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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.
Bibliografía del artículo
1. Fink JK. The hereditary spastic paraplegias: nine genes and counting. Arch Neurol 2003; 60(8):1045-1049.
2. Reid E. Science in motion: common molecular pathological themes emerge in the hereditary spastic paraplegias. J Med Genet 2003; 40(2):81-86.
3. Al-Yahyaee S, Al-Gazali LI, De Jonghe P, et al. A novel locus for hereditary spastic paraplegia with thin corpus callosum and epilepsy. Neurology 2006; 66(8):1230-1234.
4. Hazan J, Fonknechten N, Mavel D, et al. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet 1999; 23(3):296-303.
5. Zhao X, Alvarado D, Rainier S, et al. Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat Genet 2001; 29(3):326-331.
6. Rainier S, Chai JH, Tokarz D, Nicholls RD, Fink JK. NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am J Hum Genet 2003; 73(4):967-971.
7. Reid E, Kloos M, Ashley-Koch A, et al. A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am J Hum Genet 2002; 71(5):1189-1194.
8. Hansen JJ, Durr A, Cournu-Rebeix I, et al. Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. Am J Hum Genet 2002; 70(5):1328-1332.
9. Van de Warrenburg BP, Scheffer H, Van Eijk JJ, et al. BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy. Neuromuscul Disord 2006; 16(2):122-125.
10. Magre J, Delepine M, Khallouf E, et al. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 2001; 28(4):365-370.
11. Zuchner S, Wang G, Tran-Viet KN, et al. Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet 2006; 79(2):365-9.
12. Mannan AU, Krawen P, Sauter SM, et al. ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia. Am J Hum Genet 2006; 79(2):351-357.
13. Meijer IA, Hand CK, Cossette P, Figlewicz DA, Rouleau GA. Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia. Arch Neurol 2002; 59(2):281-286.
14. Orlacchio A, Gaudiello F, Totaro A, et al. A new SPG4 mutation in a variant form of spastic paraplegia with congenital arachnoid cysts. Neurology 2004; 62(10):1875-1878.
15. Orlacchio A, Kawarai T, Gaudiello F, et al. Clinical and genetic study of a large SPG4 Italian family. Mov Disord 2005; 20(8):1055-1059.
16. Higgins JJ, Loveless JM, Goswami S, et al. An atypical intronic deletion widens the spectrum of mutations in hereditary spastic paraplegia. Neurology 2001; 56(11):1482-1485.
17. Starling A, Rocco P, Passos-Bueno MR, Hazan J, Marie SK, Zatz M. Autosomal dominant (AD) pure spastic paraplegia (HSP) linked to locus SPG4 affects almost exclusively males in a large pedigree. J Med Genet 2002; 39(12):e77.
18. Orlacchio A, Kawarai T, Totaro A, et al. Hereditary spastic paraplegia: clinical genetic study of 15 families. Arch Neurol 2004; 61(6):849-55.
19. Charvin D, Cifuentes-Diaz C, Fonknechten N, et al. Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus. Hum Mol Genet 2003; 12(1):71-78.
20. Errico A, Ballabio A, Rugarli EI. Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Hum Mol Genet 2002; 11(2):153-163.
21. Tallaksen CM, Guichart-Gomez E, Verpillat P, et al. Subtle cognitive impairment but no dementia in patients with spastin mutations. Arch Neurol 2003; 60(8):1113-1118.
22. McMonagle P, Byrne P, Hutchinson M. Further evidence of dementia in SPG4-linked autosomal dominant hereditary spastic paraplegia. Neurology 2004; 62(3):407-410.
23. Winner B, Uyanik G, Gross C, et al. Clinical progression and genetic analysis in hereditary spastic paraplegia with thin corpus callosum in spastic gait gene 11 (SPG11). Arch Neurol 2004; 61(1):117-121.
24. Orlacchio A, Kawarai T, Gaudiello F, St George-Hyslop PH, Floris R, Bernardi G. New locus for hereditary spastic paraplegia maps to chromosome 1p31.1-1p21.1. Ann Neurol 2005; 58(3):423-429.
25. Stevanin G, Durr A, Brice A. Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology. Eur J Hum Genet 2000; 8(1):4-18.
26. Orlacchio A, Kawarai T, Rogaeva E, et al. Clinical and genetic study of a large Italian family linked to SPG12 locus. Neurology 2002; 59(9):1395-1401.
27. Reid E, Dearlove AM, Osborn O, Rogers MT, Rubinsztein DC. A locus for autosomal dominant "pure" hereditary spastic paraplegia maps to chromosome 19q13. Am J Hum Genet 2000; 66(2):728-732.
28. Ashley-Koch A, Bonner ER, Gaskell PC, et al. Fine mapping and genetic heterogeneity in the pure form of autosomal dominant familial spastic paraplegia. Neurogenetics 2001; 3(2):91-97.
29. Kaneko S, Kawarai T, Yip E, et al. Novel SPG6 mutation p.A100T in a Japanese family with autosomal dominant form of hereditary spastic paraplegia. Mov Disord 2006
30. Reed JA, Wilkinson PA, Patel H, et al. A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia. Neurogenetics 2005; 6(2):79-84.
31. Chen S, Song C, Guo H, et al. Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families. Hum Mutat 2005; 25(2):135-141.
32. Munhoz RP, Kawarai T, Teive HA, et al. Clinical and genetic study of a Brazilian family with spastic paraplegia (SPG6 locus). Mov Disord 2006; 21(2):279-281.
33. Matsui M, Kawarai T, Hase Y, et al. Novel mutation in SPG3A gene (atlastin) in hereditary spastic paraplegia. Journal of Neurology 2006.
34. Durr A, Camuzat A, Colin E, et al. Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia. Arch Neurol 2004; 61(12):1867-1872.
35. Sauter S, Miterski B, Klimpe S, et al. Mutation analysis of the spastin gene (SPG4) in patients in Germany with autosomal dominant hereditary spastic paraplegia. Hum Mutat 2002; 20(2):127-132.
36. Hentati A, Deng HX, Zhai H, et al. Novel mutations in spastin gene and absence of correlation with age at onset of symptoms. Neurology 2000; 55(9):1388-1390.
37. Proukakis C, Auer-Grumbach M, Wagner K, et al. Screening of patients with hereditary spastic paraplegia reveals seven novel mutations in the SPG4 (Spastin) gene. Hum Mutat 2003; 21(2):170.
38. Fonknechten N, Mavel D, Byrne P, et al. Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Hum Mol Genet 2000; 9(4):637-644.
39. Magariello A, Muglia M, Patitucci A, et al. Novel spastin (SPG4) mutations in Italian patients with hereditary spastic paraplegia. Neuromuscul Disord 2006; 16(6):387-390.
40. Sauter SM, Engel W, Neumann LM, Kunze J, Neesen J. Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus. Hum Mutat 2004; 23(1):98.
41. Namekawa M, Ribai P, Nelson I, et al. SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years. Neurology 2006; 66(1):112-114.
42. St George-Hyslop PH, Petit A. Molecular biology and genetics of Alzheimer's disease. C R Biol 2005; 328(2):119-130.
43. Pallanck L, Greenamyre JT. Neurodegenerative disease: pink, parkin and the brain. Nature 2006; 441(7097):1058.
44. Majoor-Krakauer D, Willems PJ, Hofman A. Genetic epidemiology of amyotrophic lateral sclerosis. Clin Genet 2003; 63(2):83-101.
45. Rogaeva E, Bergeron C, Sato C, et al. PS1 Alzheimer's disease family with spastic paraplegia: the search for a gene modifier. Neurology 2003; 61(7):1005-1007.
46. Panzeri C, De Palma C, Martinuzzi A, et al. The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function. Brain 2006; 129(Pt 7):1710-1719.
47. Devon RS, Helm JR, Rouleau GA, et al. The first nonsense mutation in alsin results in a homogeneous phenotype of infantile-onset ascending spastic paralysis with bulbar involvement in two siblings. Clin Genet 2003; 64(3):210-215.
48. Lesca G, Eymard-Pierre E, Santorelli FM, et al. Infantile ascending hereditary spastic paralysis (IAHSP): clinical features in 11 families. Neurology 2003; 60(4):674-682.
49. Eymard-Pierre E, Lesca G, Dollet S, et al. Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am J Hum Genet 2002; 71(3):518-527.
 
 
 
 
 
 
 
 
 
 
 
 
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