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DESCRIBEN NUEVAS MUTACIONES EN FAMILIAS CON PARAPLEJIA ESPASTICA HEREDITARIA

(especial para SIIC © Derechos reservados)
Se realizó un estudio clínico y genético en familias con paraplejía espástica hereditaria autosómica dominante (PEHAD) e identificamos tres nuevas mutaciones en SPG4, una mutación no descrita en SPG6 y otra en SPG3A. Además, definimos un nuevo locus para la PEHAD en el cromosoma 1p31.1-21.1 y limitamos el locus SPG12 en el cromosoma 19q13.
orlacchio9.jpg Autor:
Antonio Orlacchio
Columnista Experto de SIIC

Institución:
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia

Artículos publicados por Antonio Orlacchio
Coautores
Clarice Patrono* Aldo Orlacchio** Peter H St George-Hyslop*** Giorgio Bernardi**** Toshitaka Kawarai***** 
BSc (Hons), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, Roma, Italia*
PhD, Università di Perugia, Perugia, Italia**
MD (Board-certified specialist in Neurol, University of Toronto, Toronto, Canadá***
MD (Board-certified specialist in Neurol, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, Roma, Italia****
MD (Board-certified specialist in Neurol, Hyogo Brain and Heart Center, Himeji, Japón*****
Recepción del artículo
5 de Septiembre, 2006 		Aprobación
13 de Septiembre, 2006
Primera edición
15 de Diciembre, 2006 		Segunda edición, ampliada y corregida
7 de Junio, 2021

DESCRIBEN NUEVAS MUTACIONES EN FAMILIAS CON PARAPLEJIA ESPASTICA HEREDITARIA

Resumen
Las paraplejías espásticas hereditarias (PEH) son un grupo extenso de trastornos genéticamente heterogéneos, caracterizados clínicamente por alteración de la marcha debida a espasticidad y debilidad de los miembros inferiores. Varias investigaciones neuropatológicas revelaron degeneración axonal a nivel de la porción caudal de las vías corticoespinales y de las columnas posteriores. Algunos estudios genéticos recientes localizaron 33 loci vinculados con la PEH y revelaron 13 genes responsables. Las investigaciones genéticas previas demostraron que la forma de paraplejía espástica hereditaria autosómica dominante (PEHAD) más frecuente corresponde a SPG4 y la existencia de variación fenotípica en pacientes que presentan la misma mutación. Actualizamos un trabajo clínico y genético en 59 familias con PEHAD, sin parentesco, originarias de Europa, Norteamérica, Sudamérica y Japón. Los análisis de secuencia y ligamiento confirmaron que SPG4 era la causa más habitual de PEHAD en nuestros casos. Si se considera la naturaleza de las mutaciones en SPG4, la haploinsuficiencia podría resultar en degeneración del tracto corticoespinal. Además, revelamos nuevas mutaciones en SPG3A y SPG6 en pacientes japoneses, lo que indicó mayor heterogeneidad alélica y distribución mundial de los enfermos con PEH asociada a SPG3A y SPG6. No se hallaron mutaciones en ningún otro gen actualmente conocido, vinculado con la PEHAD. Nuestro estudio genético demostró la asociación de un amplio árbol genealógico de origen escocés con un nuevo locus (SPG29), cuyos integrantes presentaban una forma complicada de PEHAD con características clínicas específicas, que incluían alteración de la audición, pie cavo y hernia hiatal. Finalmente, se identificó el vínculo de una familia italiana con una variante pura de PEHAD con SPG12, y el mapeo preciso de dicha familia, junto con un estudio genético previo, restringieron más ese locus a una región de 3.3 cM.

Palabras clave
paraplejía espástica hereditaria, espastina, análisis de secuencia, estudios de ligamiento


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CLINICAL AND GENETIC STUDIES IN HEREDITARY SPASTIC PARAPLEGIA

Abstract
Hereditary spastic paraplegias (HSPs) are a large group of genetically heterogeneous disorders clinically characterized by gait disturbance due to spasticity and weakness of lower limbs. Neuropathological investigations have revealed axonal degeneration involving the caudal ends of the corticospinal tracts and posterior columns. Recent genetic studies have shown 33 loci for HSP and revealed 13 causative genes. Previous genetic studies demonstrated that the most frequent form is SPG4 in autosomal dominant HSP (ADHSP) and phenotypic variations in patients sharing the same mutation. We have updated a clinical and genetic study of 59 unrelated families with ADHSP originating from Europe, North America, South America and Japan. Linkage and sequence analyses confirmed that SPG4 was the most frequent cause in our ADHSP cases. Considering the nature of mutations in SPG4, haploinsufficiency might lead to neurodegeneration of the corticospinal tract. We revealed novel mutations in SPG3A and SPG6 in Japanese patients showing further allelic heterogeneity and world-wide distribution of SPG3A- and SPG6-HSP patients. No mutation was found in other currently known ADHSP genes. Our genetic study demonstrated one large Scottish pedigree linked to a novel ADHSP locus (SPG29), in which patients were affected by a complicated form of ADHSP with peculiar clinical features, including hearing impairment, pes cavus, and hiatal hernia. Finally, one Italian family with a pure form of ADHSP was identified to link to SPG12 and fine mapping of the family and a previous genetic study further narrow the locus to a 3.3 cM region.

Key words
hereditary spastic paraplegia, spastin, sequence analyses, linkage studies


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Especialidades
Principal: Genética Humana
Relacionadas: Bioquímica, Diagnóstico por Laboratorio, Neurología



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Enviar correspondencia a:
Antonio Orlacchio, Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC) - Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, 00143, 64 Via del Fosso di Fiorano, Roma, Italia
Patrocinio y reconocimiento:
A Hilary Giles (MA) por sus consejos y ayuda con el lenguaje y a los miembros de nuestro laboratorio por las estimulantes discusiones y los útiles comentarios acerca de este escrito. Becas PS04.2O y RF04.125O del Ministerio de Salud de Italia, y beca COFIN04.125O de la Fundación Lundbeck.
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