TABLE 1.

Clinical and genetic features of GNAO1 mutation carriers

Patient ID	Ancestry	Gender	Age at last assessment	Age at first symptoms	First symptom	Dystonia				Parkinsonism	Myoclonus	Chorea	Hypotonia	Intellectual disability	Seizures	Speech	Other	Treatment response	GNAO1 variant
						Dystonia age of onset	Topography	Progression	Acute exacerbations
Family 1	North African	Female	28 y	4 y	Seizure	12 y	Segmental: face, neck, upper limbs	No	No	Akinetic‐rigid syndrome	No	No	No	Mild	Yes	Normal	None	Mild response to levodopa, moderate improvement with trihexyphenidyl	[NM_020988.3]:c.68 T > C; p.L23P, htz
Case A
Family 2	North African	Female	5 y	By 1 y	Developmental delay (motor delay)	2 y	Generalized: oromandibular, trunk. Dystonic gait	Yes	No	No	No	No	Yes	No	No	Dysarthria	None	NA	[NM_020988.3]:c.137A > G; p.K46R, htz
Case A						4 mo
Family 3	European	Male	19 y	3 mo	Developmental delay (motor delay, hypotonia)	12 y	Generalized: left upper limb, cervical and axial dystonia. BFMDRS: 16	Yes	No	No	No	No	Yes	Mild	Yes	Dysarthria	None	No response to levodopa and tetrabenazine, minimal improvement with gabapentin and trihexyphenidyl	[NM_020988.3]:c.535A > G; p.R179G, htz
Case A
Family 4	European	Male	24 y	15 y	Dystonia	15 y	Segmental: oromandibular and cervical dystonia	No	No	No	No	No	No	No	No	Dysarthria	None	No response to levodopa and tetrabenazine, mild worsening by Gpi‐DBS	[NM_020988.3]:c.617G > A; p.R206Q, htz
Case A
Family 4	European	Female	53 y	47 y	Dystonia	47 y	Focal: cervical	No	No	No	No	No	No	No	No	Normal	None	NA
Case B
Family 4	European	Female	57 y	30 y	Dystonia	30 y	Multifocal: upper and lower limbs, laryngeal dystonia with dysarthria	No	No	No	No	No	No	No	No	Dysarthria	None	NA
Case C
Family 5	European	Female	5 y 11 mo	3 mo	Developmental delay (motor delay, hypotonia)	5 y	Multifocal: four limbs	No	No	No	No	No	Yes	No	No	Dysarthria language delay	None	NA	[NM_020988.3]:c.622G > C; p.E208N, htz
Case A
Family 6	European	Male	31 y	3 y	Dystonia	3 y	Generalized: left lower limb dystonia, bilateral upper limbs dystonia, laryngeal dystonia, abnormal axial posture. BFMDRS: 24.5	Yes	No	No	No	No	Yes	Mild	No	Dysarthria	None	Mild response to levodopa, mild response to trihexyphenidyl	[NM_020988.3]:c.644G > A; p.C215Y, htz
Case A
Family 6	European	Female	66 y	5 y	Dystonia	5 y	Generalized: laryngeal dystonia, facial dystonia, axial dystonia, abnormal posture of the left hand and bilateral pes valgus. BFMDRS: 23.5	Yes	No	No	Yes	No	No	No	No	Dysarthria	Pyramidal syndrome	Subjective response to levodopa
Case B
Family 7	European	Male	48 y	6 y	Dystonia	6 y	Generalized: oromandibular, cervical, trunk, upper limbs, left foot	Yes	No	No	No	No	No	Mild	No	Dysarthria	None	Subjective response to levodopa; no effect of trihexyphenidyl
Case A
Family 8	European	Female	16 y	6 y	Dystonia	6 y	Segmental: oropharyngeal, neck and trapezius	Yes	Yes	No	No	No	No	Mild	No	Severe dysarthria	MDD	Mild improvement with gabapentin, no benefit with trihexyphenidyl
Case A
Family 9	African American	Male	13 y	7 mo	Developmental delay (language delay)	5 y	Generalized: initially axial (opisthotonic with neck involvement) with secondary limbs and oromandibular involvement	Yes	No	No	No	No	No	Moderate	No	Dysarthria	None	No response to levodopa and trihexyphenidyl; rash with clonazepam; minimal improvement with baclofen	[NM_020988.3]:c.724‐8G > A, htz
Case A
Family 10 Case A	Moroccan	Female	15 y	1 y	Developmental delay (motor delay)	5 y	Generalized dystonia. BFMDRS: 48.5	No	No	No	No	No	No	Mild	No	Dysarthria	Exaggerated startle reflex	No response to levodopa
	Syrian Jewish
Family 11 Case A	European	Female	18 y 6 mo	By 1 y	Developmental delay (motor delay)	7 y	Generalized: cervical extension, dystonic forward trunk lean. BFMDRS: 85	Yes	No	Severe akinetic rigid syndrome	No	No	Yes	Mild	No	Anarthria	None	No response to levodopa, trihexyphenidyl, and baclofen; sustained response to bilateral Gpi‐DBS
Family 12 Case A	European	Female	21 y	By 1 y	Developmental delay (motor delay)	7 y	Generalized dystonia with severe cervical neck extension and oromandibular dystonia. BFMDRS: 64.5	Yes	No	Akinetic rigidity, facial akinesia	No	No	No	Moderate	No	Normal	None	No response to levodopa, carbamazepine, trihexyphenidyl, and baclofen; good response to Gpi‐DBS
Family 13 Case A	Caucasian	Male	20 y 2 mo	By 1 y	Developmental delay (motor delay, language delay)	11 y	Generalized: bilateral upper limb, axial, trunk, cervical, oro‐linguo‐pharygolarynx dystonia with speech and swallowing impairment; dystonic gait; BFMDRS: 45.5	Yes	Yes	Akinetic‐rigid syndrome	No	No	Yes	No	No	Severe dysarthria	ADHD	No response to amantadine and levodopa; moderate and transient response to methylphenidate and trihexyphenidyl; good response to Gpi‐DBS
Family 14 Case A	Chinese European	Male	13 y	3 y	Developmental delay (language delay) myoclonus	11 y	Segmental: bilateral upper‐limb dystonia	No	No	No	Yes (upper limbs)	No	Yes	Mild	No	Normal	ASD	No response to acetazolamide and amantadine; improvement in dystonia with trihexyphenidyl
Family 15 Case A	Mixed European	Female	11 y 8 mo	10 mo	Developmental delay	2 y	Generalized: upper and lower limbs, axial, dystonia gait	Yes	No	No	Yes (upper limbs)	Yes (left sided)	Yes	No	No	Dysarthria	ADHD	Moderate response to tetrabenazine on chorea, good response to trihexyphenidyl
Family 16 Case A	Northern European	Female	5 y 6 mo	3 mo	Developmental delay (motor delay, hypotonia)	5 y	Segmental: dystonic posturing of fingers and hands	No	No	No	No	No	Yes	Mild	No	Dysarthria	None	Good response to levodopa
Family 17 Case A	Caucasian	Male	18 y	2 y	Developmental delay (language delay)	2 y	Segmental: laryngeal, right upper limb (handwriting) and cervical	No	No	No	No	No	No	No	No	Dysarthria	None	Response to anticholinergic and levodopa	[NM_020988.3]:c.725A > C; p.N242T, htz
Family 18 Case A	European	Female	20 y 4 mo	6 y	Dystonia	6 y	Generalized dystonia. BFMDRS: 67.5	Yes	Yes	Bradyknesia‐akinesia	No	Yes generalized	Yes	Mild	No	Anarthria	None	No response to haloperidol, tetrabenazine, and trihexyphenidyl; moderate response to catapressan; excellent response to GPi‐DBS	[NM_020988.3]:c.737A > T, p.E246V, htz
Family 19 Case A	European	Female	13 y	6 y	Dystonia	6 y	Multifocal: bilateral upper limb, cervical, and oromandibular dystonia	No	No	Mild akinetic rigid syndrome	No	No	No	No	Yes	Dysarthria	None	NA	[NM_020988.3]:c.765dupT; p.N256*, htz
Family 19 Case B	European	Female	39 y	16 y	Dystonia	16 y	Multifocal: bilateral upper limb, cervical, and oromandibular dystonia	No	No	Mild akinetic rigid syndrome	No	No	No	No	No	Dysarthria	None	No response to clonazepam; sustained response to Gpi‐DBS
Family 20 Case A	Caucasian	Male	9 y	By 1 y	Developmental delay (motor delay, hypotonia)	9 y	Generalized: upper‐limb and trunk dystonia, dystonic gait	Yes	No	No	No	No	Yes	No	No	Normal	None	No response to levodopa, clonazepam, or baclofen	Heterozygous deletion in 16q12.2 (273–375 kb) encompassing GNAO1
Summary		Female 15 Male 9	Mean age at last assessment: 23.8 y	Mean age at disease onset: 6.6 y	Developmental delay: 13 Motor delay: 9 Language delay: 4 Dystonia: 10 Hypotonia: 4 Seizure: 1 Myoclonus: 1	Mean age at dystonia onset: 10.1 y	Focal: 1 Segmental: 6 Multifocal: 4 Generalized: 13	Progression 13	Exacerbation 3	Parkinsonism 7	Myoclonus 3	Chorea 2	Hypotonia 11	Intellectual disability 12	Seizures 3	Dysarthria: 19	Pyramidal syndrome: 1 MDD: 1 ADHD: 2 ASD: 1 Exaggerated startle reflex: 1

Abbreviations: htz: heterozygous, NA, not available; BFMDRS: Burke Fahn Marsden Dystonia Rating Scale, dystonia score; GPi‐DBS: globus pallidus internal deep brain stimulation; MDD, major depressive disorder; ADHD, attention deficit with hyperactivity disorder; ASD, autism spectrum disorder; ID, intellectual disability.