ABSTRACT
Two families of dogs (Australian cattle dogs and Shetland sheepdogs) with an inherited "spongiform leukoencephalomyelopathy" were identified, with widespread vacuolation of white matter of the brain and spinal cord. Affected dogs of both breeds developed tremors at 2-9 weeks of age followed by progressive neurological worsening with ataxia, paresis, paralysis, spasticity, and cranial nerve dysfunction. The modes of inheritance of both families were most likely maternal. The cerebrospinal fluid (CSF) analysis showed elevated ratio of 3-OH butyrate to acetoacetic acid. Mitochondrial DNA sequencing showed a G to A transition at 14,474 nt (G14474A, GenBank accession no. NC002008 ) that results in an amino acid change of valine-98 to methionine (V98M) of mitochondrial encoded cytochrome b. Western blot analysis showed increased levels of core I and core II but decreased level of cytochrome c1 of the complex III and cytochrome c oxidase of the complex IV of the respiratory chain.
Subject(s)
Canavan Disease/genetics , Cytochromes b/genetics , Dog Diseases/genetics , Heredodegenerative Disorders, Nervous System/genetics , Mutation, Missense , 3-Hydroxybutyric Acid/cerebrospinal fluid , Acetoacetates/cerebrospinal fluid , Animals , Blotting, Western , Canavan Disease/cerebrospinal fluid , Canavan Disease/pathology , Cytochromes c1/metabolism , DNA, Mitochondrial/genetics , Dog Diseases/cerebrospinal fluid , Dog Diseases/pathology , Dogs , Electron Transport Complex III/metabolism , Electron Transport Complex IV/metabolism , Female , Heredodegenerative Disorders, Nervous System/cerebrospinal fluid , Heredodegenerative Disorders, Nervous System/pathology , Male , Molecular Sequence Data , Nerve Fibers, Myelinated/pathology , PedigreeABSTRACT
Described are the outcomes of 11 Italian patients with Aicardi-Goutières syndrome. Neurologic symptoms progressed in the first year of life and stabilized by the end of the second year in 10 patients. White matter abnormalities remained stable; cerebral atrophy was stable in four patients and progressive in two. Calcifications increased (in number and size) in two of six patients. Serial CSF and serum interferon-alpha measurements (three patients) showed reduced CSF interferon-alpha levels.
