Upgrading the evidence for the use of ambroxol in Gaucher disease and GBA related Parkinson: Investigator initiated registry based on real life data.

Ambroxol hydrochloride is an oral mucolytic drug available over-the-counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Unfortunately, there have been no pharma-driven clinical trials to establish its use. Thus, real-world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA-Parkinson disease (GBA-PD). Clinicians treating patients with ambroxol for GD and GBA-PD were approached to collaborate in an investigator-initiated registry. Anonymized data were collected, including demographics, GD type, GD-specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5-74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1-76) months and 435 (75-1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease-modification for GBA-PD, these preliminary data may be encouraging to physicians and patients who consider an off-label use of ambroxol.

Niemann-Pick disease A or B in four pediatric patients and SMPD1 mutation carrier frequency in the Mexican population.

INTRODUCTION AND OBJECTIVES: Niemann-Pick disease type A (NPD-A) and B (NPD-B) are lysosomal storage diseases with a birth prevalence of 0.4-0.6/100,000. They are caused by a deficiency in acid sphingomyelinase, an enzyme encoded by SMPD1. We analyzed the phenotype and genotype of four unrelated Mexican patients, one with NPD-A and three with NPD-B. PATIENTS AND METHODS: Four female patients between 1 and 7 years of age were diagnosed with NPD-A or NPD-B by hepatosplenomegaly, among other clinical characteristics, and by determining the level of acid sphingomyelinase enzymatic activity and sequencing of the SMPD1 gene. Additionally, a 775bp amplicon of SMPD1 (from 11:6393835_6394609, including exons 5 and 6) was analyzed by capillary sequencing in a control group of 50 unrelated healthy Mexican Mestizos. RESULTS: An infrequent variant (c.1343A>G p.Tyr448Cys) was observed in two patients. One is the first NPD-A homozygous patient reported with this variant and the other a compound heterozygous NPD-B patient with the c.1829_1831delGCC p.Arg610del variant. Another compound heterozygous patient had the c.1547A>G p.His516Arg variant (not previously described in affected individuals) along with the c.1805G>A p.Arg602His variant. A new c.1263+8C>T pathogenic variant was encountered in a homozygous state in a NPD-B patient. Among the healthy control individuals there was a heterozygous carrier for the c.1550A>T (rs142787001) pathogenic variant, but none with the known pathogenic variants in the 11:6393835_6394609 region of SMPD1. CONCLUSIONS: The present study provides further NPD-A or B phenotype-genotype correlations. We detected a heterozygous carrier with a pathogenic variant in 1/50 healthy Mexican mestizos.

Intussusception risk and health benefits of rotavirus vaccination in Mexico and Brazil.

BACKGROUND: Because postlicensure surveillance determined that a previous rotavirus vaccine, RotaShield, caused intussusception in 1 of every 10,000 recipients, we assessed the association of the new monovalent rotavirus vaccine (RV1) with intussusception after routine immunization of infants in Mexico and Brazil. METHODS: We used case-series and case-control methods to assess the association between RV1 and intussusception. Infants with intussusception were identified through active surveillance at 69 hospitals (16 in Mexico and 53 in Brazil), and age-matched infants from the same neighborhood were enrolled as controls. Vaccination dates were verified by a review of vaccination cards or clinic records. RESULTS: We enrolled 615 case patients (285 in Mexico and 330 in Brazil) and 2050 controls. An increased risk of intussusception 1 to 7 days after the first dose of RV1 was identified among infants in Mexico with the use of both the case-series method (incidence ratio, 5.3; 95% confidence interval [CI], 3.0 to 9.3) and the case-control method (odds ratio, 5.8; 95% CI, 2.6 to 13.0). No significant risk was found after the first dose among infants in Brazil, but an increased risk, albeit smaller than that seen after the first dose in Mexico--an increase by a factor of 1.9 to 2.6 - was seen 1 to 7 days after the second dose. A combined annual excess of 96 cases of intussusception in Mexico (approximately 1 per 51,000 infants) and in Brazil (approximately 1 per 68,000 infants) and of 5 deaths due to intussusception was attributable to RV1. However, RV1 prevented approximately 80,000 hospitalizations and 1300 deaths from diarrhea each year in these two countries. CONCLUSIONS: RV1 was associated with a short-term risk of intussusception in approximately 1 of every 51,000 to 68,000 vaccinated infants. The absolute number of deaths and hospitalizations averted because of vaccination far exceeded the number of intussusception cases that may have been associated with vaccination. (Funded in part by the GAVI Alliance and the U.S. Department of Health and Human Services.).

Classic infantile-onset Pompe disease with histopathological neurologic findings linked to a novel GAA gene 4 bp deletion: A case study.

Pompe disease (PD) is an autosomal recessive disorder by a deficiency of acid α-glucosidase (GAA) with intralysosomal glycogen accumulation in multiple tissues. We present the case of a 5-month-old male with hypertrophic cardiomyopathy, hypotony, feeding difficulties, and oxygen requirement since birth. At 3 months of age, he develops heart failure, respiratory impairment, and neurological deterioration. The echocardiogram revealed concentric hypertrophic cardiomyopathy with left-diastolic dysfunction. We found increased creatine-phosphokinase, lactate dehydrogenase, and urinary glucose tetrasaccharide levels, 50% of PAS-positive vacuolated lymphocytes in the peripheral blood smear, and low GAA activity. Sequencing of coding exons and flanking intronic sequences revealed a novel homozygous 4 bp deletion in exon 15 of the GAA gene (c.2066_2069delAGCC/p.Glu689Glyfs*6). IOPD was diagnosed. At 5 months old, we started enzyme replacement therapy with an alpha-alglucosidase of 20 mg/kg weekly and immunomodulation with intravenous immunoglobulin. He developed two cardiorespiratory arrests with subsequent neurologic deterioration, convulsive crisis, and respiratory failure and died at 9 months old. We found the usual PD hallmarks in the heart, striated muscle, and liver but also we found neuronal lesions characterized by cytoplasm vacuolization with PAS-positive granules in the central nervous system and myenteric plexus. We describe a novel GAA gene pathogenic variant with a particular phenotype characterized by classic IOPD and neurologic histopathological findings. Enhancing the knowledge of lysosomal diseases is critical to improving the diagnosis and treatment of these patients.

Clinical Spectrum of COVID-19 in a Mexican Pediatric Population.

OBJECTIVE: To describe the broader clinical spectrum of COVID-19 in children. METHODS: In this descriptive, prospective study, we included confirmed pediatric patients with COVID-19 who presented to the emergency department of a pediatric tertiary care center from April to July, 2020. All patients were confirmed by the SARS-CoV-2 RT-PCR test, and we analyzed 24 symptoms and 25 signs. RESULTS: Among the 50 patients with COVID-19, the most common symptoms were fever, excessive cry and dry cough; digestive symptoms were frequently found (24%). The most common signs were pharyngeal erythema and irritability. CONCLUSIONS: Clinicians should recognize that the clinical spectrum of COVID-19 in children is wider than previously described, often with nonspecific signs and symptoms, and digestive symptoms should raise suspicion.

Restructuring of a pediatric hospital in the face of the COVID-19 pandemic.

Overview of the pandemic In December 2019, a new virus named SARS-CoV-2 was reported in Wuhan province, China. The first case of COVID-19 in Mexico was confirmed on February 28, 2020, and the World Health Organization declared the pandemic on March 11.

Renal globotriaosylceramide deposits for Fabry disease linked to uncertain pathogenicity gene variant c.352C>T/p.Arg118Cys: A family study.

BACKGROUND: Fabry disease (FD) has an extensive phenotypic expression associated with GLA gene variants. The GLA gene variant c.352C>T/p.Arg118Cys was considered with uncertain pathogenicity because of the finding of high residual alpha-galactosidase A (α-Gal A) enzyme activity, the absence of Mendelian segregation with an FD phenotype with many individuals remaining asymptomatic at old ages and the lack of globotriaosylceramide (Gb3) deposits in tissues. Gb3 deposits are found in kidneys before the progression to overt microalbuminuria and decreased glomerular filtration. METHODS: We describe a family with c.352C>T/p.Arg118Cys variant and pathognomonic signs of FD renal damage in masculine children. RESULTS: The proband died of end-stage renal failure and we analyzed GLA gene in his offspring and found the variant in all daughters and five of seven grandchildren. In patients who we measure plasma and urinary Gb3, α-Gal A enzyme activity, and plasma globotriaosylsphingosine (Lyso-Gb3), these were normal or almost normal. A kidney biopsy was performed in two boys and one girl with normal renal function and characteristic signs of FD as enlarged and vacuolated epithelial cells, myelin figures, myelin-like figures, lamellated structures in podocytes and endothelial cells, were found in boys. These boys received agalsidase beta 1 mg/kg IV infusion every other week to prevent further renal damage. CONCLUSION: This is the first report that shows a link between FD renal Gb3 deposits and c.352C>T/p.Arg118Cys variant, supporting pathogenicity of a variant considered until now with uncertain pathogenicity.

Improvement of life quality measured by Lansky Score after enzymatic replacement therapy in children with Gaucher disease type 1.

BACKGROUND: Gaucher disease type 1 (GD1, OMIM# 230800), is a condition with high impact in patient's quality of life (QoL). We report the improvement in QoL of children with GD1 measured by Lansky play-performance scale (LS) after enzymatic replacement therapy (ERT) and to describe our experience in the treatment of children with GD1. METHODS: Five children with diagnosis of GD1 received imiglucerase 60 mg/kg every two weeks. LS, hepatomegaly, splenomegaly, hemoglobin, platelets, and growth rate were measured every 6 months after beginning ERT for 30 months. RESULTS: After ERT, LS increased significantly from 28 ± 16.48 points before ERT to 70 ± 10 (P = 0.0046) and 95 ± 10 (P = 0.0022) points after 6 and 30 months of ERT, respectively; hemoglobin and platelets changed significantly from 9.28 ± 0.61 to 12.40 ± 0.85 (P = 0.0198) and from 71.50 ± 14.89 to 205.00 ± 65.34 (P = 0.0428) after 30 months of ERT, respectively. All patients demonstrated decreased hepatic and splenic size with mean reductions of 66% and 80% at 30 months of treatment and the USG longitudinal axis was reduced in both liver and spleen after ERT. CONCLUSION: The use of ERT with imiglucerase 60 mg/kg every two weeks has substantial benefits and significantly improves QoL, assessed with Lansky Score, of the five children with GD1 studied.

Consenso de expertos sobre recomendaciones basadas en evidencia para el diagnóstico, tratamiento y seguimiento de enfermedad de Fabry en pediatría / Expert Consensus on Evidence-Based Recommendations for the Diagnosis, Treatment, and Follow-Up of Fabry Disease in Pediatric Patients / Consenso de especialistas colombianos sobre recomendações baseadas em evidências para o diagnóstico, tratamento e acompanhamento da doença de Fabry em pediatria

Antecedentes: la enfermedad de Fabry (Ef) es una enfermedad rara ligada a X secundaria al depósito lisosomal de glicoesfingolípidos, debido a la deficiencia de la enzima alfa galactosidasa A (α-Gal A). A pesar de su baja frecuencia, es una condición que afecta la calidad de vida de los pacientes y disminuye su esperanza de vida. Objetivo: generar recomendaciones informadas para el diagnóstico y tratamiento de pacientes pediátricos (menores de 18 años) con Ef. Material y Métodos: revisión de literatura en bases de datos y literatura gris a partir de 2010, incluyendo guías de práctica clínica, revisiones sistemáticas y estudios primarios. La calidad de evidencia se evaluó de acuerdo con el tipo. Las recomendaciones se sometieron a consenso de expertos a través de metodología Delphi modificada. El acuerdo se definió a partir del 80 %. Resultados: A partir del análisis de la evidencia recolectada se formularon un total de 45 recomendaciones para tamización, diagnóstico y tratamiento de paciente pediátrico con Ef. El panel revisor estuvo conformado por once expertos en el tema. Las recomendaciones fueron aprobadas con puntuaciones entre 82.3 % y 100 %. Conclusiones: las recomendaciones resultantes del consenso de expertos permitirán la toma de decisiones clínicas y estandarización de la práctica en la atención de pacientes pediátricos con Ef en el país y la región. El diagnóstico temprano y oportuno garantiza una disminución del impacto en la calidad de vida de los pacientes y sus familiares

Background: Fabry disease (fD) is a rare X-linked disease characterized by the accumulation of glyco- sphingolipids in lysosomes due to the deficiency in the production of alpha-galactosidase A (α-Gal A) enzyme. Despite its low frequency, this disease has a serious impact on the life expectancy and quality. Objective: To make evidence-based recommendations for the diagnosis and treatment of fD in pediatric patients (<18 years of age). Materials and Methods: A study of databases and gray literature was conducted in 2010, including clinical practice guidelines, systematic reviews, and primary research. The type of evidence was used to determine the quality of evidence. The recommendations were submitted to an expert consensus using the modified Delphi process. The agreement was set at 80%. Conclusions: The recommendations emerging from this expert consensus will enable the standardization of care provision for pediatric patients with fD in Colombia and Latin America and clinical decision-making for disease management. Notably, making an early diagnosis ensures a reduction in the impact of this disease on the quality of life of patients and their families

Fundamento: a doença de Fabry (Df) é uma rara doença ligada ao cromossomo X secundária à deposi- ção lisossômica de glicoesfingolipídeos devido à deficiência da enzima alfa galactosidase A (α-Gal A). Apesar de sua baixa frequência, é uma condição que afeta a qualidade de vida dos pacientes e diminui sua expectativa de vida. Objetivo: gerar recomendações baseadas em evidências para o diagnóstico e tratamento de pacientes pediátricos (com menos de 8 anos de idade) com Df. Materais e Métodos: foi realizada uma revisão da literatura em bases de dados e literatura cinza a partir de 2010, incluindo diretrizes de prática clínica, revisões sistemáticas e estudos primários. A qualidade da evidência foi avaliada de acordo com o tipo de evidência. As recomendações foram submetidas ao consenso de especialistas usando a metodologia Delphi modificada. A concordância foi definida a partir de 80%. Resultados: com base na análise das evidências coletadas, foram formuladas um total de 45 recomendações para triagem, diagnóstico e tratamento de pacientes pediátricos com doença de Fabry. O painel de revisão foi composto por onze especialistas no assunto. As recomendações foram aprovadas com pontuações entre 82,3% e 100%. Conclusões: as recomendações resultantes do consenso de especialistas permitirão a tomada de decisão clínica e a padronização da prática no cuidado de pacientes pediátricos com Df em nível nacional e regional; o diagnóstico precoce e oportuno garante a redução do impacto na qualidade de vida dos pacientes e seus familiares.

Primer caso en México de un paciente con enfermedad de Pompe de inicio tardío: remisión de cardiomiopatía con terapia de reemplazo enzimático / First case of a patient with late-onset Pompe disease: Cardiomyopathy remission with enzyme replacement therapy

Introducción: La enfermedad de Pompe (EP) es un trastorno autosómico recesivo causado por deficiencia de la enzima lisosomal, α-glucosidasa ácida (GAA) humana. Este déficit produce depósitos de glucógeno en hígado y músculos. La EP en niños pequeños (inicio temprano) produce cardiomiopatía e hipotonía. Sin embargo, en el inicio tardío, la cardiomiopatía se considera poco frecuente, y se ha dicho que hay menor beneficio con la terapia de reemplazo enzimático (TRE) con GAA. Caso clínico: Paciente femenino de 8 años, que inició con síntomas a los 3 años de edad (inicio tardío) con infecciones respiratorias recurrentes y debilidad muscular progresiva. Se diagnosticó con EP por evidencia en biopsia muscular y la baja actividad de α-glucosidasa. Se realizó lobectomía derecha basal por bronquiectasias y necrosis. Desarrolló neumonía y recibió asistencia respiratoria mecánica (CPAP) por 4 semanas, con dependencia absoluta de oxígeno y BiPAP. Se aplicó TRE con GAA. Conclusiones: La evolución positiva de la paciente, especialmente en las funciones respiratoria y cardiovascular, muestra que es posible mejorar la cardiomiopatía en pacientes con EP de inicio tardío.

Background: Pompe disease (PD) is an autosomal recessive disease caused by a deficiency in the lysosomal human enzyme α-alglucosidase. Among children (early onset), PD causes cardiomyopathy, whereas late-onset disease seems unrelated to a high rate of cardiomyopathy. Patients respond less to enzyme replacement therapy (ERT) with α-alglucosidase. Case report: This is the case of an 8-year-old female patient with symptom onset at 3 years of age (late onset) with recurrent respiratory infections and progressive muscular weakness. Diagnosis for Pompe disease (PD) was established due to evidence from muscle biopsy. At baseline, a right lobectomy was performed for bronchiectasis and necrosis. The patient developed pneumonia and received mechanical respiratory support (CPAP) for 4 weeks with absolute dependence on oxygen and BPAP. ERT with α-alglucosidase was given. Conclusions: This patient's positive output and remarkable effects on cardiovascular and respiratory function suggest that ERT may reduce cardiomyopathy among late-onset PD patients.

Epidemiología de lesiones no intencionales en niños: revisión de estadísticas internacionales y nacionales / Epidemiology of accidental injuries in children: Review of international and national statistics

Las lesiones accidentales continúan siendo un importante problema de salud pública en todo el mundo. La población pediátrica está predispuesta a accidentes, y en este grupo las consecuencias son generalmente más graves. Las estadísticas internacionales y nacionales muestran que la pobreza y el nivel socio-económico bajo juegan un papel importante en la morbimortalidad por accidentes. Es evidente la heterogeneidad en las tasas de lesiones por edad, sexo y área geográfica. Se requieren más estudios científicos que analicen la epidemiología de las lesiones en la población pediátrica. Los resultados podrían ser de ayuda en el planteamiento de nuevas políticas de prevención de accidentes.

Accidental injuries remain to be an important public health problem worldwide. The pediatric population is predisposed to accidents and consequences are usually more severe. International and national statistics show that poverty and low socioeconomic level play an important role in morbidity and mortality due to accidents. Disparities in injury rates according to age, sex and geographical location are evident. Epidemiology of injury in the pediatric population needs more scientific study; these results may help to establish new policies on prevention and approach of accidents.

Validation of the Script Concordance Test as an instrument to assess clinical reasoning of residents in pediatric emergency medicine in Mexico

Background. Clinical reasoning is a crucial skill to be acquired during a residency training program. In pediatric emergency medicine, physicians are challenged by diagnostic, investigative, and treatment uncertainties. The Script Concordance Test (SCT) uses authentic clinical scenarios to compare trainee’s judgement skills with those of experts. The purpose of this study was to evaluate the clinical reasoning using a pediatric emergency medicine SCT and to determine if it would be able to differentiate between different levels of residency training, validating it in Mexico. Methods. A SCT containing 58 questions nested in 14 cases was administered to pediatric and senior residents at one academic institution. Fourteen experienced emergency medicine pediatricians were part of a reference panel to establish the basis for the scoring process. Results. Ninety six residents consented to participate. Thirteen residents were fellows of pediatric intensive care medicine or pediatric emergency medicine, and there were 83 pediatric residents. Overall, there was a significant difference in performance across levels of training. The difference between all levels was significant. Conclusions. This pediatric emergency medicine Script Concordance Test was useful to assess the progression of clinical reasoning during residency training in Mexico.

Evaluación de la calidad de las notas de envío / Evaluation of referral letters

Introducción. La sobrepoblación de los servicios médicos ha incrementado la necesidad de referir pacientes a otras unidades médicas; en esas situaciones la nota de envío representa frecuentemente la vía de comunicación entre las unidades médicas. Objetivo: evaluar con qué frecuencia las notas de envío incluyen la información requerida así como la asociación entre integridad de éstas y el tipo de formato estructurado para elaborarlas. Material y métodos. Se colectaron y evaluaron las notas de envío de pacientes referidos al Hospital Infantil de México Federico Gómez de acuerdo a las recomendaciones propuestas por la Secretaría de Salud. A cada nota se le evaluó un total de 12 apartados. Se correlacionó la información incluida de cada categoría con la presencia de un espacio especialmente reservado para esa categoría de información en el formato utilizado.Resultados. Se evaluaron 100 notas de envío de pacientes atendidos desde el 15 de noviembre de 1997 al 15 de julio de 1998. En la mayoría de las notas evaluadas no se incluían ni la información ni los apartados para cada uno los puntos relevantes. Ninguna nota incluía toda la información requerida. Sólo en 4 de los 12 puntos evaluados se pudo demostrar asociación entre la inclusión de un espacio en el formato con la inclusión de dicha información.Conclusión. Las notas de envío frecuentemente no incluyen información referente a cada uno de los reactivos que se consideran necesarios. El uso de un formato que incluya apartados para cada tipo de información pudiera mejorar la integridad de las notas de envío.