Hereditary lissencephaly and cerebellar hypoplasia in Churra lambs

BMC Veterinary Research

Juan José Arranz²  M Carmen Ferreras¹  Laetitia Delgado¹  Julio Benavides¹  Miguel Fuertes¹  Aroa Suárez-Vega²  Valentín Pérez¹ 

[1] Departamento de Sanidad Animal (Anatomía Patológica), Instituto de Ganadería de Montaña (CSIC-ULE), Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, León 24071, Spain;Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, León 24071, Spain

关键词: Autosomal recessive;    Sheep;    Agyria-pachygyria;    Cerebellar hypoplasia;    Lissencephaly;   

Others  :  1119482
DOI  :  10.1186/1746-6148-9-156

 received in 2012-12-18, accepted in 2013-08-08,  发布年份 2013

【 摘 要 】

Background

Lissencephaly is a rare developmental brain disorder in veterinary and human medicine associated with defects in neuronal migration leading to a characteristic marked reduction or absence of the convolutional pattern of the cerebral hemispheres. In many human cases the disease has a genetic basis. In sheep, brain malformations, mainly cerebellar hypoplasia and forms of hydrocephalus, are frequently due to in utero viral infections. Although breed-related malformations of the brain have been described in sheep, breed-related lissencephaly has not been previously recorded in a peer reviewed publication.

Results

Here we report neuropathological findings in 42 newborn lambs from a pure Churra breed flock, with clinical signs of weakness, inability to walk, difficulty in sucking and muscular rigidity observed immediately after birth. All the lambs showed near-total agyria with only a rudimentary formation of few sulci and gyri, and a severe cerebellar hypoplasia. On coronal section, the cerebral grey matter was markedly thicker than that of age-matched unaffected lambs and the ventricular system was moderately dilated. Histologically, the normal layers of the cerebral cortex were disorganized and, using an immunohistochemical technique against neurofilaments, three layers were identified instead of the six present in normal brains. The hippocampus was also markedly disorganised and the number and size of lobules were reduced in the cerebellum. Heterotopic neurons were present in different areas of the white matter. The remainder of the brain structures appeared normal. The pathological features reported are consistent with the type LCH-b (lissencephaly with cerebellar hypoplasia group b) defined in human medicine. No involvement of pestivirus or bluetongue virus was detected by immunohistochemistry. An analysis of pedigree data was consistent with a monogenic autosomal recessive pattern inheritance.

Conclusions

The study describes the clinical and pathological findings of lissencephaly with cerebellar hypoplasia in Churra lambs for which an autosomal recessive inheritance was the most likely cause. Histopathological features observed in the cerebral cortex and hippocampus are consistent with a possible failure in neuronal migration during brain development. This report suggests that lissencephaly should be considered in the differential diagnosis of congenital neurological disease in newborn lambs showing weakness, inability to walk and difficulty sucking.

【 授权许可】

   
2013 Pérez et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Ross ME, Walsh CA: Human brain malformations and their lessons for neuronal migration. Annu Rev Neurosci 2001, 24:1041-1470.
• [2]Guerrini R, Parrini E: Neuronal migration disorders. Neurobiol Dis 2010, 38:154-166.
• [3]Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB: A developmental and genetic classification for malformations of cortical development: update 2012. Brain 2012, 135:1348-1369.
• [4]Norman MG, Ludwin SK: Congenital malformations of the nervous system. In Textbook of Neuropathology. 3r edition. Edited by Davis RL, Robertson DM. Baltimore: Williams and Wilkins; 1997:265-330.
• [5]Walsh CA: Genetic malformations of the human cerebral cortex. Neuron 1999, 23:19-29.
• [6]Pilz DT, Stoodley N, Golden JA: Neuronal migration, cerebral cortical development and cerebral cortical anomalies. J Neuropathol Exp Neurol 2002, 61:1-11.
• [7]Pilz DT, Quarrell WJ: Syndromes with lissencephaly. J Med Genet 1996, 33:319-323.
• [8]Kuchelmeister K, Bergmann M, Gullotta F: Neuropathology of lissencephalies. Childs Nerv Syst 1993, 9:394-399.
• [9]Kroon AA, Smit BJ, Barth PG, Hennekam RS: Lissencephaly with extreme cerebral and cerebellar hypoplasia. A magnetic resonance imaging study. Neuropediatrics 1996, 27:273-276.
• [10]Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, Martin NDT, Walsh CA: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 2000, 26:93-96.
• [11]Ross ME, Swanson K, Dobyns WB: Lissencephaly with cerebellar hypoplasia (LCH): a heterogeneous group of cortical malformations. Neuropediatrics 2001, 32:256-263.
• [12]Gleeson JG, Walsh CA: Neuronal migration disorders: from genetic diseases to developmental mechanisms. TINS 2000, 23:352-359.
• [13]Reiner O, Albrecht U, Gordon M, Chianese KA, Wong C, Gal-Gerber O, Sapir T, Siracusa LD, Buchberg AM, Caskey CT, Eichele G: Lissencephaly gene (LIS1) expression in the CNS suggest a role in neuronal migration. J Neurosci 1995, 15:3730-3738.
• [14]Gleeson JG, Allen KM, Fox JW, Lamperti ED, Berkovic S, Scheffer I, Cooper EC, Dobyns WB, Minnerath SR, Ross ME, Walsh CA: Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 1998, 92:63-72.
• [15]Fallet-Bianco C, Loeuillet L, Poirier K, Loget P, Chapon F, Pasquier L, Saillour Y, Beldjord C, Chelly J, Francis F: Neuropathological phenotype of a distinct form of lissencephaly associated with mutations in TUBAIA. Brain 2008, 131:2304-2320.
• [16]Zaki FA: Lissencephaly in Lhasa Apso dogs. J Am Vet Med Assoc 1976, 169:1165-1168.
• [17]Greene CE, Vandevelde M, Braund K: Lissencephaly in two Lhasa Apso dogs. J Am Vet Med Assoc 1976, 169:405-410.
• [18]Summers BA, Cummings JF, de Lahunta A: Malformations of the central nervous system. In Veterinary Neuropathology. Edited by Summers BA, Cummings JF, de Lahunta A. St Louis: Mosby; 1995:68-94.
• [19]Herrmann A, Hecht W, Herden C: Lissencephaly and microencephaly combined with hypoplasia or corpus callosum and cerebellum in a domestic cat. Tierarztl Prax Ausg K Kleintiere Heimtiere 2011, 39:116-120.
• [20]Nettleton PF, Willoughby K: Border disease. In Diseases of Sheep. 4th edition. Edited by Aitken ID. Oxford: Blackwell; 2007:119-126.
• [21]Edwards JF, Livingston CW, Chung SI, Collisson EC: Ovine arthrogryposis and central nervous system malformations associated with in utero Cache Valley virus infection: spontaneous disease. Vet Pathol 1989, 26:33-39.
• [22]Herder V, Wohlsein P, Peters M, Hansmann F, Baumgärtner W: Salient lesions in domestic ruminants infected with the emerging so-called Schmallenberg virus in Germany. Vet Pathol 2012, 49:588-591.
• [23]Bennett RL, French KS, Resta RG, Doyle DL: Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. J Genet Couns 2008, 17:424-433.
• [24]Kirkland PD: Akabane disease. In Diseases of Sheep. 4th edition. Edited by Aitken ID. Oxford: Blackwell; 2007:473-479.
• [25]Maclachlan NJ, Drew CP, Darpel KE, Worwa G: The pathology and pathogenesis of bluetongue. J Comp Pathol 2009, 141:1-16.
• [26]Plant JW, Walker KH, Acland HM, Gard GP: Pathology in the ovine foetus caused by an ovine pestivirus. Aus Vet J 1983, 60:137-140.
• [27]García Marín JF, Pérez V, Gutiérrez MM, Corpa JM, Gómez N, Escudero A, del Río E: Lissencephaly and cerebellar hypoplasia in lambs. In Proceedings of the 15th Meeting of the European Society of Veterinary Pathology. Edited by Universitá degli Studi di Sassari. Italy: Sassari-Alghero; 1997:132.
• [28]Kerner B, Graham JM, Golden JA, Pepkowitz SH, Dobyns WB: Familial lissencephaly with cleft palate and severe cerebellar hypoplasia. Am J Med Genet 1999, 87:40-445.
• [29]Miyata H, Chute DUJ, Fink J, Villablanca P, Vinters HV: Lissencephaly with agenesis of corpus callosum and rudimentary dysplastic cerebellum: a subtype of lissencephaly with cerebellar hypoplasia. Acta Neuropathol 2004, 107:69-81.
• [30]D’Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JL, Curran T: A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 1995, 374:719-723.
• [31]Tissir F, Goffinet AM: Reelin and brain development. Nat Rev Neurosci 2003, 4:496-505.
• [32]González JL, Russo CJ, Goldowitz D, Sweet HO, Davisson MT, Walsh CA: Birthdate and cell marker analysis of scrambler: a novel mutation affecting cortical development with a reeler-like phenotype. J Neurosci 1997, 17:9204-9211.
• [33]Howell BW, Hawkes R, Soriano P, Cooper JA: Neuronal position in the developing brain is regulated by mouse disabled-1. Nature 1997, 389:733-737.
• [34]Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J, Hammer RE, Richardson JA, Herz J: Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 1999, 97:689-701.
• [35]Ayala R, Shu T, Tsai LH: Trekking across the brain: the journey of neuronal migration. Cell 2007, 128:29-43.
• [36]Lecourtois M, Poirier K, Friocourt G, Jaglin X, Goldenberg A, Saugier-Veber P, Chelly J, Laquerriêre A: Human lissencephaly with cerebellar hypoplasia due to mutations in TUBA1A: expansion of the foetal neuropathological phenotype. Acta Neuropathol 2010, 119:779-789.
• [37]Kumar RA, Pilz DT, Babatz TD, Cushion TD, Harvey K, Topf M, Yates L, Robb S, Uyanik G, Mancini GM, Rees MI, Harvey RJ, Dobyns WB: TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins. Hum Mol Genet 2010, 19:2817-2827.
• [38]Friocourt G, Marcorelles P, Saugier-Veber P, Quille ML, Marret S, Laquerriêre A: Role of cytoskeletal abnormalities in the neuropathology and pathophysioloy of type I lissencephaly. Acta Neuropathol 2011, 121:149-270.
• [39]Rice DS, Curran T: Role of the reelin signaling pathway in central nervous system development. Annu Rev Neurosci 2001, 24:1005-1039.
• [40]Miller SA, Dykes DD, Polesky HF: A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988, 16:1215.
• [41]Glowatzki-Mullis ML, Muntwyler J, Gaillard D: Cost-effective parentage verification with 17-plex PCR for goats and 19-plex PCR for sheep. Anim Genet 2007, 38:86-88.