Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort
| Autor: | Patrick Frosk, Stefan Kölker, Marc R. Del Bigio, Asuri N. Prasad, Sven W. Sauer, Christopher B R Funk, Cheryl R. Greenberg |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Adult
Male medicine.medical_specialty Aging Oxidoreductases Acting on CH-CH Group Donors Adolescent Glutaryl-CoA dehydrogenase Cell Count Glutaric aciduria type 1 Glutaric acid Biology medicine.disease_cause White matter Pathogenesis Glutarates chemistry.chemical_compound Atrophy Fatal Outcome Basal Ganglia Diseases Internal medicine medicine Humans RNA Messenger Child Amino Acid Metabolism Inborn Errors Retrospective Studies Neurons Mutation Glutaryl-CoA Dehydrogenase Brain Infant medicine.disease Corpus Striatum Endocrinology medicine.anatomical_structure chemistry Child Preschool Female Neurology (clinical) Tomography X-Ray Computed Neuroscience Glutaric Acidemia Type 1 |
| Zdroj: | Brain : a journal of neurology. 128(Pt 4) |
| ISSN: | 1460-2156 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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