Brain Advance Access originally published online on February 2, 2005
Brain 2005 128(4):711-722; doi:10.1093/brain/awh401
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Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort
Departments of 1 Pathology, 2 Human Anatomy and Cell Science, 3 Biochemistry and Medical Genetics and 4 Pediatrics and Child Health, Faculty of Medicine, University of Manitoba, 5 Manitoba Institute of Child Health, Winnipeg, 6 Department of Pediatrics, University of Western Ontario, London, Ontario, Canada and 7 Department of General Pediatrics, Division of Metabolic and Endocrine Diseases, University Children's Hospital, Heidelberg, Germany.
Correspondence to: Marc R. Del Bigio MD PhD FRCPC, Canada Research Chair in Developmental Neuropathology, Department of Pathology, University of Manitoba, D212-770 Bannatyne Avenue, Winnipeg MB, R3E 0W3, Canada E-mail: delbigi{at}cc.umanitoba.ca
Glutaric acidemia type 1 (GA-1) is an autosomal recessive disorder characterized by a deficiency of glutaryl-CoA dehydrogenase (GCDH) activity. GA-1 is often associated with an acute encephalopathy between 6 and 18 months of age that causes striatal damage resulting in a severe dystonic movement disorder. Ten autopsy cases have been previously described. Our goal is to understand the disorder better so that treatments can be designed. Therefore, we present the neuropathological features of six additional cases (8 months–40 years), all North American aboriginals with the identical homozygous mutation. This cohort displays similar pathological characteristics to those previously described. Four had macroencephaly. All had striatal atrophy with severe loss of medium-sized neurons. We present several novel findings. This natural time course study allows us to conclude that neuron loss occurs shortly after the encephalopathical crisis and does not progress. In addition, we demonstrate mild loss of large striatal neurons, spongiform changes restricted to brainstem white matter and a mild lymphocytic infiltrate in the early stages. Reverse transcriptase-PCR to detect the GCDH mRNA revealed normal and truncated transcripts similar to those in fibroblasts. All brain regions demonstrated markedly elevated concentrations of GA (3770–21 200 nmol/g protein) and 3-OH-GA (280–740 nmol/g protein), with no evidence of striatal specificity or age dependency. The role of organic acids as toxic agents and as osmolytes is discussed. The pathogenesis of selective neuronal loss cannot be explained on the basis of regional genetic and/or metabolic differences. A suitable animal model for GA-1 is needed.
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