RESUMO

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders that impair degradation of glycosaminoglycans (GAG). The specific GAGs that accumulate depend on the type of MPS, leading to unique characteristic clinical features. Development of guidelines for treatment of MPS has traditionally been multifaceted and largely based on palliative care. In the last three decades, hematopoietic stem cell transplantation and enzyme replacement therapy have been developed based on experimental and clinical studies. Guidelines have been established with the accumulation of the clinical data from natural history of the disease and therapeutic consequences, mainly sponsored by pharmaceutical companies. In recent years, committees in three countries, Australia (2015), Japan (2017), and Brazil (2018) have adopted guidelines for the treatment of MPS II, sponsored and authorized by each government. As novel treatments for MPS including substrate reduction therapy, pharmacological chaperone therapy, and gene therapy become clinically available, it is increasingly necessary to establish the optimal guideline for each type of MPS, considering multiple factors including therapeutic efficacy, adverse effects, age, disease stage, prognosis, feasibility and availability of access to treatment, and cost- performance. In this article, we discuss the historical guidelines for specific MPS types and the most recently adopted guidelines for MPS II and propose the development of future guidelines without conflict of interest and bias leading to mutual benefits to all parties including patients and families, professionals, tax payers, and governments.

Assuntos

Gerenciamento Clínico , Terapia de Reposição de Enzimas , Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose II/terapia , Guias de Prática Clínica como Assunto , Austrália , Brasil , Ensaios Clínicos como Assunto , Terapia Genética , Glicosaminoglicanos/metabolismo , Humanos , Japão , Mucopolissacaridoses/terapia

RESUMO

Abstract Major progress occurred in understanding inborn errors of ketone body transport and metabolism between the International Congresses on Inborn Errors of Metabolism in Barcelona (2013) and Rio de Janeiro (2017). These conditions impair either ketogenesis (presenting as episodes of hypoketotic hypoglycemia) or ketolysis (presenting as ketoacidotic episodes); for both groups, immediate intravenous glucose administration is the most critical and (mHGGCS, HMGCS2) effective treatment measure. Ketogenesis Deficiencies: New biomarkers were described for mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHGGCS, HMGCS2) deficiency. New patient series refined clinical knowledge of 3-hydroxy-3-methylglutaryl-CoA lyase (HGGCL, HMGCL) deficiency. Although affected humans have not been described, two animal model phenotypes are pertinent: zebrafish deficient in monocarboxylate transporter 7 (MCT7, slc16a6) (decreased ketone body exit from hepatocytes) or mice lacking D-3-hydroxy-n-butyrate dehydrogenase (BDH1, BDH1) (isolated hyperacetoacetatemia; fatty liver). Ketolysis Deficiencies: Monocarboxylate transporter 1 (MCT1, SLC16A1) deficiency is a newly described defect of ketone body transport, joining deficiencies of succinyl-CoA:3-oxoacid CoA transferase (SCOT, OXCT1) and methylacetoacetyl-CoA thiolase (MAT, ACAT1). Some heterozygotes for MCT1 or SCOT deficiency develop ketoacidosis.

RESUMO

There is limited information regarding the long-term outcomes of hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis II (MPS II). In this study, clinical, biochemical, and radiologic findings were assessed in patients who underwent HSCT and/or enzyme replacement therapy (ERT). Demographic data for 146 HSCT patients were collected from 27 new cases and 119 published cases and were compared with 51 ERT and 15 untreated cases. Glycosaminoglycan (GAG) levels were analyzed by liquid chromatography tandem mass spectrometry in blood samples from HSCT, ERT, and untreated patients as well as age-matched controls. Long-term magnetic resonance imaging (MRI) findings were investigated in 13 treated patients (6 ERT and 7 HSCT). Mean age at HSCT was 5.5 years (range, 2 to 21.4 years) in new patients and 5.5 years (range, 10 months to 19.8 years) in published cases. None of the 27 new patients died as a direct result of the HSCT procedure. Graft-versus-host disease occurred in 8 (9%) out of 85 published cases, and 9 (8%) patients died from transplantation-associated complications. Most HSCT patients showed greater improvement in somatic features, joint movements, and activity of daily living than the ERT patients. GAG levels in blood were significantly reduced by ERT and levels were even lower after HSCT. HSCT patients showed either improvement or no progression of abnormal findings in brain MRI while abnormal findings became more extensive after ERT. HSCT seems to be more effective than ERT for MPS II in a wide range of disease manifestations and could be considered as a treatment option for this condition.

Assuntos

Terapia de Reposição de Enzimas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Mucopolissacaridose II/terapia , Adolescente , Criança , Pré-Escolar , Glicosaminoglicanos/sangue , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Imageamento por Ressonância Magnética , Adulto Jovem

RESUMO

Mucopolysaccharidoses (MPSs) and mucolipidoses (ML) are groups of lysosomal storage disorders in which lysosomal hydrolases are deficient leading to accumulation of undegraded glycosaminoglycans (GAGs), throughout the body, subsequently resulting in progressive damage to multiple tissues and organs. Assays using tandem mass spectrometry (MS/MS) have been established to measure GAGs in serum or plasma from MPS and ML patients, but few studies were performed to determine whether these assays are sufficiently robust to measure GAG levels in dried blood spots (DBS) of patients with MPS and ML. MATERIAL AND METHODS: In this study, we evaluated GAG levels in DBS samples from 124 MPS and ML patients (MPS I=16; MPS II=21; MPS III=40; MPS IV=32; MPS VI=10; MPS VII=1; ML=4), and compared them with 115 age-matched controls. Disaccharides were produced from polymer GAGs by digestion with chondroitinase B, heparitinase, and keratanase II. Subsequently, dermatan sulfate (DS), heparan sulfate (HS-0S, HS-NS), and keratan sulfate (mono-sulfated KS, di-sulfated KS, and ratio of di-sulfated KS in total KS) were measured by MS/MS. RESULTS: Untreated patients with MPS I, II, VI, and ML had higher levels of DS compared to control samples. Untreated patients with MPS I, II, III, VI, and ML had higher levels of HS-0S; and untreated patients with MPS II, III and VI and ML had higher levels of HS-NS. Levels of KS were age dependent, so although levels of both mono-sulfated KS and di-sulfated KS were generally higher in patients, particularly for MPS II and MPS IV, age group numbers were not sufficient to determine significance of such changes. However, the ratio of di-sulfated KS in total KS was significantly higher in all MPS patients younger than 5years old, compared to age-matched controls. MPS I and VI patients treated with HSCT had normal levels of DS, and MPS I, VI, and VII treated with ERT or HSCT had normal levels of HS-0S and HS-NS, indicating that both treatments are effective in decreasing blood GAG levels. CONCLUSION: Measurement of GAG levels in DBS is useful for diagnosis and potentially for monitoring the therapeutic efficacy in MPS.

Assuntos

Teste em Amostras de Sangue Seco/métodos , Glicosaminoglicanos/sangue , Mucolipidoses/diagnóstico , Mucopolissacaridoses/diagnóstico , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Cromatografia Líquida , Dermatan Sulfato/sangue , Feminino , Heparitina Sulfato/sangue , Humanos , Lactente , Recém-Nascido , Sulfato de Queratano/sangue , Masculino , Mucolipidoses/metabolismo , Mucopolissacaridoses/metabolismo , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem , Adulto Jovem

RESUMO

Abstract Succinyl-CoA:3-oxoacid CoA transferase (SCOT) deficiency is an autosomal recessive disorder of ketone body utilization that is clinically characterized with intermittent ketoacidosis crises. We report here the second Turkish case with SCOT deficiency. She experienced 3 ketoacidotic episodes: The first ketoacidotic crisis mimicked diabetic ketoacidosis because of the associated hyperglycemia. Among patients with SCOT deficiency, the blood glucose levels at the first crises were variable, and this case had the highest ever reported blood glucose level. She is a compound heterozygote with 2 novel mutations, c.517A>G (K173E) and c.1543A>G (M515V), in exons 5 and 17 of the OXCT1 gene, respectively. In patient's fibroblasts, SCOT activity was deficient and, by immunoblot analysis, SCOT protein was much reduced. The patient attained normal development and had no permanent ketosis. The accurate diagnosis of SCOT deficiency in this case had a vital impact on the management strategy and outcome.

RESUMO

Abstract Beta-ketothiolase deficiency is an inherited disorder of ketone body metabolism and isoleucine catabolism. It typically manifests as recurrent ketoacidotic episodes with characteristic abnormalities in the urinary organic acid profile. However, several challenges in the diagnosis of beta-ketothiolase deficiency have been encountered: atypical presentations have been reported and some other disorders, such as succinyl-CoA:3-oxoacid CoA transferase and 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiencies, can mimic the clinical and/or biochemical signs of beta-ketothiolase deficiency. A final diagnosis of beta-ketothiolase deficiency requires an enzymatic assay and/or a molecular analysis, but some caveats must be considered. Despite the reported missed cases, screening programs have successfully identified an increasing number of patients with beta-ketothiolase deficiency. Early diagnosis and management of beta-ketothiolase deficiency will enable prevention of its serious acute and chronic complications and ultimately improve the prognosis.