroglutamic acid is a rare cause of high anion gap metabolic acidosis. In the pediatric population, the congenital form of pyroglutamic acidemia has been extensively described. However, there are scarce reports of the acquired form of this condition in children. The urine test for organic acids confirms the diagnosis of pyroglutamic acidemia. We report the case of a 16-month-old girl who developed transient 5-oxoprolinemia associated with malnutrition and the use of acetaminophen and ampicillin for the treatment of acute otitis media and abdominal pain. The patient received 21-hour course of n-acetylcysteine with improvement of metabolic acidosis. This report highligts the need of considering pyroglutamic acidemia in the differencial diagnosis for high anion gap metabolic acidosis in pediatric patients with malnutrition and other risk factors

A systematic review and meta-analysis of enzyme replacement therapy in late-onset Pompe Disease

Pompe disease (PD) is a glycogen storage disorder caused by deficient activity of acid alpha-glucosidase (GAA). We sought to review the latest available evidence on the safety and efficacy of recombinant human GAA enzyme replacement therapy (ERT) for late-onset PD (LOPD). Methods: We systematically searched the MEDLINE (via PubMed), Embase, and Cochrane databases for prospective clinical studies evaluating ERT for LOPD on pre-specified outcomes. A meta-analysis was also performed. Results: Of 1601 articles identified, 22 were included. Studies were heterogeneous and with very low certainty of evidence for most outcomes. The following outcomes showed improvements associated with GAA ERT, over a mean follow-up of 32.5 months: distance walked in the 6-min walking test (6MWT) (mean change 35.7 m (95% confidence interval [CI] 7.78, 63.75)), physical domain of the SF-36 quality of life (QOL) questionnaire (mean change 1.96 (95% CI 0.33, 3.59)), and time on ventilation (TOV) (mean change -2.64 h (95% CI -5.28, 0.00)). There were no differences between the pre- and post-ERT period for functional vital capacity (FVC), Walton and Gardner-Medwin Scale score, upper-limb strength, or total SF-36 QOL score. Adverse events (AEs) after ERT were mild in most cases. Conclusion: Considering the limitations imposed by the rarity of PD, our data suggest that GAA ERT improves 6MWT, physical QOL, and TOV in LOPD patients. ERT was safe in the studied population. PROSPERO register: 135102

Liver involvement in patients with Gaucher disease types I and III

Background & aims Gaucher disease (GD) is a multisystemic disease. Liver involvement in GD is not well characterised and ranges from hepatomegaly to cirrhosis and hepatocellular carcinoma. We aim to describe, and assess the effect of treatment, on the hepatic phenotype of a cohort of patients with GD types I and II. Methods Retrospective study based on the review of the medical files of the Gaucher Reference Centre of the Hospital de Clínicas de Porto Alegre, Brazil. Data from all GD types I and III patients seen at the centre since 2003 were analysed. Variables were compared as pre- (“baseline”) and post-treatment (“follow-up”). Results Forty-two patients (types I: 39, III: 3; female: 22; median age: 35 y; enzyme replacement therapy: 37; substrate reduction therapy: 2; non-treated: 3; median time on treatment-MTT: 124 months) were included. Liver enzyme abnormalities, hepatomegaly, and steatosis at baseline were seen in 19/28 (68%), 28/42 (67%), and 3/38 patients (8%), respectively; at follow-up, 21/38 (55%), 15/38 (39%) and 15/38 (39%). MRI iron quantification showed overload in 7/8 patients (treated: 7; MTT: 55 months), being severe in 2/7 (treated: 2/2; MTT: 44.5 months). Eight patients had liver biopsy (treated: 6; MTT: 58 months), with fibrosis in 3 (treated: 1; time on treatment: 108 months) and steatohepatitis in 2 (treated: 2; time on treatment: 69 and 185 months). One patient developed hepatocellular carcinoma. Conclusions GD is a heterogeneous disease that causes different patterns of liver damage even during treatment. Although treatment improves the hepatocellular damage, it is associated with an increased rate of steatosis. This study highlights the importance of a follow-up of liver integrity in these patients

Enzyme replacement therapy for mucopolysaccharidosis type I among patients followed within the MPS Brazil network

Mucopolysaccharidosis type I (MPS I) is a rare lysosomal disorder caused by deficiency of alpha-L-iduronidase. Few clinical trials have assessed the effect of enzyme replacement therapy (ERT) for this condition. We conducted an exploratory, open-label, non-randomized, multicenter cohort study of patients with MPS I. Data were collected from questionnaires completed by attending physicians at the time of diagnosis (T1; n = 34) and at a median time of 2.5 years later (T2; n = 24/34). The 24 patients for whom data were available at T2 were allocated into groups: A, no ERT (9 patients; median age at T1 = 36 months; 6 with severe phenotype); B, on ERT (15 patients; median age at T1 = 33 months; 4 with severe phenotype). For all variables in which there was no between-group difference at baseline, a delta of ≥ ± 20% was considered clinically relevant. The following clinically relevant differences were identified in group B in T2: lower rates of mortality and reported hospitalization for respiratory infection; lower frequency of hepatosplenomegaly; increased reported rates of obstructive sleep apnea syndrome and hearing loss; and stabilization of gibbus deformity. These changes could be due to the effect of ERT or of other therapies which have also been found more frequently in group B. Our findings suggest MPS I patients on ERT also receive a better overall care. ERT may have a positive effect on respiratory morbidity and overall mortality in patients with MPS I. Additional studies focusing on these outcomes and on other therapies should be performed.Mucopolysaccharidosis type I (MPS I) is a rare lysosomal disorder caused by deficiency of alpha-L-iduronidase. Fewclinical trials have assessed the effect of enzyme replacement therapy (ERT) for this condition. We conducted an exploratory, open-label, n3712329CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOsem informaçã