Mutational spectrum and genotype-phenotype correlation in Mexican patients with infantile-onset and late-onset Pompe disease.

BACKGROUND: Pompe Disease (PD) is a metabolic myopathy caused by variants in the GAA gene, resulting in deficient enzymatic activity. We aimed to characterize the clinical features and related genetic variants in a series of Mexican patients. METHODS: We performed a retrospective study of clinical records of patients diagnosed with LOPD, IOPD or pseudodeficiency. RESULTS: Twenty-nine patients were included in the study, comprising these three forms. Overall, age of symptom onset was 0.1 to 43 years old. The most frequent variant identified was c.-32-13T>G, which was detected in 14 alleles. Among the 23 different variants identified in the GAA gene, 14 were classified as pathogenic, 5 were likely pathogenic, and 1 was a variant of uncertain significance. Two variants were inherited in cis arrangement and 2 were pseudodeficiency-related benign alleles. We identified two novel variants (c.1615 G>A and c.1076-20_1076-4delAAGTCGGCGTTGGCCTG). CONCLUSION: To the best of our knowledge, this series represent the largest phenotypic and genotypic characterization of patients with PD in Mexico. Patients within our series exhibited a combination of LOPD and IOPD associated variants, which may be related to genetic diversity within Mexican population. Further population-wide studies are required to better characterize the incidence of this disease in Mexican population.

Infantile-onset Pompe disease in seven Mexican children.

INTRODUCTION: Pompe disease (PD) is a rare form of metabolic myopathy; the classic infantile presentation is severe, with death occurring before reaching one year of life, and the non-classical form is of slower progression and survival can exceed one year. OBJECTIVE: To describe the genotype and characteristics of Mexican patients with infantile-onset PD. METHODS: Seven patients with PD confirmed by enzymatic activity determination and GAA gene molecular analysis were included. Mutations were reviewed in genomic databases. RESULTS: Median age at symptom onset was four months (1-12 months) and age at diagnosis was eight months (4-16 months). All patients had cardiomyopathy: four who died before one year of age had mutations that predicted severe disease (c.2431dup, c.2560C>T, c.655G>A, c.1987delC) and were negative for cross-reactive immunologic material (CRIM). Three patients survived after one year of age with enzyme replacement therapy; one survived almost five years, another 18 months, and one girl was almost three years of age at the time of this report; their pathogenic variants predicted potentially less severe disease (c.1979G>A, c.655G>A, c.1447G>A) and they were positive for CRIM. CONCLUSION: There was a good correlation between genotype and phenotype in children with Pompe disease.

INTRODUCCIÓN: La enfermedad de Pompe (EP) es una forma rara de miopatía metabólica; la presentación infantil clásica es severa y el fallecimiento acontece antes del año de vida, y la forma no clásica es de progresión más lenta y la sobrevivencia puede superar el año. OBJETIVO: Describir genotipo y características de pacientes mexicanos con EP de inicio infantil. MÉTODOS: Se incluyeron siete pacientes con enfermedad confirmada mediante actividad enzimática y estudio molecular del gen GAA. Se revisaron las mutaciones en bases de datos genómicas. RESULTADOS: La mediana de la edad de inicio de los síntomas fue de cuatro meses (1-12 meses) y la edad de diagnóstico fue de ocho meses (4-16 meses). Todos los pacientes tenían cardiomiopatía: cuatro que fallecieron antes del año presentaron mutaciones que predicen enfermedad severa (c.2431dup, c.2560C>T, c.655G>A, c.1987delC) y CRIM (cross-reactive immunologic material) negativo; tres sobrevivieron después del año de edad con terapia de reemplazo enzimático, uno casi cinco años, otro 18 meses y una niña tenía casi tres años al momento de este informe; sus variantes patogénicas predecían enfermedad potencialmente menos severa (c.1979G>A, c.655G>A, c.1447G>A) y CRIM positivo. CONCLUSIÓN: Existió buena correlación entre genotipo y fenotipo en niños con enfermedad de Pompe.

Enfermedad de Pompe de inicio infantil en siete niños mexicanos / Infantile-onset Pompe disease in seven Mexican children

Resumen Introducción: La enfermedad de Pompe (EP) es una forma rara de miopatía metabólica; la presentación infantil clásica es severa y el fallecimiento acontece antes del año de vida, y la forma no clásica es de progresión más lenta y la sobrevivencia puede superar el año. Objetivo: Describir genotipo y características de pacientes mexicanos con EP de inicio infantil. Métodos: Se incluyeron siete pacientes con enfermedad confirmada mediante actividad enzimática y estudio molecular del gen GAA. Se revisaron las mutaciones en bases de datos genómicas. Resultados: La mediana de la edad de inicio de los síntomas fue de cuatro meses (1-12 meses) y la edad de diagnóstico fue de ocho meses (4-16 meses). Todos los pacientes tenían cardiomiopatía: cuatro que fallecieron antes del año presentaron mutaciones que predicen enfermedad severa (c.2431dup, c.2560C>T, c.655G>A, c.1987delC) y CRIM (cross-reactive immunologic material) negativo; tres sobrevivieron después del año de edad con terapia de reemplazo enzimático, uno casi cinco años, otro 18 meses y una niña tenía casi tres años al momento de este informe; sus variantes patogénicas predecían enfermedad potencialmente menos severa (c.1979G>A, c.655G>A, c.1447G>A) y CRIM positivo. Conclusión: Existió buena correlación entre genotipo y fenotipo en niños con enfermedad de Pompe.

Abstract Introduction: Pompe disease (PD) is a rare form of metabolic myopathy; the classic infantile presentation is severe, with death occurring before reaching one year of life, and the non-classical form is of slower progression and survival can exceed one year. Objective: To describe the genotype and characteristics of Mexican patients with infantile-onset PD. Methods: Seven patients with PD confirmed by enzymatic activity determination and GAA gene molecular analysis were included. Mutations were reviewed in genomic databases. Results: Median age at symptom onset was four months (1-12 months) and age at diagnosis was eight months (4-16 months). All patients had cardiomyopathy: four who died before one year of age had mutations that predicted severe disease (c.2431dup, c.2560C>T, c.655G>A, c.1987delC) and were negative for cross-reactive immunologic material (CRIM). Three patients survived after one year of age with enzyme replacement therapy; one survived almost five years, another 18 months, and one girl was almost three years of age at the time of this report; their pathogenic variants predicted potentially less severe disease (c.1979G>A, c.655G>A, c.1447G>A) and they were positive for CRIM. Conclusion: There was a good correlation between genotype and phenotype in children with Pompe disease.

[Characterisation of factors associated with carotid stenosis in a population at high risk]. / Caracterizacion de factores asociados con estenosis carotidea en una poblacion de alto riesgo.

INTRODUCTION: Moderate to severe stenosis is the less prevalent among the forms of carotid atherosclerotic disease), but it carries a high risk of ischaemic stroke. AIM: To characterise factors associated with moderate to severe carotid stenosis in a high-risk population. PATIENTS AND METHODS: We performed an analysis on traditional risk factors associated with carotid stenosis ≥50% in 533 patients who received Doppler ultrasound due to a history of stroke (34%) or who had = 2 of the risk factors: age ≥55 years (86%), hypertension (65%), dyslipidemia (52%), obesity (42%), diabetes (40%) or smoking (40%). RESULTS: The prevalence of carotid stenosis ≥50% was 7.1%, symptomatic (associated with stroke in congruent territory) in 5.6%, bilateral in 2.1% and bilateral symptomatic in 1.5%. A 36.8% of patients had moderate to severe load (≥4) of atherosclerotic plaques (25.9% moderate: 4-6 plaques, and 10.9% severe: ≥7 plaques). By multivariate analysis we identified the age ≥75 years, dyslipidemia, and smoking as factors independently associated with carotid stenosis ≥50%, and hypertension and smoking with symptomatic stenosis. The number of risk factors was strongly associated with the prevalence of carotid stenosis. Notably, neither diabetes nor obesity explained the degree of moderate to severe carotid stenosis. CONCLUSIONS: As forms of carotid atherosclerotic disease, moderate to severe stenosis is less frequent than a high burden of atherosclerotic plaques. Advanced age, smoking, dyslipidemia and hypertension are the main traditional risk factors associated with the degree of carotid stenosis.

TITLE: Caracterizacion de factores asociados con estenosis carotidea en una poblacion de alto riesgo.Introduccion. La estenosis moderada a grave es la forma de enfermedad carotidea aterosclerosa menos prevalente, pero que implica un alto riesgo de ictus isquemico. Objetivo. Caracterizar los factores asociados con la estenosis carotidea moderada a grave en una poblacion de alto riesgo. Pacientes y metodos. Realizamos un analisis de los factores de riesgo tradicionales asociados a estenosis carotidea >= 50% en 533 pacientes que recibieron evaluacion mediante ultrasonograma Doppler por historia de ictus (34%), o que contaban con al menos dos de los factores de riesgo: edad >= 55 años (86%), hipertension (65%), dislipidemia (52%), obesidad (42%), diabetes (40%) o tabaquismo (40%). Resultados. La prevalencia de estenosis carotidea >= 50% fue del 7,1%, sintomatica (asociada a ictus en territorio congruente) en el 5,6%, bilateral en el 2,1% y sintomatica bilateral en el 1,5%. Un 36,8% de los pacientes presento carga moderada a grave (>= 4) de placas de ateroma (25,9%, moderada: 4-6 placas; y 10,9%, grave: >= 7 placas). Mediante analisis multivariable se identifico la edad >= 75 años, la dislipidemia y el tabaquismo como factores asociados con estenosis >= 50%, y la hipertension arterial y el tabaquismo con estenosis sintomatica. El numero de factores de riesgo se asocio fuertemente con la prevalencia de estenosis carotidea. Notablemente, ni la diabetes ni la obesidad explicaron el grado de estenosis moderada a grave. Conclusiones. Como formas de enfermedad carotidea aterosclerosa, la frecuencia de estenosis moderada a grave es menor que una carga alta de placas de ateroma. La edad avanzada, el tabaquismo, la dislipidemia y la hipertension son los principales factores tradicionales que se asocian con el grado de estenosis carotidea.