Infantile-onset Pompe disease: Diagnosis and management. / Enfermedad de Pompe infantil: Diagnóstico y tratamiento.

Pompe disease, also known as acid maltase deficiency or glycogenosis type II, is a rare severe, autosomal, recessive, and progressive genetic disorder caused by deficiency in alpha-glucosidase. The classic infantile-onset is the most broadly known form of Pompe disease, which presents with severe heart involvement and clear hypotonia, while the non-classic presentation occurs with early motor involvement. Late-onset Pompe disease develops in adults, but it may also occur during childhood or adolescence. Here we update the available clinical and diagnostic findings because an early management with enzyme replacement therapy may improve patients' survival and quality of life. We also review the benefits and adverse effects of available treatments and new lines of therapeutic research.

La enfermedad de Pompe, o deficiencia de maltasa ácida o glucogenosis tipo II, es una grave enfermedad genética, autosómica recesiva, progresiva, poco frecuente, causada por la deficiencia en la enzima alfa glucosidasa. En la edad pediátrica, puede presentarse con la "forma clásica", la más conocida, con grave compromiso cardíaco y franca hipotonía, o con la "forma no clásica", con comienzo temprano del compromiso motor. La "forma de comienzo tardío" del adulto también puede ocurrir en la infancia o en la adolescencia. Se actualizan los hallazgos clínicos y de diagnóstico disponibles, ya que un tratamiento temprano con reemplazo de la enzima faltante puede mejorar la supervivencia y la calidad de vida del paciente. Se revisan los beneficios y los efectos adversos del tratamiento disponible y nuevas líneas de investigación terapéutica.

Association of anti-nuclesome and anti C1q antibodies with lupus nephritis in an Egyptian cohort of patients with systemic lupus erythematosus

Abstract Introduction: Anti-nucleosome and anti-C1q antibodies demonstrated an association with the development of glomerulonephritis in systemic lupus erythematosus (SLE). Some investigators have proposed that monitoring anti- C1q and anti-nucleosome antibodies might be valuable for making predictions about lupus nephritis (LN) and assessment of disease activity as a non-invasive biological marker of renal disease. Objectives: The current study was proposed to investigate the presence of anti-C1q and anti-nucleosome antibodies in the sera of Egyptian patients with SLE and their association with LN. Methods: Eighty patients with SLE were included. Patients were classified into, a LN group including 40 cases with active LN (based on the results of renal biopsy and renal SLEDAI≥4) and a non renal SLE group including 40 patients (with no clinical or laboratory evidence of renal involvement that were attributed in the past or present to SLE). They were subjected to full medical history taking, clinical examination, routine laboratory investigations, measurement of antinuclear antibody (ANA), anti-ds DNA, anti-C1q & anti-nucleosome antibodies. Results: Anti-C1q antibody showed a statistically significant association with the presence of vasculitis and nephritis while anti-nucleosome antibody didn't show a significant association with the presence of any clinical features. Double positivity of anti-nucleosome and anti-C1q antibodies showed a statistically significant association with the presence of vasculitis and photosensitivity, high ECLAM score, elevated ESR, low serum albumin and low C3 levels. Conclusion: Serum anti-C1q antibody has a significant association with LN while double positive antibodies have a significant association with vasculitis and low C3 levels in Egyptian patients with SLE.

[Argentine consensus on late-onset Pompe's disease]. / Consenso argentino sobre enfermedad de Pompe de inicio tardío.

Pompe's disease (PD) is an infrequent metabolic autosomic recessive disorder produced by the lack or deficiency of the acid alpha-glucosidase lysosomal enzyme in tissues of involved individuals. Delayed-onset PD is considered whenever symptoms onset start after one year of age. We present an update of the recommendations for the management of delayed-onset PD, taking as reference the guidelines from the Argentine Consensus for diagnosis, treatment and follow-up of PD published in 2013. The present consensus gathered several experts in PD in the areas of internal medicine, laboratory diagnosis, neuropathology, pulmonology, nutrition, neurology, metabolic and neuromuscular disorders as well as rehabilitation to perform an update of the literature of delayed-onset PD, with special attention on relevant information published within the last 4 years. The entire working group approved the final version of the consensus. Each participant provided a declaration of conflict of interest. As a result, it is an update of the previous Argentine PD Consensus with focus on the delayed-onset presentation of the disease. Being such infrequent disorder, available data were rather limited and thus, the recommendations represent expert opinions.

Consenso argentino sobre enfermedad de Pompe de inicio tardío / Argentine consensus on late-onset Pompe's disease

La enfermedad de Pompe (EP) es un desorden metabólico autosómico recesivo infrecuente, producido por la ausencia o deficiencia de la enzima lisosomal alfa-glucosidasa ácida en los tejidos de los individuos afectados. Se considera enfermedad de Pompe de inicio tardío (EPIT) en aquellos individuos de más de un año de edad al comienzo de los síntomas. El objetivo del presente consenso es el de actualizar las pautas y recomendaciones para un correcto tratamiento de los pacientes con EPIT, tomando como referencia los lineamientos del Consenso Argentino para el diagnóstico, seguimiento y tratamiento de la enfermedad de Pompe publicado en el año 2013. Se organizó un consenso que reunió profesionales con experiencia en la EP en las áreas de clínica médica, diagnóstico de laboratorio, neuropatología, neumonología, nutrición, neurología, enfermedades metabólicas, enfermedades neuromusculares y rehabilitación. Se realizó una actualización de la bibliografía sobre EPIT, con especial atención en las publicaciones relevantes de los últimos cuatro años. Los términos finales del documento fueron consensuados por todo el grupo de trabajo. Cada participante proporcionó su declaración de conflicto de intereses. El resultado es una actualización del último Consenso Argentino para la EP, con particular enfoque en su forma de comienzo tardío. Tratándose de una afección infrecuente, en la que los datos disponibles son limitados, las presentes recomendaciones deben ser consideradas como opinión de expertos.

Pompe's disease (PD) is an infrequent metabolic autosomic recessive disorder produced by the lack or deficiency of the acid alpha-glucosidase lysosomal enzyme in tissues of involved individuals. Delayed-onset PD is considered whenever symptoms onset start after one year of age. We present an update of the recommendations for the management of delayed-onset PD, taking as reference the guidelines from the Argentine Consensus for diagnosis, treatment and follow-up of PD published in 2013. The present consensus gathered several experts in PD in the areas of internal medicine, laboratory diagnosis, neuropathology, pulmonology, nutrition, neurology, metabolic and neuromuscular disorders as well as rehabilitation to perform an update of the literature of delayed-onset PD, with special attention on relevant information published within the last 4 years. The entire working group approved the final version of the consensus. Each participant provided a declaration of conflict of interest. As a result, it is an update of the previous Argentine PD Consensus with focus on the delayed-onset presentation of the disease. Being such infrequent disorder, available data were rather limited and thus, the recommendations represent expert opinions.

Severe Cardiac Involvement Is Rare in Patients with Late-Onset Pompe Disease and the Common c.-32-13T>G Variant: Implications for Newborn Screening.

Based on a review of a large patient cohort, published literature, and 3 newborn screening cohorts, we concluded that children diagnosed through newborn screening with late-onset Pompe disease and the common heterozygous c.-32-13T>G variant require frequent cardiac follow-up with electrocardiography for arrhythmias. However, there is limited evidence for performing repeated echocardiography for cardiomyopathy.

Blunted Hypercapnic Respiratory Drive Response in Subjects With Late-Onset Pompe Disease.

BACKGROUND: Patients with late-onset Pompe disease develop progressive hypercapnic respiratory failure that can be disproportionate to the respiratory muscle compromise and/or thoracic restriction. Although recent studies have reported the presence of a blunted hypercapnic respiratory response in some subjects with neuromuscular disorders and chronic hypercapnia, no study has evaluated the integrity of the respiratory drive in subjects with late-onset Pompe disease. Thus, we endeavor to determine the CO2 rebreathing response in subjects with late-onset Pompe disease. METHODS: Respiratory muscle strength was assessed by measuring the maximum inspiratory pressure, and the maximum expiratory pressure. The maximum inspiratory pressure reflects the strength of the diaphragm and other inspiratory muscles, whereas the maximum expiratory pressure reflects the strength of the abdominal muscles and other expiratory muscles. We studied the hypercapnic drive response (measured as the ratio of the change in airway-occlusion pressure 0.1 s after the start of inspiration and end-tidal PCO2 in 13 subjects with late-onset Pompe disease and 51 healthy controls. RESULTS: Overall inspiratory muscle strength was within normal limits or slightly diminished in the late-onset Pompe disease group. Five subjects (38.5%) were chronically hypercapnic, and 9 (69.2%) had an increased breath-holding time. Compared with controls, the change in airway-occlusion pressure 0.1 s/change in end-tidal CO2 pressure slope (hypercapnic respiratory drive) was lower in the late-onset Pompe disease group (median 0.050 [interquartile range 0.027-0.118] vs 0.183 [0.153-0.233], P < .001). Nine subjects (69.2%) had a blunted change in airway-occlusion pressure 0.1 s/change in end-tidal carbon dioxide pressure slope. CONCLUSIONS: Subjects with late-onset Pompe disease had an impaired hypercapnic respiratory drive response. The clinical impact of this phenomenon in this subject subset deserves further investigation.

[Thymic neuroendocrine carcinoma with Pompe's disease of the adult]. / Carcinoma neuroendocrino de timo con enfermedad de Pompe del adulto.

Pompe disease (glycogenosis type II) is an inherited autosomal recessive lysosomal storage disease caused by a deficiency of acid alpha-glucosidase. Thymic neuroendocrine tumors, are primary thymic neoplasms with neuroendocrine differentiation that generally present as a mass within the anterior mediastinum. Both diseases are considered rare. To our knowledge the co-existence of Pompe disease and thymic neuroendocrine tumor in the same patient has not been previously reported. We could not find biological plausibility between both diseases. Further studies are needed to confirm the finding and to further increase our understanding of this association. Clinical data from epidemiological studies, case reports, case series and small formal open or controlled clinical trials may define both clinical plausibility and causality between the two conditions.

Carcinoma neuroendocrino de timo con enfermedad de pompe del adulto / Thymic neuroendocrine carcinoma with Pompe's disease of the adult

La enfermedad de Pompe (glucogenosis tipo II) es una enfermedad de depósito lisosomal, autosómica recesiva causada por una deficiencia de ácido alfa-glucosidasa. Los tumores neuroendocrinos tímicos son neoplasias primarias con diferenciación neuroendocrina que generalmente se presentan como una masa en el mediastino anterior. Ambas enfermedades se consideran raras en sí mismas. En nuestro conocimiento, la enfermedad de Pompe y un tumor neuroendocrino del timo en el mismo paciente no ha sido antes comunicada. No pudimos encontrar la plausibilidad biológica entre ambas enfermedades. Se necesitan más estudios para confirmar el hallazgo y para aumentar aún más nuestra comprensión de esta asociación. Los datos clínicos de los estudios epidemiológicos, los informes de casos, las series de casos y los pequeños ensayos clínicos abiertos o controlados pueden definir tanto la plausibilidad clínica como la causalidad entre las dos enfermedades.

Pompe disease (glycogenosis type II) is an inherited autosomal recessive lysosomal storage disease caused by a deficiency of acid alpha-glucosidase. Thymic neuroendocrine tumors, are primary thymic neoplasms with neuroendocrine differentiation that generally present as a mass within the anterior mediastinum. Both diseases are considered rare. To our knowledge the co-existence of Pompe disease and thymic neuroendocrine tumor in the same patient has not been previously reported. We could not find biological plausibility between both diseases. Further studies are needed to confirm the finding and to further increase our understanding of this association. Clinical data from epidemiological studies, case reports, case series and small formal open or controlled clinical trials may define both clinical plausibility and causality between the two conditions.

Pompe disease, the must-not-miss diagnosis: A report of 3 patients.

INTRODUCTION: Pompe disease is a progressive and debilitating neuromuscular disorder that presents with a heterogeneous array of signs and symptoms including proximal muscle weakness, respiratory insufficiency, and/or elevated creatine kinase levels. It mimics other neuromuscular disorders, making its diagnosis challenging and often significantly delayed, thereby increasing morbidity and early mortality of the disease. METHODS: Three Pompe disease patients are discussed to highlight the challenging path to diagnosis and the common cluster of symptoms that could lead to timely and accurate diagnosis. RESULTS: After significant delays in diagnosis, Pompe disease was diagnosed on the basis of the pattern of proximal weakness. CONCLUSIONS: Suspicion and recognition of the characteristic symptoms of Pompe disease may improve both the timing and accuracy of the diagnosis, which will improve clinical outcomes and minimize disease progression.

A novel homozygous mutation at the GAA gene in Mexicans with early-onset Pompe disease.

Glycogen-storage disease type II, also named Pompe disease, is caused by the deficiency of the enzyme acid alpha-glucosidase, which originates lysosomal glycogen accumulation leading to progressive neuromuscular damage. Early-onset Pompe disease shows a debilitating and frequently fulminating course. To date, more than 300 mutations have been described; the majority of them are unique to each affected individual. Most early-onset phenotypes are associated with frameshift mutations leading to a truncated alpha-glucosidase protein with loss of function. Founder effects are responsible from many cases from few highprevalence world regions. Herein we described two apparently unrelated cases affected with classical early-onset Pompe disease, both pertaining to a small region from Central Mexico (the State of San Luis Potosí), the same novel homozygous frameshift mutation at gene GAA (c.1987delC) was demonstrated in both cases. This GAA gene deletion implies a change of glutamine to serine at codon 663, and a new reading frame that ends after 33 base pairs, which leads to the translation of a truncated protein. This report contributes to widen the knowledge on the effect of pathogenic mutations in Pompe disease. Here we postulate the existence of a founder effect.

Reversal of cardiac dysfunction after enzyme replacement in patients with infantile-onset Pompe disease.

OBJECTIVE: To compare the effects of enzyme replacement therapy (ERT) on cardiac performance in symptomatic and symptom-free infants with Pompe disease. STUDY DESIGN: Patients diagnosed between 1983 and 2008 were identified. Before the initiation of ERT, systolic dysfunction appeared only in patients > or = 5 months; thus we used this cut-point in age to divide clinically symptomatic patients into early and late treatment groups (Clin-E and Clin-L). Newborn screening (NBS) identified symptom-free patients. RESULTS: Among a total of 40 patients, 14 received ERT: 5 in the Clin-L, 4 in the Clin-E, and 5 in the NBS groups. All patients showed cardiomegaly, hypertrophic myocardium, and elevated B-type natriuretic peptide (measured in the Clin-E and NBS groups). ERT improved the survival and outcomes. Regressed myocardial hypertrophy and lowered B-type natriuretic peptide level occurred after 1 to 6 months of ERT. Nonetheless, there were 2 deaths and 2 survivors requiring ventilator support in the Clin-L group. Despite the regressed QRS voltage and shortened QT dispersion, life-threatening arrhythmias were still observed in 3, but none in the NBS group. CONCLUSION: ERT may restore the cardiac function in both symptomatic and symptom-free patients, but the beneficial effect may be unpredictable if given after the age of 5 months.

[Respiratory aspects of Pompe disease: case report]. / Aspectos respiratórios da doença de Pompe: relato de caso.

We report the case of a 38 years-old female patient with Pompe disease, diagnosed eight years ago. Respiratory complaints appeared five years ago progressing to chronic respiratory failure. Nocturnal CPAP (continuous positive airway pressure) was prescribed last year, presenting progressive clinical worsening. She was referred to Hospital Universitário de Brasília, on account of respiratory failure and cor pulmonale. Thus, she began non-invasive ventilation (NIV) with bi-level positive airways pressure, and a polysomnography showed the need of spontaneous/timed mode associated with adjustments in breathing pressures to improve ventilation during sleep. There was significant clinical improvement after NIV support was established.

Chinese hamster ovary cell-derived recombinant human acid alpha-glucosidase in infantile-onset Pompe disease.

OBJECTIVE: To conduct an open-label, multinational, multicenter study examining the safety and efficacy of recombinant human acid alpha-glucosidase (rhGAA) in treatment of infantile-onset Pompe disease. STUDY DESIGN: We enrolled 8 infant patients who had Pompe disease with GAA activity <1% of normal, cardiomyopathy, and hypotonia. In the 52-week initial phase, rhGAA was infused intravenously at 10 mg/kg weekly; an extension phase continued survivors' treatment with 10 to 20 mg/kg of rhGAA weekly or 20 mg/kg every 2 weeks for as long as 153 weeks. Safety measurements included adverse events, laboratory tests, and anti-rhGAA antibody titers. Efficacy evaluations included survival, ventilator use, echocardiograms, growth, and motor and cognitive function. RESULT: After 52 weeks of treatment, 6 of 8 patients were alive, and 5 patients were free of invasive ventilator support. Clinical improvements included ameliorated cardiomyopathy and improved growth and cognition. Five patients acquired new motor milestones; 3 patients walked independently. Four patients died after the initial study phase; the median age at death or treatment withdrawal for all patients was 21.7 months, significantly later than expected for patients who were not treated. Treatment was safe and well tolerated; no death was drug-related. CONCLUSION: rhGAA improved ventilator-free survival, cardiomyopathy, growth, and motor function in patients with infantile-onset Pompe disease compared with outcomes expected for patients without treatment.

A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease.

OBJECTIVE: To characterize the natural progression of infantile-onset Pompe disease. STUDY DESIGN: Retrospective chart reviews of 168 patients with documented acid alpha-glucosidase deficiency and symptom onset by 12 months of age; Kaplan-Meier analysis of total and ventilator-free survival time; Cox proportional hazards regression modeling of mortality risk factors. RESULTS: The median age at symptom onset was 2.0 months (range 0 to 12 months), 4.7 months at diagnosis (range: prenatal to 4.2 months), 5.9 months at first ventilator support (range 0.1 to 31.1 months), and 8.7 months at death (range 0.3 to 73.4 months). Survival rates at 12 months of age were 25.7% overall and 16.9% ventilator-free; at 18 months 12.3% and 6.7%. Cardiomegaly (92%), hypotonia (88%), cardiomyopathy (88%), respiratory distress (78%), muscle weakness (63%), feeding difficulties (57%), and failure to thrive (53%) appeared after a median age of approximately 4.0 months. Multiple covariate analysis confirmed that early symptom onset increased risk of early death. CONCLUSION: Despite frequent therapeutic interventions, infantile-onset Pompe disease remains lethal.

Glicogenose tipo II / Glycogenosis type II

Objetivo: A Glicogenose tipo II ou Doença de Pompe é uma doença de armazenamento do glicogênio causada por deficiência enzimática. Pode manifestar-se em lactantes com hipotonia, cardiomegalia e hepatomegalia. As enzimas musculares estão elevadas, o ECG mostra intervalo PR curto, a radiografia de tórax apresenta cardiomegalia importante e a ecocardiografia mostra hipertrofia miocárdica. Firma-se diagnóstico através de análise histopatológica em biópsia de músculo estriado. Material e método: Os autores descrevem um caso de Glicogenose tipo II(Doença de Pompe) que cursou com insuficiência respiratória secundária a insuficiência cardíaca severa e discutem o diagnóstico, a terapêutica e a orientação a família utilizadas nesta doença potencialmente fatal. Conclusões: A Glicogenose tipo II, apesar de rara, dever ser considerada no diagnóstico diferencial nos quadros de insuficiência cardíaca relacionados a miocardiopatia, nos primeiros meses de vida

Identification of two subtypes of infantile acid maltase deficiency.

Infantile patients with acid maltase deficiency have severe hypertrophic cardiomyopathy, left ventricular outflow obstruction, and generalized muscle weakness and die before 1 year of age. We identified 12 infants with acid maltase deficiency who had a similar clinical presentation but less severe cardiomyopathy and absence of left ventricular outflow obstruction, and 9 of 12 had longer survival with assisted ventilation and supplemental intubation.

Diagnóstico clínico-bioquímico de la enfermedad de Pompe

La enfermedad de Pompe es una de las glicogenosis o enferemdad de depósito del glucógeno, que se transmite con carácter autosómico recesivo y es producida por la deficiencia de la enzima maltasa ácida que degrada glicógeno en los lisosomas. Se dintinguen tres tipos de enferemdad de Pompe : el tipo infantil que se acracteriza por la acumulación de glicógeno en el hígado, músculo esquelético y cardíaco y células del sistema nervioso central; los pacientes fallecen usaulamente antes de los dos años por falla cardiorespiratoria; el fenotipo juvenil se presenta en niños o jóvenes, no siempre involucra el sistema nervioso central o el músculo cardíaco y los pacientes fallecen generalmente durante la segunda década de vida; el tipo adulto cursa con distrofia muscular, algunas veces asociada con deficiencia respiratoria por compromiso de los músculos diagragma e intercostales. El pronóstico depende del grado de la falla respiratoria, la cual es causa principal de la muerte de estos pacientes. En este trabajo se informa el caso de un niño de seis meses de edad, afectado por cardiomegalia, retardo psicomotor e hipotonía. La confirmación bioquímica de la enfermedad se hizo determinando la actividad de la alfa-glucosidasa en leucocitos por dos métodos diferentes, usando como sustrato maltasa o el sustrato fluorescente 4-metil-umbeliferil-glucósido. La actividad de la maltasa ácida en leucocitos, usando maltosa como sustrato fue de 6,36Umol glucosa/min/g, con un valor de referencia entre 16-63 Umoles/glucosa/min/g de proteína. Con el sustrato fluorogénico, la activida en el paciente fue de 34.48 nanomoles/h/mg, de proteína, para un valor de referencia entre 194 y 258. La actividad en leucocitos tanto del padre como de la madre corresponde a un 60 por ciento del valor normal, hallado en personas en cuya familia no se sospecha dicha enfermedad.