Características clínicas y evaluación de la expresión proteica de la disferlina en los pacientes con fenotipo clínico de disferlinopatías que presentan las nuevas variantes c.251C>A (p.Ala84Asp) y 4491G>T (p.Lys1497Asn) en el gen DYSF identificadas en familias de Antioquía – Colombia
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Fecha
2023
Autores
Villarreal Pérez, Liliana María
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Ediciones Universidad Simón Bolívar
Facultad de Ciencias Básicas y Biomédicas
Facultad de Ciencias Básicas y Biomédicas
Resumen
En las disferlinopatías, un subgrupo de distrofias musculares, se observa un defecto en la proteína disferlina por mutaciones en el gen DYSF. El diagnóstico se basa en la detección de dos variantes patogénicas en homocigosis o heterocigosis. Se describen las características clínicas y expresión proteica mediante inmunohistoquímica en neutrófilos, en un grupo de pacientes antioqueños con fenotipo clínico de disferlinopatías, con las dos variantes nuevas: c.251C>A p.Ala84Asp) y 4491G>T (p.Lys1497Asn). Se incluyeron 16 pacientes (11 familias), con media de edad de inicio de 25,44 (±11,413), con media de evolución de 20,31 años (±10,855), media de tiempo hasta el diagnóstico de 18,13 años (10,513). Los fenotipos de inicio más frecuentes fueron miopatía de Miyoshi (37.5%) y fenotipo PD (37.5%). El 75% de casos (n:12) aún deambulantes, auque la gran mayoría con algún tipo de ayuda de marcha. Se realizó la determinación de la expresión de disferlina en neutrófilos de extendido de sangre periférica, mediante la cual se encontró disminución o ausencia de la expresión proteica neutrófilos en todos los sujetos evaluados excepto en un caso (en el que previamente se demostró ausencia en biopsia de músculo. Está técnica muestra su utilidad como una prueba de fácil acceso y bajo costo para la evaluación y confirmación de disferlinopatías. Las nuevas variantes estudiadas: c.251C>A p.Ala84Asp) y 4491G>T (p.Lys1497Asn) en el gen DYSF implican cada una un cambio de aminoácidos que conlleva a alteración de las diferentes propiedades físico – químicas de la proteína.
Este estudio representa la primera cohorte de pacientes con disferlinopatías en población colombiana y describe dos nuevas variantes en el gen Dysf.
In dysferlinopathies, a subgroup of muscular dystrophies, a defect in the dysferlin protein is observed by mutations in the DYSF gene. The diagnosis is based on the detection of two pathogenic variants in homozygosis or heterozygosis. Our study describes clinical characteristics, as well as protein expression by immunohistochemistry in neutrophils from patients with clinical dysferlinopathy phenotypes in Antioquia, Colombia, with two new variants: 251C>T (p.Ala84Asp) and 4491G>T (p.Lys1497Asn). We included 16 patients (11 families), with mean age of onset of 25.44 (± 11.413), with mean progression of 20.31 years (± 10.855), mean time to diagnosis of 18.13 years (10.513). The most common initial phenotypes were Miyoshi myopathy (37.5%) and PD phenotype (37.5%). 75% of cases (n: 12) are still with preserved ambulation although most of these require some kind of walking aid. Dysferlin expression was observed in neutrophils of peripheral blood films by enhanced immunohistochemical methods; decreased or absent neutrophil protein expression was found in all of the subjects evaluated except one (which previously showed absence in muscle biopsy). This technique shows usefulness as an easily accessible and inexpensive test for the evaluation and confirmation of dysferlinopathies. The new variants studied in the DYSF gene each involve a change of amino acids that leads to alteration of the different physical - chemical properties of the protein. This study represents the first cohort of patients with dysferlinopathies in the Colombian population and describes two novel variants in the Dysf gene.
In dysferlinopathies, a subgroup of muscular dystrophies, a defect in the dysferlin protein is observed by mutations in the DYSF gene. The diagnosis is based on the detection of two pathogenic variants in homozygosis or heterozygosis. Our study describes clinical characteristics, as well as protein expression by immunohistochemistry in neutrophils from patients with clinical dysferlinopathy phenotypes in Antioquia, Colombia, with two new variants: 251C>T (p.Ala84Asp) and 4491G>T (p.Lys1497Asn). We included 16 patients (11 families), with mean age of onset of 25.44 (± 11.413), with mean progression of 20.31 years (± 10.855), mean time to diagnosis of 18.13 years (10.513). The most common initial phenotypes were Miyoshi myopathy (37.5%) and PD phenotype (37.5%). 75% of cases (n: 12) are still with preserved ambulation although most of these require some kind of walking aid. Dysferlin expression was observed in neutrophils of peripheral blood films by enhanced immunohistochemical methods; decreased or absent neutrophil protein expression was found in all of the subjects evaluated except one (which previously showed absence in muscle biopsy). This technique shows usefulness as an easily accessible and inexpensive test for the evaluation and confirmation of dysferlinopathies. The new variants studied in the DYSF gene each involve a change of amino acids that leads to alteration of the different physical - chemical properties of the protein. This study represents the first cohort of patients with dysferlinopathies in the Colombian population and describes two novel variants in the Dysf gene.
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Palabras clave
Distrofia muscular, Disferlina, Disferlinopatía, LGMD, Miopatía de Miyoshi, Inmunohistoquímica en sangre periférica, Técnica expresión de disferlina, Muscular dystrophy, Dysferlin, Dysferlinopathy, Miyoshi myopathy, Inmunohistochemistry in blood film, Dysferlin expression technique
