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[ES] La Enfermedad de Pompe es un trastorno poco frecuente de depósito lisosomal causado por una deficiencia de la enzima lisosomal alfa-glucosidasa ácida (GAA). Existen dos fenotipos clínicos: la Enfermedad de Pompe Infantil (IOPD) considerada como la forma clásica y la Enfermedad de Pompe de aparición tardía (LOPD). La forma más grave de este trastorno es la IOPD en la cual hay muy poco residuo enzimático (<1% generalmente). Se caracteriza por una miocardiopatía hipertrófica severa, así como una profunda debilidad muscular en los primeros meses de vida. Sin tratamiento, la muerte ocurre dentro de los primeros 2 años de vida. Aunque la terapia enzimática sustitutiva (TES) con alglucosidasa alfa ha mejorado la supervivencia de estos pacientes, en muchos casos el resultado del tratamiento no es bueno y depende en gran medida de la edad de inicio. La finalidad del presente estudio es (a) analizar las diferentes etapas en el procedimiento diagnóstico e inicio del tratamiento específico en dos pacientes con IOPD seguidos en la Unidad Metabólica del Hospital Universitario Cruces y (b) comparar los resultados clínicos y bioquímicos en función de la edad de inicio de la TES (< 1 mes de edad vs. < 3 meses de edad). En este estudio mostramos resultados clínicos y bioquímicos satisfactorios en dos pacientes con IOPD después del inicio temprano del tratamiento antes de los 3 meses de vida con terapia inmunomoduladora inicial (ITI) previa a TES a dosis altas desde el principio. Además, el paciente que inició tratamiento antes del primer mes de vida presentó una evolución aún mejor que el paciente que inició tratamiento antes del tercer mes de vida.

The homeostasis of the most important nitrogen-containing intermediates, ammonia and glutamine, is a tightly regulated process in which the gut-liver axis plays a central role. Several studies revealed that nitrogen metabolism is altered in Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD), a consensus-driven novel nomenclature for Non-Alcoholic Fatty Liver Disease (NAFLD), the most common chronic liver disease worldwide. Both increased ammonia production by gut microbiota and decreased ammonia hepatic removal due to impaired hepatic urea cycle activity or disrupted glutamine synthetase activity may contribute to hepatic ammonia accumulation underlying steatosis, which can eventually progress to hyperammonemia in more advanced stages of steatohepatitis and overt liver fibrosis. Furthermore, our group recently showed that augmented hepatic ammoniagenesis via increased glutaminase activity and overexpression of the high activity glutaminase 1 isoenzyme occurs in Fatty Liver Disease. Overall, the improved knowledge of disrupted nitrogen metabolism and metabolic miscommunication between the gut and the liver suggests that the reestablishment of altered gut-liver axis nitrogenous balance is an appealing and attractive therapeutic approach to tackle Fatty Liver Disease, a growing and unmet health problem.

Background Hereditary fructose intolerance (HFI) is a rare inborn error of fructose metabolism caused by the deficiency of aldolase B. Since treatment consists of a fructose-, sucrose- and sorbitol-restrictive diet for life, patients are at risk of presenting vitamin deficiencies. Although there is no published data on the status of these vitamins in HFI patients, supplementation with vitamin C and folic acid is common. Therefore, the aim of this study was to assess vitamin C and folate status and supplementation practices in a nationwide cohort of HFI patients. Methods Vitamin C and folic acid dietary intake, supplementation and circulating levels were assessed in 32 HFI patients and 32 age- and sex-matched healthy controls. Results Most of the HFI participants presented vitamin C (96.7%) and folate (90%) dietary intake below the recommended population reference intake. Up to 69% received vitamin C and 50% folic acid supplementation. Among HFI patients, 15.6% presented vitamin C and 3.1% folate deficiency. The amount of vitamin C supplementation and plasma levels correlated positively (R = 0.443; p = 0.011). Interestingly, a higher percentage of non-supplemented HFI patients were vitamin C deficient when compared to supplemented HFI patients (30% vs. 9.1%; p = 0.01) and to healthy controls (30% vs. 3.1%; p < 0.001). Conclusions Our results provide evidence for the first time supporting vitamin C supplementation in HFI. There is great heterogeneity in vitamin supplementation practices and, despite follow-up at specialised centres, vitamin C deficiency is common. Further research is warranted to establish optimal doses of vitamin C and the need for folic acid supplementation in HFI.

Classic infantile Pompe disease (IPD) is a rare lysosomal storage disorder characterized by severe hypertrophic cardiomyopathy and profound muscle weakness. Without treatment, death occurs within the first 2 years of life. Although enzyme replacement therapy (ERT) with alglucosidase alfa has improved survival, treatment outcome is not good in many cases and is largely dependent on age at initiation. The objective of the study was (a) to analyse the different stages in the diagnosis and specific treatment initiation procedure in IPD patients, and (b) to compare clinical and biochemical outcomes depending on age at ERT initiation (<1 month of age vs. <3 months of age). Here, we show satisfactory clinical and biochemical outcomes in two IPD patients after early treatment initiation before 3 months of life with immunomodulatory therapy in the ERT-naïve setting, with a high ERT dose from the beginning. Despite the overall good evolution, the patient who initiated treatment <1 month of life presented even better outcomes than the patient who started treatment <3 months of life, with an earlier normalization of hypertrophic cardiomyopathy, along with CK normalization, highlighting the importance of early treatment initiation in this progressive disease before irreversible muscle damage has occurred.

Hereditary Fructose Intolerance (HFI) is an autosomal recessive inborn error of metabolism characterised by the deficiency of the hepatic enzyme aldolase B. Its treatment consists in adopting a fructose-, sucrose-, and sorbitol (FSS)-restrictive diet for life. Untreated HFI patients present an abnormal transferrin (Tf) glycosylation pattern due to the inhibition of mannose-6-phosphate isomerase by fructose-1-phosphate. Hence, elevated serum carbohydrate-deficient Tf (CDT) may allow the prompt detection of HFI. The CDT values improve when an FSS-restrictive diet is followed; however, previous data on CDT and fructose intake correlation are inconsistent. Therefore, we examined the complete serum sialoTf profile and correlated it with FSS dietary intake and with hepatic parameters in a cohort of paediatric and adult fructosemic patients. To do so, the profiles of serum sialoTf from genetically diagnosed HFI patients on an FSS-restricted diet (n = 37) and their age-, sex- and body mass index-paired controls (n = 32) were analysed by capillary zone electrophoresis. We found that in HFI patients, asialoTf correlated with dietary intake of sucrose (R = 0.575, p < 0.001) and FSS (R = 0.475, p = 0.008), and that pentasialoTf+hexasialoTf negatively correlated with dietary intake of fructose (R = −0.386, p = 0.024) and FSS (R = −0.400, p = 0.019). In addition, the tetrasialoTf/disialoTf ratio truthfully differentiated treated HFI patients from healthy controls, with an area under the ROC curve (AUROC) of 0.97, 92% sensitivity, 94% specificity and 93% accuracy.

tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) deficiency causes an early onset potentially reversible acute liver failure, so far reported in less than 30 patients. We describe two new unrelated patients with an acute liver failure and a neuroimaging compatible with Leigh syndrome (LS) due to TRMU deficiency, a combination not previously reported. Our report enlarges the phenotypical spectrum of TRMU disease

Mutations in the MMADHC gene cause cobalamin D disorder (cblD), an autosomal recessive inborn disease with defects in intracellular cobalamin (cbl, vitamin B12) metabolism. CblD patients present methylmalonic aciduria (MMA), homocystinuria (HC), or combined MMA/HC, and usually suffer developmental delay and cognitive deficits. The most frequent MMADHC genetic alterations associated with disease generate MMADHC truncated proteins, in many cases due to mutations that create premature termination codons (PTC). In this study, we have performed a comprehensive and global characterization of MMADHC protein variants generated by all annotated MMADHC PTC mutations in cblD patients, and analyzed the potential of inducible translational PTC readthrough to reconstitute MMADHC biosynthesis. MMADHC protein truncation caused by disease-associated PTC differentially affected the alternative usage of translation initiation sites, protein abundance, and subcellular localization of MMADHC. Aminoglycoside compounds induced translational PTC readthrough of MMADHC truncated variants, allowing the biosynthesis of full-length MMADHC in a PTC-specific manner. Our results suggest that translational PTC readthrough-based interventions could complement current therapies for cblD patients carrying specific MMADHC PTC mutations.

[ES]La Intolerancia Hereditaria a la Fructosa (IHF) es un error congénito del metabolismo poco frecuente causado por el déficit del enzima aldolasa B. Este enzima participa en la ruta metabólica de la descomposición de fructosa, por lo que estos pacientes, al ingerir fructosa, no la metabolizan adecuadamente y se acumula en el organismo, provocando daños. El único escalón terapéutico es la exclusión de fructosa, sorbitol y sacarosa, presentes sobre todo en frutas y verduras. Los pacientes IHF no podrán ingerir estos alimentos por lo que presentan riesgo de déficit vitamínico. En este estudio se han comparado pacientes IHF con sujetos sanos para comprobar cómo afecta la enfermedad en el estado vitamínico de los pacientes y la necesidad de éstos de suplementarse con vitaminas.

[ES] Introducción: El déficit de vitamina D ha sido previamente relacionado con la obesidad tanto en niños como en adultos. Objetivo: El objetivo de este estudio es analizar la prevalencia del déficit de vitamina D en niños y analizar la relación entre los niveles medios de 25-hidroxivitamina D (25(OH)D) en plasma y diferentes indicadores de obesidad [índice de masa corporal (IMC), tejido adiposo visceral (VAT) y tejido adiposo subcutáneo (SAT)]. Material y métodos: Estudio descriptivo transversal de 125 niños y adolescentes, en el cual se recogieron datos sobre peso y talla, niveles medios de 25(OH)D, VAT y SAT. Resultados: Se estudian 125 niños y adolescentes (edad media ± SD 12,9 ± 2,1 años de edad, 45% obesos, 54% mujeres). La media ± SD de niveles plasmáticos 25(OH)D en la población estudiada fue de 22 ± 7,6 ng/ml. La prevalencia de hipovitaminosis D (25(OH)D <29 ng/ml) es del 90%. Los pacientes obesos (IMC ≥ percentil 95) tienen niveles plasmáticos medios de 25(OH) significativamente menores que los pacientes no obesos (IMC

Hyperammonemia is a metabolic condition characterized by elevated levels of ammonia and a common event in acute liver injury/ failure and chronic liver disease. Even though hepatic ammonia levels are potential predictive factors of patient outcome, easy and inexpensive methods aiming at the detection of liver ammonia accumulation in the clinical setting remain unavailable. Thus, herein we have developed a morphological method, based on the utilization of Nessler A s reagent, to accurately and precisely detect the accumulation of ammonia in biological tissue. We have validated our method against a commercially available kit in mouse tissue samples and, by using this modified method, we have confirmed the hepatic accumulation of ammonia in clinical and animal models of acute and chronic advanced liver injury as well as in the progression of fatty liver disease. Overall, we propose a morphological method for ammonia detection in liver that correlates well with the degree of liver disease severity and therefore can be potentially used to predict patient outcome.