Clinical Guidance

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 . 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 [, , , , ]. Table 2. GNAO1-Related Disorder: Genotype-Phenotype Correlations

Source: GeneReviews — "GNAO1-Related Disorder"

Diagnostic Criteria

No consensus clinical diagnostic criteria for GNAO1-related disorder have been published.

Suggestive Findings

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

Clinical findings

• Epilepsy

Source: GeneReviews — "GNAO1-Related Disorder"

Differential Diagnosis

The phenotypic features associated with GNAO1-related disorder are not sufficient to diagnose this condition clinically. Developmental and epileptic encephalopathy. All disorders with infantile-onset severe seizures, central hypotonia, global developmental delay, and severe intellectual disability should be considered in the differential diagnosis. See OMIM Phenotypic Series: Developmental and epileptic encephalopathy. Dystonia. See Hereditary Dystonia Overview for genes associated with dystonia. Movement disorder with epilepsy. Examples of other genes associated with both seizures and paroxysmal hyperkinetic, dystonic, and/or choreiform movement disorder phenotypes include the following :

• ATP1A2-related disorders (OMIM 182340)

• ATP1A3-related neurologic disorders

Source: GeneReviews — "GNAO1-Related Disorder"

Management Guidelines

No clinical practice guidelines for GNAO1-related disorder have been published.

Evaluations Following Initial Diagnosis

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

Table 3.

GNAO1-Related Disorder: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Neurologic

| Eval by pediatric or adult neurologist | • For evidence of DD/ID, epilepsy, movement disorder

• For those w/abnormal movements, eval by movement specialist is recommended.

• Perform EEG if seizures are a concern. Distinguishing between dystonia seizure can be a challenge.

• Consider brain MRI if not previously performed.

Dysarthria

| Communication assessment/ speech-language therapy assessment | • For all persons w/speech delay, ensure hearing is normal.

• Evaluate need for communication aids.

Development

| Developmental assessment cognitive function eval | • To incl motor, adaptive, cognitive, speech-language eval

• Eval for early intervention/ individual education program

Neurobehavioral/Psychiatric

| Neuropsychiatric eval | Screening for behavior concerns incl sleep disturbances, ADHD, anxiety, /or findings suggestive of ASD

Musculoskeletal/ADL

| Orthopedics/ physical medicine rehab/ PT OT eval | To incl assessment of:

Source: GeneReviews — "GNAO1-Related Disorder"

Therapies Under Investigation

Using Caenorhabditis elegans models of two specific GNAO1 variants, researchers found that caffeine reduced abnormal movements . 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.

Source: GeneReviews — "GNAO1-Related Disorder"

Surveillance Guidelines

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

Table 5.

GNAO1-Related Disorder: Surveillance

System/Concern | Evaluation | Frequency

Feeding

| • Measurement of growth parameters

• Eval of nutritional status safety of oral intake

| At each visit

Gastrointestinal

| Monitor for constipation.

Respiratory

| Monitor for evidence of aspiration, respiratory insufficiency.

Neurologic

| • Monitor those w/seizures as clinically indicated.

• Assess for new manifestations such as seizures, changes in tone, movement disorders.

Development

| Monitor developmental progress educational needs.

Neurobehavioral/Psychiatric

| Behavioral assessment for anxiety, attention, aggressive or self-injurious behavior

Musculoskeletal

| Physical medicine, OT/PT assessment of mobility, self-help skills; clinical eval of hip spine for those who are non-ambulatory /or severely hypotonic

Family/Community

| Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).

OT = occupational therapy; PT = physical therapy

Source: GeneReviews — "GNAO1-Related Disorder"