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Hereditary lissencephaly and cerebellar hypoplasia in Churra lambs.

Pérez V, Suárez-Vega A, Fuertes M, Benavides J, Delgado L, Ferreras MC, Arranz JJ - BMC Vet. Res. (2013)

Bottom Line: 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.The hippocampus was also markedly disorganised and the number and size of lobules were reduced in the cerebellum.Histopathological features observed in the cerebral cortex and hippocampus are consistent with a possible failure in neuronal migration during brain development.

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Affiliation: 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. vperp@unileon.es

ABSTRACT

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.

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Pedigree of the lissencephaly and cerebellar hypoplasia affected Churra sheep. The pattern is compatible with an autosomal recessive inheritance model. The pedigree relationships were confirmed using 19 microsatellite markers. Symbols used in the pedigree are those proposed in humans by the “Pedigree Standardization Work Group of the National Society of Genetic Counselors”[23]. Briefly, square represent male, circle female, shaded square-affected male, shaded circle-affected female. A diamond for the individual symbol is used to indicate animals with gender not specified (males and females). Numbers inside the symbol represent multiple individuals.
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Figure 8: Pedigree of the lissencephaly and cerebellar hypoplasia affected Churra sheep. The pattern is compatible with an autosomal recessive inheritance model. The pedigree relationships were confirmed using 19 microsatellite markers. Symbols used in the pedigree are those proposed in humans by the “Pedigree Standardization Work Group of the National Society of Genetic Counselors”[23]. Briefly, square represent male, circle female, shaded square-affected male, shaded circle-affected female. A diamond for the individual symbol is used to indicate animals with gender not specified (males and females). Numbers inside the symbol represent multiple individuals.

Mentions: The analysis of the three pedigrees, including 14 affected animals, with available DNA, was consistent with a monogenic autosomal recessive inheritance (Figure 8). In the three families some additional healthy lambs were analyzed. Overall, four rams were involved: ram #11 mated 46 ewes that lambed 63 unaffected lambs, 7 ewes that lambed 8 affected labs and one ewe that lambed a non-affected ewe which, when matted to ram #112 produced an affected lamb; ram #21 matted 23 ewes that produced 30 non-affected lambs and 4 ewes that lambed 4 affected and 1 non-affected lambs; ram #31 matted 16 ewes that produced 20 non-affected lamb s and one ewe that produced an affected lamb in one pregnancy and a non-affected lamb in a subsequent parturition.


Hereditary lissencephaly and cerebellar hypoplasia in Churra lambs.

Pérez V, Suárez-Vega A, Fuertes M, Benavides J, Delgado L, Ferreras MC, Arranz JJ - BMC Vet. Res. (2013)

Pedigree of the lissencephaly and cerebellar hypoplasia affected Churra sheep. The pattern is compatible with an autosomal recessive inheritance model. The pedigree relationships were confirmed using 19 microsatellite markers. Symbols used in the pedigree are those proposed in humans by the “Pedigree Standardization Work Group of the National Society of Genetic Counselors”[23]. Briefly, square represent male, circle female, shaded square-affected male, shaded circle-affected female. A diamond for the individual symbol is used to indicate animals with gender not specified (males and females). Numbers inside the symbol represent multiple individuals.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750509&req=5

Figure 8: Pedigree of the lissencephaly and cerebellar hypoplasia affected Churra sheep. The pattern is compatible with an autosomal recessive inheritance model. The pedigree relationships were confirmed using 19 microsatellite markers. Symbols used in the pedigree are those proposed in humans by the “Pedigree Standardization Work Group of the National Society of Genetic Counselors”[23]. Briefly, square represent male, circle female, shaded square-affected male, shaded circle-affected female. A diamond for the individual symbol is used to indicate animals with gender not specified (males and females). Numbers inside the symbol represent multiple individuals.
Mentions: The analysis of the three pedigrees, including 14 affected animals, with available DNA, was consistent with a monogenic autosomal recessive inheritance (Figure 8). In the three families some additional healthy lambs were analyzed. Overall, four rams were involved: ram #11 mated 46 ewes that lambed 63 unaffected lambs, 7 ewes that lambed 8 affected labs and one ewe that lambed a non-affected ewe which, when matted to ram #112 produced an affected lamb; ram #21 matted 23 ewes that produced 30 non-affected lambs and 4 ewes that lambed 4 affected and 1 non-affected lambs; ram #31 matted 16 ewes that produced 20 non-affected lamb s and one ewe that produced an affected lamb in one pregnancy and a non-affected lamb in a subsequent parturition.

Bottom Line: 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.The hippocampus was also markedly disorganised and the number and size of lobules were reduced in the cerebellum.Histopathological features observed in the cerebral cortex and hippocampus are consistent with a possible failure in neuronal migration during brain development.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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. vperp@unileon.es

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus