RESUMEN
Glycogen storage disease type Ib (GSD Ib, biallelic variants in SLC37A4) is a rare disorder of glycogen metabolism complicated by neutropenia/neutrophil dysfunction. Since 2019, the SGLT2-inhibitor empagliflozin has provided a mechanism-based treatment option for the symptoms caused by neutropenia/neutrophil dysfunction (e.g. mucosal lesions, inflammatory bowel disease). Because of the rarity of GSD Ib, the published evidence on safety and efficacy of empagliflozin is still limited and does not allow to develop evidence-based guidelines. Here, an international group of experts provides 14 best practice consensus treatment recommendations based on expert practice and review of the published evidence. We recommend to start empagliflozin in all GSD Ib individuals with clinical or laboratory signs related to neutropenia/neutrophil dysfunction with a dose of 0.3-0.4 mg/kg/d given as a single dose in the morning. Treatment can be started in an outpatient setting. The dose should be adapted to the weight and in case of inadequate clinical treatment response or side effects. We strongly recommend to pause empagliflozin immediately in case of threatening dehydration and before planned longer surgeries. Discontinuation of G-CSF therapy should be attempted in all individuals. If available, 1,5-AG should be monitored. Individuals who have previously not tolerated starches should be encouraged to make a new attempt to introduce starch in their diet after initiation of empagliflozin treatment. We advise to monitor certain safety and efficacy parameters and recommend continuous, alternatively frequent glucose measurements during the introduction of empagliflozin. We provide specific recommendations for special circumstances like pregnancy and liver transplantation.
Asunto(s)
Compuestos de Bencidrilo , Glucósidos , Enfermedad del Almacenamiento de Glucógeno Tipo I , Neutropenia , Humanos , Neutrófilos/metabolismo , Consenso , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo I/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Neutropenia/tratamiento farmacológico , Neutropenia/etiología , Proteínas de Transporte de Monosacáridos , Antiportadores/metabolismoRESUMEN
Empagliflozin has been successfully repurposed for treating neutropenia and neutrophil dysfunction in patients with glycogen storage disease type 1b (GSD 1b), however, data in infants are missing. We report on efficacy and safety of empagliflozin in infants with GSD 1b. This is an international retrospective case series on 21 GSD 1b infants treated with empagliflozin (total treatment time 20.6 years). Before starting empagliflozin (at a median age of 8.1 months with a median dose of 0.3 mg/kg/day) 12 patients had clinical signs and symptoms of neutrophil dysfunction. Six of these previously symptomatic patients had no further neutropenia/neutrophil dysfunction-associated findings on empagliflozin. Eight patients had no signs and symptoms of neutropenia/neutrophil dysfunction before start and during empagliflozin treatment. One previously asymptomatic individual with a horseshoe kidney developed a central line infection with pyelonephritis and urosepsis during empagliflozin treatment. Of the 10 patients who were treated with G-CSF before starting empagliflozin, this was stopped in four and decreased in another four. Eleven individuals were never treated with G-CSF. While in 17 patients glucose homeostasis remained stable on empagliflozin, four showed glucose homeostasis instability in the introductory phase. In 17 patients, no other side effects were reported, while genital (n = 2) or oral (n = 1) candidiasis and skin infection (n = 1) were reported in the remaining four. Empagliflozin had a good effect on neutropenia/neutrophil dysfunction-related signs and symptoms and a favourable safety profile in infants with GSD 1b and therefore qualifies for further exploration as first line treatment.
Asunto(s)
Compuestos de Bencidrilo , Glucósidos , Enfermedad del Almacenamiento de Glucógeno Tipo I , Neutropenia , Neutrófilos , Humanos , Enfermedad del Almacenamiento de Glucógeno Tipo I/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Neutropenia/tratamiento farmacológico , Masculino , Femenino , Lactante , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/administración & dosificación , Estudios Retrospectivos , Neutrófilos/efectos de los fármacos , Glucósidos/uso terapéutico , Glucósidos/farmacología , Glucósidos/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Resultado del Tratamiento , Factor Estimulante de Colonias de Granulocitos/uso terapéuticoRESUMEN
Hepatic glycogen storage diseases constitute a group of disorders due to defects in the enzymes and transporters involved in glycogen breakdown and synthesis in the liver. Although hypoglycemia and hepatomegaly are the primary manifestations of (most of) hepatic GSDs, involvement of the endocrine system has been reported at multiple levels in individuals with hepatic GSDs. While some endocrine abnormalities (e.g., hypothalamicpituitary axis dysfunction in GSD I) can be direct consequence of the genetic defect itself, others (e.g., osteopenia in GSD Ib, insulin-resistance in GSD I and GSD III) may be triggered by the (dietary/medical) treatment. Being aware of the endocrine abnormalities occurring in hepatic GSDs is essential (1) to provide optimized medical care to this group of individuals and (2) to drive research aiming at understanding the disease pathophysiology. In this review, a thorough description of the endocrine manifestations in individuals with hepatic GSDs is presented, including pathophysiological and clinical implications.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno , Humanos , Enfermedad del Almacenamiento de Glucógeno/metabolismo , Enfermedad del Almacenamiento de Glucógeno/fisiopatología , Hepatopatías/metabolismo , Hepatopatías/fisiopatología , Hepatopatías/etiología , Enfermedades del Sistema Endocrino/metabolismo , Enfermedades del Sistema Endocrino/fisiopatología , Hígado/metabolismo , Hígado/fisiopatologíaRESUMEN
Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen. SGLT2 inhibitors act on apical glucose reabsorption of renal proximal tubular cells. The purpose of this study was to retrospectively describe the first experiences with repurposing the SGLT2 inhibitor empagliflozin to treat the generalized tubulopathy in Fanconi-Bickel syndrome. A case series was conducted of seven persons from five families (five males, two females; three children, who were 14y5m, 2y9m, and 1y6m old) with genetically confirmed Fanconi-Bickel syndrome, off-label treated with empagliflozin. Median (range) age at start of empagliflozin was 27 years (1y6m - 61y) and duration of follow-up under empagliflozin treatment was 169 days (57-344). Under empagliflozin (up to 25 mg/d), biochemical parameters of tubular cell integrity (urinary N-acetyl-glucosaminidase) and/or tubular functions (including urinary α1-microglobulin) improved in all persons with Fanconi-Bickel syndrome, albeit to varying degrees. Clinically, supplementations (i.e., phosphate, alkali, carnitine, and alfacalcidol) could be completely discontinued in the three children, whereas results in the four adult patients were more variable and not as significant. Empagliflozin was well-tolerated and no symptomatic hypoglycemia was observed. In conclusion, SGLT2 inhibitors such as empagliflozin shift the metabolic block in Fanconi-Bickel syndrome, that is, they intervene specifically in the underlying pathophysiology and can thus attenuate renal proximal tubulopathy, especially when started in early childhood.
RESUMEN
Off-label repurposing of empagliflozin allows pathomechanism-based treatment of neutropenia/neutrophil-dysfunction in glycogen storage disease type Ib (GSDIb). From a value-based healthcare (VBHC) perspective, we here retrospectively studied patient-reported, clinical and pharmacoeconomic outcomes in 11 GSDIb individuals before and under empagliflozin at two centers (the Netherlands [NL], Austria [AT]), including a budget impact analysis, sensitivity-analysis, and systematic benefit-risk assessment. Under empagliflozin, all GSDIb individuals reported improved quality-of-life-scores. Neutrophil dysfunction related symptoms allowed either granulocyte colony-stimulating factor cessation or tapering. Calculated cost savings per patient per year ranged between 6482-14 190 (NL) and 1281-41 231 (AT). The budget impact analysis estimated annual total cost savings ranging between 75 062-225 716 (NL) and 37 697-231 790 (AT), based on conservative assumptions. The systematic benefit-risk assessment was favorable. From a VBHC perspective, empagliflozin treatment in GSDIb improved personal and clinical outcomes while saving costs, thereby creating value at multiple pillars. We emphasize the importance to reimburse empagliflozin for GSDIb individuals, further supported by the favorable systematic benefit-risk assessment. These observations in similar directions in two countries/health care systems strongly suggest that our findings can be extrapolated to other geographical areas and health care systems.
Asunto(s)
Compuestos de Bencidrilo , Glucósidos , Enfermedad del Almacenamiento de Glucógeno Tipo I , Atención Médica Basada en Valor , Humanos , Estudios Retrospectivos , Medición de RiesgoRESUMEN
BACKGROUND: Monogenetic inborn errors of metabolism cause a wide phenotypic heterogeneity that may even differ between family members carrying the same genetic variant. Computational modelling of metabolic networks may identify putative sources of this inter-patient heterogeneity. Here, we mainly focus on medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common inborn error of the mitochondrial fatty acid oxidation (mFAO). It is an enigma why some MCADD patients-if untreated-are at risk to develop severe metabolic decompensations, whereas others remain asymptomatic throughout life. We hypothesised that an ability to maintain an increased free mitochondrial CoA (CoASH) and pathway flux might distinguish asymptomatic from symptomatic patients. RESULTS: We built and experimentally validated, for the first time, a kinetic model of the human liver mFAO. Metabolites were partitioned according to their water solubility between the bulk aqueous matrix and the inner membrane. Enzymes are also either membrane-bound or in the matrix. This metabolite partitioning is a novel model attribute and improved predictions. MCADD substantially reduced pathway flux and CoASH, the latter due to the sequestration of CoA as medium-chain acyl-CoA esters. Analysis of urine from MCADD patients obtained during a metabolic decompensation showed an accumulation of medium- and short-chain acylcarnitines, just like the acyl-CoA pool in the MCADD model. The model suggested some rescues that increased flux and CoASH, notably increasing short-chain acyl-CoA dehydrogenase (SCAD) levels. Proteome analysis of MCADD patient-derived fibroblasts indeed revealed elevated levels of SCAD in a patient with a clinically asymptomatic state. This is a rescue for MCADD that has not been explored before. Personalised models based on these proteomics data confirmed an increased pathway flux and CoASH in the model of an asymptomatic patient compared to those of symptomatic MCADD patients. CONCLUSIONS: We present a detailed, validated kinetic model of mFAO in human liver, with solubility-dependent metabolite partitioning. Personalised modelling of individual patients provides a novel explanation for phenotypic heterogeneity among MCADD patients. Further development of personalised metabolic models is a promising direction to improve individualised risk assessment, management and monitoring for inborn errors of metabolism.
Asunto(s)
Errores Innatos del Metabolismo Lipídico , Metabolismo de los Lípidos , Humanos , Acil-CoA Deshidrogenasa/genética , Coenzima A , Errores Innatos del Metabolismo Lipídico/genéticaRESUMEN
Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by mutations in the G6PC gene, encoding the catalytic subunit of glucose-6-phosphatase. Early symptoms include severe fasting intolerance, failure to thrive and hepatomegaly, biochemically associated with nonketotic hypoglycemia, fasting hyperlactidemia, hyperuricemia and hyperlipidemia. Dietary management is the cornerstone of treatment aiming at maintaining euglycemia, prevention of secondary metabolic perturbations and long-term complications, including liver (hepatocellular adenomas and carcinomas), kidney and bone disease (hypovitaminosis D and osteoporosis). As impaired vitamin A homeostasis also associates with similar symptoms and is coordinated by the liver, we here analysed whether vitamin A metabolism is affected in GSD Ia patients and liver-specific G6pc-/- knock-out mice. Serum levels of retinol and retinol binding protein 4 (RBP4) were significantly increased in both GSD Ia patients and L-G6pc-/- mice. In contrast, hepatic retinol levels were significantly reduced in L-G6pc-/- mice, while hepatic retinyl palmitate (vitamin A storage form) and RBP4 levels were not altered. Transcript and protein analyses indicate an enhanced production of retinol and reduced conversion the retinoic acids (unchanged LRAT, Pnpla2/ATGL and Pnpla3 up, Cyp26a1 down) in L-G6pc-/- mice. Aberrant expression of genes involved in vitamin A metabolism was associated with reduced basal messenger RNA levels of markers of inflammation (Cd68, Tnfα, Nos2, Il-6) and fibrosis (Col1a1, Acta2, Tgfß, Timp1) in livers of L-G6pc-/- mice. In conclusion, GSD Ia is associated with elevated serum retinol and RBP4 levels, which may contribute to disease symptoms, including osteoporosis and hepatic steatosis.
Asunto(s)
Glucosa-6-Fosfatasa/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo I/metabolismo , Hígado/metabolismo , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Vitamina A/sangre , Adolescente , Adulto , Animales , Diterpenos/metabolismo , Hígado Graso/metabolismo , Femenino , Glucosa-6-Fosfatasa/genética , Enfermedad del Almacenamiento de Glucógeno Tipo I/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo I/enzimología , Enfermedad del Almacenamiento de Glucógeno Tipo I/patología , Humanos , Inflamación/genética , Inflamación/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Noqueados , Osteoporosis/metabolismo , Ácido Retinoico 4-Hidroxilasa/genética , Ácido Retinoico 4-Hidroxilasa/metabolismo , Proteínas Plasmáticas de Unión al Retinol/genética , Ésteres de Retinilo , Vitamina A/análogos & derivados , Vitamina A/metabolismoRESUMEN
PURPOSE: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). METHODS: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. RESULTS: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. CONCLUSION: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo I , Neutropenia , Adolescente , Adulto , Compuestos de Bencidrilo , Niño , Preescolar , Glucósidos , Enfermedad del Almacenamiento de Glucógeno Tipo I/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo I/patología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Lactante , Recién Nacido , Neutropenia/tratamiento farmacológico , Estudios Retrospectivos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND AND AIMS: Patients with glycogen storage disease type 1a (GSD-1a) primarily present with life-threatening hypoglycemia and display severe liver disease characterized by hepatomegaly. Despite strict dietary management, long-term complications still occur, such as liver tumor development. Variations in residual glucose-6-phosphatase (G6PC1) activity likely contribute to phenotypic heterogeneity in biochemical symptoms and complications between patients. However, lack of insight into the relationship between G6PC1 activity and symptoms/complications and poor understanding of the underlying disease mechanisms pose major challenges to provide optimal health care and quality of life for GSD-1a patients. Currently available GSD-1a animal models are not suitable to systematically investigate the relationship between hepatic G6PC activity and phenotypic heterogeneity or the contribution of gene-gene interactions (GGIs) in the liver. APPROACH AND RESULTS: To meet these needs, we generated and characterized a hepatocyte-specific GSD-1a mouse model using somatic CRISPR/CRISPR-associated protein 9 (Cas9)-mediated gene editing. Hepatic G6pc editing reduced hepatic G6PC activity up to 98% and resulted in failure to thrive, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly, hepatic steatosis (HS), and increased liver tumor incidence. This approach was furthermore successful in simultaneously modulating hepatic G6PC and carbohydrate response element-binding protein, a transcription factor that is activated in GSD-1a and protects against HS under these conditions. Importantly, it also allowed for the modeling of a spectrum of GSD-1a phenotypes in terms of hepatic G6PC activity, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly and HS. CONCLUSIONS: In conclusion, we show that somatic CRISPR/Cas9-mediated gene editing allows for the modeling of a spectrum of hepatocyte-borne GSD-1a disease symptoms in mice and to efficiently study GGIs in the liver. This approach opens perspectives for translational research and will likely contribute to personalized treatments for GSD-1a and other genetic liver diseases.
Asunto(s)
Proteína 9 Asociada a CRISPR/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Modelos Animales de Enfermedad , Edición Génica/métodos , Heterogeneidad Genética , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Fenotipo , Animales , Vectores Genéticos , Glucosa-6-Fosfatasa/genética , Glucosa-6-Fosfatasa/metabolismo , Hepatocitos/enzimología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Neutropenia and neutrophil dysfunction cause serious infections and inflammatory bowel disease in glycogen storage disease type Ib (GSD-Ib). Our discovery that accumulating 1,5-anhydroglucitol-6-phosphate (1,5AG6P) caused neutropenia in a glucose-6-phosphatase 3 (G6PC3)-deficient mouse model and in 2 rare diseases (GSD-Ib and G6PC3 deficiency) led us to repurpose the widely used antidiabetic drug empagliflozin, an inhibitor of the renal glucose cotransporter sodium glucose cotransporter 2 (SGLT2). Off-label use of empagliflozin in 4 GSD-Ib patients with incomplete response to granulocyte colony-stimulating factor (GCSF) treatment decreased serum 1,5AG and neutrophil 1,5AG6P levels within 1 month. Clinically, symptoms of frequent infections, mucosal lesions, and inflammatory bowel disease resolved, and no symptomatic hypoglycemia was observed. GCSF could be discontinued in 2 patients and tapered by 57% and 81%, respectively, in the other 2. The fluctuating neutrophil numbers in all patients were increased and stabilized. We further demonstrated improved neutrophil function: normal oxidative burst (in 3 of 3 patients tested), corrected protein glycosylation (2 of 2), and normal neutrophil chemotaxis (1 of 1), and bactericidal activity (1 of 1) under treatment. In summary, the glucose-lowering SGLT2 inhibitor empagliflozin, used for type 2 diabetes, was successfully repurposed for treating neutropenia and neutrophil dysfunction in the rare inherited metabolic disorder GSD-Ib without causing symptomatic hypoglycemia. We ascribe this to an improvement in neutrophil function resulting from the reduction of the intracellular concentration of 1,5AG6P.
Asunto(s)
Compuestos de Bencidrilo/uso terapéutico , Glucósidos/uso terapéutico , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Hexosafosfatos/sangre , Neutropenia/tratamiento farmacológico , Neutrófilos/patología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Compuestos de Bencidrilo/efectos adversos , Glucemia/análisis , Quimiotaxis de Leucocito/efectos de los fármacos , Preescolar , Reposicionamiento de Medicamentos , Resistencia a Medicamentos , Femenino , Glucósidos/efectos adversos , Enfermedad del Almacenamiento de Glucógeno Tipo I/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo I/inmunología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Granulocitos/química , Humanos , Recién Nacido , Proteína 2 de la Membrana Asociada a los Lisosomas/sangre , Masculino , Neutropenia/sangre , Uso Fuera de lo Indicado , Estallido Respiratorio/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Adulto JovenRESUMEN
Value-based healthcare (VBHC) intends to achieve better outcomes for patients, to improve quality of patient care, with reduced costs. Four dimensions define a model of intimately related value-pillars: personal value, allocative value, technical value, and societal value. VBHC is mostly applied in common diseases, and there are fundamental challenges in applying VBHC strategies to low volume, high complex healthcare situations, such as rare diseases, including inherited metabolic disorders. This article summarizes current practices at various academical domains (i.e., research, healthcare, education, and training) that (aim to) increase values at various value-pillars for persons with liver glycogen storage diseases or fatty acid oxidation disorders and their families. Future perspectives may include facilitating virtual networks to function as integrated practice units, improving measurement of outcomes, and creating information technology platforms to overcome the ethical, legal, societal, and technical challenges of data sharing for healthcare and research purposes.
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Acidosis , Enfermedad del Almacenamiento de Glucógeno , Errores Innatos del Metabolismo Lipídico , Enfermedades Musculares , Humanos , Atención a la Salud/métodos , Ácidos Grasos , Enfermedad del Almacenamiento de Glucógeno/terapia , Errores Innatos del Metabolismo Lipídico/terapia , HígadoRESUMEN
Our aim was to study the effect of secondary carnitine deficiency (SCD) and carnitine supplementation on important outcome measures for persons with medium-chain Acyl-CoA dehydrogenase deficiency (MCADD). We performed a large retrospective observational study using all recorded visits of persons with MCADD in the University Medical Center Groningen, the Netherlands, between October 1994 and October 2019. Frequency and duration of acute unscheduled preventive hospital visits, exercise tolerance, fatigue, and muscle pain were considered important clinical outcomes and were studied in relation to (acyl)carnitine profile and carnitine supplementation status. The study encompassed 1228 visits of 93 persons with MCADD. >60% had SCD during follow-up. This included only persons with severe MCADD. Carnitine supplementation and SCD were unrelated to the frequency and duration of the acute unscheduled preventive hospital visits (P > 0.05). The relative risk for fatigue, muscle ache, or exercise intolerance was equal between persons with and without SCD (RR 1.6, 95% CI 0.48-5.10, P = 0.4662). No episodes of metabolic crisis were recorded in non-carnitine-supplemented persons with MCADD and SCD. In some persons with MCADD, SCD resolved without carnitine supplementation. There is absence of real-world evidence in favor of routine carnitine analysis and carnitine supplementation in the follow-up of persons with MCADD.
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Errores Innatos del Metabolismo de los Aminoácidos , Errores Innatos del Metabolismo Lipídico , Humanos , Acil-CoA Deshidrogenasa , Errores Innatos del Metabolismo Lipídico/metabolismo , Estudios RetrospectivosRESUMEN
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is included in many newborn screening (NBS) programs. Acylcarnitine-based NBS for LCHADD not only identifies LCHADD, but also the other deficiencies of the mitochondrial trifunctional protein (MTP), a multi-enzyme complex involved in long-chain fatty acid ß-oxidation. Besides LCHAD, MTP harbors two additional enzyme activities: long-chain enoyl-CoA hydratase (LCEH) and long-chain ketoacyl-CoA thiolase (LCKAT). Deficiency of one or more MTP activities causes generalized MTP deficiency (MTPD), LCHADD, LCEH deficiency (not yet reported), or LCKAT deficiency (LCKATD). To gain insight in the outcomes of MTP-deficient patients diagnosed after the introduction of NBS for LCHADD in the Netherlands, a retrospective evaluation of genetic, biochemical, and clinical characteristics of MTP-deficient patients, identified since 2007, was carried out. Thirteen patients were identified: seven with LCHADD, five with MTPD, and one with LCKATD. All LCHADD patients (one missed by NBS, clinical diagnosis) and one MTPD patient (clinical diagnosis) were alive. Four MTPD patients and one LCKATD patient developed cardiomyopathy and died within 1 month and 13 months of life, respectively. Surviving patients did not develop symptomatic hypoglycemia, but experienced reversible cardiomyopathy and rhabdomyolysis. Five LCHADD patients developed subclinical neuropathy and/or retinopathy. In conclusion, patient outcomes were highly variable, stressing the need for accurate classification of and discrimination between the MTP deficiencies to improve insight in the yield of NBS for LCHADD. NBS allowed the prevention of symptomatic hypoglycemia, but current treatment options failed to treat cardiomyopathy and prevent long-term complications. Moreover, milder patients, who might benefit from NBS, were missed due to normal acylcarnitine profiles.
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Cardiomiopatías , Hipoglucemia , Errores Innatos del Metabolismo Lipídico , Rabdomiólisis , 3-Hidroxiacil-CoA Deshidrogenasas , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Humanos , Recién Nacido , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/metabolismo , Miopatías Mitocondriales , Proteína Trifuncional Mitocondrial/deficiencia , Biología Molecular , Tamizaje Neonatal , Enfermedades del Sistema Nervioso , Países Bajos , Estudios Retrospectivos , Rabdomiólisis/diagnóstico , Rabdomiólisis/genéticaRESUMEN
Continuous glucose monitoring (CGM) systems have great potential for real-time assessment of glycemic variation in patients with hepatic glycogen storage disease (GSD). However, detailed descriptions and in-depth analysis of CGM data from hepatic GSD patients during interventions are scarce. This is a retrospective in-depth analysis of CGM parameters, acquired in a continuous, real-time fashion describing glucose management in 15 individual GSD patients. CGM subsets are obtained both in-hospital and at home, upon nocturnal dietary intervention (n = 1), starch loads (n = 11) and treatment of GSD Ib patients with empagliflozin (n = 3). Descriptive CGM parameters, and parameters reflecting glycemic variation and glycemic control are considered useful CGM outcome parameters. Furthermore, the combination of first and second order derivatives, cumulative sum and Fourier analysis identified both subtle and sudden changes in glucose management; hence, aiding assessment of dietary and medical interventions. CGM data interpolation for nocturnal intervals reduced confounding by physical activity and diet. Based on these analyses, we conclude that in-depth CGM analysis can be a powerful tool to assess glucose management and optimize treatment in individual hepatic GSD patients.
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Glucemia , Enfermedad del Almacenamiento de Glucógeno , Adolescente , Automonitorización de la Glucosa Sanguínea , Niño , Preescolar , Conjuntos de Datos como Asunto , Femenino , Glucosa , Humanos , Masculino , Análisis de Regresión , Estudios Retrospectivos , Adulto JovenRESUMEN
Patients with inborn errors of metabolism causing fasting intolerance can experience acute metabolic decompensations. Long-term data on outcomes using emergency letters are lacking. This is a retrospective, observational, single-center study of the use of emergency letters based on a generic emergency protocol in patients with hepatic glycogen storage diseases (GSD) or fatty acid oxidation disorders (FAOD). Data on hospital admissions, initial laboratory results, and serious adverse events were collected. Subsequently, the website www.emergencyprotocol.net was generated in the context of the CONNECT MetabERN eHealth project following multiple meetings, protocol revisions, and translations. Representing 470 emergency protocol years, 127 hospital admissions were documented in 54/128 (42%) patients who made use of emergency letters generated based on the generic emergency protocol. Hypoglycemia (here defined as glucose concentration < 3.9 mmol/L) was reported in only 15% of hospital admissions and was uncommon in patients with ketotic GSD and patients with FAOD aged >5 years. Convulsions, coma, or death was not documented. By providing basic information, emergency letters for individual patients with hepatic GSD or the main FAOD can be generated at www.emergencyprotocol.net, in nine different languages. Generic emergency protocols are safe and easy for home management by the caregivers and the first hour in-hospital management to prevent metabolic emergencies in patients with hepatic GSD and medium-chain Acyl CoA dehydrogenase deficiency. The website www.emergencyprotocol.net is designed to support families and healthcare providers to generate personalized emergency letters for patients with hepatic GSD and the main FAOD.
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Tratamiento de Urgencia/métodos , Enfermedad del Almacenamiento de Glucógeno Tipo I/metabolismo , Hipoglucemia/terapia , Errores Innatos del Metabolismo Lipídico/metabolismo , Telemedicina , Adolescente , Adulto , Niño , Preescolar , Ayuno , Ácidos Grasos/metabolismo , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo I/fisiopatología , Humanos , Hipoglucemia/etiología , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico/fisiopatología , Masculino , Persona de Mediana Edad , Oxidación-Reducción , Estudios Retrospectivos , Adulto JovenRESUMEN
Glycogen storage disease type IIIa (GSDIIIa) is an inborn error of carbohydrate metabolism caused by a debranching enzyme deficiency. A subgroup of GSDIIIa patients develops severe myopathy. The purpose of this study was to investigate whether acute nutritional ketosis (ANK) in response to ketone-ester (KE) ingestion is effective to deliver oxidative substrate to exercising muscle in GSDIIIa patients. This was an investigator-initiated, researcher-blinded, randomized, crossover study in six adult GSDIIIa patients. Prior to exercise subjects ingested a carbohydrate drink (~66 g, CHO) or a ketone-ester (395 mg/kg, KE) + carbohydrate drink (30 g, KE + CHO). Subjects performed 15-minute cycling exercise on an upright ergometer followed by 10-minute supine cycling in a magnetic resonance (MR) scanner at two submaximal workloads (30% and 60% of individual maximum, respectively). Blood metabolites, indirect calorimetry data, and in vivo 31 P-MR spectra from quadriceps muscle were collected during exercise. KE + CHO induced ANK in all six subjects with median peak ßHB concentration of 2.6 mmol/L (range: 1.6-3.1). Subjects remained normoglycemic in both study arms, but delta glucose concentration was 2-fold lower in the KE + CHO arm. The respiratory exchange ratio did not increase in the KE + CHO arm when workload was doubled in subjects with overt myopathy. In vivo 31 P MR spectra showed a favorable change in quadriceps energetic state during exercise in the KE + CHO arm compared to CHO in subjects with overt myopathy. Effects of ANK during exercise are phenotype-specific in adult GSDIIIa patients. ANK presents a promising therapy in GSDIIIa patients with a severe myopathic phenotype. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT03011203.
Asunto(s)
Bebidas , Ejercicio Físico , Enfermedad del Almacenamiento de Glucógeno Tipo III/dietoterapia , Cetosis/inducido químicamente , Enfermedades Musculares/dietoterapia , Adulto , Glucemia/análisis , Metabolismo de los Hidratos de Carbono , Estudios Cruzados , Dieta Cetogénica , Carbohidratos de la Dieta , Ésteres/administración & dosificación , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo III/metabolismo , Humanos , Cetonas/administración & dosificación , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Enfermedades Musculares/metabolismo , Países Bajos , FenotipoRESUMEN
D,L-3-hydroxybutyrate (D,L-3-HB, a ketone body) treatment has been described in several inborn errors of metabolism, including multiple acyl-CoA dehydrogenase deficiency (MADD; glutaric aciduria type II). We aimed to improve the understanding of enantiomer-specific pharmacokinetics of D,L-3-HB. Using UPLC-MS/MS, we analyzed D-3-HB and L-3-HB concentrations in blood samples from three MADD patients, and blood and tissue samples from healthy rats, upon D,L-3-HB salt administration (patients: 736-1123 mg/kg/day; rats: 1579-6317 mg/kg/day of salt-free D,L-3-HB). D,L-3-HB administration caused substantially higher L-3-HB concentrations than D-3-HB. In MADD patients, both enantiomers peaked at 30 to 60 minutes, and approached baseline after 3 hours. In rats, D,L-3-HB administration significantly increased Cmax and AUC of D-3-HB in a dose-dependent manner (controls vs ascending dose groups for Cmax : 0.10 vs 0.30-0.35-0.50 mmol/L, and AUC: 14 vs 58-71-106 minutes*mmol/L), whereas for L-3-HB the increases were significant compared to controls, but not dose proportional (Cmax : 0.01 vs 1.88-1.92-1.98 mmol/L, and AUC: 1 vs 380-454-479 minutes*mmol/L). L-3-HB concentrations increased extensively in brain, heart, liver, and muscle, whereas the most profound rise in D-3-HB was observed in heart and liver. Our study provides important knowledge on the absorption and distribution upon oral D,L-3-HB. The enantiomer-specific pharmacokinetics implies differential metabolic fates of D-3-HB and L-3-HB.
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Ácido 3-Hidroxibutírico/administración & dosificación , Ácido 3-Hidroxibutírico/farmacocinética , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/tratamiento farmacológico , Acil-CoA Deshidrogenasa/genética , Administración Oral , Animales , Cromatografía Liquida , Humanos , Masculino , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/genética , Ratas , Ratas Wistar , Espectrometría de Masas en TándemRESUMEN
There is paucity of literature on dietary treatment in glycogen storage disease (GSD) type IV and formal guidelines are not available. Traditionally, liver transplantation was considered the only treatment option for GSD IV. In light of the success of dietary treatment for the other hepatic forms of GSD, we have initiated this observational study to assess the outcomes of medical diets, which limit the accumulation of glycogen. Clinical, dietary, laboratory, and imaging data for 15 GSD IV patients from three centres are presented. Medical diets may have the potential to delay or prevent liver transplantation, improve growth and normalize serum aminotransferases. Individual care plans aim to avoid both hyperglycaemia, hypoglycaemia and/or hyperketosis, to minimize glycogen accumulation and catabolism, respectively. Multidisciplinary monitoring includes balancing between traditional markers of metabolic control (ie, growth, liver size, serum aminotransferases, glucose homeostasis, lactate, and ketones), liver function (ie, synthesis, bile flow and detoxification of protein), and symptoms and signs of portal hypertension.
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Suplementos Dietéticos , Enfermedad del Almacenamiento de Glucógeno Tipo IV/dietoterapia , Glucógeno/metabolismo , Hígado/metabolismo , Adolescente , Adulto , Biomarcadores , Niño , Preescolar , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo IV/patología , Humanos , Lactante , Comunicación Interdisciplinaria , Hígado/patología , Trasplante de Hígado , Masculino , Resultado del Tratamiento , Adulto JovenRESUMEN
Prevention of hypertriglyceridemia is one of the biomedical targets in Glycogen Storage Disease type Ia (GSD Ia) patients, yet it is unclear how hypoglycemia links to plasma triglyceride (TG) levels. We analyzed whole-body TG metabolism in normoglycemic (fed) and hypoglycemic (fasted) hepatocyte-specific glucose-6-phosphatase deficient (L-G6pc-/- ) mice. De novo fatty acid synthesis contributed substantially to hepatic TG accumulation in normoglycemic L-G6pc-/- mice. In hypoglycemic conditions, enhanced adipose tissue lipolysis was the main driver of liver steatosis, supported by elevated free fatty acid concentrations in GSD Ia mice and GSD Ia patients. Plasma very-low-density lipoprotein (VLDL) levels were increased in GSD Ia patients and in normoglycemic L-G6pc-/- mice, and further elevated in hypoglycemic L-G6pc-/- mice. VLDL-TG secretion rates were doubled in normo- and hypoglycemic L-G6pc-/- mice, while VLDL-TG catabolism was selectively inhibited in hypoglycemic L-G6pc-/- mice. In conclusion, fasting-induced hypoglycemia in L-G6pc-/- mice promotes adipose tissue lipolysis and arrests VLDL catabolism. This mechanism likely contributes to aggravated liver steatosis and dyslipidemia in GSD Ia patients with poor glycemic control and may explain clinical heterogeneity in hypertriglyceridemia between GSD Ia patients.
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Glucosa/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Hipertrigliceridemia/etiología , Hipoglucemia/etiología , Lipoproteínas VLDL/metabolismo , Triglicéridos/metabolismo , Adulto , Anciano , Animales , Modelos Animales de Enfermedad , Hígado Graso/etiología , Femenino , Glucosa-6-Fosfatasa/genética , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Enfermedad del Almacenamiento de Glucógeno Tipo I/metabolismo , Hepatocitos/metabolismo , Humanos , Hipertrigliceridemia/prevención & control , Hipoglucemia/metabolismo , Metabolismo de los Lípidos , Masculino , Ratones , Persona de Mediana EdadRESUMEN
PURPOSE: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a life-threatening, ultrarare inborn error of metabolism. Case reports described successful D,L-3-hydroxybutyrate (D,L-3-HB) treatment in severely affected MADD patients, but systematic data on efficacy and safety is lacking. METHODS: A systematic literature review and an international, retrospective cohort study on clinical presentation, D,L-3-HB treatment method, and outcome in MADD(-like) patients. RESULTS: Our study summarizes 23 MADD(-like) patients, including 14 new cases. Median age at clinical onset was two months (interquartile range [IQR]: 8 months). Median age at starting D,L-3-HB was seven months (IQR: 4.5 years). D,L-3-HB doses ranged between 100 and 2600 mg/kg/day. Clinical improvement was reported in 16 patients (70%) for cardiomyopathy, leukodystrophy, liver symptoms, muscle symptoms, and/or respiratory failure. D,L-3-HB appeared not effective for neuropathy. Survival appeared longer upon D,L-3-HB compared with historical controls. Median time until first clinical improvement was one month, and ranged up to six months. Reported side effects included abdominal pain, constipation, dehydration, diarrhea, and vomiting/nausea. Median D,L-3-HB treatment duration was two years (IQR: 6 years). D,L-3-HB treatment was discontinued in 12 patients (52%). CONCLUSION: The strength of the current study is the international pooling of data demonstrating that D,L-3-HB treatment can be effective and safe in MADD(-like) patients.