Overall Clinical Features
Three female and 3 male patients were enrolled and evaluated. All clinical features are summarized in Table 1. Five patients were referred to the clinic due to hypotonia or global developmental delay which was noticed at different ages (3 months old on median, range 0–75 months). Four patients (patients 2–5) had severely retarded development in motor, language, and social manner. Patient 4 showed weak crying and respiratory difficulty after birth, and was treated in a neonatal intensive care unit. She started unsteady gait without support at 4 years old, but no further achievement was shown till the most recent follow-up at her age of 8.8 years. Only 1 case (patient 4) had focal epilepsy, which started at 6 years old and was well controlled with valproate monotherapy. Patient 3 had neither movement disorder nor epilepsy. He presented as having infantile hypotonia and profound developmental delay. Generalized spasticity developed and progressed over time, dominantly on lower extremities.
Table 1. clinical features of six patients with GNAO1 variants
|
Patient 1
|
Patient 2
|
Patient 3
|
Patient 4
|
Patient 5
|
Patient 6
|
Sex, Age
|
Female, 16.9y
|
Male, 7.2y
|
Male, 3.3y
|
Female, 8.8y
|
Female, 7.7y
|
Male, 4.0y
|
Genotype
Variant
Inheritance
Reference
|
p.Ala338del
de novo
novel
|
p.Glu246Lys
de novo
saitsu et al. 2016
|
p.Ala301del
de novo
novel
|
p.Ala227Val
De novo
Saitsu 2016
|
p.Arg209His
Maternal mosaicism
Kulkani 2016
|
p.Arg206Leu
de novo
novel
|
Onset age
|
6.3y
|
3m
|
3m
|
Since birth
|
3m
|
34m
|
Initial symptom
|
Clumsiness on hands
|
Hypotonia
|
Hypotonia
|
Hypotonia
|
Hypotonia
|
Developmental delay
|
Motor development
|
Walk alone (18m)
|
No achievement
(near bed-ridden)
|
Sit up
|
Unsteady gait (4y)
No progression
|
Unsteady gait (5.8y)
Then regressed
|
Unsteady gait (2y)
No progression
|
Language development
|
Sentences
Intellectual disability
|
No achievement
|
2 words
|
2 words
|
50 words,
Then regressed
|
2 words
|
Epilepsy
(onset) age)
|
No
|
No
|
No
|
Focal epilepsy
(6Y)
|
No
|
No
|
EEG findings
|
Normal
|
Normal
|
Normal
|
Focal spikes
|
Normal
|
Normal
|
Movement disorder
(onset age)
|
Myoclonus,
focal dystonia
(10Y)
|
Severe chorea
Focal dystonia
(2Y)
|
No
|
Hand stereotypi
(NA)
|
Orofacial dyskinesia
Chorea
Focal dystonia
(around 1Y)
|
Focal dystonia
(2Y)
|
Others
|
Spasticity
Scoliosis
Difficulties on fine motor function
|
Progressive generalized spasticity
|
Progressive spasticity (lower extremity dominant)
|
-
|
Progressive spasticity
|
Ataxia
|
Brain MRI
(performed age)
|
Normal (14y)
|
Atrophy of bilateral head of caudate nucleus (6y)
|
Normal (2.5y)
|
Normal (6Y)
|
Normal (5y)
|
Normal (2.5y)
|
y, years; m, months
Phenotypic Spectrum of Movement Disorder
Movement disorder was identified in 5 patients in a different manner. Patient 1 initially visited the rehabilitation clinic because of poor hand skills at 6 years old, but no further tests were given because her symptoms were quite subjective without any progression nor abnormalities on neurological examination. However, intermittent nonepileptic truncal myoclonus followed by focal dystonic gait was recognized at the age of 10 years. She underwent several genetic tests for dystonia including Segawa disease, but no sequence variants in known genes were noticed. Her symptoms had progressed slowly and spasticity of lower extremities and increased knee jerk was noted at the latest clinical follow-up (17 years old).
Patient 2 started his choreoathetosis around 2 years old. His chorea was accompanied by brief focal dystonia, which lasted all day long and disappeared during sleep. It was not much deteriorated with advancing age (see Additional file 1).
Patient 5 was initially reported to have intermittent hyperkinesia with brief jerking and truncal dystonia triggered by emotional upset which started at 1 year old (see Additional file 2-1). At the age of 5 years, orofacial dyskinesia developed and became prominent (see Additional file 2-2). Brief dystonia on her neck and shoulder also occurred and her movement presentations progressed over time (see Additional file 2-3, at 8 years old). Eventually she found it difficult to walk or crawl. Her movements showed acute exacerbations during febrile illness.
Patient 6 showed ataxia before 1 year of age without significant worsening. He started walking independently at 16 months old, but his gait has remained unstable till the most recent follow-up. Brief focal dystonia of lower extremities was also noted during walking (see Additional file 3-1 and 3-2, at 24 and 27 months old, respectively).
Mutation Analysis and Genotype–Phenotype Association
Six different variants from 6 patients were identified using WES (Table 1). Patients 1–3 underwent trio-WES whereas patients 4–6 had WES for proband only. All variants were classified as pathogenic or likely pathogenic according to the ACMG guidelines. Five variants were confirmed to be de novo mutations, but patient 5 inherited her variant from her mother who carried the mosaic variant, a state identified through amplicon sequencing (Fig. 1). In this cohort, 4 variants (from patients 2, 4, 5, and 6) were located in a mutational hot spot and 3 of them (p.Glu246Lys of patient 2, p.Ala227Val of patient 4, p.Arg209His of patient 5) were reported previously [2, 4, 6, 7]. We reviewed previously reported cases and compared detailed phenotypes (Table 2). Patients with the variant of p.Glu246Lys or p.Arg209His showed quite homogeneous phenotypes: e.g., infantile hypotonia, profound development delay, or severe choreoathetosis started in early childhood. In particular, patients with p.Arg209His were reported to have severe exacerbation and required multiple admissions.
Table 2. phenotype review of the patients with the variant p.Glu246Lys and p.Arg209His
No.
|
Reference
|
Age/Sex
|
Initial symptom
(onset age)
|
Epilepsy
(onset age)
|
Movement disorder
(onset age)
|
Max motor achievement
|
Max speech achievement
|
Brain MRI
|
p.Glu246Lys
|
1
|
This report
(patient 2)
|
M/7.2y
|
Hypotonia (3m)
|
None
|
Chorea, dystonia (2y)
|
None
|
None
|
Atrophy of bilateral head of caudate nucleus (6y)
|
2
|
Saitsu7
|
F/13y
|
Developmental delay (4m)
|
None
|
Severe athetosis
(NA)
|
None
|
None
|
Normal (12y)
|
3*
|
Ananth6
|
M/5.5y
|
Hypotonia (3m)
|
None
|
Chorea (4y)
|
None
|
None
|
Normal (12m)
|
4*
|
Ananth6
|
F/5.5y
|
Hypotonia (3m)
|
None
|
Chorea (4y)
|
None
|
None
|
Global atrophy (5.5y)
|
5
|
Ananth6
|
F/10.3y
|
Hypotonia (6m)
|
None
|
Chorea (4y)
|
None
|
None
|
Global atrophy, T2 hypointensity in globus pallidi (9y)
|
6
|
Ananth6
|
M/15y
|
Hypotonia (5m)
|
None
|
Chorea (4y)
|
None
|
None (simple non-verbal communication)
|
T2 hypointensity in globus pallidi (14y)
|
7†
|
Schorling4
|
M/8y
|
Myoclonic twitching (1m)
|
None
|
Myoclonus (1m), Dystonia (2y)
|
None
|
NA
|
Normal (18m)
|
8†
|
Schorling4
|
F/3y
|
Developmental delay (5m)
|
Focal epilepsy
(7m)
|
Dystonia (NA)
|
Head control
|
NA
|
Atrophy, thin corpus callosum (2y)
|
p.Arg209His
|
1
|
This report
(patient 5)
|
F/7.7y
|
Hypotonia (3m)
|
None
|
Orofacial dyskinesia
Chorea
Focal dystonia
Myoclonus (2y)
|
Stand (regressed)
|
50 words
|
Normal (5y)
|
2‡
|
Kulkani2
|
M/8y
|
Hypotonia (18m)
|
None
|
Sever Chorea
Athetosis (34m)
|
NA
|
NA
|
Normal (7y)
|
3‡
|
Kulkani2
|
M/6y
|
Hyperkinesia (2y)
|
None
|
Severe Chorea
Athetosis (2y)
|
NA
|
NA
|
Normal (6y)
|
4
|
Ananth6
|
M/16y
|
Hypomotor (6m)
|
|
Chorea (3y)
|
Head control
|
Monosyllable words
|
Global atrophy (15y)
|
* They were dizygotic twins from non-consanguineous parents
† They were siblings from non-consanguineous parents
‡ They were siblings from on-consanguineous pare