GNB1-Related Encephalopathy and G-Protein-Related Neurodevelopmental Disorders

Autosomal dominant intellectual developmental disorder 42 (MRD42), GNB1-related neurodevelopmental disorder and differential diagnosis with the Gα and Gβ subunit disorders and with SBIDDS syndrome (PRMT7)

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

GNB1-related encephalopathy (GNB1-E, GNB1 encephalopathy), also termed GNB1-related neurodevelopmental disorder (GNB1-NDD), corresponds in the OMIM catalogue (Online Mendelian Inheritance in Man) to autosomal dominant intellectual developmental disorder 42 (MRD42, OMIM 616973), caused by heterozygous variants in the GNB1 gene (OMIM 139380), at 1p36.33, which encodes the β1 subunit of heterotrimeric G proteins (Gβ1) [1–3]. The acronym SBIDDS has at times been associated with GNB1; this acronym designates a different disorder, short stature, brachydactyly, impaired intellectual development and seizures syndrome (OMIM 617157, ORPHA:464288), which is autosomal recessive and caused by biallelic PRMT7 variants, at 16q22.1 [4–6]. SBIDDS is therefore treated as a differential diagnosis, alongside the other neurodevelopmental disorders due to G-protein subunits (GNAO1, GNB5, GNAI1); the GNAO1-related disorder, the most frequent in the class, has its own subsections in each section. Somatic GNB1 variants in haematological neoplasms and the 1p36 deletion that includes the gene are related entities with a distinct mechanism and counselling.

1. Introduction

1.1. From phototransduction protein to disease gene

The β1 subunit of G proteins was characterised in the 1980s as a component of transducin, the G protein of retinal rods: in 1986, Fong and colleagues deduced the 340-amino-acid bovine sequence and Codina and colleagues showed that the human liver protein was identical to that of bovine rods [2]. The gene was mapped to chromosome 1 in 1987 and regionally assigned to 1p36 in the following years [2]. For almost three decades, GNB1 was studied as a component of receptor-coupled signal transduction, with no association with inherited human disease.

The first link with human pathology emerged in cancer. In 2015, Yoda and colleagues described recurrent somatic GNB1 and GNB2 variants in haematological and solid neoplasms, with cytokine-independent growth, activation of the PI3K–AKT–mTOR and MAPK pathways and resistance to kinase inhibitors [13]. The following year, Petrovski and colleagues published the founding article on the germline disorder: among 5,855 individuals sequenced for undiagnosed genetic diseases, they identified 13 unrelated patients with de novo missense variants in GNB1, with global developmental delay, hypotonia and seizures; the probability of observing 13 or more de novo variants in this gene by chance was 7.1 × 10⁻²¹, a value that withstands correction for the 18,669 genes tested [14]. Eight of these 13 patients carried the germline variant at one of the residues that are targets of recurrent somatic variants in tumours [14].

1.2. Successive series and broadening of the spectrum

In 2016, Steinrücke and colleagues described a German girl with generalised dystonia, hypotonia and intellectual disability, which brought movement disorders into the core of the phenotype [34]. In 2017, Lohmann and colleagues gathered 16 patients with 14 variants, including the first truncating and splicing variants, demonstrated autosomal dominant transmission of the p.(Arg96Leu) variant in three families and showed, by bioluminescence resonance energy transfer (BRET) and bimolecular fluorescence complementation (BiFC) assays, that several variants alter assembly and activation of the heterotrimer [35]. Hemati and colleagues added a further 18 patients in 2018, one of them mosaic, and described cutaneous mastocytosis and genitourinary and gastrointestinal anomalies as part of the picture [36]. There followed the description of the first case of acute lymphoblastic leukaemia (ALL) in a germline carrier [37], of Japanese patients with spastic diplegia, dyskinetic quadriplegia and infantile spasms [38], of myoclonus-dystonia responsive to deep brain stimulation (DBS) [39] and, in 2020, of evidence of haploinsufficiency as a mechanism, with a milder phenotype associated with obesity [16].

The dedicated GeneReviews was published on 5 March 2020 and revised on 15 April 2021, with 58 patients published at that date [3]. Subsequent literature added rod-cone dystrophy in adults [40, 41], infection-triggered acute encephalopathy [42], the association between loss-of-function variants and syndromic obesity [22], transmission from an asymptomatic mosaic parent [17] and mouse models that clarify the role of GIRK potassium channels [27, 43].

1.3. Nomenclature

OMIM names the disorder «intellectual developmental disorder, autosomal dominant 42» (MRD42), a name derived from the former «mental retardation, autosomal dominant 42» [1]. GeneReviews uses «GNB1 encephalopathy» (GNB1-E) [3]; part of the recent literature prefers «GNB1-related neurodevelopmental disorder» (GNB1-NDD) [16, 22]. Orphanet classifies the entity as a malformation syndrome, under the descriptive name «Global developmental delay-neuro-ophthalmological abnormalities-seizures-intellectual disability syndrome» (ORPHA:488613) [7]. The designation «GNB1-related encephalopathy» is used here because it encompasses patients with and without epilepsy.

The acronym SBIDDS designates a different, autosomal recessive disorder caused by biallelic variants in PRMT7 (protein arginine methyltransferase 7), described in 2015 in six women from three families with short stature, brachydactyly, obesity, learning difficulties and mild seizures, in a picture reminiscent of Albright hereditary osteodystrophy [4, 44]. The partial overlap of manifestations (intellectual disability, seizures, obesity in some cases) justifies its inclusion in the differential diagnosis, but the mechanism, inheritance and counselling are unrelated to GNB1.

1.4. The class of neurodevelopmental disorders due to heterotrimeric G proteins

Heterotrimeric G proteins are formed by an α subunit (Gα), a β subunit (Gβ) and a γ subunit (Gγ) and transmit the signal from G protein-coupled receptors (GPCR) [3]. The genes GNB1 to GNB5 encode the Gβ subunits; Gβ1 to Gβ4 share 80–90% sequence similarity and Gβ5 is expressed mainly in neural tissue [27]. Several subunits with which Gβ1 interacts are associated with Mendelian disease, and the GNAI1 GeneReviews expressly states that various G-protein subunit genes are implicated in neurodevelopmental disorders and epilepsy [14, 45]. The sources consulted do not describe a formal classification of this «class»; the closest grouping is that of Galosi and colleagues (2022), who bring together the motor, epileptic and developmental phenotypes of the disorders of the GPCR–cAMP pathway: GNAO1, GNB1, GNAL, ADCY5, PDE10A, PDE2A and HPCA [21]. The following table organises the members of this family with clinical relevance for the diagnosis of a child with intellectual disability, epilepsy or a movement disorder.

AD: autosomal dominant.

The comparison shows that GNB1 encephalopathy shares with GNAO1 and GNAI1 the de novo occurrence and the combination of intellectual disability, epilepsy and movement disorder, and with GNB5 the combination of visual and neurological involvement, being distinguished from the latter by inheritance and by the absence of bradycardia [48, 50].

1.5. GNAO1-related disorder

GNAO1-related disorder (GNAO1-RD) is the member of the class with the most published patients and the only systematised therapeutic experience, and therefore has its own subsections in each section of the article. Nakamura and colleagues described it in 2013 in four Japanese girls with early-onset epileptic encephalopathy, three with tonic seizures in the first weeks of life and a burst-suppression pattern compatible with Ohtahara syndrome, and two of them with involuntary movements [18, 51]. In 2016, series from Japan, Israel, the United States and the Netherlands showed that recurrent variants in the same gene caused developmental delay with severe choreoathetosis and dystonia without epilepsy, which led OMIM to create two separate entries: developmental and epileptic encephalopathy 17 (DEE17, OMIM 615473, formerly termed EIEE17) and neurodevelopmental disorder with involuntary movements (NEDIM, OMIM 617493) [18, 19]. The 2023 GeneReview abandoned this dichotomy and describes a continuum with three groupings by age at onset: infantile-onset developmental and epileptic encephalopathy, with or without a movement disorder; prominent movement disorder with onset in infancy or early childhood, with a neurodevelopmental disorder and with or without epilepsy of another type; and movement disorder with onset in later childhood or adulthood, with variable cognitive impairment [9]. The German cohort of 2023 reached the same conclusion from 25 patients and rejected the idea of two main phenotypes [52]. Orphanet groups the spectrum in a single entry (ORPHA:592564, «GNAO1-related developmental delay-seizures-movement disorder spectrum») and also associates the gene with early infantile-onset developmental and epileptic encephalopathy (ORPHA:1934) [10, 20].

2. Molecular Genetics and Pathophysiology

2.1. The GNB1 gene and the Gβ1 protein

GNB1 is located at 1p36.33 and the MANE Select reference transcript (Matched Annotation from NCBI and EMBL-EBI) is NM_002074.5, which encodes the 340-amino-acid protein NP_002065.1 [2, 12]. Literature prior to 2021 uses NM_002074.4, whose coding and protein numbering coincides with that of MANE, and some reports use the alternative transcript NM_001282539.1, also with the same coding numbering [12]. The Gβ1 sequence (UniProt P62873) is identical in humans, mice, rats and cattle and differs at four residues in zebrafish, reflecting extreme evolutionary conservation [53]. The gene is expressed in all brain regions, is enriched in retinal rods and in striatal medium spiny neurons and is co-expressed with Gαo in the cortex, hippocampus and striatum [21, 53]. In neurons derived from induced pluripotent stem cells, expression is high in cortical, striatal and dopaminergic neurons [34].

Gβ1 has a β-propeller structure with seven WD40 repeats; Gγ binds one face of the propeller and Gα the opposite face, and functional residues are distributed across almost the whole protein, so that variants outside the most frequently affected regions can also be damaging [53]. Gβ1 forms an obligate dimer with Gγ, required for G-protein activity, for GDP-to-GTP exchange on Gα and for effector coupling; it also participates in bitter, sweet and umami taste transduction [11].

2.2. Gβγ signalling and neuronal effectors

In the inactive state, GDP-bound Gα covers the interaction sites of the Gβγ dimer. Agonist activation of the GPCR catalyses the exchange of GDP for GTP on Gα, which dissociates from Gβγ; both parts then regulate their own effectors [3, 14]. Gβγ effectors include adenylyl cyclase 2, β-adrenergic receptor kinase 1 (GRK2), voltage-gated calcium channels, G-protein-coupled inwardly rectifying potassium channels (GIRK, or Kir3), phospholipase C-β2 and class IB phosphoinositide 3-kinase (PI3K), as well as the MAPK pathways [3, 14]. In the neuron, Gβγ reduces excitability through three main routes: it inhibits presynaptic calcium channels (Cav2.1 and Cav2.2), activates GIRK channels and inhibits vesicular release through the synaptic vesicle fusion complex (SNARE) [21, 27]. In the striatum, Gβ1 associates with Gαolf in coupling to the dopamine D1 receptor, which links the disorder to basal ganglia physiology and explains part of the overlap with the GNAL and ADCY5 dystonias [21, 34]. Studies from 2025 added an effector: Gβ1γ2 inhibits the Nav1.1 and Nav1.6 sodium channels, with subtype-selective effects [54].

2.3. Variant spectrum and critical regions

Most pathogenic variants are missense, many recurrent, and the great majority of those tested arose de novo [3]. In GeneReviews, 73% of the 30 different missense variants were located in exons 6 and 7, and p.(Ile80Thr) was the most frequent, present in 20% of affected individuals [3]. The review by Da Silva and colleagues, with 58 patients, counted 25 of 51 missense variants (49%) in exon 6 and 20 (39%) in exon 7, that is, 88% of the missense variants in these two exons; 13 patients (25%) had p.(Ile80Thr) [53]. In the founding study, 9 of the 13 variants were located in exon 6, which corresponds to 6.4% of the coding sequence (p = 1.0 × 10⁻⁸) and encodes the region of interaction between Gα and Gβγ [14]. The residues at the interface with Gα include those of the switch interface (57, 59, 98, 99, 101, 117, 119, 143, 186, 228, 332) and those of the amino-terminal interface (55, 78, 80, 89) [14].

The gene is under intense purifying selection. In the ExAC database, only 27.6% of the 105 unique coding variants were non-synonymous, against 77.6% expected (p = 2.1 × 10⁻²⁷) [14]; in gnomAD, GNB1 is intolerant to missense (Z = 3.83) and loss-of-function variation (pLI = 1), with no single-nucleotide loss-of-function variants observed [16]. ClinGen classifies the gene–disease relationship as definitive, with autosomal dominant inheritance, and GenCC records «definitive» (ClinGen, Ambry, Illumina, G2P) and «strong» (Labcorp Genetics, PanelApp Australia) classifications [11]. In the ClinGen dosage curation, haploinsufficiency evidence scores 1 (little evidence) and triplosensitivity scores 0 [11].

The table gathers the variants of clinical or functional relevance, normalised in VariantValidator to the MANE transcript (GRCh38) according to Human Genome Variation Society (HGVS) nomenclature; the truncating variants of Lohmann and of Schultz-Rogers keep the notation published by the authors on NM_002074.4, which has the same numbering [12, 16, 35].

The review by Da Silva and colleagues records Lohmann's frameshift variant as p.His91Profs*9, and Schultz-Rogers as p.His91Profs*10; the difference does not alter the interpretation, and the Schultz-Rogers form is the one that accompanies the complete c. notation [16, 53]. The variant c.88C>T p.(Leu30Phe), described by Lohmann without functional alteration and present in 2 of about 8,000 South Asian individuals in ExAC, was considered likely benign, as were p.(His91Arg) and p.(Lys337Gln), which behaved like the wild type [35].

2.4. Mechanisms: loss of function, gain of function and haploinsufficiency

The mechanism is not uniform. Petrovski and colleagues proposed two models: disruption of the Gα–Gβγ interface, with constitutively free Gβγ, or disruption of the effector-contact residues, with reduced signalling [14]. Tumour studies had shown that p.(Asp76Gly), p.(Ile80Thr) and p.(Ile80Asn) reduce binding to almost all Gα subunits and activate the PI3K–AKT–mTOR and MAPK pathways, which is compatible with gain of function in these pathways [1, 13].

Lohmann's assays, in HEK293T cells with the D1 receptor–Gαolf–β1γ7 system, separated four behaviours: p.(Gly64Val) and p.(Ala106Thr) reduce dimer formation and expression, through instability of residues buried in the propeller; p.(Pro94Ser) and p.(Arg96Leu) increase binding to Gαolf; p.(Ala92Thr) increases the basal signal, suggesting free Gβγ, similarly to the tumour variants; p.(Arg52Gly) and p.(Asp118Gly) reduce the agonist response. The authors interpreted the seven altered missense variants as loss of function and the truncating variants as haploinsufficiency [35].

Analysis of GIRK channels showed that variants in the same hotspot can have opposite effects. In Xenopus oocytes, p.(Lys78Arg), p.(Ile80Asn) and p.(Ile80Thr) do not alter GPCR–Gi/o coupling or Cav2.2 regulation, but do alter GIRK channel regulation: p.(Lys78Arg) behaves as gain of function and p.(Ile80Thr/Asn) as loss of function, in a manner dependent on the subunit composition of the channel [28]. p.(Asp76Gly) and above all p.(Met101Val) reduce surface expression, and p.(Leu95Pro) reduces Gβ1 expression and, even with compensated expression, does not activate GIRK2 or GIRK1/2, suggesting destabilisation and misfolding [28, 57]. Colombo and colleagues interpreted the paradox (gain and loss of function in the same channel, both with epilepsy) as an imbalance between excitation and inhibition that depends on cell type and channel composition [27].

Haploinsufficiency received direct support in 2020: the splicing variant c.700-1G>T rendered the protein undetectable and the variant c.987_988del greatly reduced it, and neither activated the G protein nor formed a dimer with Gγ2 in the BRET and BiFC assays [16]. The Database of Genomic Variants (DGV) contains no whole-gene deletions in the population, and DECIPHER records 63 pathogenic deletions that include it [16]. GeneReviews considers the pathogenicity of loss of function unresolved, because the mouse heterozygous for the null allele does not differ from the wild type, unlike the mouse carrying the human missense variant [3]. The current interpretation is that the disorder is driven mainly by missense variants with altered function and that loss-of-function variants cause a milder phenotype, with frequent obesity and hyperphagia [11, 16, 22].

2.5. Animal models

The Gβ1−/− mouse has neural tube defects in about 40% of embryos, owing to abnormal actin organisation in the neuroepithelium; embryos without this defect have microencephaly and die within the first 48 hours of life, with abnormal proliferation of neural precursors [62]. In the Rd4/+ mouse, a chromosomal inversion that disrupts the second intron of Gnb1 reduces retinal messenger RNA and protein to 50% and causes dominant retinal degeneration, which provides the biological basis for the rod-cone dystrophy described in adults [2, 40].

The first model of the human disease was the Gnb1 K78R/+ knock-in mouse: homozygosity is embryonic lethal and heterozygotes have lower weight, delayed milestones, fewer ultrasonic vocalisations, impaired spatial learning and a lower seizure threshold [27]. On 24-hour electroencephalography (EEG), these animals show 1,723 ± 108.9 generalised spike-wave discharges per day, against 11.7 ± 6.5 in the wild type, with a dominant frequency of 7.3 Hz, an absence-type seizure phenotype; the heterozygous null allele (Del71/+) does not lower the seizure threshold [27]. The discharges occur mainly during wakefulness, are modulated by sensory stimuli and depend on the thalamocortical circuit [63]. In parvalbumin-positive interneurons of K78R/+ mice there is reduced GABAergic transmission and reduced sodium current [54]. A preprint from August 2026, not yet peer reviewed, describes the Gnb1 I80T/+ mouse, with developmental delay, increased anxiety, simplified dendrites, GIRK loss of function and increased dendritic excitability reversed by the GIRK activator ML297 [43].

2.6. Genotype–phenotype correlations

The proposed correlations are not conclusive. Fifty-five per cent of patients with dystonia have substitutions at Ile80; three of the four patients with cutaneous mastocytosis described up to 2021 had p.(Ile80Thr); and p.(Ile80Thr) has been associated with severe axial hypotonia or hypotonic quadriplegia [3]. In the founding study, 4 of 5 patients with a substitution at Ile80 had growth delay, against 2 of 8 of the remainder, and the two carriers of p.(Met101Val) had autism spectrum disorder [14]. Ile80 and Leu95Pro are associated with seizures beginning in the first year, often spasms with hypsarrhythmia [21]. Four of five patients with p.(Leu95Pro) had cleft palate, a statistically significant association (p = 0.00013) [1, 58]. Lohmann found no relationship between the degree of functional alteration and clinical severity [35]. Variability within the same variant is marked: p.(Gly77Ser) was associated with absence of walking and p.(Lys78Arg) with mild intellectual disability with walking and speech [16]. Truncating and splicing variants are associated with obesity in 75% of carriers, against 19% among all patients with known weight status [22].

2.7. Penetrance, expressivity and mosaicism

GeneReviews expects 100% penetrance [3]. This estimate coexists with four carrier parents described without clinical data and with families in which the variant was transmitted by parents with a mild phenotype, reflecting variable expressivity [3, 16]. One patient with a milder phenotype was mosaic for p.(Cys114Tyr) [1, 36], and in 2026 transmission of p.(Ile80Asn) from an asymptomatic mosaic father was described, whose allele fraction is not given in the published abstract [17].

2.8. Somatic variants and allelic disorders

Somatic GNB1 and GNB2 variants cluster at five residues (Lys57, Lys78, Ile80, Lys89 and Met101) on the surface of interaction with Gα and effectors; the eleven variants at Lys57 occurred in myeloid neoplasms and seven of eight at Ile80 in B-cell neoplasms [2, 13]. In Cdkn2a-deficient mouse marrow, mutated GNB1 induced myeloid or B-cell neoplasms, and the PI3K–mTOR inhibitor BEZ235 suppressed signalling and prolonged survival; the variants coexisted with BCR-ABL, JAK2 V617F (NM_004972.4:c.1849G>T p.(Val617Phe)) and BRAF V600K (NM_004333.6:c.1798_1799delinsAA p.(Val600Lys)) and conferred resistance to kinase inhibitors [13]. The acquired variant p.(Lys89Met) was described as a cause of imatinib resistance in an ETV6-ABL1 leukaemia line, through restoration of the PI3K/Akt/mTOR and MAPK pathways [25]. OMIM records ALL (613065), myelodysplastic syndrome (MDS, 614286) and chronic lymphocytic leukaemia as somatic phenotypes [2]. GeneReviews does not recognise allelic germline phenotypes other than the encephalopathy [3]; rod-cone dystrophy and the syndromic obesity of the loss-of-function forms are now treated as extensions of the spectrum of the same disorder [22, 40, 41]. The 1p36 deletion that includes GNB1 is a contiguous gene syndrome; the minimal region of 174 kb, with GNB1 and four other genes, is associated with straight eyebrows, a broad nasal root, a pointed chin and intellectual disability, a dysmorphism not shared by patients with point variants [8, 14].

2.9. GNAO1: gene, protein, mechanisms and genotype-phenotype correlations

The GNAO1 gene (OMIM 139311), at 16q13, encodes Gαo, the most abundant α subunit in the nervous system; the MANE Select transcript is NM_020988.3, which encodes the NP_066268.1 isoform [12, 15]. Gαo couples to inhibitory receptors (α2-adrenergic, dopamine D2, μ-opioid, somatostatin and muscarinic M2); receptor activation releases Gαo-GTP and Gβγ, and Gαo modulates, through the release of Gβγ, the response of type 5 adenylyl cyclase (AC5) to Gαs/olf stimuli, controlling the production of cyclic adenosine monophosphate (cAMP) in the striatum [9]. The reduction in cAMP is the pathophysiological link shared with ADCY5 dyskinesia and explains the similarity between the two movement disorders [9]. The same Go heterotrimer contains Gβ1, which directly links this disorder to GNB1 encephalopathy [21].

Mechanisms differ from variant to variant. Most missense variants behave as loss of function in receptor signal transmission, through deficient binding to Gβγ or deficient downstream signalling, and some also exert a dominant-negative effect on the normal protein [9]. In variants at codons Gly203, Arg209 and Glu246, displacement of Gln205, a residue required for GTP hydrolysis, accelerates GTP uptake and abolishes its hydrolysis; the protein remains GTP-bound without adopting the active conformation and establishes abnormal interactions with signalling partners, and the same defect occurs in variants at Gln52 [9]. In the Spanish study of 2024 (18 patients), the pathogenic variants showed abnormal GTP binding and hydrolysis, inability to interact with cellular partners and reduced receptor coupling, and reduced localisation of Gαo at the plasma membrane was associated with the DEE17 phenotype [64]. Haploinsufficiency variants, including whole-gene deletions and 16q12.2-q21 deletions encompassing GNAO1, are associated with mild phenotypes, without epileptic encephalopathy [9, 64].

Five recurrent residues (Gly40, Gly203, Arg209, Glu237 and Glu246) and one intronic variant account for about half of the published patients, and it is in these that the genotype-phenotype correlation is most robust [9]. The table uses the MANE Select transcript; all descriptions were confirmed in VariantValidator. The GeneReview gives the reference sequence as «NM_029988.3», which is a typographical error for NM_020988.3, and presents the intronic variant sometimes as c.724-8G>A and sometimes as c.724-8A>G; only the former notation matches the reference sequence (NC_000016.10:g.56351376G>A) [9, 12].

Source: 2023 GeneReview, with notation confirmed in VariantValidator [9, 12]. Dashes «—» indicate absence of disaggregated data.

The correlations are consistent for the recurrent variants, but prediction for novel variants remains limited. In the German cohort of 25 patients, in silico prediction programs did not anticipate the phenotype, and the authors did not identify an overall correlation [52]. Conversely, the GNAO1-RD severity score, developed in Barcelona in 16 patients with 12 variants, gave similar results in patients with the same variant and correlated with the molecular profile of each variant, and in the 2026 international cohort the functional analysis of 20 of the 31 missense variants correlated with the clinical score [24, 65]. In the Spanish study, variants at codon 203 were associated with DEE and those at codon 209 with NEDIM [64]. The divergence is explained partly by cohort composition: the correlations hold for recurrent variants with functional study and do not extend to private variants without such study. In the mouse, the heterozygous gain-of-function variant p.Gly184Ser causes seizures and early sudden death, unlike heterozygous loss of the gene, and the mouse with p.Arg209His has hyperactivity without seizures [18, 66].

3. Clinical Spectrum and Manifestations by System

3.1. Overall frequencies and data sources

The clinical data come from case series accumulated by exome sequencing in patients referred for developmental delay, which favours severe and paediatric phenotypes. No prospective natural history study has been published, and most patients described are children and young adults, with no systematic distinction between spontaneous course and course modified by treatment [3, 55]. The table gathers the GeneReviews frequencies (58 patients up to 2021), with the denominator for each manifestation, alongside those of the founding study and of Lohmann's aggregate of 26 patients.

Sources: [3, 14, 35]. SD: standard deviations.

Later reviews confirm the distribution. Galosi and colleagues, with about 64 patients and 38 variants up to May 2022, counted epilepsy in 30, movement disorder in 23, nystagmus in 18 and feeding difficulties in 15 [21]. Nasvytis and colleagues summarise the literature up to 2024 with intellectual disability in 74–87%, absence of verbal language in 40–72% and nystagmus in 36–46%, depending on the series [55].

3.2. Neurodevelopment, motor function and language

Developmental delay is moderate to severe in almost all patients [3]. About half do not achieve independent walking; those who do achieve it late, often after 3 years of age, with abnormal gait and falls, and one patient began walking alone at 9 years after intensive physiotherapy [3, 21, 55]. Language is more affected than motor function and expression more than comprehension: about 40% of the GeneReviews patients were non-verbal and, in the Hemati series, more than half had neither walking nor verbal language [3, 36, 55]. In two patients with normal hearing, sign language improved communication [3]. Intellectual disability is mild to severe in about 74%; two patients older than 6 years had no intellectual disability, and cognition is poorly documented in older patients [3, 35]. Regression is rare (3 of 57 patients): one infant became visually inattentive, hypotonic and lethargic at 8 weeks and regressed again with the onset of spasms at 7 months, and two lost language before 3 years of age [3, 55].

3.3. Muscle tone and movement disorders

The characteristic pattern is infantile axial hypotonia evolving to appendicular hypertonia and spasticity [3, 55]. Hemiplegia, severe dyskinetic quadriplegia and spastic diplegia have been described, the last in a patient initially diagnosed with cerebral palsy [3, 38, 67]. Dystonia is the most frequent movement disorder, with onset between 2 and 16 years, and ranges from mild dystonic posturing of the fingers to generalised dystonia with cranial involvement [3, 55]. In the Galosi review, of the 23 patients with a movement disorder, 12 had dystonia (more often with p.(Ile80Thr), p.(Leu95Pro), p.(Asp118Tyr) and p.(Asp118Gly)), 2 myoclonus-dystonia, 5 ataxia, 3 choreoathetosis, 4 stereotypies, 2 tics, 1 bradykinesia, 3 episodic exacerbations or status dystonicus and 6 spasticity [21]. In the Lohmann series, 4 had ataxia, 1 chorea and 1 dystonia, and 4 had ophthalmoplegia [35].

Paroxysmal exacerbations bring the disorder close to GNAO1 and ADCY5. An Italian man with p.(Asn119Lys) had, at 20 years of age, two severe dyskinetic episodes during pneumonia, requiring intensive care admission, and subsequently had episodes on awakening, lasting 2 to 4 hours, two to three times a month [59]. Status dystonicus with dystonic hypertonia was described in a Japanese patient [3, 38]. A rare variant in exon 11 was associated with dystonia, myoclonus and vertical supranuclear gaze palsy [68]. Dystonia cohorts show that GNB1 also appears in patients whose dominant presentation is motor: in a Turkish national cohort of 81 children, GNB1 explained 1 case (1.2%), and in an exome study of 1,924 patients with dystonia, mostly isolated and late-onset, one of the six de novo variants found was in GNB1 [69, 70]. In an Indian series of 32 children with genetic DEE and movement disorder, GNB1 was among the genes with paroxysmal dyskinesias [71].

3.4. Epilepsy and electroencephalogram

Epilepsy occurs in about half of patients (27/51 in GeneReviews; 16/31 in the Petrovski and Hemati series) and, according to the authors of the mouse model, in almost 60% [3, 16, 27]. Seizures usually begin between the first and fourth years, but there are epileptic spasms from 4 to 7 months [14, 27]. The types described include tonic seizures, absences, myoclonic, atonic, generalised tonic-clonic, focal, hemiclonic and sleep-related hypermotor seizures, epileptic spasms and convulsive and non-convulsive status epilepticus, sometimes preceded by febrile status epilepticus [3, 14, 21]. GNB1 was identified as a candidate gene for West syndrome in a Chinese cohort of 56 families, and several patients had infantile spasms with hypsarrhythmia [3, 38, 72]. Epilepsy is often drug-resistant or controlled only with two or more antiseizure medications (ASMs) [21]. The EEG may be normal in the first years; later, hypsarrhythmia, burst-suppression, slow generalised discharges and multifocal discharges appear, mainly temporal and abundant in sleep [3, 14]. In the Italian adult with p.(Asn119Lys), drug-resistant epilepsy beginning at 12 months resolved in late adolescence [59]. In the International League Against Epilepsy (ILAE) nosology, these patients fall within the developmental and epileptic encephalopathies, with each patient classified by syndrome (for example, infantile epileptic spasms syndrome) and by aetiology [73, 74].

3.5. Neuroimaging

MRI is normal in about half of patients, especially in the first years [3]. The abnormalities described include abnormal or delayed myelination, corpus callosum abnormalities, loss of brain volume, ventriculomegaly, widening of the subarachnoid spaces, cerebellar hypoplasia, diffuse periventricular white matter changes, caudate nucleus abnormalities and, in one patient with p.(Ile80Asn), bilateral polymicrogyria [3, 14, 55]. In the Lithuanian adult woman with p.(Asp76Asn), MRI showed bilateral hypointensity of the globi pallidi on T2 and FLAIR (fluid-attenuated inversion recovery), corresponding to calcification on computed tomography, with slight progression and new lesions of the dentate nuclei four years later [55].

3.6. Vision and hearing

Ophthalmological abnormalities occur in about 60% of patients [3]. Nystagmus is the most common finding (36%), horizontal, vertical, rotatory or multivectorial, and improved with age in two patients [3]. Strabismus, upward vertical gaze palsy, gaze deviation, slow ocular pursuit, continuous reverse ocular dipping and ophthalmoplegia also occur [3, 35]. Cortical visual impairment or optic atrophy affects 11%, with one patient legally blind [3]. Ocular albinism and possible cone-rod dystrophy have been described in patients with no other genetic cause [3]. In 2023 the first GNB1-related rod-cone dystrophy was confirmed in a 45-year-old adult with a mild neurological phenotype, and in 2024 a second case, consistent with the function of Gβ1 in transducin and with the Rd4 mouse model [2, 40, 41]. Severe sensorineural hearing loss, unilateral or bilateral, is rare (6%); one patient had hypoplasia of the right cochlear nerve and another mixed hearing loss [3].

3.7. Growth, feeding, digestive system and obesity

About half of patients with a documented neonatal history have poor weight gain and feeding difficulty, which most (8 of 11) overcome; growth delay persists in 20% [3]. Reviews indicate growth delay in the first years in 38–50%, with later catch-up in most [55]. Digestive complaints include recurrent constipation, cyclical vomiting, gastro-oesophageal reflux and abdominal distension with colic, and in the Hemati series 61% of patients had gastrointestinal anomalies [3, 36]. Severely affected patients may require tube feeding or gastrostomy [21].

Obesity is a manifestation specific to loss-of-function variants. In the Kleinendorst review (genetic obesity centres in Amsterdam, Rotterdam and Porto), among 42 patients with known weight status, 8 (19%) were obese, a proportion that rose to 75% in the subgroup with truncating or splicing variants [22]. The cases described combine hyperphagia, obesity refractory to diet and exercise and intellectual disability, with initial suspicion of Prader-Willi or fragile X syndrome [16, 61, 75]. The authors relate GNB1 to the hypothalamic leptin–melanocortin pathway and propose it as a candidate gene for obesity in the 1p36 deletion [22].

3.8. Other systems

In boys, genitourinary anomalies include cryptorchidism, bifid scrotum, duplication of the collecting system and hydronephrosis, present in 50% of the boys in the Hemati series [3, 36]; a Polish girl had severe vesicoureteral reflux with unilateral nephrectomy [1]. The cardiovascular defects described are a ventricular septal defect and a duplicated superior vena cava [3]. Cleft palate occurred in five patients, often with p.(Leu95Pro), and craniosynostosis in three [3, 58]. Congenital peripheral hypothyroidism and subclinical hypothyroidism (one case each), autoimmune thyroiditis in an obese adolescent girl and congenital hypothyroidism with transient hyperoxaluria in a 2-year-old child have been described [3, 61]. Dysmorphic features, when present, are mild and non-specific, without a recognisable gestalt [1, 3].

3.9. Cutaneous mastocytosis

Cutaneous mastocytosis was described in 4 of 34 patients assessed in GeneReviews, including monozygotic twins; the case of Lattanzio and colleagues, in 2022, was added to the four previous ones [3, 76]. The most common presentation is urticaria pigmentosa (maculopapular cutaneous mastocytosis), and in a Polish girl the lesions appeared at the end of the first year and were confirmed by biopsy [1, 3]. Exome sequencing of the twins' fibroblasts found no other causal variants, loss of heterozygosity or somatic KIT or JAK2 variants [3]. The 2016 European and American consensus distinguishes the polymorphic form, typical of children and which may resolve around puberty, from the monomorphic form, typical of adults and more persistent when it arises in childhood [77]. In children younger than 5 years, cutaneous mastocytosis is generally benign and rarely progresses to systemic mastocytosis [3, 78]. Saudubray's textbook includes the mastocytosis of GNB1 encephalopathy, as a defect of the G-protein signalling pathway, in the table of dermatological signs in the clinical approach to inborn errors of metabolism in children [79].

3.10. Haematological neoplasms

ALL was described in a child from Singapore with a de novo germline variant [37]. Because somatic variants at the same residues are oncogenic in myeloid and B-cell neoplasms, Petrovski proposed prospective observation of the risk [13, 14]. None of the 13 patients in the founding series had a neoplasm, and there are no incidence data; the evidence base is a single case [3, 14].

3.11. Behaviour and mental health

Behavioural problems affect 42% of patients assessed and include stereotypies, repetitive behaviours, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) [3]. In less severely affected patients, behavioural disturbances may be the main source of disability: the Portuguese girl with p.(Ala73Thr) had, at 15 years, self-directed and other-directed aggression and obsessive behaviour as the dominant problems [53], and the patients with loss-of-function variants described by Schultz-Rogers had depression, violent behaviour, psychiatric episodes and suicidal ideation in adulthood [16]. There are repeated reports of extrapyramidal effects with antipsychotics [53].

3.12. Acute encephalopathy

Two Japanese patients had acute encephalopathy with severe sequelae: an 8-month-old infant girl with p.(Leu95Pro), influenza A and generalised seizures, who progressed to diffuse cerebral atrophy, spastic tetraplegia, severe intellectual disability and refractory epilepsy; and a 17-year-old boy with p.(Ile80Thr), respiratory arrest of unidentified cause and refractory seizures, with basal ganglia hyperintensity, cortical and white matter atrophy and regression [42]. The authors recommend considering this course in the face of acute neurological deterioration [42].

3.13. Adulthood

Life expectancy and causes of death are unknown. One child died at 4 years of age of an undetermined cause [3]. In 2021, three patients older than 18 years had been published and one aged 38 years was unpublished, in addition to four carrier parents [3]. Subsequent reports of adults (34, 40, 45 and 25 years) show progressive dystonia with loss of walking, epilepsy that may resolve, obesity, psychiatric disease and retinal dystrophy [16, 40, 55, 59]. GeneReviews acknowledges that adults may be under-recognised, because many adults with disabilities have never undergone genomic testing [3].

3.14. GNAO1-related disorder: clinical spectrum and natural history

The data come from published series (more than 200 patients up to 2023), from three national cohorts and from an international cohort with prospective follow-up. In the international cohort coordinated in Barcelona (66 patients, aged 3 months to 25 years, data collection from 2021 to 2024), the first manifestations were motor delay or hypotonia (54.5%), epilepsy (28.8%) and movement disorder (12.1%); 45.5% had no head control, 22.7% walked unsupported and 65% had no expressive language [24]. Movement disorder was present in 95.5%, mainly dystonia (86%) and chorea (63.6%), with a mean onset at 2.37 years (half of the patients already had it at 12 months); dyskinetic crises occurred in 54.5%, with a mean onset at 4.54 years [24]. Epilepsy affected 51.5%, with 82.3% of cases drug-resistant and half of the epilepsies beginning by 2 months of age; 39.4% required gastrostomy [24]. In the German cohort (25 patients up to 2023), symptoms began in the first months with central hypotonia or seizures, almost all developed a movement disorder in the first year with dystonia (84%) and choreoathetosis (52%), 48% had life-threatening hyperkinetic crises and 60% had epilepsy with poor response to treatment [52]. In the Spanish series of 18 patients, 11 had neurological deterioration with recurrent hyperkinetic crises, partial recovery and a distinct post-crisis state, and three died of secondary complications; the authors emphasise the fluctuation of the movement disorder over the course of the day [64].

Epilepsy occurs in 50–65% of published patients; DEE accounts for 69% of the epilepsies, sometimes begins on the first day of life and usually in the first 3 months, with epileptic spasms, tonic seizures or resistant focal seizures, and may evolve into infantile spasms syndrome or Lennox-Gastaut syndrome [9]. The electroencephalogram has no specific pattern: burst-suppression in early infantile-onset DEE, hypsarrhythmia in spasms and slow spike-wave in Lennox-Gastaut syndrome [9]. In the forms without DEE, focal or generalised tonic-clonic seizures begin between 3 and 10 years, may be rare or well controlled and contrast with a resistant movement disorder [9]. Axial hypotonia is often the first manifestation, and about 80% of patients never walk; dysarthria affects 60–80% and anarthria 20–30%, 20–40% need help with eating and 30–50% need a gastrostomy or nasogastric tube [9]. Language comprehension is relatively preserved, and some patients communicate with eye-tracking systems [9]. Magnetic resonance imaging is normal in most, especially before 5 years; in older children cortical and cerebellar atrophy, white matter changes and changes of the thalami and globi pallidi appear [9, 19].

Dyskinetic crises define the severity of the disorder. A Delphi consensus of 13 experts (2024) defined them as abrupt, paroxysmal episodes of abnormal involuntary movements in several body regions, distinct from the baseline movement disorder, lasting minutes to hours and less often days or weeks, which may recur several times a day and are triggered mainly by emotional stress, anxiety, excitement, pain and respiratory or urinary infections [80]. In the most severe form, termed status dyskineticus (synonymous with status dystonicus in this disorder), rhabdomyolysis, renal failure, hyperthermia, malnutrition, respiratory difficulty and long-bone fractures occur [80]. Almost half of the published patients have prolonged exacerbations, and recovery may take weeks to months [9]. Natural history followed prospectively in 21 patients for up to four years showed stability or slight improvement in cognition, language, adaptive skills and motor function, without global neurodegeneration; in severely affected patients, however, the movement disorder worsened progressively and accumulated disability [24]. In the multinational cohort of 609 patients with epilepsy-dyskinesia syndromes, GNAO1 was one of the three most frequent genes, alongside MECP2 and ATP1A3 [81].

4. Clinical Recognition and Warning Signs

4.1. When to suspect the disorder

The phenotype does not allow a clinical diagnosis, and suspicion is mainly pattern-based [3]. GeneReviews describes as suggestive moderate to profound developmental delay or intellectual disability associated with one or more of the following features, in infancy or childhood: generalised hypotonia that may evolve to hypertonia and spasticity; feeding difficulty and poor weight gain; movement disorder (dystonia, tics, ataxia, chorea); generalised, focal or mixed epilepsy or infantile spasms; stereotypies, ADHD or ASD; macrocephaly; slow growth; visual impairment due to optic atrophy or cortical visual impairment, or abnormal eye movements (strabismus, nystagmus); chronic constipation, cyclical vomiting, reflux or abdominal distension with colic; cleft palate or craniosynostosis [3].

4.2. Warning and emergency signs

Epileptic spasms require prompt diagnosis and treatment, because a short interval to treatment may improve the developmental prognosis [82, 83]. Acute neurological deterioration during an infection (refractory seizures, respiratory arrest) should lead to consideration of acute encephalopathy, described in two patients with severe sequelae [42]. Severe and prolonged dyskinetic or dystonic exacerbations, particularly with fever, may progress to status dystonicus and required intensive care admission in one adult [38, 59]. Easy bruising, as a sign of thrombocytopenia, should prompt a full blood count, given the association described with ALL; GeneReviews recommends teaching families this sign [3, 37]. Choking, recurrent respiratory infections and food refusal suggest dysphagia with a risk of aspiration [3].

4.3. Newborn screening

There is no newborn screening for this disorder; in the Portuguese girl described, metabolic screening and neonatal otoacoustic emissions were normal [53]. Identification depends on genomic testing requested for developmental delay or epilepsy.

4.4. GNAO1-related disorder: when to suspect it and emergency signs

GNAO1-related disorder should be considered in the infant with axial hypotonia and global delay who develops choreoathetosis or dystonia, especially if the movements worsen with fever, pain, excitement or voluntary movement, and in the neonate or infant with resistant epilepsy, spasms or burst-suppression on the electroencephalogram [9]. In the older child, adolescent or adult, isolated dystonia or dystonia with mild cognitive impairment also justifies testing of the gene, especially if there is vertical transmission [9]. Distinguishing paroxysmal dystonia from an epileptic seizure may require video-electroencephalography [9].

Emergency signs are a prolonged dyskinetic crisis or one that does not respond to home rescue treatment, loss of sleep, dehydration, fever, sweating, tachycardia or hypertension during a crisis, respiratory difficulty and dark urine [19, 80]. In these cases, the consensus calls for exclusion of rhabdomyolysis, electrolyte disturbances and kidney injury, which entails measuring creatine kinase, electrolytes and renal function [80]. In the ZINCGNAO1 trial, a dyskinetic crisis was defined operationally as an acute exacerbation above the usual severity lasting more than 1 hour with autonomic signs, such as sweating, tachycardia or insomnia [30].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal clinical criteria [3]. The diagnosis is established in a proband with suggestive findings by identification of a heterozygous pathogenic or likely pathogenic variant in GNB1; for clinical purposes, the two classes of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) are equivalent [3]. There is no laboratory biomarker: full blood count, copper, caeruloplasmin, amino acids, organic acids and cerebrospinal fluid neurotransmitters are normal, and MRI and EEG characterise the phenotype without indicating the aetiology [11, 34, 55].

5.2. Algorithm and order of testing

GeneReviews proposes two steps: first, chromosomal microarray (CMA, oligonucleotide or single-nucleotide polymorphism) in a child with developmental delay or intellectual disability, which detects 1p36 deletions including GNB1; if CMA is not diagnostic, an intellectual disability multigene panel with detection of deletions and duplications, exome or genome [3]. Single-gene testing is rarely useful and is not recommended, because specific clinical suspicion is difficult [3]. Some intellectual disability panels do not include GNB1, and panel composition should be checked before ordering [3]. The 2021 ACMG guideline recommends, on the basis of evidence graded by the GRADE method, considering exome or genome as a first- or second-line test in patients with congenital anomalies with onset before 1 year of age or with developmental delay or intellectual disability with onset before 18 years, given the higher yield and possible cost-effectiveness of early testing [26]. In practice, the sequence is as follows: clinical assessment and documentation of the phenotype; CMA, or trio exome/genome as first line when available; in patients with epileptic spasms or DEE, an epilepsy panel or exome; targeted parental testing to establish de novo origin; and complementary assessment of each system after diagnosis (section 11). In a trio exome study of 21 children with infantile spasms, the yield was 5/21, including a likely pathogenic de novo variant in GNB1 [84].

5.3. Yield and limitations of testing

Of the 58 GeneReviews probands, 57 had a variant detectable by sequencing and 1 had an intragenic deletion of exons 2 to 5, recorded in DECIPHER with limited clinical information [3]. These proportions refer to patients already diagnosed and are not equivalent to the clinical sensitivity of the tests [3]. In undiagnosed-disease exome databases, GNB1 variants accounted for less than 0.5% of more than 10,000 exomes, and no carrier was found among about 100 patients tested by Sanger sequencing (51 Germans with epilepsy and intellectual disability and 40 Serbians with a Rett-like picture) [35].

A negative result does not exclude the diagnosis. The exome has limited coverage of deletions and duplications of one or a few exons, and GeneReviews suggests an exome array when the exome is not diagnostic [3]. Deep intronic variants and splicing variants outside the canonical dinucleotides may not be recognised: the variant c.700-1G>T was only interpreted with SpliceAI prediction and blood RNA, in which 18% of reads used a cryptic acceptor [16]. Low-level mosaicism in the proband or in a parent may escape routine sequencing, and the variant p.(Ile80Thr) once appeared in the ExAC database as a low-confidence singleton with 13% alternative reads, interpreted as a post-zygotic event or artefact [14, 17]. Patients with contiguous gene deletions at 1p36 are not included in the statistics for the point-variant disorder [3].

5.4. Variant interpretation and report content

The report should state the gene, the transcript with version (NM_002074.5, MANE Select), the HGVS (Human Genome Variation Society) c. and p. nomenclature and the genomic coordinate with the genome build, the zygosity, the origin (confirmed de novo, inherited or unknown) and the ACMG/AMP classification with the criteria applied [3, 12]. For variants described on NM_001282539.1, the genomic coordinate allows conversion to MANE; for example, NM_001282539.1:c.217G>A corresponds to NM_002074.5:c.217G>A p.(Ala73Thr) [12]. Elements supporting the pathogenicity of a novel missense variant include confirmed de novo origin, location in exons 6 and 7 or at an interface with Gα, Gγ or effectors, absence from the population in a gene with a missense Z of 3.83, coincidence with residues of variants already classified and functional demonstration in BRET/BiFC or GIRK channel assays [16, 28, 35, 53]. In the Portuguese girl, classification as pathogenic was based on criteria PS2 (de novo) and PS3 (functional study), according to the authors [53].

Variants of uncertain significance (VUS) require segregation studies and, where possible, functional assessment. Variants outside the most frequently affected regions, such as those in exon 11, may be pathogenic, and variants with normal behaviour in assays, far from the interfaces and present in the population, such as p.(Leu30Phe), tend to be benign [35, 68]. A variant inherited from an apparently healthy parent does not exclude pathogenicity, because there is transmission by parents with a mild phenotype and through mosaicism [17, 35]. Concomitant secondary findings should be interpreted with caution: one of the Schultz-Rogers patients also had a variant of uncertain significance in SPTBN1 [16].

5.5. Complementary investigations guided by the diagnosis

After diagnosis, awake and sleep EEG is recommended even without clinical seizures, to detect subtle or subclinical seizures, together with brain MRI [3, 55]. In infancy, the ILAE classifies MRI as a standard test in tertiary care (level A), genetic assessment of the epileptic encephalopathies as available in tertiary care (level C) and video-EEG as useful for abnormal movements with a non-diagnostic EEG (level U) [82]. The remaining assessments (ophthalmology, audiology, echocardiography, renal ultrasound, thyroid function, full blood count, skin) are listed in section 11.

5.6. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing (PGT) are possible when the familial variant is known, both in families with a carrier parent and, because of the possibility of germline mosaicism, in couples with an apparently de novo variant [3]. The sources consulted do not describe characteristic prenatal ultrasound findings, and the 2024 review found no data on the effects of the disorder on pregnancy or delivery [55].

5.7. GNAO1-related disorder: diagnosis

There are no consensus clinical criteria; the diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic or likely pathogenic GNAO1 variant, and a variant of uncertain significance neither confirms nor excludes the diagnosis [9]. The recommended approach begins with chromosomal microarray in the child with developmental delay and continues with an epilepsy or movement disorder panel that includes GNAO1, or with exome or genome; single-gene testing is rarely useful [9]. Among published patients, sequencing detects 98.5% of pathogenic variants and targeted deletion/duplication analysis 1.5% (one whole-gene deletion and one intragenic deletion); these percentages describe the proportion of variants detectable by each method and not the clinical sensitivity of the test [9]. At least four contiguous gene deletions at 16q12.2-q21 including GNAO1 have been identified by microarray, with seizures in four patients and a movement disorder in one [9]. The somatic mosaicism described in the first study (35–50% of cells) and the intronic variant c.724-8G>A, which falls outside some exome filters centred on coding regions, are possible causes of a false-negative result [9, 51]. The authors of the GeneReview offer to review GNAO1 variants of uncertain significance, and the severity score and the molecular profile of the variant help to estimate the prognosis [9, 65].

6. Differential Diagnosis

6.1. Principles

Because the phenotype is non-specific, the differential diagnosis covers all causes of intellectual disability and early-onset epilepsy without other distinguishing findings, including the OMIM phenotypic series of autosomal dominant, autosomal recessive and X-linked intellectual disability and of early infantile epileptic encephalopathy [3]. In practice, the useful differential is organised into four groups: other disorders of G proteins and of the GPCR–cAMP pathway, with a combination of epilepsy and movement disorder; chromosomal and contiguous gene syndromes; syndromes with obesity and hyperphagia, for the loss-of-function forms; and genetic dystonias with onset in childhood.

6.2. GNAO1: the closest differential

Gαo forms with Gβ1 the Go heterotrimer, co-expressed in the cortex, hippocampus and striatum, and the two disorders share the combination of encephalopathy and hyperkinetic movement disorder [21, 51]. Nakamura and colleagues described in 2013 four patients with epileptic encephalopathy and de novo GNAO1 variants, two with involuntary movements and one with somatic mosaicism in 35–50% of cells [51]. In GNAO1-related disorder, epilepsy occurs in 50–65% and, among these, 69% have DEE, often in the first 3 months; the movement disorder begins between 1 and 4 years, with exacerbations triggered by fever, stress or illness that may reach status dystonicus and have caused death in at least five children [9]. In GNB1 encephalopathy, movement disorder affects more than a third of patients and the sources consulted describe no deaths during hyperkinetic crises, but paroxysmal episodes triggered by fever do occur and justify the same vigilance [21, 59]. OMIM summarises two lines of genotype-phenotype correlation in GNAO1, which is located at 16q13. In the review of 26 published patients by Menke and colleagues (2016), the recurrent variants at codons 209 and 246, located in CpG dinucleotides susceptible to spontaneous deamination (p.(Arg209His), p.(Arg209Cys), p.(Arg209Gly) and p.(Glu246Lys)), were associated with developmental delay with hyperkinetic movement disorder and without seizures (NEDIM), whereas variants at other residues were associated with infantile-onset DEE17; from sibling pairs with the same de novo variant, the authors estimated a recurrence risk of 5–15% after one affected child [15]. Feng and colleagues (2017) studied 15 de novo variants in HEK293 cells: nine showed loss of function in cAMP inhibition, generally with reduced protein quantity, and were associated with DEE17; six had normal function or gain of function and were associated with movement disorders with or without epilepsy, among them p.(Gly203Arg), described in two girls with neonatal-onset seizures or infantile opisthotonus, followed by severe chorea [15]. In the mouse, the heterozygous gain-of-function variant p.Gly184Ser caused severe seizures and early sudden death, which did not occur in the heterozygous mouse with loss of the gene [15]. Only genetic testing reliably distinguishes the two entities.

6.3. GNB5: the other Gβ subunit

Lodder-Merla syndrome is autosomal recessive and combines sinus bradycardia or sinus node dysfunction, retinal disease, intellectual disability, reflux, hypotonia and seizures [46, 50]. Severity correlates with variant type: homozygous null alleles cause type 1, with severe intellectual disability and arrhythmia, and biallelic missense variants cause type 2, with language delay, mild intellectual disability and variable arrhythmia [46–48]. The practical distinction from GNB1 is recessive inheritance, frequent consanguinity and bradycardia; the GNB5 GeneReviews recommends avoiding parasympathomimetics, because of the risk of asystole, and β-blockers [48].

6.4. GNAI1

GNAI1-related disorder was defined in 2021 in 24 patients, 23 with a de novo variant and 1 with a variant inherited from a mosaic parent, with global delay, intellectual disability, hypotonia, self-limited to refractory epilepsy, behavioural changes and mild dysmorphism, a picture overlapping with that of GNB1 [85]. Obesity with insatiable appetite in some patients with GNAI1 resembles the phenotype of GNB1 loss-of-function variants [22, 45].

6.5. 1p36 deletion

The 1p36 deletion is the most frequent terminal deletion syndrome in humans, with about 1 in 5,000 births, and combines characteristic facial dysmorphism, cardiomyopathy, hearing loss, seizures and intellectual disability [8]. Rosenfeld and colleagues described five patients with interstitial deletions of 200 to 823 kb at 1p36.33, whose minimal region of 174 kb included GNB1; these patients shared straight eyebrows, a broad nasal root, a pointed chin and low-set ears, features absent in patients with point variants [8, 14]. Deletions limited to GNB1 are a form of the encephalopathy itself through haploinsufficiency.

6.6. SBIDDS (PRMT7)

SBIDDS was described in 2015 by the DDD study (Deciphering Developmental Disorders), which found biallelic PRMT7 variants in six women from three families, aged between 6 and 23 years, walking between 2 and 5 years, with learning difficulties or mild intellectual disability, short stature (−1.4 to −2.9 SD), obesity, brachydactyly and short metacarpals and metatarsals, in a picture reminiscent of Albright hereditary osteodystrophy; two sisters had pseudohypoparathyroidism and four patients had mild, controlled seizures [4, 44]. In 2017, an Afghan boy of consanguineous parents with a homozygous 15,309 bp deletion, which removes the transcription start of PRMT7, had severe intellectual disability, microcephaly of −4 SD, dysmorphism, brachydactyly, cryptorchidism and seizures from 4 years of age; his cells showed reduced arginine methylation of histones H2B and H4 and altered Wnt signalling [4, 87]. Agolini and colleagues reviewed seven published patients and added three from two consanguineous Italian families, suggesting a relationship between variant type and severity [86]. In 2023, two dizygotic twin girls with compound heterozygous variants, one of them with growth hormone deficiency, were treated with somatropin and gained 0.52 and 0.88 SD in height in the first year; 15 cases had been published by 2022 [23]. Proportionate short stature with brachydactyly, recessive inheritance and the pseudohypoparathyroidism phenocopy distinguish it from GNB1 encephalopathy, in which short stature occurs in 20% and there are no skeletal anomalies of the hands [3].

6.7. Loss-of-function forms with obesity

In children and adults with mild intellectual disability, hyperphagia and obesity, GNB1 encephalopathy due to a truncating or splicing variant enters the differential diagnosis of syndromic obesity, alongside Prader-Willi and fragile X syndromes, which were the first hypotheses in the Schultz-Rogers patients [16]. The overlap with the obesity of the 1p36 deletion and with that of GNAI1 reinforces the relationship between G-protein signalling and hypothalamic control of appetite [22, 45].

7. Treatments and Risk Management Strategies

7.1. General principles and evidence base

There is no disease-modifying treatment and no specific guideline or consensus for GNB1 encephalopathy; management is symptomatic and multidisciplinary and is based on GeneReviews, on an evidence base of case series and expert opinion, without clinical trials [3, 11, 55]. The pharmacological recommendations are therefore extrapolated from the guidelines for analogous conditions (infantile epileptic spasms, infantile epilepsy, paediatric spasticity and dystonia, cutaneous mastocytosis) and from official labels. In the dosing tables below, the guideline dose is the reference where one exists; where the guideline sets no dose, the label dose is used, comparing the United States Food and Drug Administration (FDA) label with the Summary of Product Characteristics (SmPC) approved by INFARMED in Portugal. All uses are, in relation to GNB1 encephalopathy, symptomatic and not aetiological.

7.2. Epilepsy

GeneReviews recommends treatment with standard ASMs, chosen by an experienced neurologist, and emphasises that many ASMs may be effective but none has shown specific efficacy in this disorder [3]. The 2024 review confirms that there is no proven preference for any drug [55]. Epilepsy is often drug-resistant and often controlled only with two or more ASMs [21]. The 2015 ILAE recommendations for infants apply by analogy: in infantile epileptic encephalopathies, rapid introduction and escalation of ASMs (expert opinion); in focal seizures, strong evidence of efficacy for levetiracetam; in generalised seizures, weak evidence for levetiracetam, valproate, lamotrigine, topiramate and clobazam; insufficient evidence for vagus nerve stimulation [82]. Dosing of these ASMs follows that of the corresponding epilepsy syndromes.

7.2.1. Infantile epileptic spasms

For epileptic spasms, the ILAE considers corticotropin (ACTH) preferable for short-term control (level B), oral corticosteroids probably effective (level C) and a short interval to treatment potentially favourable for developmental prognosis (level C) [82]. The 2012 update of the American Academy of Neurology and the Child Neurology Society (AAN/CNS), since retired by the AAN, concluded that low-dose ACTH is probably as effective as high-dose ACTH, that ACTH or vigabatrin are useful in the short term with a preference for ACTH (except in tuberous sclerosis) and that hormonal therapy may be preferred to vigabatrin in spasms without an identified cause, because of the possibility of better development [83]. In GNB1 encephalopathy, an infant with spasms at 4 months remitted with ACTH and relapsed 6 months later, and another with West syndrome relapsed after the first course and became seizure-free after a second course, with a subsequent EEG without epileptiform activity [38, 55].

Vigabatrin deserves a specific weighing in this disorder: about 60% of patients already have a visual abnormality, with cortical visual impairment, optic atrophy, nystagmus or retinal dystrophy, which makes retinal toxicity difficult to detect and reduces visual reserve. This consideration is an inference from the safety profile of the drug and the phenotype, not a published recommendation for GNB1 [3, 40, 91].

7.2.2. Absence-type seizures and the rationale for ethosuximide

The K78R/+ mouse model has absence-type seizures that ethosuximide (200 mg/kg intraperitoneally; n = 21) and valproate (200 mg/kg; n = 21) almost abolished acutely, whereas phenytoin (30 mg/kg; n = 7) had no effect [27]. In cortical neuron cultures, ethosuximide at 750 µM, within the human therapeutic range estimated by the authors (300–750 µM), restored a near-normal firing pattern, with no effect at 250 µM and excessive suppression at 2 mM; ethosuximide blocks GIRK channels with greater affinity when they are activated by Gβγ [27]. These data are exclusively preclinical and refer to a GIRK gain-of-function variant; in loss-of-function variants, such as p.(Ile80Thr), the mechanistic rationale points instead to GIRK activators, also only in models [28, 43]. In patients with absence seizures, ethosuximide is used within its approved indication; choosing it because of the genotype would be use outside an aetiological indication.

7.3. Dystonia, myoclonus and paroxysmal dyskinesias

The pharmacological response of the movement disorder is generally limited: in 2022 there were only three reports of pharmacological treatment, no drug markedly improved the movement disorder, levodopa was ineffective and DBS improved dystonia in two patients [21]. The 2024 review summarises the responses described: trihexyphenidyl had limited benefit (it reduced myoclonus and caused agitation); levodopa worsened dystonia; clonazepam had no effect on dystonia; risperidone, dantrolene and phenobarbital had limited success; clobazam, haloperidol, valproate, methylphenidate and olanzapine worsened symptoms or had no effect [55]. In the German girl with p.(Asp118Gly), levodopa with benserazide (Madopar®) worsened dystonia [34]. By analogy, the GeneReviews for GNAO1-related disorder lists for severe movement disorder tetrabenazine, gabapentin, clonidine, trihexyphenidyl, oral baclofen, benzodiazepines and, in refractory forms and hyperkinetic crises, DBS of the globus pallidus internus or the subthalamic nucleus [9].

The only detailed regimen published for GNB1 is that of the Italian adult with paroxysmal dyskinesias: lorazepam 3 mg/day combined with tetrabenazine 25 mg/day greatly reduced the frequency and severity of the episodes, trihexyphenidyl 6 mg/day was useful for the baseline dystonia and buccal midazolam 10 mg was effective in the paroxysmal episodes [59]. These doses come from a single adult patient, in off-label use, and do not constitute recommended dosing.

7.3.1. Deep brain stimulation

Bilateral pallidal DBS is the preferred neuromodulation in refractory dystonia [55]. In an Australian patient with p.(Asp118Tyr) and myoclonus-dystonia, DBS of the globus pallidus internus at 15 years immediately improved the myoclonus and transiently improved the dystonia [39, 55]. A Croatian and Slovenian report from 2023 described another response to DBS [98], and the Lithuanian adult woman with p.(Asp76Asn) was proposed for DBS by multidisciplinary decision in January 2024, after levodopa, baclofen and clonazepam had failed [55]. The international DBS MatchMaker registry (NCT06912841), which includes GNB1 among its conditions, aims to gather the scattered experience of DBS in rare movement disorders [99]. The public page of the registry, maintained by the Ebrahimi-Fakhari laboratory at Boston Children's Hospital, listed on 29 October 2026 a total of 253 cases in 90 genes, with GNAO1 as the most represented gene (26 cases) and GNB1 among the genes with fewer than five cases; the public text does not break down benefit by patient, and therefore does not allow the response to DBS in GNB1 encephalopathy to be estimated [100]. In the Turkish cohort of childhood dystonia, the genetic diagnosis changed treatment, pharmacological or with DBS, in 60.5% of patients, which reinforces the value of molecular diagnosis before surgery [69].

7.3.2. Acute exacerbations

In the Italian adult, the most severe dyskinetic episodes occurred during pneumonia and required intensive care admission, and buccal midazolam was effective in the subsequent paroxysmal episodes [59]. The sources consulted do not describe a treatment protocol for these exacerbations in GNB1 encephalopathy. In GNAO1-related disorder, emergency DBS has been used in refractory hyperkinetic crises [9]. In the face of acute neurological deterioration during infection, the acute encephalopathy described in two patients should be considered [42].

7.4. Spasticity and hypertonia

For hypertonia and dystonia, GeneReviews lists baclofen, tizanidine, botulinum toxin, antiparkinsonian drugs and orthopaedic procedures, without doses [3]. The dosing below is that of the labels for spasticity of other causes, applied by analogy; in GNB1 encephalopathy, oral baclofen up to 5 mg three times daily caused drowsiness without benefit in one adult woman and was stopped after one month [55]. The response to oral baclofen does not predict the response to intrathecal baclofen [55].

7.5. Cutaneous mastocytosis

Treatment is directed by dermatology, with avoidance of substances and environments that activate mast cells and long-acting, non-sedating H1 antihistamines for pruritus and mediator-release symptoms [3, 78]. GeneReviews recommends serial photographs of the lesions [3]. Because the polymorphic form of childhood may regress around puberty, the approach is conservative [77]. Cetirizine serves as an example of an H1 antihistamine with labelled paediatric dosing; its use in cutaneous mastocytosis is extrapolated from the approved indications.

7.6. Behaviour and psychopharmacology

Behavioural interventions, including applied behaviour analysis, are the foundation; ADHD medication may be used when indicated, and severe aggression warrants child psychiatry [3]. In the Portuguese girl, antipsychotics, antidepressants, mood stabilisers and stimulants had mixed results, with several episodes of extrapyramidal effects with antipsychotics [53]. In the 2024 review, haloperidol, olanzapine and methylphenidate worsened or did not improve the movement disorder [55]. The Lithuanian adult woman with depression was treated with sertraline [55]. In the forms with obesity, the authors recommend caution with medicines that increase weight [22].

7.7. Rehabilitation, feeding, communication and education

From 0 to 3 years, early intervention is recommended with occupational therapy, physiotherapy, speech and feeding therapy, infant mental health support, special education and sensory specialists; from 3 to 5 years, adapted preschool education; at all ages, follow-up by a developmental paediatrician and an individualised education plan reviewed annually, with vision and hearing consultants and a transition plan in adolescence [3]. GeneReviews describes these supports within the United States framework (federal early intervention programme, individualised education plan, 504 plan, services up to 21 years of age); their application in other countries depends on the national early intervention and inclusive education networks [3].

Physiotherapy aims at mobility and the prevention of contractures, scoliosis and hip dislocation, with wheelchairs, walkers, bath chairs, orthoses and adapted strollers; occupational therapy works on fine motor skills [3]. Physiotherapy and occupational therapy also prevent falls [55]. Oromotor function should be assessed at each visit, with clinical or radiological swallowing assessment if there is choking, poor weight gain, recurrent respiratory infections or food refusal; measures include thickening or chilling foods and, in severe cases, a nasogastric tube or gastrostomy [3]. Augmentative and alternative communication (AAC), from low-technology systems and picture exchange to speech-generating devices, should be assessed by a speech and language therapist and does not hinder speech development [3]. Cortical visual impairment has no specific treatment, but early visual stimulation intervention is recommended [3].

7.8. Regulatory status

No medicine has an approved indication for GNB1 encephalopathy, and no regulatory applications or orphan medicinal product designations were identified in the sources consulted, although the orphan designation databases of the FDA and the European Medicines Agency (EMA) were not searched directly [108]. The table summarises the status of the symptomatic medicines used by analogy.

7.9. Trials, registries and preclinical studies

A search of ClinicalTrials.gov in October 2026 found no interventional trials directed at GNB1 encephalopathy; the existing registries are observational [108]. GeneReviews had already warned that there might be no trials for this disorder [3]. The table gathers the studies with therapeutic relevance, all preclinical or observational.

The available data do not allow clinical efficacy to be estimated. The preclinical studies use models of a single variant, intraperitoneal doses with no direct correspondence to human dosing and electrophysiological outcomes; the opposite mechanisms of K78R and I80T in the same channel mean that a result does not transfer to another variant [27, 28, 43]. There are no registered negative trials, which reflects the absence of trials and not a demonstration of inefficacy.

7.10. Developments in the last 6 to 12 months

Between November 2025 and October 2026 the following publications appeared, none with regulatory impact: a case report of transmission of p.(Ile80Asn) from an asymptomatic mosaic father (May 2026; case report) [17]; an Indian cross-sectional study that includes GNB1 among the causes of paroxysmal dyskinesias in genetic DEE (2026; observational study) [71]; a Turkish national cohort of childhood dystonia with one patient with GNB1 (June 2026; multicentre retrospective cohort) [69]; and the Gnb1 I80T mouse model with GIRK loss of function and rescue by the activator ML297 (August 2026; preclinical preprint not peer reviewed) [43]. The study by Denomme and colleagues on sodium channel modulation by Gβ1γ2 (2025; preclinical) and the functional study of p.(Leu95Pro) (2025; preclinical) complete the recent mechanistic picture [54, 57]. No sponsor announcements, opinions or authorisations relating to this disorder were identified.

7.11. Medicines to be used with caution

Levodopa had no benefit and worsened dystonia in described patients [34, 55]. Antipsychotics caused repeated extrapyramidal effects in one case, and haloperidol and olanzapine worsened or did not improve the motor picture in others [53, 55]. Vigabatrin requires additional weighing because of the visual involvement inherent to the disorder (inference described in section 7.2.1) [3, 91]. In cutaneous mastocytosis, substances and environments that activate mast cells should be avoided [3, 78]. In the forms with obesity, medicines that increase weight call for caution [22]. The restrictions on parasympathomimetics and β-blockers apply to GNB5 disease, with bradycardia, and have not been described for GNB1 [48].

7.12. Pregnancy, perioperative care and transition

The sources consulted contain no data on pregnancy in affected women, and the 2024 review found no data on the effect of the disorder on pregnancy or delivery [55]. There are also no specific anaesthesia data; the clinically relevant elements in the perioperative period are dysphagia with risk of aspiration, epilepsy, axial hypotonia, the possibility of dystonic exacerbation during acute illness and, in patients with cutaneous mastocytosis, avoidance of mast cell activation triggers [3, 59]. Transition to adult care should be planned in adolescence, integrating the education plan and social support; with the increasing detection of adults, progressive dystonia, psychiatric disease, obesity and retinal dystrophy now have to be followed by adult teams [3, 16, 40, 59].

7.13. Recommendations and divergences between sources

The only source of specific management recommendations is the 2021 GeneReviews; the 2024 review confirms the absence of standardised guidelines [3, 55]. There is a divergence regarding haematological surveillance: GeneReviews recommends a full blood count every 6 to 12 months and family education on the signs of haematological neoplasia, whereas the curated GeneGuidance registry does not recommend oncological surveillance [3, 11]. The GeneReviews recommendation, adopted in this article, rests on a single case of ALL and on the biology of the somatic variants, without incidence data [13, 37]. For infantile spasms, the ILAE (2015) and the AAN/CNS (2012) agree on the preference for hormonal therapy over vigabatrin outside tuberous sclerosis, but the American guideline has been retired by the AAN and there is no numerical ACTH dose in the recommendations consulted, which leaves the label dosing as the reference [82, 83, 88].

7.14. GNAO1-related disorder: treatment

There is no curative treatment and no clinical practice guideline; the 2023 GeneReview summarises multidisciplinary symptomatic management, a 2024 Delphi consensus defines and guides the treatment of dyskinetic crises, and a 2026 consensus (27 health professionals and 10 parents) recommended 17 domains of the International Classification of Functioning, Disability and Health (ICF) and 26 assessment instruments for an international follow-up and treatment registry [9, 80, 111]. The 2024 consensus did not establish individualised doses [80].

Epilepsy. Treatment follows the electroclinical syndrome: epileptic spasms are treated with hormonal therapy (adrenocorticotropic hormone or prednisolone) or vigabatrin, at the doses given in section 7.2.1, and patients with persistent seizures tried on average 3.1 antiepileptic drugs [9]. No antiepileptic drug has shown specific efficacy, and benzodiazepines are limited by tolerance and adverse effects [9]. In the 2026 international cohort, five patients followed a ketogenic diet, which was the most effective treatment in one of them, and four responded to sodium channel blockers [24]. Although sudden unexpected death in epilepsy had not been described up to 2023, the 2026 cohort recorded one case, which reinforces the reduction of tonic-clonic seizures, treatment adherence and nocturnal monitoring [9, 24].

Baseline movement disorder. Treatment combines medicines and rehabilitation. The GeneReview proposes tetrabenazine, gabapentin, clonidine, trihexyphenidyl and oral baclofen, with benzodiazepines as first-line add-on therapy, botulinum toxin for focal dystonia and early physiotherapy to prevent contractures, scoliosis and hip dislocation [9]. In the 2024 consensus, the preferred medicines for the baseline movement disorder were tetrabenazine, clonazepam, gabapentin and clonidine [80]. Topiramate reduced the frequency and severity of chorea in a 19-year-old woman with p.(Arg209Cys), and tetrabenazine partially controlled the dyskinesias in two of seven patients in the Italian series [19]. The doses of tetrabenazine and trihexyphenidyl are given in the table in section 7.3; use in this disorder is off-label.

Levodopa is a point of divergence between sources. The GeneReview acknowledges some benefit in certain patients, based on an Italian series from 2019, whereas the multinational study of 609 patients with epilepsy-dyskinesia syndromes identified worsening of motor symptoms with levodopa and carbidopa in patients with GNAO1 and MECP2 variants [9, 81]. Given this disagreement, a therapeutic trial of levodopa requires close monitoring of the movement disorder.

Dyskinetic crises. From diagnosis, the family should receive information on the nature of the crises and a written emergency plan, and triggers (infection, pain, electrolyte disturbances, sleep deprivation, constipation) should be avoided or treated [9, 80]. The table summarises the approach.

Deep brain stimulation. DBS is the intervention with the most data. The Oxford Desk Reference recommends referral to a specialised centre to assess DBS in GNAO1 dystonias [112]. A systematic review with individual-data meta-analysis (18 studies, 28 patients, generalised dystonia in 20 of 22) found, with pallidal DBS, an improvement of 32.5 points (37.9%) in the motor part of the Burke-Fahn-Marsden scale (BFMDRS) and of 5.8 points (21.5%) in the disability part, 80% responders (reduction of at least 25%), resolution of all reported status dystonicus episodes and skin erosion or infection in 18% [113]. The 2026 international multicentre study, conducted through the DBSMatchMaker platform in 17 centres, included 46 implanted patients with a mean age of 10.4 years followed for a mean of 4.5 years (maximum 17); 52.2% were implanted as an emergency, during status dyskineticus [29]. Dyskinetic crises decreased in 38 of 40 patients (95%) and intensive care admissions by 86.1%; the motor BFMDRS improved by 27.5%, the clinical global impression improved in 93.5%, with more benefit in chorea than in dystonia, and pain, sleep and medication burden improved, but functional classification hardly changed; complications affected 19.6%, mainly in emergency implantations [29]. The authors interpret DBS as an intervention that prevents crises and modifies symptoms, not as a restorative intervention, and advocate elective implantation before repeated crises accumulate morbidity [29]. In the German cohort, 9 of 25 patients (38%) received bilateral pallidal DBS, which reduced hyperkinetic symptoms and prevented new crises; in the 2026 cohort, 17 of 66 (25.7%) were implanted with variable results; in the Spanish series, DBS improved hyperkinetic crises but had inconsistent benefit for dystonia [24, 52, 64]. These studies are retrospective, without a control group and with selection by severity, and the percentages are not comparable with one another.

Oral zinc. In vitro, the Zn²⁺ ion replaces Mg²⁺ in the active site of dysfunctional Gαo and restores GTP hydrolysis and cellular interactions, without affecting the normal protein; 16 missense variants fall into three classes of response to zinc [30, 114]. The first human use was in a 3-year-old child with p.(Gly203Arg) treated with 50 mg/day of zinc, as zinc acetate, for 11 months, with cessation of daily dyskinetic crises, improvement of the motor BFMDRS and reduction of epileptic seizures [114]. The ZINCGNAO1 pilot trial (Cologne, Germany; NCT06412653; open-label, single-arm, 6 months) included 13 patients with 11 different variants, aged 0.5 to 25.1 years (mean 8.0), of whom 11 completed follow-up [30]. Feasibility was 84.6%, there were no serious treatment-related adverse events, nine patients had nausea or vomiting in the first two weeks, resolving spontaneously, and zinc levels normalised at 3 months in all, with supraphysiological values in eight at 6 months, without copper deficiency or low ferritin [30]. In the exploratory outcomes, movement disorder severity did not change, but the disability BFMDRS fell from 25.5 to 23.5, the GMFM-66 (Gross Motor Function Measure) rose from 33.1 to 37.8 and performance and satisfaction on the COPM (Canadian Occupational Performance Measure) increased, with nominal p values [30]. The authors conclude that zinc was safe and feasible and that efficacy requires larger controlled trials [30]. Use outside a trial is experimental and off-label.

The trial doses coincide with the age-based regimen of the Wilson disease SmPC, but the indication is different; the GNAO1-RD dose is that of the trial, and the labels serve only for comparison.

None of these studies has a control group, and the zinc trial was not designed to measure efficacy. In preclinical research, allele-specific antisense oligonucleotides for p.(Glu246Lys) reduced the mutant allele and corrected cAMP accumulation in patient-derived models [119]; gene therapy with AAV9 vectors expressing normal Gαo reversed the hyperactivity of the p.Arg209His mouse after intrastriatal injection, without increasing seizure susceptibility [66]; neonatal intracerebroventricular injection of AAV with normal Gαo corrected the motor and neuronal abnormalities of the p.Cys215Tyr mouse and showed efficacy in C. elegans strains with several variants [120]; and caffeine reduced abnormal movements in C. elegans models with two variants, without human data [9].

Developments in the last 6 to 12 months. Between November 2025 and October 2026, the first longitudinal natural history study (April 2026), the consensus on domains and instruments for a follow-up registry (February 2026), the multicentre study of pallidal DBS in 46 patients (July 2026), the zinc pilot trial (July 2026) and the gene therapy study in the p.Cys215Tyr mouse (July 2026) were published, and the trial of the oligonucleotide ASO-GNAO1 was registered (January 2026) [24, 29, 30, 111, 117, 120]. These are, respectively, an observational study, a consensus, a retrospective study, a single-arm trial, a preclinical study and a trial registration without results; no medicine has obtained authorisation for this disorder.

8. Reproductive Options and Family Counselling

8.1. Mode of transmission

GNB1 encephalopathy has autosomal dominant inheritance and, in most probands whose parents have been tested, results from a de novo variant [3]. Up to 2020, of the 52 published patients, 48 had a de novo variant, 1 was of unknown origin and 3 had inherited p.(Arg96Leu) from a parent, in families of different origins with no apparent relationship; the degree to which these parents were affected and the search for mosaicism were not described [16, 35]. A fourth transmission, of p.(Thr243Ala) from the mother, is recorded in DECIPHER without maternal clinical data [3, 60]. The family of Schultz-Rogers' patient 1 showed autosomal dominant segregation of the splicing variant c.700-1G>T, present in the patient, in her mother (mild to moderate intellectual disability and obesity) and in a maternal half-brother with seizures, ADHD and speech delay, and absent in the unaffected maternal grandmother [16]. In the Lithuanian family, the mother, who died at 43 years, had a picture similar to her daughter's, and a brother is more severely affected, which is compatible with dominant transmission, although the relatives declined testing [55]. By 2024, five cases with an inherited variant had been described [55].

Parental mosaicism is no longer merely theoretical. GeneReviews, in 2021, knew of no cases of parental germline mosaicism in GNB1 and noted that a parent with somatic and germline mosaicism might be mildly affected [3]. In 2026, transmission of p.(Ile80Asn) was published in a boy with global delay, hypotonia, bilateral sensorineural deafness, nystagmus and transient neonatal focal seizures, from an asymptomatic mosaic father [17]. In the epileptic encephalopathies in general, one study found parental somatic and, by inference, germline mosaicism in about 10% of asymptomatic parents of patients with an apparently de novo variant [121].

8.2. Recurrence risks by scenario

8.3. Parental and cascade testing

Molecular testing of both parents is recommended to distinguish a de novo from an inherited variant [3]. When the variant is found in a parent, the other children and, depending on the pedigree, at-risk relatives should be assessed, bearing in mind that a carrier may have a mild phenotype [3, 16]. When the variant appears de novo, low-level parental mosaicism may not be detected by routine methods, as shown by the epileptic encephalopathy study and the 2026 case of paternal transmission [17, 121]. For healthy siblings of a proband, information on reproductive risk and on prenatal and preimplantation diagnosis should be given when they reach adulthood, respecting autonomy and the right not to know [55].

8.4. Prenatal and preimplantation diagnosis

Once the variant has been identified in the family, prenatal diagnosis and PGT are technically possible [3]. GeneReviews recommends determining genetic risk and discussing these options before pregnancy and offering counselling to the parents of affected children; even when the parents are not carriers, prenatal testing and PGT may be considered because of the possibility of germline mosaicism [3]. Perspectives on the use of prenatal diagnosis for termination of pregnancy vary among professionals and families [3].

8.5. Content of counselling

Counselling should explain that the diagnosis does not, in itself, change treatment, but reduces uncertainty and has an impact on counselling, given that almost all variants are de novo [35]; it also guides the targeted surveillance described in section 11 [3]. It should also convey the variability of prognosis (from severe forms without walking or language to mild forms with intellectual disability and obesity), the manifestations that warrant surveillance (epilepsy, dystonia, vision, full blood count, skin) and the existence of registries and associations (section 9.4) [3, 16].

8.6. GNAO1-related disorder: counselling

The disorder is autosomal dominant and almost always results from a de novo variant. In the severe phenotypes (DEE, severe delay or early-onset movement disorder), almost all probands whose parents have been tested have a de novo variant or one inherited from an unaffected mosaic parent; recurrence in siblings through presumed germline mosaicism has been described in several families, including two siblings with p.(Arg209His) and dizygotic twins [9, 19]. When the variant is not detected in the leucocytes of either parent, the GeneReview considers the risk to siblings slightly higher than that of the general population, whereas Menke and colleagues estimated 5–15% after one affected child; testing parental leucocytes does not detect exclusively germline mosaicism [9, 19]. Vertical transmission has been documented in three families with mild phenotypes, with late-onset dystonia, normal intelligence and absence of seizures, as with the variants p.(Arg206Gln) and p.(Cys215Tyr); each child of an affected person has a 50% probability of inheriting the variant, and no patients with severe phenotypes are known to have had children [9]. Once the variant has been identified, prenatal diagnosis and preimplantation genetic diagnosis are possible, and the ideal time to discuss them is before pregnancy [9].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

There is no population estimate of prevalence or incidence based on an epidemiological study. Orphanet assigns the prevalence class <1/1,000,000, supported by the 26 cases of the 2017 Lohmann series [7]. The following figures measure published cases and not frequency in the population: 58 patients up to 2021 in GeneReviews, about 64 up to May 2022 in the Galosi review and 68 in the 2024 Kleinendorst review [3, 21, 22]. In undiagnosed-disease exome databases, GNB1 variants accounted for less than 0.5% of the more than 10,000 exomes analysed (5,866 from Petrovski and 4,377 from the Centogene laboratory), which measures yield in a referred population and not prevalence [35]. As a class comparison, the GNAI1 GeneReviews cites an estimated prevalence of 0.6 per 100,000 and an incidence of 1.3 per 100,000 for that disorder, values that cannot be transposed to GNB1 [45].

9.2. Geographical distribution and ancestry

GeneReviews reports no increased prevalence in any population and no founder variants [3]. The recurrent variants arise de novo in patients of diverse origins: the founding study included patients of Ashkenazi, Sephardic, North African, European, European-American and Hispanic ancestry, recruited in New York, Nantes, Seattle and Melbourne [14]; the Lohmann series included patients from Saudi Arabia, Qatar, Egypt, Kuwait, Algeria, Israel, Mexico, India and Germany [35]; and the variant p.(Arg96Leu) was transmitted in three families of different origins [35]. There are reports from the United States, Canada, Germany, Poland, Italy, the Netherlands, Greece, Lithuania, North Macedonia, Croatia, Japan, China, Singapore, India, Turkey and Australia [17, 22, 34, 36–39, 55, 56, 59, 61, 68, 69, 71, 72, 98]. In Greece, one of the patients was of Roma ethnicity [61].

In Portugal, a case was published in Porto, with a novel de novo variant, p.(Ala73Thr), and a phenotype dominated by behaviour, without epilepsy or movement disorder (section 10) [53]; researchers from Porto also took part in the 2024 review on obesity [22]. The sources consulted contain no data from Brazil, which does not demonstrate the absence of diagnosed patients.

9.3. Special populations

Adults are probably under-represented, because many adults with intellectual disability have never undergone genomic testing; the detection of adults with isolated or predominant dystonia in dystonia cohorts suggests that some cases present outside neurodevelopmental paediatrics [3, 70]. Patients with loss-of-function variants and a mild phenotype may be seen in obesity clinics rather than in neurology [22]. In families with vertical transmission, carrier parents may have a mild or undiagnosed phenotype [16, 17]. The diversity of the origins described shows that the disorder should be considered in any population group, including ethnic minorities with less access to genomic testing [35, 61].

9.4. Reference networks, registries and patient associations

In the European Union, patients fall within two European Reference Networks: ERN ITHACA, for rare congenital anomalies and rare intellectual disability, and ERN EpiCARE, for rare and complex epilepsies [31, 32]. GeneReviews lists the GNB1 Advocacy Group and the international GNB1 registry, in partnership with Sanford Research on the CoRDS platform, as well as general resources for intellectual disability and epilepsy (American Association on Intellectual and Developmental Disabilities, American Epilepsy Society, Canadian Epilepsy Alliance) [3]. The 2026 search found the GNB1 Advocacy Group as a parent group with a fundraising page intended to fund a natural history study, with no official website or legal status identified [122]. The Simons Searchlight study and the CoRDS registry recruit families with GNB1 for natural history [109, 110].

9.5. GNAO1-related disorder: epidemiology and resources

There is no population estimate of prevalence; more than 200 patients had been published by 2023, and the GeneReview acknowledges underdiagnosis, especially of adults with mild phenotypes who have never undergone broad genetic testing [9]. The largest clinical cohort (66 patients, 2026) brought together centres in Europe (Spain, Italy, Germany, the United Kingdom, Sweden, Belgium, Croatia and Portugal, with the Hospital Central do Funchal), the Americas, Asia and the Middle East, without figures by country [24]. In the multinational cohort of 609 patients with epilepsy-dyskinesia syndromes, with centres in 25 countries, including Brazil, GNAO1 was among the three most frequent genes; in the Turkish cohort of childhood-onset dystonia it accounted for 8.6% of diagnoses [69, 81]. These figures measure frequency among patients already tested and not population prevalence. The sources consulted describe no founder variants.

Patients in the European Union fall within ERN EpiCARE, for epilepsy, ERN-RND (European Reference Network for Rare Neurological Diseases), for the movement disorder, and ERN ITHACA, for intellectual disability; several authors of the consensus documents belong to ERN-RND and ERN EpiCARE [31–33, 80]. The GeneReview lists patient associations in Spain (Asociación GNAO1 España), Italy (Famiglie GNAO1), Finland (GNAO1 Tuki ry), the United Kingdom (Mondo GNAO1 UK) and the Netherlands (Stichting GNAO1 NL), the Bow Foundation and the GNAO1 International Registry; there is also a German registry, based in Cologne, which gave rise to the 2023 cohort and the zinc trial [9, 30, 52].

10. Illustrative Clinical Case

10.1. Portuguese case: novel variant with a behavioural phenotype

Da Silva and colleagues, from Porto, described in 2021 a girl followed up to 15 years and 8 months of age [53]. She was born at 36 weeks by caesarean section, for prolonged labour, weighing 2,880 g (21st centile), 47 cm long (12th centile) and with a head circumference of 33 cm (23rd centile), normal Apgar scores, and normal metabolic screening and otoacoustic emissions. The parents, aged 30 and 33 years, were healthy and non-consanguineous, and the younger brother was healthy. The social smile appeared at 2 months, sitting at 9 months and independent walking at 17 months, but first words appeared only at 4 years and sentences at 5. She met ASD criteria at 18 months, and ADHD, oppositional defiant disorder, mild to moderate intellectual disability (intelligence quotient of 52 on the WISC-III scale; general quotient of 52 on the Griffiths III scale at 9 years), mixed language disorder and developmental coordination disorder were later diagnosed; puberty proceeded normally [53].

She had no dystonia or other movement disorder, epilepsy, deafness, visual abnormalities or dysmorphism; MRI at 3 and 15 years and EEG at 18 months were normal [53]. The karyotype was normal and 180K array comparative genomic hybridisation (array CGH) showed two inherited copy number variations, considered non-pathogenic. The intellectual disability and developmental delay panel identified the variant NM_001282539.1:c.217G>A p.(Ala73Thr) in GNB1, absent in the parents by Sanger sequencing, which corresponds to NM_002074.5:c.217G>A on the MANE transcript; the authors classified it as pathogenic with criteria PS2 and PS3, supported by concordant predictors (SIFT 0.000; PolyPhen-2 0.976), and considered a concomitant variant in HIVEP2 likely benign [12, 53]. Structural modelling placed Ala73 in a core β-sheet of a WD40 repeat, less than 4 Å from Ile58, Tyr59, Ala60, Ser72, Ser74, Lys78, Cys79, Val100 and Cys103, in a region close to the exon 6 hotspot [53]. Figure 1 of the article shows the pedigree and the Sanger chromatograms (https://pmc.ncbi.nlm.nih.gov/articles/PMC8504539/figure/F1/) and figure 2 the structural modelling of the protein (https://pmc.ncbi.nlm.nih.gov/articles/PMC8504539/figure/F2/); the legends were read in the full text [53].

At 15 years, the most disabling problem was behaviour, with self-directed and other-directed aggression, attention deficit and obsessive behaviour. Antipsychotics, antidepressants, mood stabilisers and stimulants had mixed results, and there were several episodes of extrapyramidal effects with antipsychotics [53]. The case illustrates three points: the existence of forms without epilepsy, without movement disorder and with normal MRI, which only a panel or exome identifies; the importance of normalising variants described on other transcripts to MANE; and the susceptibility to extrapyramidal effects, which calls for caution in the use of antipsychotics. The psychopharmacological choice in the report reflects the individual management of the patient and does not constitute a recommended regimen; GeneReviews favours behavioural interventions and reserves medication for specific indications [3].

10.2. Lithuanian adult case: dystonia with onset in adolescence

Nasvytis and colleagues described in 2024 a 25-year-old woman with abnormal speech and gait, limb rigidity and abrupt involuntary movements since the age of 16 years, with speech delay in childhood and special education interrupted in the 7th year of schooling [55]. Her mother, who died at 43 years of unknown cause, had similar symptoms from 16 years of age, and a 15-year-old brother is more severely affected. On examination, in the autumn of 2023, there was generalised dystonia with dystonic facies, laterocaput, spasmodic limb postures, dysarthria, anisocoria and grade III horizontal nystagmus, with independent walking of more than 500 m. The variant NM_002074.5:c.226G>A p.(Asp76Asn), in exon 6, was classified as likely pathogenic. MRI in 2020 showed bilateral hypointensity of the globi pallidi, corresponding to calcification on the 2013 computed tomography, and MRI in 2024 slightly larger pallidal lesions and new hypointensities of the dentate nuclei (figures 1 and 2 of the article). Awake and sleep EEG was normal; cognitive scales showed mild cognitive impairment and mood scales depression and anxiety, treated with sertraline. Levodopa was poorly tolerated, baclofen up to 5 mg three times daily caused drowsiness without benefit and clonazepam improved insomnia without effect on dystonia; in January 2024, the multidisciplinary team decided to propose DBS [55]. The case documents the course in adulthood, probable maternal transmission and the lack of response to the usual dystonia medicines.

10.3. GNAO1 case: dyskinetic crises controlled by elective pallidal stimulation

The 2024 international consensus on dyskinetic crises described, in its supplementary material (video S1), a boy with the de novo variant NM_020988.3:c.139A>G, p.(Ser47Gly), confirmed in VariantValidator [12, 80]. At 10 years he had several severe dyskinetic crises per day, with generalised dystonia and choreoathetosis lasting 5 to 30 minutes, on a baseline movement disorder with generalised dystonic postures, and underwent elective DBS of the globus pallidus internus [80]. Shortly after implantation he had a severe crisis that progressed to status dyskineticus and required sedation; thereafter, the crises became rare and easier to control, with fewer than one episode per month, and the episodes recorded between 11 and 12 years were triggered by fever [80]. At 12 years he remained on tetrabenazine and lorazepam, as well as carbamazepine for epilepsy, and had a GNAO1-RD severity score of 7 points (moderate) [80]. The case illustrates the pattern described in the multicentre study: DBS reduced the frequency and severity of the crises without eliminating the baseline movement disorder, and the perioperative period and febrile infections remained times of risk [29]. The management corresponds to the consensus recommendation to consider elective DBS early when crises are frequent [80].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

The developmental prognosis is guarded in most patients: about half do not achieve independent walking and about 40% do not develop verbal language, although there are mild forms with walking, speech and mild intellectual disability, especially with loss-of-function variants [3, 16]. Regression is rare (3 of 57) and, when it occurs, is associated with the onset of spasms or with acute encephalopathy [42, 55]. Epilepsy is often drug-resistant, but may resolve in late adolescence, and dystonia may progress in adulthood with loss of walking [21, 59]. In epileptic spasms, ACTH induced remission in two patients, with relapse 6 months later in one and the need for a second course in the other [55].

Life expectancy is unknown. One death at 4 years of age, of undetermined cause, has been described, and survival is documented up to 34, 38, 40 and 45 years [3, 16, 40, 59]. The absence of congenital anomalies with high morbidity and mortality led GeneReviews and the 2024 review to suggest a favourable survival prognosis with appropriate care, an inference and not a cohort finding [3, 55]. The identifiable risks of morbidity and mortality are refractory epilepsy with status epilepticus, aspiration, dystonic exacerbations during infections, acute encephalopathy and, with evidence limited to a single case, ALL [37, 42, 59].

11.2. Assessment after diagnosis

11.3. Surveillance

Haematological surveillance follows GeneReviews and is an expert recommendation based on a single case of ALL; the GeneGuidance registry does not recommend it (section 7.13) [3, 11]. The row on retinal dystrophy derives from the two cases published in adults and does not appear in the 2021 GeneReviews [40, 41].

11.4. GNAO1-related disorder: prognosis and surveillance

It is not known whether life expectancy can be normal. By 2023, at least six children had died in early infancy with resistant epilepsy and at least five during an exacerbation of the movement disorder, all with hypotonia and delay in the first year of life; several young adults have, however, been described [9]. In the cohort of 66 patients, 6 (9%) died during the study, three from infections, two from dyskinetic crises or status dyskineticus and one from sudden unexpected death in epilepsy [24]. The risk of hyperkinetic crises is greater in patients with onset in infancy and severe motor delay and lower in those who walk and have normal intelligence or mild impairment [9]. The overall course is stable or slightly improving, except in severely affected patients, in whom the movement disorder progresses [24].

12. Summary and Final Considerations

GNB1-related encephalopathy is an autosomal dominant neurodevelopmental disorder, almost always caused by de novo variants in the gene for the β1 subunit of heterotrimeric G proteins. Since the 2016 description, between 58 and 68 patients have been published, with no population estimate of prevalence. The picture combines global developmental delay in all patients, intellectual disability in about three-quarters, axial hypotonia evolving to limb hypertonia, epilepsy in about half, visual abnormalities in 60%, with frequent nystagmus, and dystonia in about one-fifth, accompanied by less common manifestations that guide suspicion: cutaneous mastocytosis, cleft palate associated with p.(Leu95Pro), craniosynostosis, genitourinary anomalies and, in loss-of-function variants, obesity with hyperphagia.

The diagnosis is molecular and does not depend on clinical criteria. Microarray followed by a panel, exome or genome, or exome as first line according to the ACMG, identifies most patients, and the report should use the MANE transcript NM_002074.5. Variant interpretation benefits from the clustering of missense variants in exons 6 and 7, from the intolerance of the gene to variation and from functional assays, but must deal with variable expressivity, transmission from parents with a mild phenotype and parental mosaicism, documented in 2026.

The mechanisms are heterogeneous. Variants in the same hotspot behave as gain or loss of function on GIRK channels, and truncating variants cause haploinsufficiency with a milder phenotype. This heterogeneity explains why the preclinical data with ethosuximide, in a gain-of-function model, and with GIRK activators, in a loss-of-function model, point to variant-stratified treatments that do not yet have any clinical trial.

Treatment is symptomatic and multidisciplinary: antiseizure medications according to the syndrome, with hormonal therapy or vigabatrin for spasms, weighing visual reserve; treatment of dystonia with limited pharmacological response, levodopa without benefit and pallidal DBS with favourable results in isolated cases; rehabilitation, safe feeding, augmentative communication and educational support; and caution with antipsychotics and with medicines that increase weight. Surveillance includes assessment at each visit of the affected domains, a full blood count every 6 to 12 months according to GeneReviews and skin examination for mastocytosis. Counselling should convey a recurrence risk that is low but higher than that of the population in de novo cases, and of 50% for the offspring of carriers. A revision of GeneReviews after 2021, prospective natural history data and clinical trials of the mechanism-directed therapeutic hypotheses are still lacking.

GNAO1-related disorder, the most frequent member of the class, is distinguished by the severity of dyskinetic crises, which cause most of the morbidity and part of the mortality, and it is the only one for which there are international consensus documents, a prospective natural history study, a multicentre deep brain stimulation series and a pilot trial of targeted therapy. Pallidal stimulation prevents crises in almost all treated patients without restoring function, oral zinc showed safety in a single-arm trial, and antisense oligonucleotides and gene therapy remain at the preclinical or early trial stage.

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