Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL

The EARS2 nuclear gene encodes mitochondrial glutamyl-tRNA synthetase, a member of the class I family of aminoacyl-tRNA synthetases (aaRSs) that plays a crucial role in mitochondrial protein biosynthesis by catalyzing the charging of glutamate to mitochondrial tRNA(Glu). Pathogenic EARS2 variants have been associated with a rare mitochondrial disorder known as leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). The targeted sequencing of 150 nuclear genes encoding respiratory chain complex subunits and proteins implicated in the oxidative phosphorylation (OXPHOS) function was performed. The oxygen consumption rate (OCR), and the extracellular acidification rate (ECAR), were measured. The enzymatic activities of Complexes I-V were analyzed spectrophotometrically. We describe a patient carrying two heterozygous EARS2 variants, c.376C>T (p.Gln126*) and c.670G>A (p.Gly224Ser), with infantile-onset disease and a severe clinical presentation. We demonstrate a clear defect in mitochondrial function in the patient’s fibroblasts, suggesting the molecular mechanism underlying the pathogenicity of these EARS2 variants. Experimental validation using patient-derived fibroblasts allowed an accurate characterization of the disease-causing variants, and by comparing our patient’s clinical presentation with that of previously reported cases, new clinical and radiological features of LTBL were identified, expanding the clinical spectrum of this diseaseThis study was supported with a competitive PhD grant from a pre-Doctoral scholarship for research groups of the Health Research Institute of Santiago (IDIS)S

Leigh Syndrome Associated with TRMU Gene Mutations

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 diseaseThe Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), is an initiative of the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovacion, Spain). This study was supported by the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) (2014: SGR 393) and the CERCA Programme/Generalitat de Catalunya. The present study was supported by the Department de Salut, Generalitat de Catalunya (URDCAT project, SLT002/16/00174

Leigh syndrome associated with TRMU gene mutations

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

Importance of Timely Treatment Initiation in Infantile-Onset Pompe Disease, a Single-Centre Experience

Abstract 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.This work was partially funded by the Basque Department of Education (IT1281-19)

Transferrin Isoforms, Old but New Biomarkers in Hereditary Fructose Intolerance

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.This work was supported by Exp. No. 2018111095, Basque Government, Health Department to J.D.H., and by FEDER; Federación Española de Enfermedades Raras (FI18053)

Vitamin C and folate status in hereditary fructose intolerance

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.This work was supported by Exp. No. 2018111095, Basque Government, Health Department; FEDER, the Spanish Federation for Rare Diseases (FI18053); and Danone-Nutricia-Metabolics, which was not involved in the study hypothesis/design, execution, analysis, or interpretation

El cribado metabólico del recién nacido como modelo asistencial de la medicina de precisión. Perspectiva desde la Asociación Española para el Estudio de los Errores Congénitos del Metabolismo (AECOM)

Los programas de cribado de enfermedades congénitas en los recién nacidos tienen como objetivo lograr un diagnóstico presintomático y temprano de trastornos tratables, con el fin de prevenir o reducir significativamente la morbilidad y/o mortalidad. Muchas de las condiciones incluidas en es estos programas son errores innatos del metabolismo (EIM); sin embargo, la detección de enfermedades endocrinas, hematológicas, inmunológicas, cardiovasculares, y la hipoacusia congénita también se incluyen en muchos de ellos. Las pruebas de detección de recién nacidos no son diagnósticas y, por tanto, se necesitan pruebas complementarias para con firmar o excluir la sospecha diagnóstica. La demanda social y profesional de la mano de los avances tecnológicos y de nuevas opciones de tratamiento, permiten la expansión continua del cribado neonatal; este progreso conlleva un claro beneficio para los pacientes, pues gracias al diagnóstico y al tratamiento precoz de su enfermedad pueden tener un mejor pronóstico y una mejor calidad de vida. Los criterios de inclusión de las diferentes enfermedades no deben ser valorados exclusivamente con el prisma del momento en que se realiza la evaluación, es necesario aplicar una visión de oportunidad a largo plazo basada en las fortalezas del sistema sanitario. Hoy en día, tras 50 años de recorrido, podemos asegurar que los programas de cribado neonatal constituyen uno de los avances más significativos que se han producido en salud pública, su práctica generalizada ha significado uno de los grandes logros asistenciales en pediatría y están marcando la organización asistencial de muchas unidades de adultos. De la mano de los avances en genética y genómica, los programas de cribado del recién nacido continuarán expandiéndose para aquellos trastornos en los que una intervención temprana pueda modificar significativamente el curso de la enfermedad