GNAO1‐Associated Movement Disorder

Whole‐exome sequencing (WES) has revolutionized the diagnostic approach to patients with rare disorders and has helped clinicians solve “diagnostic odyssey cases.” We describe a child with a progressive movement disorder who had a de novo mutation identified in the guanine nucleotide‐binding protein, α‐activating activity polypeptide O (GNAO1) gene using WES.

Case Report

The proband presented at age 5 years to the University of Virginia. He was the product of a full‐term pregnancy and was born vaginally after an uncomplicated delivery. He was noted to be hypotonic at birth. Developmental delay was noted around 3 to 4 months of age. Abnormal movements were first noted at 10 months of age, when he began to sit. The hyperkinetic movements involved all of his extremities. They were initially present only with action but progressed to be present even at rest (Video S1). Family history was noncontributory. Both his older brother (age 7 years) and his younger sister (age 3 years) were healthy. His general physical examination was unremarkable, and his neurological examination was significant for hypotonia—a combination of chorea and dystonia affecting his limbs and gait. There was no nocturnal worsening of his abnormal movements.

Previous investigations had included a normal brain magnetic resonance imaging (MRI) scan, a normal chromosome microarray, negative sequencing and gene dosage analyses of thyroid transcription factor‐1 (TITF1) (to rule out benign hereditary chorea), and a normal cerebrospinal fluid‐to‐plasma glucose ratio (to rule out glucose transporter defect).

Initially, the most prominent hyperkinetic movement was chorea affecting limbs and gait (Video S1). Clonazepam was tried but was discontinued due to excessive sedation and drooling. Tetrabenazine was then initiated (at age 3 years) with slow titration to a maximum dosage of 3.5 mg/kg divided 3 times daily, resulting in significant improvement of his chorea, increased ability to feed himself, and improved quality of life. The degree of dystonic movements in the upper trunk, upper limbs (particularly on the right), and associated pain began increasing at age 5 years. Subsequently, he lost the ability to self‐feed and to perform most manual tasks. Given the degree of disability due to dystonia and a prior report of success with deep brain stimulation without untoward effect,1 the patient was evaluated for bilateral pallidal deep brain stimulation. Before implantation, he was tried on trihexyphenidyl and, as of the most recent follow‐up, has responded well to a dose of 2 mg twice daily. He has decreased trunk and limb dystonic movements and has begun to feed himself, and his parents report less pain.

Adenylate cyclase 5 (ADCY5)‐related dyskinesia2 was entertained. However, due to phenotypic variability and genetic heterogeneity of movement disorders, it was felt that WES would be the most cost‐effective way to obtain a diagnosis for this patient. At age 5 years, he underwent clinical WES (GeneDx, Gaithersburg, MD). Genomic DNA was extracted from whole blood from the affected child and his parents. Exome sequencing at GeneDx was performed on exon targets that were isolated by capture with the Clinical Research Exome kit (Agilent Technologies, Santa Clara, CA). The DNA sequence was mapped to the reference human genome sequence (UCSC Genome Browser hg19; University of California, Santa Cruz, Santa Cruz, CA) with the latest internally validated version of the Burrows‐Wheeler Aligner (BWA) software package. A minimum depth of 10× was required for inclusion in downstream analysis. All coding exons and surrounding intron‐exon boundaries were analyzed. Automated filtering was used to remove common sequence changes (defined as >10% frequency present in 1000 genomes). The targeted coding exons and splice junctions of the known protein‐coding reference sequence (RefSeq) genes were assessed for the average depth of coverage and data‐quality threshold values. Variants were filtered on the basis of inheritance patterns, lists of genes of interest, and phenotype and population frequencies, as appropriate. The resources used for evaluating genes and detecting sequence changes of interest included the Human Gene Mutation Database; 1000 Genomes; the National Heart, Lung, and Blood Institute (NHLBI) Exome Variant Server; Online Mendelian Inheritance in Man (OMIM); PubMed; and ClinVar.3

It was discovered that the patient harbored a heterozygous de novo pathogenic variant in GNAO1 (combinational DNA: codon 626 [c.626] G>A mutation). No other pathogenic variants were identified.

GNAO1 codes for the Gαo subunit of G protein‐coupled receptors, which are highly expressed in brain and modulate neuronal excitability.4 There is a murine model of GNAO1‐associated epileptic encephalopathy and sudden death. In that model, it was demonstrated that a gain‐of‐function knock‐in mutation prevented the turn off of Go by regulatory proteins, and electroencephalographic monitoring of these animals demonstrated the presence of frequent interictal epileptiform discharges.5

Mutations in this gene were first described in 3 patients (c.836 T>A mutation, c.521 A>G mutation, and c.572_592 deletion) with severe epileptic encephalopathy (Ottahara syndrome) and, in 1 child, with a later onset epilepsy (c.607 G>A mutation). All 4 of these patients had de novo mutations, and 2 of the 4 also were described as having abnormal movements.6

The phenotype was later expanded to include patients who had a movement disorder with or without seizures. Four patients who had GNAO1 variants were described in a subsequent series (c.680 C>T mutation, c.607 G>A mutation, c.736 G>A mutation, and c.625 C>T mutation) with progressive movement disorders, but only 2 of the 4 had epileptic encephalopathy.7 The phenotypes associated with all of the variants reported in literature are shown in Table 1.

Table 1.

Phenotype Associated with All Reported GNAO1 Variants

Variant	No. of Patients	Phenotype
c.626 G>A	3	Severe chorea and athetosis; hypotonia
c.836 T>A	1	Ottahara syndrome
c.521 A>G	1	Ottahara syndrome
c.572_592	1	Ottahara syndrome; dystonia
c.607 G>A	2	Epileptic encephalopathy; chorea
c.680 C>T	1	Epileptic encephalopathy; hand stereotypies
c.736 G>A	1	Epileptic encephalopathy; athetosis
c.625 C>T	1	Epileptic encephalopathy; chorea

GNAO1, guanine nucleotide‐binding protein, α‐activating activity polypeptide O.

The mutation that our patient harbors has been described previously in 2 brothers who have hypotonia, severe chorea, and athetosis that responded to deep brain stimulation.1 The clinical findings from those 2 patients and from our current patient are compared in Table 2.

Table 2.

Comparison of Clinical Findings in Reported Patients in the Literature with a GNAO1 Mutation (Codon 626 G>A Mutation)

Patient Series	Kulkarni et al., 2016a	Kulkarni et al., 2016a	Authors' Patient
Gender	Male	Male	Male
Age at diagnosis, y	8	6	5
Inheritance	De novo (germline mosaicism)	De novo (germline mosaicism)	De novo
Phenotype	Severe chorea and athetosis, hypotonia, developmental delay	Severe chorea and athetosis, developmental delay	Severe chorea, dystonia, hypotonia, developmental delay
Seizures	No	No	No
Brain MRI	Normal	Normal	Normal

^aThese were 2 brothers who were reported in the same article.

GNAO1, guanine nucleotide‐binding protein, α‐activating activity polypeptide O; MRI, magnetic resonance imaging.

WES has not only enabled us to solve diagnostic odyssey cases but has also helped us expand the phenotypes associated with known gene mutations like our patient. The use of tetrabenazine for hyperkinetic movement disorders in children is off‐label but has been found to be safe in previous studies.8, 9 Its use in GNAO1‐related movement disorder has not been reported previously.

Our case adds to the existing literature on this rare genetic cause of movement disorder in children who initially may be responsive to pharmacotherapy.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

R.D.: 1C, 3A, 3B

J.W.M.: 3A, 3B

B.B.S.: 3A, 3B

H.P.G.: 1A, 3A, 3B

Disclosures

Funding Sources and Conflict of Interest: Jonathan W. Mink is a consultant to Biomarin, Inc., Medtronic, Inc., and Albeona, Inc., and serves on an independent Data and Safety and Monitoring Board of Edison Pharmaceuticals, Inc. Radhika Dhamija, Binit B. Shah, and Howard P. Goodkin report no sources of funding and no conflicts of interest.

Financial Disclosures for the previous 12 months: Jonathan W. Mink receives grant funding from the National Institutes of Health, the US Food and Drug Administration, and the Batten Research Alliance. Howard P. Goodkin receives grant funding from the National Institutes of Health. Radhika Dhamija and Binit B. Shah report no sources of funding and no conflicts of interest.

Supporting information

A video accompanying this article is available in the supporting information here.

Video S1. Gait dysfunction related to limb dystonia, severe chorea, chorea superimposed on dystonic posturing, and dystonia of the left upper extremity are shown.