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Coronal section (fixed tissue) of normal (a) and lissencephalic (b) brains. A marked increase of thickness of the cerebral cortex is seen in the affected lamb (b). Note that the corpus callosum is normally developed.
Source publication
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 hy...
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Context 1
... coronal sections of the brain, in addition to agyria, a marked pachygyria was observed in all the regions of the cerebral cortex. It was characterized by the presence of a thick grey matter layer, with a depth of 9 mm in average, with broad gyri and very shallow sulci, when present ( Figure 2). The white matter was narrow, leading to an inverted grey to white matter ratio. ...Context 2
... cerebral grey matter-white matter interface was linear and well defined with rare interdigitations. Macroscopically, the remaining areas of the forebrain (corpus callosum, cingulate gyrus ( Figure 2) and hippocampus) and brain stem appeared normally developed. The posterior part of the lateral ventricles was moderately dilated in 13 lambs but no physical obstruction of CSF flow was detected. ...Citations
... In addition to humans, lissencephaly has been reported in dogs including Lhasa Apsos (LEE et al., 2011), wire fox terriers, Irish setters, samoyeds, in undefined breeds, a Korat cat (DE LAHUNTA & GLASS 2009), goats (SANTOS et al., 2013) and sheep (PÉREZ et al., 2013). In most cases, lissencephaly occurs with other brain malformations, such as microcephaly, cerebellar hypoplasia and hypoplasia of the corpus callosum. ...
A case of lissencephaly-pachygyria and cerebellar hypoplasia diagnosed in a Charolais x Tabapuã calf is described. The calf presented since birth, clinical signs characterized by apathy, prolonged recumbency, tremors of the head and neck, ataxia, hypermetria, difficulty walking, blindness and swelling of the joints of the four limbs. Due to the unfavorable prognosis, the animal was euthanized and necropsied at 34 days of age. At necropsy, a rudimentary development of the brain folds (gyri) and grooves (sulci) was observed, and the cerebellum was hypoplastic. The cut surface of the brain exhibited thickening of the gray matter (pachygyria) in the frontal, parietal, temporal and occipital cortices and narrowing of the white matter. In the organs of the thoracic and abdominal cavities, no significant lesions were observed. Histologically, cerebral cortex was thick and exhibited neuronal disorganization of the gray matter. The cerebellum had a thin molecular layer, and neuronal disorganization with ectopia of the Purkinje neurons in the region of the granular and molecular layers. There were no bacterial growths in cultures of joint swabs. This was the only case on the property, which suggests that this malformation, which has not previously been described in cattle, was a sporadic case, and it was not possible to determine its cause. Neurological lesions and clinical sings presented here should be considered in the differential diagnosis of congenital diseases of the central nervous systems of cattle.
... Pathological examination showed alterations in the brain characterized by agyria, pachygyria and cerebellar hypoplasia. The segregation of this disease in the affected pedigrees was consistent with a recessive mode of Mendelian inheritance [10]. ...
... The microscopically normal layering of the cerebral cortex was disorganized, and immunohistochemical staining of the neurofilaments revealed a three-layered cortex instead of the six layers that appear in normal brains. All these findings were consistent with LCH [10]. ...
... The pedigree was constructed to confirm the monogenic autosomic mode of inheritance of this ovine disease reported [10] and to identify the common founder responsible of the establishment of the disease in this flock. For this purpose, we used CraneFoot software [17]. ...
Lissencephaly is an inherited developmental disorder in which neuronal migration is impaired. A type of lissencephaly associated with cerebellar hypoplasia (LCH) was diagnosed in a commercial flock of Spanish Churra sheep. The genotyping of 7 affected animals and 33 controls with the OvineSNP50 BeadChip enabled the localization of the causative mutation for ovine LCH to a 4.8-Mb interval on sheep chromosome 4 using genome-wide association and homozygosity mapping. The RELN gene, which is located within this interval, was considered a strong positional and functional candidate because it plays critical roles in neuronal migration and layer formation. By performing a sequencing analysis of this gene's specific mRNA in a control lamb, we obtained the complete CDS of the ovine RELN gene. The cDNA sequence from an LCH-affected lamb revealed a deletion of 31 bp (c.5410_5440del) in predicted exon 36 of RELN, resulting in a premature termination codon. A functional analysis of this mutation revealed decreased levels of RELN mRNA and a lack of reelin protein in the brain cortex and blood of affected lambs. This mutation showed a complete concordance with the Mendelian recessive pattern of inheritance observed for the disease. The identification of the causal mutation of LCH in Churra sheep will facilitate the implementation of gene-assisted selection to detect heterozygous mutants, which will help breeders avoid at-risk matings in their flocks. Moreover, the identification of this naturally occurring RELN mutation provides an opportunity to use Churra sheep as a genetically characterized large animal model for the study of reelin functions in the developing and mature brain.
Cerebellar hypoplasia is a heterogeneous neurological condition in which the cerebellum is smaller than usual or not completely developed. The condition can have genetic origins, with Mendelian‐effect mutations described in several mammalian species. Here, we describe a genetic investigation of cerebellar hypoplasia in White Swiss Shepherd dogs, where two affected puppies were identified from a litter with a recent common ancestor on both sides of their pedigree. Whole genome sequencing was conducted for 10 dogs in this family, and filtering of these data based on a recessive transmission hypothesis highlighted five protein‐altering candidate variants – including a frameshift‐deletion of the Reelin (RELN) gene (p.Val947*). Given the status of RELN as a gene responsible for cerebellar hypoplasia in humans, sheep and mice, these data strongly suggest the loss‐of‐function variant as underlying these effects. This variant has not been found in other dog breeds nor in a cohort of European White Swiss Shepherds, suggesting a recent mutation event. This finding will support the genotyping of a more diverse sample of dogs, and should aid future management of the harmful allele through optimised mating schemes.
These diseases are presented together here because there is a proven, suspected or possible relationship with the patients’ genotype, even though in utero insults can be responsible for some of the syndromes. Thus most diseases are acquired or inherited and congenital, or are early or late delayed and inherited. As the full nucleic and mitochondrial genomes for our large animal species are unravelled more consistent and precise genetic coding can be applied to the diagnosis of these disorders through genetic screening that is more widely available nowdays. The diseases are ordered to follow the anatomic groupings: diffuse brain, forebrain, brainstem, cerebellum, spinal cord, peripheral nerves, neuromuscular junction, muscle.
Las enfermedades hereditarias son una causa de preocupación creciente a nivel mundial. Las técnicas actuales de mejoramiento genético en bovinos han llevado a propagar en todo el mundo características productivas económicamente valiosas, pero también algún gen recesivo defectuoso. El progreso genético ha ido acompañado de la aparición con alta incidencia de enfermedades hereditarias letales, con gran impacto en la fertilidad de los rodeos y la salud animal. Estas enfermedades se asocian con determinadas razas o líneas dentro de cada raza. La alta incidencia de estas enfermedades diagnosticadas en los últimos años en la zona Este de Uruguay hace sospechar que la proporción de animales portadores en algunos rodeos es alta y que las mutaciones pueden estar difundidas. Se hace necesario desarrollar métodos de diagnóstico genéticos apropiados y que se investigue la incidencia y difusión de los genes involucrados para lo cual se realizó un estudio de prevalencia de las tres enfermedades hereditarias de mayor relevancia en la zona Este, como lo son la Osteopetrosis y la Sindactilia en Aberdeen Angus y el MSUD en Hereford. Para MSUD y Osteopetrosis se realizó extracción de pelos de la cola de 124 toros de pedigrí Hereford (de 23 cabañas) y 92 Aberdeen Angus (de 20 cabañas) respectivamente, durante las exposiciones ganaderas de Melo, Minas, Treinta y Tres en los años 2015 y 2016. También se realizó extracción de sangre de 86
vacas en un predio con antecedentes de MSUD. Para sindactilia se realizó necropsia y se procesó sangre de un ternero Aberdeen Angus con diagnóstico de la enfermedad. Luego de la extracción de ADN, las muestras fueron procesadas por PCR-HRM y secuenciación en las muestras pertenecientes a la raza Polled Hereford y Hereford y
PCR tiempo final en la raza Aberdeen Angus. En el rodeo con antecedentes de MSUD se confirmó por secuenciación la presencia de 3 (3.5%) vacas portadoras de la mutación, confirmando que la mutación se encuentra en los rodeos de cría de nuestro país. De los 124 toros Polled Hereford y Hereford, solamente presentaban calidad de ADN aceptable el 4 % de las muestras. De los 92 toros Aberdeen Angus analizados, en una (1.6%) se comprobó la delección responsable de la Osteopetrosis. Se confirmó mediante patología, PCR y secuenciación un caso de Sindactilia hereditaria en Aberdeen Angus.
Case report:
A 6-year-old neutered male Australian Kelpie presented with a 2-year history of seizures. Neurological examination was consistent with a generalised prosencephalic lesion. Serum biochemical testing was performed in addition to magnetic resonance imaging of the brain and cerebrospinal fluid analysis. Magnetic resonance imaging revealed a reduction in the number of sulci and gyri in addition to cortical thickening, resulting in a diagnosis of lissencephaly. The dog was treated with anticonvulsants and follow-up information obtained from the referring veterinarian 11 months after diagnosis indicated that the dog had good seizure control.
Conclusion:
This is the first report of lissencephaly in the Australian Kelpie and would suggest that some dogs with the condition can be managed with long-term anticonvulsant medication.
