Our observation not only emphasizes the central role of mGluR1-mediated signaling in cerebellar function and neurodevelopment but also provides valuable insights into the early clinical signs of recessive ataxia due to GRM1 pathogenic variants that were not reported previously.
In a previous study, homozygous mice lacking mGlu1 receptors (Grm1<sup>crv4/crv4</sup>) and exhibiting ataxia presented cerebellar overexpression of mGlu5 receptors, that was proposed to contribute to the mouse phenotype.
Downstream of mGluR1, dysregulation of calcium homeostasis has been hypothesized as a key pathological event in genetic forms of ataxia but the underlying mechanisms remain unclear.
However, mGluR1 imaging was more strongly associated with the SARA scores than <sup>18</sup>F-FDG imaging was, suggesting that mGluR1 imaging can be a more specific technique than <sup>18</sup>F-FDG imaging for evaluating cerebellar ataxia.
Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile-onset ataxia and intellectual disability.
Although ataxia lymphoblastoid cell lines expressed GRM1 at levels comparable to those of control cells, the aberrant transcripts skipped exon 8 or ended in intron 8 and encoded various species of nonfunctional receptors either lacking the transmembrane domain and containing abnormal intracellular tails or completely missing the tail.
Studies with a large number of controls including 2 patients with cerebellar ataxia and mGluR1 antibodies showed that mGluR5 was only identified by sera of the 2 patients with the Ophelia syndrome, and that despite the homology of this receptor with mGluR1 each autoantigen was specific for a distinct syndrome.