Clinical characteristics.

GNAO1-related disorder encompasses a broad phenotypic continuum that includes hyperkinetic movement disorders and/or epilepsy and is typically associated with developmental delay and intellectual disability. Viewed by age of onset, three clusters in this continuum can be observed: (1) infantile-onset developmental and epileptic encephalopathy (DEE) with or without prominent movement disorder; (2) infantile- or early childhood-onset prominent movement disorder and neurodevelopmental disorder with or without childhood-onset epilepsy with varying seizure types; (3) later childhood- or adult-onset movement disorder with variable developmental delay and intellectual disability.

Epilepsy can be either DEE (onset typically within the first year of life of drug-resistant epilepsy in which developmental delays are attributed to the underlying diagnosis as well as the impact of uncontrolled seizures) or varying seizure types (onset typically between ages three and ten years of focal or generalized tonic-clonic seizures that may be infrequent or well controlled with anti-seizure medications).

Movement disorders are characterized by dystonia and choreoathetosis, most commonly a mixed pattern of persistent or paroxysmal dyskinesia that affects the whole body. Exacerbations of the hyperkinetic movement disorder, which can be spontaneous or triggered (e.g., by intercurrent illness, emotional stress, voluntary movements), can last minutes to weeks. Hyperkinetic crises (including status dystonicus) are characterized by temporarily increased and nearly continuous involuntary movements or dystonic posturing that can be life-threatening.

Deaths in early childhood have been reported due to medically refractory epilepsy or hyperkinetic crises, but the phenotypic spectrum includes milder presentations, including in adults. As many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with GNAO1-related disorder are underrecognized and underreported.

Diagnosis/testing.

The diagnosis of GNAO1-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in GNAO1 identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no cure for GNAO1-related disorder. Supportive care to improve quality of life, maximize function, and reduce complications can include multidisciplinary care by specialists in child neurology, adult neurology, neurosurgery, physical medicine and rehabilitation, physical therapy, occupational therapy, orthopedic surgery, speech-language therapy, and psychology.

Surveillance: Frequent evaluations by treating specialists are necessary to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Genetic counseling.

GNAO1-related disorder is an autosomal dominant disorder most often caused by a de novo pathogenic variant. Individuals with severe GNAO1-related disorder phenotypes (i.e., DEE, severe developmental delay and/or intellectual disability, and/or an early-onset movement disorder) typically represent simplex cases (i.e., the only family member known to be affected) and have the disorder as the result of a de novo pathogenic variant; however, recurrence of severe GNAO1-related disorder phenotypes in affected sibs due to presumed parental germline mosaicism has been reported. Vertical transmission from an affected parent to an affected child has been reported in several families with the milder phenotype (i.e., later childhood- or adult-onset movement disorder with variable developmental delay and intellectual disability). Once the GNAO1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

GNAO1-related disorder should be considered in individuals with the following clinical findings and family history.

Clinical findings

• Epilepsy
  • Developmental and epileptic encephalopathy (DEE). Early-onset (typically within the first year of life) drug-resistant epilepsy where developmental delays are attributed to the underlying diagnosis as well as the impact of uncontrolled seizures.
  • Non-DEE epilepsy. Later-onset focal seizures or generalized tonic-clonic seizures (ages 3-10 years). Seizures may be infrequent or well controlled with anti-seizure medications.
• Movement disorder. Most commonly presenting in infancy or early childhood consisting of choreoathetosis and dystonia with distinct risk for exacerbations of hyperkinetic movement disorder. Onset in later childhood and adulthood has been reported.
• Axial hypotonia. Typically present from birth or evident within the first few months of life.
• Mild-to-profound intellectual disability initially presenting as global developmental delay; reported in most but not all
• Feeding difficulties, most prominently in infancy

Family history. Because GNAO1-related disorder is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of GNAO1-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in GNAO1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of a heterozygous GNAO1 variant of uncertain significance does not establish or rule out the diagnosis.

Approach to molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with chromosomal microarray analysis (CMA). Other options include use of a multigene panel or exome sequencing. Note: Single-gene testing (sequence analysis of GNAO1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• A multigene panel for epilepsy or movement disorders that includes GNAO1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved but may require relevant clinical details. Exome sequencing is most commonly used and yields results similar to an intellectual disability multigene panel, with the additional advantage that exome sequencing includes genes recently identified as causing intellectual disability, whereas some multigene panels may not. Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

GNAO1-related disorder encompasses a spectrum of hyperkinetic movement disorders and/or epilepsy, typically associated with global developmental delay and intellectual disability.

To date, information on more than 200 individuals with GNAO1-related disorder have been published [Nakamura et al 2013, EuroEPINOMICS-RES Consortium et al 2014, Law et al 2015, Talvik et al 2015, Zhu et al 2015, Ananth et al 2016, Dhamija et al 2016, Gawlinski et al 2016, Helbig et al 2016, Kulkarni et al 2016, Marcé-Grau et al 2016, Menke et al 2016, Saitsu et al 2016, Yilmaz et al 2016, Arya et al 2017, Danti et al 2017, Schorling et al 2017, Bruun et al 2018, Honey et al 2018, Koy et al 2018, Okumura et al 2018, Waak et al 2018, Benato et al 2019, Kelly et al 2019, Malaquias et al 2019, Muir et al 2019, Schirinzi et al 2019, Arisaka et al 2020, Kim et al 2020, Yamashita et al 2020, Turro et al 2020, Akasaka et al 2021, Dzinovic et al 2021, Chaib et al 2022, Chopra et al 2022, Fung et al 2022, Krenn et al 2022, Krygier et al 2022, Liu et al 2022, Pérez-Dueñas et al 2022, Di Rocco et al 2023, Domínguez-Carral et al 2023, Galosi et al 2023, Gambardella et al 2023, Garofalo et al 2023, Hu et al 2023, Li et al 2023, Novelli et al 2023, Thiel et al 2023, Vasconcellos et al 2023]. The following description of the phenotypic features associated GNAO1-related disorder is based on these reports.

Genotype-Phenotype Correlations

More than 200 individuals with pathogenic variants in GNAO1 have been reported in the literature to date.

To date, genotype-phenotype correlations have been described for several recurrent GNAO1 variants: one splicing variant and variants at five hot spot residues (p.Gly40, p.Gly203, p.Arg209, p.Glu237, and p.Glu246). These recurrent variants account for approximately half of affected individuals reported to date [Kelly et al 2019, Schirinzi et al 2019] (see Table 2).

In addition, accumulating data may point to haploinsufficiency variants being associated with milder phenotypes, without epileptic encephalopathy or severe global developmental delay or intellectual disability [Krenn et al 2022, Wirth et al 2022a, Wirth et al 2022b, Galosi et al 2023, Thiel et al 2023].

Prevalence

Approximately 200 individuals have been reported with GNAO1-related disorder to date. However, this disorder may be underreported, particularly given the recent reports of individuals with milder phenotypes [Wirth et al 2022a].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GNAO1-related disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for GNAO1-related disorder. Supportive care to improve quality of life, maximize function, and reduce complications can include multidisciplinary care by specialists in child neurology, adult neurology, neurosurgery, physical medicine and rehabilitation, physical therapy, occupational therapy, orthopedic surgery, speech-language therapy, and psychology (see Table 4).

Prolonged exacerbation of the hyperkinetic movement disorder requires hospitalization and, when severe, intensive care management. Infections or catabolic states are often triggers, while in some individuals, potential causes are unknown. The often poor nutritional status due to feeding problems can prolong hospital stays.

Although sudden unexpected death in epilepsy (SUDEP) has not specifically been reported in GNAO1-related disorder, generally recommended practices to reduce the risk of SUDEP include reduction in the frequency of generalized tonic-clonic seizures when possible, adherence to anti-seizure medication, and nocturnal supervision [Trivisano et al 2022].

While immune dysfunction has not been described in GNAO1-related disorder, infections can lead to hyperkinetic crises and need for hospitalization. Dysphagia and seizures can increase the risk of aspiration-related events, which may result in hospitalization for respiratory support.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Using Caenorhabditis elegans models of two specific GNAO1 variants, researchers found that caffeine reduced abnormal movements [Di Rocco et al 2023]. This finding has not yet been explored with other variants, in other model systems, or in humans with GNAO1-related disorder.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

GNAO1-related disorder is an autosomal dominant disorder most often caused by a de novo pathogenic variant. Individuals with a severe phenotype (i.e., developmental and epileptic encephalopathy, severe developmental delay and/or intellectual disability, and/or early-onset movement disorder) typically represent simplex cases (i.e., the only family member known to be affected) and have the disorder as the result of a de novo pathogenic variant. However, recurrence of severe phenotypes in affected sibs due to presumed parental germline mosaicism has been reported [Kulkarni et al 2016, Schorling et al 2017].

Vertical transmission from an affected parent to an affected child has been reported in several families with milder phenotypes [Wirth et al 2022a].

Risk to Family Members

Parents of a proband

• Almost all probands reported to date with severe GNAO1-related disorder phenotypes whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant or a pathogenic variant inherited from an unaffected, mosaic parent.
• Some probands with milder GNAO1-related disorder phenotypes have the disorder as the result of a pathogenic variant inherited from an affected parent.
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with apparent germline (or somatic and germline) mosaicism * [Ananth et al 2016, Kulkarni et al 2016, Schorling et al 2017, Kelly et al 2019, Kim et al 2020, Yang et al 2021, Al Masseri & AlSayed 2022, Miyamoto et al 2022]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * A parent with somatic and germline mosaicism for a GNAO1 pathogenic variant may be mildly/minimally affected, although this has not been reported to date.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If the GNAO1 pathogenic variant present in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Ananth et al 2016, Kulkarni et al 2016, Schorling et al 2017, Kelly et al 2019, Kim et al 2020, Yang et al 2021, Al Masseri & AlSayed 2022, Miyamoto et al 2022].
• If a parent of the proband is known to have the GNAO1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.

Offspring of a proband

• Each child of an individual with GNAO1-related disorder has a 50% chance of inheriting the GNAO1 pathogenic variant. Three individuals with milder phenotypes, including normal intellect and no seizures, have been documented to have had affected children [Wirth et al 2020, Wirth et al 2022a].
• Individuals with severe GNAO1-related disorder phenotypes are not known to reproduce.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the GNAO1 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the GNAO1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

GNAO1 encodes guanine nucleotide-binding protein G(o) subunit alpha, the alpha subunit of heterotrimeric guanine nucleotide-binding proteins o (Gαo). Heterotrimeric G proteins are a large family of signal-transducing proteins, essential for the function of G protein-coupled receptors (GPCRs). Together, the subunits α, β, and γ form the heterotrimeric G protein complex. Gα is responsible for binding to guanine nucleotides (GDP and GTP) and to cognate GPCRs [Savitsky et al 2020].

Gαo, the major G protein α subunit in the nervous system, is essential for nervous system development and functionality [Bromberg et al 2008, Solis & Katanaev 2017]. Gαo couples to inhibitory GPCRs such as α2-adrenergic, D2 dopamine, μ-opioid, somatostatin, and M2-muscarinic. The activation of GPCRs through GDP results in a release of Gßγ and Gα-GTP [Pierce et al 2002]. Gαo modulates the responsiveness of adenyl cyclase type 5 (AC5) to stimulatory Gαs/olf inputs by controlling the release of Gßγ [Muntean et al 2021], and therefore regulates the production of cyclic adenosine monophosphate (cAMP). The manifestations of movement disorders are caused by a reduced level of cAMP, as previously proven with ADCY5 variants (see ADCY5 Dyskinesia) that reduce the activity of AC5 [Carapito et al 2015, Chang et al 2016].

Mechanism of disease causation. Different molecular mechanisms explain the disease-causing mechanisms of different GNAO1 variants.

Muntean et al [2021] proposed a model in which the majority of variants show loss-of-function behavior in transmission of GPCR signals from distinct mechanisms that affect the G protein cycle, including impairment in binding to Gβγ and inability to promote downstream signaling. Furthermore, Muntean et al [2021] demonstrated that some variants also showed dominant-negative effects that interfered with the function of normal Gαo. They concluded that the combination of these two mechanisms disrupt the GPCR signaling.

Larasati et al [2022] showed that displacement of Gln205, which is critical for GTP hydrolysis, in GNAO1 variants that affect codons Gly203, Arg209, or Glu246 accelerates GTP uptake and inactivates GTP hydrolysis. Although this leads to constitutive GTP binding by Gαo, the variants fail to adopt the activated conformation and display aberrant interactions with signaling partners. The deficit in binding and hydrolyzing GTP was also found in variants affecting the Gln52 codon [Solis et al 2021].

Author Notes

All authors contributed equally to this work and should be considered co-first authors.

Lauren C Briere, MS CGC

Department of Pediatrics and Center for Genomic Medicine

Massachusetts General Hospital, Boston, Massachusetts

Email: ude.dravrah.hgm@ereirbl

Lauren is a Genetic Counselor and Study Coordinator for the Undiagnosed Diseases Network, Harvard Clinical Site, Massachusetts General Hospital. She has extensive experience in prenatal and general genetics counseling and a focus on rare and undiagnosed diseases and variant interpretation.

Dr Moritz Thiel

University Hospital of Cologne, Cologne Germany

Email: [email protected]

Dr Thiel is a resident in pediatric neurology and a clinician-scientist with a research focus on GNAO1. He hosts the German GNAO1 registry and recruits for the international Natural History of GNAO1-Associated Neurologic Disease study (PI: Amy Viehoever) in Europe.

Web page: kinderklinik.uk-koeln.de/erkrankungen-therapien/neuropaediatrie/bewegungsstoerungen/

Dr David Sweetser

Chief of Medical Genetics and Metabolism

MGH Site Director Undiagnosed Diseases Network

Co-Director Harvard Affiliated Hospitals NORD Rare Disease Center of Excellence

Department of Pediatrics and Center for Genomic Medicine

Massachusetts General Hospital, Boston, Massachusetts

Dr Sweetser is a biochemical and medical genetics clinician-researcher with a focus on understanding and diagnosing rare and undiagnosed diseases. He has a clinical and research focus on rare neurodevelopmental disorders.

Web pages:

• www.massgeneral.org/doctors/17525/david-sweetser
• www.massgeneral.org/children/genetics

Dr Anne Koy

Consultant Pediatric Neurology

University hospital of cologne, cologne, germany

email: [email protected]

Dr Koy is a pediatric neurologist and clinician-scientist with a clinical and research interest in movement disorders and deep brain stimulation in children. She is involved in the German GNAO1 registry and the international Natural History of GNAO1-Associated Neurologic Disease study (PI: Amy Viehoever) in Europe.

Web page: kinderklinik.uk-koeln.de/erkrankungen-therapien/neuropaediatrie/bewegungsstoerungen/

Dr Erika Axeen

Assistant Professor of Neurology and Pediatrics, University of Virginia

Email: ude.ainigriv@h2ate

Dr Axeen is a pediatric neurologist and epileptologist with an interest in genetic epilepsies. She serves on the scientific advisory board for the Bow Foundation and is the epileptologist for the Natural History of GNAO1-Associated Neurologic Disease study (PI: Amy Viehoever) and is working to further describe GNAO1-related epilepsy.

Web pages:

• uvahealth.com/findadoctor/profile/erika-j-axeen
• braininstitute.virginia.edu/erika-axeen

Drs Thiel, Koy, and Axeen are actively involved in clinical research regarding individuals with GNAO1-related disorder. They would be happy to communicate with persons who have any questions regarding diagnosis of GNAO1-related disorder or other considerations. They may be contacted to inquire about review of GNAO1 variants of uncertain significance.

Acknowledgments

We want to thank all the patients and their families for taking part in different studies, trials, and registries all around the world. We would also like to thank the parents for supporting scientists focusing on GNAO1. These efforts enlarged the understanding of this ultra-rare disease.

Dr Axeen has received a grant from the Bow Foundation in support of her ongoing work with GNAO1-related disorder. Dr Sweetser would also like to acknowledge the support of the Caitlin and Rich Hill Family Fund for Undiagnosed Diseases and the American Institute for Neuro Integrative Development (AIND) for their support of rare disease research at Massachusetts General Hospital.

Revision History

• 9 November 2023 (bp) Review posted live
• 21 February 2023 (ds) Original submission

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