Women with Gaucher Disease.

Gaucher disease is an inherited disorder in which there is a deficiency of the enzyme glucocerebrosidase, which leads to the accumulation of glucosylceramide. Although much scientific evidence is now available, there is still limited data on the impact on the different life stages of women with this disease. Among other alterations, a delay in menarche has been described, although it has not been related to fertility problems. Menorrhagia is relatively frequent, being related to the presence of thrombocytopenia, thrombocytopathies or coagulation disorders. On the other hand, pregnancy planning is an increasingly frequent concern. All patients should undergo genetic counseling, and it is important to monitor the appearance or worsening of organomegaly, bone and hematologic abnormalities to establish clinical and therapeutic recommendations. Management during the puerperium will depend on the evolution of gestation, and, during the lactation period, the potential appearance of bone complications should be assessed. An early onset of menopause, compared to the general population, has also been described, which may accelerate the development of osteopenia. Finally, although the usual screening protocols for neoplasms are currently being performed, it is recommended to watch for early signs of liver or renal neoplasms when examining the results of imaging tests performed during evaluations for this disease.

New challenges in management of phenylketonuria in pregnancy: a case report.

BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive disease that belongs to a group of disorders resulting from inborn errors of protein metabolism. It was the first disease included in neonatal screening. Neonatal screening has allowed an early diagnosis and treatment of the disease. As a result, an increasing number of women diagnosed with phenylketonuria have reached the reproductive phase of life in good health, and management of pregnancy in women with PKU is becoming more frequent. CASE PRESENTATION: In this study, we report the case of a 28-year-old Caucasian patient being followed up for phenylketonuria at Ramón y Cajal Hospital's Metabolic Diseases Unit. We describe the patient's gestation, impacted by her and her partner's diagnosis of PKU, classic and mild phenotypes, respectively, resulting in the fetus affectation. CONCLUSIONS: The description of PKU management-diagnosis, follow-up, and treatment-for both that of patient and that of the gestation with fetus affectation covers a wide sample scenario that shows the effectiveness of pregnancy planning and monitoring of females with PKU and questions the need to carry out a genetic study of gene PKU in the study of fertility.

Clinical Outcomes of Patients with Chronic Neuropathic Form of Gaucher Disease in the Spanish Real-World Setting: A Retrospective Study.

This was a retrospective, multicenter study that aimed to report the characteristics of type 3 Gaucher disease (GD3) patients in Spain, including the genotype, phenotype, therapeutic options, and treatment responses. A total of 19 patients with GD3 from 10 Spanish hospitals were enrolled in the study (14 men, 5 women). The median age at disease onset and diagnosis was 1 and 1.2 years, respectively, and the mean age at follow-up completion was 12.37 years (range: 1-25 years). Most patients exhibited splenomegaly (18/19) and hepatomegaly (17/19) at the time of diagnosis. The most frequent neurological abnormalities at onset were psychomotor retardation (14/19) and extrinsic muscle disorders (11/19), including oculomotor apraxia, supranuclear palsy, and strabismus. The L444P (c.1448T>C) allele was predominant, with the L444P (c.1448T>C) homozygous genotype mainly associated with visceral manifestations like hepatosplenomegaly, anemia, and thrombocytopenia. All patients received enzyme replacement therapy (ERT); other treatments included miglustat and the chaperone (ambroxol). Visceral manifestations, including hepatosplenomegaly and hematological and bone manifestations, were mostly controlled with ERT, except for kyphosis. The data from this study may help to increase the evidence base on this rare disease and contribute to improving the clinical management of GD3 patients.

Improving emergency department care of infants with acute bronchiolitis by reducing the use of unrecommended drugs: a quality-of-care initiative in a Spanish autonomous community. / Iniciativa de mejora para reducir el uso de fármacos no recomendados en el manejo de lactantes con bronquiolitis aguda en los servicios de urgencias de una comunidad autónoma.

OBJECTIVES: To evaluate the impact of a quality-of-care improvement program implemented in emergency departments (EDs) in a Spanish autonomous community with the aim of reducing the use of unrecommended drugs when treating infants for acute bronchiolitis. MATERIAL AND METHODS: Before-after quasi-experimental intervention study. We retrospectively included infants aged 12 months or less who were treated for acute bronchiolitis in 24 Spanish national health system hospital EDs in December during 2 epidemic periods: in 2018, before implementing the program, and in 2019, after implementation. Data collected included epidemiologic information, clinical and care details, and clinical course. The program consisted of providing informative material and training sessions before the epidemic period started. RESULTS: A total of 7717 episodes (4007 in 2018 and 2710 in 2019) were identified. Epidemiologic and clinical characteristics did not differ between the 2 periods. ED use of the following treatments decreased between the 2 periods: salbutamol, from 29.4% (95% CI, 28.8%-30.8%) in 2018 to 10.6% (95% CI, 9.6%-11.6%) in 2019; epinephrine from 6.0% (95% CI, 5.3%-6.8%) to 0.9% (95% CI, 0.7%-1.3%); and hypertonic saline solution fell from 8.2% (95% CI, 7.3%-9.1%) to 2.1% (95% CI, 1.7%-2.6%) (P.001, all comparisons). Prescriptions for salbutamol on discharge fell from 38.7% (95% CI, 36.9%-40.4%) to 10.6% (95% CI, 9.6%-11.6%) (P.001). Admissions and readmissions did not change, and the median time (interquartile range) spent in the ED fell from 81 (44-138) minutes to 66 (37-127) minutes (P.001). CONCLUSION: The quality-of-care improvement initiative was able to decrease the number of unrecommended therapeutic interventions for acute bronchiolitis. However, we identified great variations between EDs, suggesting that training and assessment of impact should continue.

OBJETIVO: Evaluar el impacto de una iniciativa de mejora realizada en los servicios de urgencias (SU) de una comunidad autónoma para reducir el uso de fármacos no recomendados en lactantes con bronquiolitis aguda (BA). METODO: Estudio cuasi-experimental analítico del tipo "antes y después de una intervención". Se incluyeron de forma retrospectiva todas las BA en niños # 12 meses atendidas en los SU de 24 hospitales públicos durante el mes de diciembre de dos periodos epidémicos: 2018 (preintervención) y 2019 (postintervención). Se recogieron variables epidemiológicas, clínicas, asistenciales y evolutivas. La intervención consistió en difundir material informativo y realizar actividades formativas previas al periodo epidémico. RESULTADOS: Se incluyeron 7.717 episodios (2018: 4.007 y 2019: 3.710). No existieron diferencias en las características epidemiológicas y clínicas. El empleo de salbutamol en los SU descendió del 29,4% [intervalo de confianza del 95% (IC 95%): 28,8-30,8] en 2018 al 10,6% (IC 95%: 9,6-11,6) en 2019 (p 0,001), el de adrenalina del 6,0% (IC 95%: 5,3-6,8) al 0,9% (IC 95%: 0,7-1,3) y el de suero salino hipertónico del 8,2% (IC 95%: 7,3-9,1) al 2,1% (IC 95%: 1,7-2,6) (p 0,001). La prescripción al alta de salbutamol se redujo del 38,7% (IC 95%: 36,9-40,4) al 10,6% (IC 95%: 9,6-11,6) (p 0,001). La tasa de ingreso y la tasa de readmisión no cambiaron y la mediana de tiempo de estancia en los SU se redujo 81 minutos [rango intercuartil (RIC) 44-138] a 66 (RIQ: 37-127) (p 0,001). CONCLUSIONES: La iniciativa de mejora ha conseguido disminuir la tasa de intervenciones terapéuticas no indicadas en BA. Sin embargo, existe una gran variabilidad entre los diferentes SU por lo que la estrategia y la medición de su impacto deben mantenerse en el tiempo.

Newborn screening for propionic, methylmalonic acidemia and vitamin B12 deficiency. Analysis of 588,793 newborns.

OBJECTIVES: We present the results of our experience in the diagnosis and follow up of the positive cases for propionic, methylmalonic acidemias and cobalamin deficiencies (PA/MMA/MMAHC) since the Expanded Newborn Screening was implemented in Madrid Region. METHODS: Dried blood samples were collected 48 h after birth. Amino acids and acylcarnitines were quantitated by MS/MS. Newborns with alterations were referred to the clinical centers for follow-up. Biochemical and molecular genetic studies for confirmation of a disease were performed. RESULTS: In the period 2011-2020, 588,793 children were screened, being 953 of them were referred to clinical units for abnormal result (192 for elevated C3 levels). Among them, 88 were false positive cases, 85 maternal vitamin B12 deficiencies and 19 were confirmed to suffer an IEM (8 PA, 4 MMA, 7 MMAHC). Ten out 19 cases displayed symptoms before the NBS results (6 PA, 1 MMA, 3 MMAHC). C3, C16:1OH+C17 levels and C3/C2 and C3/Met ratios were higher in newborns with PA/MMA/MMAHC. Cases diagnosed with B12 deficiency had mean B12 levels of 187.6 ± 76.9 pg/mL and their mothers 213.7 ± 95.0; 5% of the mothers were vegetarian or had poor eating while 15% were diagnosed of pernicious anemia. Newborns and their mothers received treatment with B12 with different posology, normalizing their levels and the secondary alterations disappeared. CONCLUSIONS: Elevated C3 are a frequent cause for abnormal result in newborn screening with a high rate of false positive cases. Presymptomatic diagnosis of most of PA and some MMA/MMAHC is difficult. Vitamin B12 deficiency secondary to maternal deprivation is frequent with an heterogenous clinical and biochemical spectrum.

Plasma CoQ10 Status in Patients with Propionic Acidaemia and Possible Benefit of Treatment with Ubiquinol.

Propionic acidaemia (PA) is an innate error of metabolism involving a deficiency in the enzyme propionyl-CoA carboxylase. Better control of acute decompensation episodes together with better treatment and monitoring have improved the prognosis of patients with this problem. However, long-term complications can arise in those in whom good metabolic control is achieved, the result of mitochondrial dysfunction caused by deficient anaplerosis, increased oxidative stress, and reduced antioxidative capacity. Coenzyme Q10 (CoQ10) is a nutritional supplement that has a notable antioxidative effect and has been shown to improve mitochondrial function. The present prospective, interventional study examines the plasma concentration of CoQ10 in patients with PA, their tolerance of such supplementation with ubiquinol, and its benefits. Seven patients with PA (aged 2.5 to 20 years, 4 males) received supplements of CoQ10 in the form of ubiquinol (10 mg/kg/day for 6 months). A total of 6/7 patients showed reduced plasma CoQ10 concentrations that normalized after supplementation with ubiquinol (p-value < 0.001), which was well tolerated. Urinary citrate levels markedly increased during the study (p-value: 0.001), together with elevation of citrate/methlycitrate ratio (p-value: 0.03). No other significant changes were seen in plasma or urine biomarkers of PA. PA patients showed a deficiency of plasma CoQ10, which supplementation with ubiquinol corrected. The urinary excretion of Krebs cycle intermediate citrate and the citrate/methylcitrate ratio significantly increased compared to the baseline, suggesting improvement in anaplerosis. This treatment was well tolerated and should be further investigated as a means of preventing the chronic complications associated with likely multifactorial mitochondrial dysfunction in PA.

Recommendations for the Diagnosis and Therapeutic Management of Hyperammonaemia in Paediatric and Adult Patients.

Hyperammonaemia is a metabolic derangement that may cause severe neurological damage and even death due to cerebral oedema, further complicating the prognosis of its triggering disease. In small children it is a rare condition usually associated to inborn errors of the metabolism. As age rises, and especially in adults, it may be precipitated by heterogeneous causes such as liver disease, drugs, urinary infections, shock, or dehydration. In older patients, it is often overlooked, or its danger minimized. This protocol was drafted to provide an outline of the clinical measures required to normalise ammonia levels in patients of all ages, aiming to assist clinicians with no previous experience in its treatment. It is an updated protocol developed by a panel of experts after a review of recent publications. We point out the importance of frequent monitoring to assess the response to treatment, the nutritional measures that ensure not only protein restriction but adequate caloric intake and the need to avoid delays in the use of specific pharmacological therapies and, especially, extrarenal clearance measures. In this regard, we propose initiating haemodialysis when ammonia levels are >200−350 µmol/L in children up to 18 months of age and >150−200 µmol/L after that age.

Mitochondrial bioenergetic is impaired in Monocarboxylate transporter 1 deficiency: a new clinical case and review of the literature.

BACKGROUND: Monocarboxylate transporter 1 (MCT1) deficiency has recently been described as a rare cause of recurrent ketosis, the result of impaired ketone utilization in extrahepatic tissues. To date, only six patients with this condition have been identified, and clinical and biochemical details remain incomplete. RESULTS: The present work reports a patient suffering from severe, recurrent episodes of metabolic acidosis and psychomotor delay, showing a pathogenic loss-of-function variation c.747_750del in homozygosity in SLC16A1 (which codes for MCT1). Persistent ketotic and lactic acidosis was accompanied by an abnormal excretion of organic acids related to redox balance disturbances. Together with an altered bioenergetic profile detected in patient-derived fibroblasts, this suggests possible mitochondrial dysfunction. Brain MRI revealed extensive, diffuse bilateral, symmetric signal alterations for the subcortical white matter and basal ganglia, together with corpus callosum agenesia. CONCLUSIONS: These findings suggest that the clinical spectrum of MCT1 deficiency not only involves recurrent atacks of ketoacidosis, but may also cause lactic acidosis and neuromotor delay with a distinctive neuroimaging pattern including agenesis of corpus callosum and other brain signal alterations.

Lymphocyte Medium-Chain Acyl-CoA Dehydrogenase Activity and Its Potential as a Diagnostic Confirmation Tool in Newborn Screening Cases.

The determination of acylcarnitines (AC) in dried blood spots (DBS) by tandem mass spectrometry in newborn screening (NBS) programs has enabled medium-chain acyl-coA dehydrogenase deficiency (MCADD) to be identified in presymptomatic newborns. Nevertheless, different confirmatory tests must be performed to confirm the diagnosis. In this work, we have collected and analyzed the NBS results and confirmatory test results (plasma AC, molecular findings, and lymphocyte MCAD activity) of forty individuals, correlating them with clinical outcomes and treatment, with the aim of obtaining useful diagnostic information that could be applied in the follow-up of the patients. Our results led us to classify patients into two groups. The first group (14 cases) had high increased octanoylcarnitine (C8) levels, biallelic pathogenic variants, and severe impaired enzyme activity (<10% of the intra-assay control (IAC)); all of these cases received nutritional therapy and required carnitine supplementation during follow-up, representing the most severe form of the disease. The second group (16 patients) was a heterogeneous group presenting moderate increases in C8, biallelic likely pathogenic/pathogenic variants, and intermediate activity (<41% IAC). All of them are currently asymptomatic and could be considered as having a milder form of the disease. Finally, eight cases presented a normal−mild increase in plasma C8, with only one pathogenic variant detected, and high−intermediate residual activity (15−100%). Based on our results, we confirm that combined evaluation of acylcarnitine profiles, genetic findings, and residual enzyme activities proves useful in predicting the risk of future metabolic decompensation, in making decisions regarding future treatment or follow-up, and also in confirming the clinical effects of unknown clinical variants.

Diagnosis of inborn errors of metabolism within the expanded newborn screening in the Madrid region.

We present the results of our experience in the diagnosis of inborn errors of metabolism (IEM) since the Expanded Newborn Screening was implemented in our Region. Dried blood samples were collected 48 h after birth. Amino acids and acylcarnitines were quantitated by mass spectrometry (MS)/MS. Newborns with alterations were referred to the clinical centers for follow-up. Biochemical and molecular genetic studies for confirmation of a disease were performed. In the period 2011 to 2019, 592 822 children were screened: 902 of them were referred for abnormal results. An IEM was confirmed in 222 (1/2670): aminoacidopathies: 89 hyperphenylalaninemia (HPA) (51 benign HPA, 32 phenylketonuria, 4 DNAJC12 defect, and 2 primapterinuria), 6 hypermethioninemia, 3 tyrosinemia type 1 (TYR-1), 1 TYR-3, 4 maple syrup urine disease (MSUD), 2 branched-chain amino acid transferase 2 deficiency, 2 homocystinuria, 1 cystinuria, 2 ornithine transcarbamylase (OTC) deficiency, 2 citrullinemia type I (CTLN1); FAO defects: 43 medium-chain acyl-CoA dehydrogenase deficiency (MCADD), 13 very long-chain acyl-CoA dehydrogenase deficiency, 2 long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), 1 multiple acyl-coA dehydrogenation deficiency, 11 systemic primary carnitine deficiency, 2 carnitine palmitoyltransferase type 2 (CPT-II) deficiency, 1 CPT-I deficiency; organic acidurias: 12 glutaric aciduria type 1 (GA-1), 4 methylmalonic acidemia (MMA), 7 MMA including combined cases with homocystinuria (MMAHC), 6 propionic acidemia (PA), 7 3-methylcrotonyl-CoA carboxylase, 1 3-hydroxy-3-methylglutaryl-CoA lyase deficiency lyase deficiency. Only 19 infants (8.5%) were symptomatic at newborn screening result (1 LCHADD, 5 PA, 1 CPT-II deficiency, 1 MMA, 3 MMAHC, 2 MSUD, 2 OTC deficiency, 1 CTLN1, 1 MCADD, 2 TYR-1). No false negative cases were identified. Genetic diagnosis was conclusive in all biochemically confirmed cases, except for two infants with HPA, identifying pathogenic variants in 32 different genes. The conditions with the highest incidence were HPA (1/6661) and MCAD deficiencies (1/13 787).

Interorgan amino acid interchange in propionic acidemia: the missing key to understanding its physiopathology.

BACKGROUND: Propionic acidemia is an inborn error of metabolism caused by a deficiency in the mitochondrial enzyme propionyl-CoA carboxylase that converts the propionyl CoA to methyl malonyl CoA. This leads to profound changes in distinct metabolic pathways, including the urea cycle, with consequences in ammonia detoxification. The implication of the tricarboxylic acid cycle is less well known, but its repercussions could explain both some of the acute and long-term symptoms of this disease. MATERIALS AND METHODS: The present observational study investigates the amino acid profiles of patients with propionic acidemia being monitored at the Hospital Ramón y Cajal (Madrid, Spain), between January 2015 and September 2017, comparing periods of metabolic stability with those of decompensation with ketosis and/or hyperammonemia. RESULTS: The concentrations of 19 amino acids were determined in 188 samples provided by 10 patients. We identified 40 metabolic decompensation episodes (22 only with ketosis and 18 with hyperammonemia). Plasma glutamine and alanine levels were reduced during these metabolic crises, probably indicating deficiency of anaplerosis (p < 0.001 for both alanine and glutamine). Hypocitrulllinemia and hypoprolinemia were also detected during hyperammonemia (p < 0.001 and 0.03, respectively). CONCLUSIONS: The amino acid profile detected during decompensation episodes suggests deficient anaplerosis from propionyl-CoA and its precursors, with implications in other metabolic pathways like synthesis of urea cycle amino acids and ammonia detoxification.

Severe anemia in patients with Propionic acidemia is associated with branched-chain amino acid imbalance.

BACKGROUND: Propionic acidemia (PA), an inborn error of metabolism, is caused by a deficiency in propionyl-CoA carboxylase. Patients have to follow a diet restricted in the propiogenic amino acids isoleucine (Ile), valine (Val), methionine (Met) and threonine (Thr); proper adherence can prevent and treat acute decompensation and increase life expectancy. However, chronic complications occur in several organs even though metabolic control may be largely maintained. Bone marrow aplasia and anemia are among the more common. MATERIALS AND METHODS: In this retrospective study, data for patients with PA being monitored at the Hospital Ramón y Cajal (Madrid, Spain) (n = 10) in the past 10 years were examined to statistically detect relationships between persistent severe anemia outside of metabolic decompensation episodes and dietary practices such as natural protein intake and medical food consumption (special mixture of precursor-free amino acids) along with plasma levels of branched-chain amino acids (BCAA). High ferritin levels were deemed to indicate that a patient had received repeated transfusions for persistent anemia since data on hemoglobin levels at the moment of transfusion were not always passed on by the attending centers. RESULTS: Three patients had severe, persistent anemia that required repeated blood transfusions. Higher medical food consumption and plasma Leu levels were associated with iron overload. Notably, natural protein intake and plasma Val were negatively correlated with ferritin levels. We also observed an inverse relationship between plasma Val/Leu and Ile/Leu ratios and ferritin. CONCLUSION: The present results suggest that severe anemia in patients with PA might be associated with low natural protein intake and BCAA imbalance.

Long-term follow-up with filter paper samples in patients with propionic acidemia.

BACKGROUND: Propionic acidemia (PA) is an inherited disorder caused by deficiency of propionyl CoA carboxylase. Most patients with this disorder are diagnosed during the neonatal period because of severe metabolic acidosis and hyperammonemia. Patients are required to undergo blood and urine analysis at least 3 to 4 times per year, depending on age and metabolic control. METHODS: We designed a prospective study in which we investigated the results from blood and urinary samples collected monthly in filter paper from 10 PA patients followed in a single metabolic reference center from January 2015 to September 2017. The aim of this study was to evaluate the usefulness of filter paper samples in the follow-up of the PA patients. RESULTS: During the follow-up period, 163 dried blood spot (DBS) and 119 urine dried spot samples were analyzed and compared with 160 plasma and 103 liquid urine specimens; 64 specimens of plasma were analyzed for odd-numbered long-chain fatty acids (OLCFAs). A total of 40 metabolic crises, 18 of them with hyperammonemia were documented. We observed a strong correlation between the filter paper and the urine/plasma samples for the main PA parameters both in stable metabolic conditions as well as in acute decompensations. Also, there was a strong correlation between OLCFAs measured in plasma and quantification of odd number acylcarnitines in DBS. CONCLUSIONS: We conclude that filter paper blood and urinary samples can be used for the follow-up of the patients with PA, correctly reflecting their metabolic situation.

[Newborn Screening Program in the Community of Madrid: evaluation of positive cases.] / Análisis de casos positivos de cribado neonatal de errores congénitos del metabolismo en la Comunidad de Madrid.

OBJECTIVE: Tandem mass spectrometry (MS/MS) is being used for newborn screening since this laboratory testing technology increases the number of metabolic disorders that can be detected from dried blood-spot specimens. In the Community of Madrid, it was implemented in March 2011 and it includes 13 aminoacidopathies, fatty acid oxidation disorders and organic acidemias. The aim of this study was to describe our experience and evaluate the screening positive cases in a period of 9 years (2011-2019). METHODS: During the period of the study, a total of 592.822 neonates were screened with this expanded program by MS/MS in the Community of Madrid. Amino acids, acylcarnitines, and succinylacetone were quantified in all samples that met the quality criteria. Means, medians, percentiles and standard deviation of the analytes and ratios of interest were calculated. RESULTS: 901 patients (0,15 %) with a positive screening test were referred to clinical evaluation. 230 patients were diagnosed of 30 different inborn errors of metabolism (prevalence 1:2577), 11 of which were not included as a target in the Community of Madrid newborn screening program. The global positive predictive value was 25,6 %. During this period of time, two false negative cases were detected. The most prevalent disorders were phenylketonuria/hyperphenylalaninemia and medium chain acyl-CoA dehydrogenase deficiency (1:6444 and 1:13174 respectively). 93 % of the patients were detected in the presymptomatic stage. CONCLUSIONS: During the last 9 years a large number of cases of IEM have been detected with an acceptable global positive predictive value. These results confirm the utility of inborn errors of metabolism newborn screening as a public health program.

OBJETIVO: La tecnología de espectrometría de masas en tándem (MS/MS) en los programas de cribado neonatal ha permitido la detección de gran número de errores congénitos del metabolismo (ECM). En la comunidad de Madrid se implementó en marzo de 2011 incluyendo 13 aminoacidopatías, defectos de la ß-oxidación de ácidos grasos y acidemias orgánicas. El objetivo de este estudio fue describir nuestra experiencia y analizar los casos positivos de cribado en un periodo de 9 años (2011-2019). METODOS: Durante el periodo de estudio se realizó el cribado mediante MS/MS a 592822 recién nacidos en la Comunidad de Madrid. Se cuantificaron aminoácidos, acilcarnitinas y succinilacetona en todas las muestras que cumplieron los criterios de calidad. Se calcularon medias, medianas, percentiles y desviación típica de los analitos y ratios de interés. RESULTADOS: Se derivaron a las unidades clínicas de seguimiento por sospecha de una ECM un total de 901 (0,15 %) casos. Se confirmaron 230 casos de 30 ECM diferentes (prevalencia 1:2577), 11 de los cuales no eran inicialmente objetivo de detección del programa. El valor predictivo positivo global fue de 25,6 %. Durante este periodo se detectaron dos falsos negativos. Las enfermedades con mayor prevalencia fueron fenilcetonuria/hiperfenilalaninemia y deficiencia de acil-CoA deshidrogenasa de cadena media (1:6444 y 1: 13174 respectivamente). 93 % de los casos fueron detectados en fase presintomática. CONCLUSIONES: En estos 9 años de experiencia se han detectado numerosos casos de ECM con un valor predictivo positivo global aceptable. Estos resultados confirman la utilidad del cribado neonatal de ECM como programa de salud pública.

Beneficial Effect of N-Carbamylglutamate in a Neonatal Form of Multiple Acyl-CoA Dehydrogenase Deficiency.

Background. Multiple acyl-CoA dehydrogenase deficiency is an autosomal recessive disorder of the amino acid metabolism and fatty acid oxidation due to the deficiency of the electron transfer protein or electron transfer protein ubiquinone oxidoreductase. The clinical picture ranges from a severe neonatal lethal presentation to late myopathic forms responsive to riboflavin. Up to now, there is no effective treatment for the neonatal form, which exhibits severe metabolic acidosis, hyperammonemia, hypoketotic hypoglycemia, and rhabdomyolysis. We present the case of a child who has had a good long-term outcome after a typical neonatal onset, with a dramatic drop in ammonia levels during the initial metabolic decompensation crisis and adequate control even during intercurrent diseases thereafter with N-carbamylglutamate treatment.

New variants in Spanish Niemann-Pick type c disease patients.

Niemann-Pick type C (NPC) disease is a rare inherited disease, with progressive neurodegeneration as the main symptom. It is a lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes, leading to a lysosomal cholesterol trafficking impairment. Disease indicators are the clinical suspicion and biomarker levels. However, a genetic study is mandatory for the diagnosis, which is complicated due to the different variants with unknown significance. The aim of this work was to identify the variants responsible for NPC in our pediatric population. Twenty-two samples from non-related infants believed to have NPC disease were analyzed during the last 3 years. Surrogate biomarkers of the disease were evaluated whenever possible. Sanger sequencing for both genes is reported for all samples. Complementary genetic studies were performed when necessary. NPC disease was confirmed in 31.8% of subjects due to homozygous or compound heterozygous genetic variants in NPC1. The following four novel variants were identified: a gross deletion variant composed of the gene promoter and the first exon, NM_000271.3:c.385delT, NM_000271.3:c.1553+1342_1655-291del, and NM_000271.3:c.1757delA. None had functional activity and all resulted in important structural changes in the protein.

Análisis de casos positivos de cribado neonatal de errores congénitos del metabolismo en la Comunidad de Madrid / Newborn Screening Program in the Community of Madrid: evaluation of positive cases

OBJETIVO: La tecnología de espectrometría de masas en tándem (MS/MS) en los programas de cribado neonatal ha permitido la detección de gran número de errores congénitos del metabolismo (ECM). En la comunidad de Madrid se implementó en marzo de 2011 incluyendo 13 aminoacidopatías, defectos de la beta-oxidación de ácidos grasos y acidemias orgánicas. El objetivo de este estudio fue describir nuestra experiencia y analizar los casos positivos de cribado en un periodo de 9 años (2011-2019). MÉTODOS: Durante el periodo de estudio se realizó el cribado mediante MS/MS a 592822 recién nacidos en la Comunidad de Madrid. Se cuantificaron aminoácidos, acilcarnitinas y succinilacetona en todas las muestras que cumplieron los criterios de calidad. Se calcularon medias, medianas, percentiles y desviación típica de los analitos y ratios de interés. RESULTADOS: Se derivaron a las unidades clínicas de seguimiento por sospecha de una ECM un total de 901 (0,15 %) casos. Se confirmaron 230 casos de 30 ECM diferentes (prevalencia 1:2577), 11 de los cuales no eran inicialmente objetivo de detección del programa. El valor predictivo positivo global fue de 25,6 %. Durante este periodo se detectaron dos falsos negativos. Las enfermedades con mayor prevalencia fueron fenilcetonuria/hiperfenilalaninemia y deficiencia de acil-CoA deshidrogenasa de cadena media (1:6444 y 1: 13174 respectivamente). 93 % de los casos fueron detectados en fase presintomática. CONCLUSIONES: En estos 9 años de experiencia se han detectado numerosos casos de ECM con un valor predictivo positivo global aceptable. Estos resultados confirman la utilidad del cribado neonatal de ECM como programa de salud pública

OBJECTIVE: Tandem mass spectrometry (MS/MS) is being used for newborn screening since this laboratory testing technology increases the number of metabolic disorders that can be detected from dried blood-spot specimens. In the Community of Madrid, it was implemented in March 2011 and it includes 13 aminoacidopathies, fatty acid oxidation disorders and organic acidemias. The aim of this study was to describe our experience and evaluate the screening positive cases in a period of 9 years (2011-2019). METHODS: During the period of the study, a total of 592.822 neonates were screened with this expanded program by MS/MS in the Community of Madrid. Amino acids, acylcarnitines, and succinylacetone were quantified in all samples that met the quality criteria. Means, medians, percentiles and standard deviation of the analytes and ratios of interest were calculated. RESULTS: 901 patients (0,15 %) with a positive screening test were referred to clinical evaluation. 230 patients were diagnosed of 30 different inborn errors of metabolism (prevalence 1:2577), 11 of which were not included as a target in the Community of Madrid newborn screening program. The global positive predictive value was 25,6 %. During this period of time, two false negative cases were detected. The most prevalent disorders were phenylketonuria/hyperphenylalaninemia and medium chain acyl-CoA dehydrogenase deficiency (1:6444 and 1:13174 respectively). 93 % of the patients were detected in the presymptomatic stage. CONCLUSIONS: During the last 9 years a large number of cases of IEM have been detected with an acceptable global positive predictive value. These results confirm the utility of inborn errors of metabolism newborn screening as a public health program