A Nonsense Mutation in the Acid α-Glucosidase Gene Causes Pompe Disease in Finnish and Swedish Lapphunds

Seppälä, Eija H.; Reuser, Arnold; Lohi, Hannes

doi:10.1371/journal.pone.0056825

Cited by 28 publications

(19 citation statements)

References 22 publications

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“…Se han encontrado numerosos cambios en la secuencia, de los cuales 75% son patógenos, lo cual puede afectar el mecanismo de corte y empalme de los exones, la estabilidad del ARN mensajero y biosíntesis de la proteína ocasionando que la enzima no actue. Deseamos resaltar que en el caso del paciente estudiado, se ha encontrado una variante que no ha sido reportada en la literatura, por sus características de homocigocidad (8). Este diagnóstico molecular puede tener dificultades en la interpretación.…”

Section: Discussionunclassified

Enfermedad de Pompe: reporte de caso

Arias

Gómez

Fernández

et al. 2016

nova

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ResumenObjetivo. Se describe el caso de un paciente masculino de siete meses de edad, evaluado por cardiología a los quince días de vida por antecedente de muerte súbita cardíaca de hermana a los cuatro meses, no se sospechó nada pese a consanguinidad de padres y diagnóstico temprano del paciente de cardiomiopatía. Evoluciona con un cuadro clínico de infecciones respiratorias a repetición desde los tres meses (bronquiolitis recurrente), falla de medro y cuadro de neumonía reciente y fallece a los ocho días de la consulta con la genetista. Métodos. El abordaje inicial fue la realización de un ecocardiograma a los quince días de nacido por antecedente de muerte súbita de hermana a los cuatro meses por cardiomegalia y consanguinidad de los padres. Continúa con deterioro clínico a través de los meses por lo que se remite a genética, se toman pruebas enzimáticas en gota de sangre seca, el paciente fallece antes de recibir el diagnóstico de Enfermedad de Pompe. Resultados. Se enfocó al paciente con un posible diagnóstico de Enfermedad de Pompe solicitándose enzima lisosomal alfaglucosidasa (GAA) en muestra de gota de sangre seca y reporte final de la secuenciación genética.Palabras Clave: Enfermedad de Pompe, GAA (α-1,4 glucosidasa lisosomal (maltasa ácida), consanguinidad, cardiomiopatía, hipotonía. AbstractObjective. It is a case of a seven months male patient, evaluated by cardiology fifteen days after he was born secondary, to sudden cardiac death of his sister of four months, nothing suspicious despite consanguinity of parents and early diagnosis of the patient with Cardiomyopathy. Evolved with the following clinical conditions recurrent respiratory infections from three months (recurrent bronchiolitis), widespread malnutrition and recent pneumonia. Died eight days after the consultation with the geneticist. Methods. The initial approach was to perform echocardiogram at fifteen days old, because of history of the sudden death of his sister of four months, cardiomegaly and parental consanguinity. Clinical deterioration continues through months so he is referred to genetic, enzymatic tests, taken in dried blood, the patient dies before receiving the diagnosis of Pompe disease. Results. The patient was focused with a possible diagnosis of Pompe Disease so lysosomal enzyme α -glucosidase (GAA) sample was requested in dried blood and genetic sequencing final report to define diagnosis.

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Section: Discussionunclassified

Enfermedad de Pompe: reporte de caso

Arias

Gómez

Fernández

et al. 2016

nova

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“…The underlying genetic defects have been identified in Brahman and Shorthorn cattle breeds in Australia, in quails (AMD quails), and Finnish and Swedish Lapphunds. Curiously, the two Scandinavian dog breeds, which share a common origin and physical appearance, have been recently shown (Seppala et al, 2013) to contain a frameshift mutation similar to that found in patients with the infantile form of the disease (the finding points to a "hot spot" in the GAA gene). The presence of residual GAA activity in quails (due to the expression of other alpha-glucosidases) accounts for the milder form of the disease, which mimics human childhood or adult forms without cardiac dysfunction; the birds show progressive muscle weakness, difficulty in lifting their wings or turning from the supine position.…”

Section: Models Of Pompe Diseasementioning

confidence: 90%

Pompe disease: From pathophysiology to therapy and back again

Raben

2016

Molecular Genetics and Metabolism

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“…Glycogen accumulations consisting of membrane bound vacuoles were present in the heart, skeletal, and smooth muscle. The genetic basis was a c.2237G>A change corresponding to the nonsense mutation p.W746* in the acid α-glucosidase gene [7]. …”

Section: Potential For Clinical Development Of Gene Therapy In Pompe mentioning

confidence: 99%

Preclinical Development of New Therapy for Glycogen Storage Diseases

Sun¹,

Brooks²,

Koeberl

2015

CGT

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Glycogen storage disease (GSD) consists of more than 10 discrete conditions for which the biochemical and genetic bases have been determined, and new therapies have been under development for several of these conditions. Gene therapy research has generated proof-of-concept for GSD types I (von Gierke disease) and II (Pompe disease). Key features of these gene therapy strategies include the choice of vector and regulatory cassette, and recently adeno-associated virus (AAV) vectors containing tissue-specific promoters have achieved a high degree of efficacy. Efficacy of gene therapy for Pompe disease depend upon the induction of immune tolerance to the therapeutic enzyme. Efficacy of von Gierke disease is transient, waning gradually over the months following vector administration. Small molecule therapies have been evaluated with the goal of improving standard of care therapy or ameliorating the cellular abnormalities associated with specific GSDs. The receptor-mediated uptake of the therapeutic enzyme in Pompe disease was enhanced by administration of β2 agonists. Rapamycin reduced the liver fibrosis observed in GSD III. Further development of gene therapy could provide curative therapy for patients with GSD, if efficacy from preclinical research is observed in future clinical trials and these treatments become clinically available.

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A Nonsense Mutation in the Acid α-Glucosidase Gene Causes Pompe Disease in Finnish and Swedish Lapphunds

Cited by 28 publications

References 22 publications

Enfermedad de Pompe: reporte de caso

Enfermedad de Pompe: reporte de caso

Pompe disease: From pathophysiology to therapy and back again

Preclinical Development of New Therapy for Glycogen Storage Diseases

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