glutaminase and Ataxia

Glutaminase deficiency has recently been associated with ataxia and developmental delay due to repeat expansions in the 5'UTR of the glutaminase (GLS) gene. Patients with the described GLS repeat expansion may indeed remain undiagnosed due to the rarity of this variant, the challenge of its detection and the recency of its discovery. In this study, we combined advanced bioinformatics screening of ~3000 genomes and ~1500 exomes with optical genome mapping and long-read sequencing for confirmation studies. We identified two GLS families, previously intensely and unsuccessfully analyzed. One family carries an unusual and complex structural change involving a homozygous repeat expansion nested within a quadruplication event in the 5'UTR of GLS. Glutaminase deficiency and its metabolic consequences were validated by in-depth biochemical analysis. The identified GLS patients showed progressive early-onset ataxia, cognitive deficits, pyramidal tract damage and optic atrophy, thus demonstrating susceptibility of several specific neuron populations to glutaminase deficiency. This large-scale screening study demonstrates the ability of bioinformatics analysis-validated by latest state-of-the-art technologies (optical genome mapping and long-read sequencing)-to effectively flag complex repeat expansions using short-read datasets and thus facilitate diagnosis of ultra-rare disorders.

Topics: 5' Untranslated Regions; Ataxia; Glutaminase; Humans

Hyperammonemia plays a main role in the neurological impairment in cirrhotic patients with hepatic encephalopathy. Rats with chronic hyperammonemia reproduce the motor incoordination of patients with minimal hepatic encephalopathy, which is due to enhanced GABAergic neurotransmission in cerebellum as a consequence of neuroinflammation. Extracellular vesicles (EVs) could play a key role in the transmission of peripheral alterations to the brain to induce neuroinflammation and neurological impairment in hyperammonemia and hepatic encephalopathy. EVs from plasma of hyperammonemic rats (HA-EVs) injected to normal rats induce neuroinflammation and motor incoordination, but the underlying mechanisms remain unclear. The aim of this work was to advance in the understanding of these mechanisms. To do this we used an ex vivo system. Cerebellar slices from normal rats were treated ex vivo with HA-EVs. The aims were: 1) assess if HA-EVs induce microglia and astrocytes activation and neuroinflammation in cerebellar slices of normal rats, 2) assess if this is associated with activation of the TNFR1-NF-kB-glutaminase-GAT3 pathway, 3) assess if the TNFR1-CCL2-BDNF-TrkB pathway is activated by HA-EVs and 4) assess if the increased TNFα levels in HA-EVs are responsible for the above effects and if they are prevented by blocking the action of TNFα. Our results show that ex vivo treatment of cerebellar slices from control rats with extracellular vesicles from hyperammonemic rats induce glial activation, neuroinflammation and enhance GABAergic neurotransmission, reproducing the effects induced by hyperammonemia

Topics: Animals; Ataxia; Brain-Derived Neurotrophic Factor; Cerebellum; Extracellular Vesicles; Glutaminase; Hepatic Encephalopathy; Hyperammonemia; Liver Cirrhosis; Neuroinflammatory Diseases; NF-kappa B; Rats; Rats, Wistar; Receptors, Tumor Necrosis Factor, Type I; Tumor Necrosis Factor-alpha

We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5' untranslated region of the gene encoding glutaminase (

Topics: Amino Acid Metabolism, Inborn Errors; Ataxia; Atrophy; Cerebellum; Child, Preschool; Developmental Disabilities; Female; Genotype; Glutaminase; Glutamine; Humans; Male; Microsatellite Repeats; Mutation; Phenotype; Polymerase Chain Reaction; Whole Genome Sequencing

Topics: Animals; Antibiotics, Antineoplastic; Asparagine; Aspartate Aminotransferases; Aspartic Acid; Ataxia; Azo Compounds; Carbon Radioisotopes; Carboxy-Lyases; Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury; Diarrhea; DNA; Formates; Glutamate Dehydrogenase; Glutamate-Ammonia Ligase; Glutamates; Glutaminase; Lethal Dose 50; Ligases; Liver Neoplasms; Malate Dehydrogenase; Mice; Mice, Inbred Strains; Protein Biosynthesis; Seizures; Spleen; Time Factors