Movement disorder is difficult to evaluate, especially in children, because they are in a developmental process and their symptoms evolve over time. Comprehensive phenotyping is quite important for diagnosis of these patients, even in the genomic era. In our cohort, all except 1 patient had multiple genetic testing including diagnostic exome sequencing and gene panel sequencing before participation in KUDP. After the diagnosis, we reviewed the patient’s clinical course including previous videos. We found some quite unique presentations of patients with some recurrent GNAO1 variants (p.Glu246Lys and p.Arg209His). As previously reported, patients initially presented with profound infantile hypotonia and developmental delay, and severe choreoathetosis movement developed in all patients during early childhood [2, 4, 6, 7]. Patient 2 in our cohort showed movement symptoms since he was about 2 years old. The symptoms persisted, but were not much progressed or suddenly exacerbated, as reported in patients with a p.Glu246Lys variant. Patient 5 was reported to have orofacial dyskinesia starting at 4 years old, but was eventually found to have early hyperkinetic movement. She was also admitted several times for pneumonia and accompanying aggravation of neck dystonia. Patients with the variant p.Arg209His also experienced several dystonic exacerbations and sometimes needed treatment in an intensive care unit [2, 6]. This indicated a quite homogeneous clinical course. Most of those patients visited a clinic for their hypotonia or developmental delay, which are nonspecific and common for a pediatric neurologist. However, if we noticed unexplained early onset dystonia or chorea as well as severe developmental delay, GNAO1 might be initially considered as a genetic cause. Early diagnosis based on clinical presentation is important because of additional treatment options. Deep brain stimulation and tetrabenazine were reported to be effective, especially for acute exacerbation [2, 9, 16]. Patients in this cohort have not yet been treated using those options, but these options are still considered in cases with exacerbation or rapid progression.
There were also atypical cases in our cohort. Patient 1 did not show obvious movement presentation till 10 years old. Patient 3 with the novel variant p.Aal301del showed severe developmental delay and progressive spasticity without any obvious paroxysmal movements. Patient 4, who carried the variant p.Ala227Val, presented with infantile hypotonia without early-onset epilepsy, unlike a previous report of infantile spasm and early-onset epileptic encephalopathy as a main presentation in patients with the same variant [7, 17]. It is obvious that a genotype–phenotype correlation exists, at least in certain loci. Many functional studies were performed, especially for recurrent mutations to date. Some variants work as GOM, whereas others work as loss-of-function mutations [1, 2, 11]. Different functional alteration may contribute to different phenotypes of GNAO1 encephalopathy [11, 12]. Further studies are expected to evaluate other variants in GNAO1 and its related pathway, which will allow us to know more about the disease and its possible treatment.
We verified maternal mosaicism from 1 family (patient 5) by additional amplicon sequencing. We suspected mosaicism in this patient, based on confirmative Sanger sequencing for the patient’s mother, indicating a low heterozygous peak. This verification is crucial for the family counselling. Three familial cases were already reported in spite of a small number of total patients, which suggested parental mosaicism might be common in GNAO1 encephalopathy [2, 4, 6]. Therefore, testing for the mosaicism should be conducted if parents have plan to have another child.
In conclusion, we reported 6 cases of GNAO1 encephalopathy focusing on their movement phenotypes with their video clips (Additional files). Early-onset chorea with profound developmental problems is quite characteristic for patients with a movement-dominant phenotype. We also reported atypical and novel findings for GNAO1 encephalopathy including proven mosaicism in parents, which is important to guide genetic counselling.