GNAO1 is a rare genetic neurodevelopmental disorder arising from a mutation of the eponymous gene. Today roughly 100 people worldwide have been diagnosed with the GNAO1 disorder arising from de novo mutations of the gene.

The GNAO1 disorder was first characterised in 2013 by a Japanese research team studying DNA mutations in four Japanese children. Subsequent diagnoses of this rare disorder arose with families seeking to understand why their children were missing developmental milestones and in many cases suffering epileptic seizures and abnormal movements.

In the last three years, the number of GNAO1 diagnoses has multiplied with the increased availability of genetic testing. Previously misdiagnosed and undiagnosed cases have since been reassigned as GNAO1 cases.

The Clinical Picture of GNAO1

GNAO1 (G Protein Subunit Alpha O1) is an alpha subunit of the heterotrimeric guanine nucleotide-binding proteins (G proteins), a large family of signal-transducing molecules. The G protein family is essential in the complex chain of molecular communication entailing the transmission of signals across cell membranes. The GNAO1 protein is encoded by a gene located on the long arm of chromosome 16 at position 13 (16q13).

The GNAO1 disorder was initially defined as early infantile epileptic encephalopathy. However, the severity of epilepsy can vary significantly, and some GNAO1 patients do not have epilepsy.

A broad spectrum of symptoms has emerged in recent years, of which the most common are:

  • Developmental delay
  • Hypotonia: low muscle tone
  • Epilepsy
  • Movement disorders
    • Chorea: rapid, irregular, non-stereotyped involuntary movements
    • Dystonia: involuntary muscle contractions resulting in twisting or repetitive movements and abnormal postures, which in severe episodes can lead to status dystonicus

There are many variants of the GNAO1 mutation. Studies published in 2017 and 2019 suggest that different symptoms correlate to different genetic variants. The type and severity of symptoms vary from one patient to another and sometimes differ even in patients with mutations of the same variant. The reasons for the great clinical variability remain unclear and require further study.

Despite the growing number of clinical cases of GNAO1, there is still very little known about the general clinical picture and the course of the disorder. The limited data available indicate that the GNAO1 disorder is not degenerative, but rather a stable condition, although with severe disability. The epidemiology is also unknown. To date there are about 150 cases all over the world, but experts believe this figure is likely to be significantly underestimated.