GNAO1 encephalopathy: Broadening the phenotype and evaluating treatment and outcome

Abstract

Objective: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease.

Methods: We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques.

Results: Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16.

Conclusions: Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia.

Figure 1. Membrane topology modeling of GNAO1

Membrane topology was predicted using the Protter online tool (P09471, GNAO_HUMAN). Known GNAO1 missense mutations are indicated in green, the deletion is in yellow. Mutations found in this report and already described in the literature are indicated in light blue, novel mutations in red.

Figure 2. MRI characteristics of 7 patients with GNAO1 mutations

For patients 1–6, a set of 3 images including an axial (A, D, G, J, M, and S), coronal (B, E, H, K, N, and T), and sagittal midline (C, F, I, L, O, and U) sequences is shown. For patient 5, in addition, 1 axial (P) and 2 coronal (Q and R) images are shown to illustrate better the neoplastic lesion in the left frontal lobe (arrows). For patient 7, axial images of 2 different investigations (V and W) and a sagittal image are shown to illustrate better the progression of atrophic changes. Images are at 1.5–3T. Images A–E, G, J, K, N, O, Q, S, T, and W are T2 weighted. Images F, I, L, U, and X are T1 weighted. Images H, M, P, and R are acquired as fluid attenuation inversion recovery (FLAIR) sequences. Patient 1: axial and coronal images show mild ventricular enlargement in the frontal horns, with concomitant hypoplasia of the caudate nuclei. The sagittal section shows a thin corpus callosum. Patient 2: axial and coronal images show mild ventricular enlargement in the frontal horns, with mild hypoplasia of the caudate nuclei, likewise seen in patient 1. The sagittal section shows a thin corpus callosum and a hypoplastic inferior vermis. Patient 3: axial and coronal images show moderate cortical atrophy, with ventricular enlargement and small caudate nuclei. The sagittal image shows a dysmorphic corpus callosum. Patient 4: no structural abnormality is visible on MRI. Patient 5: MRI shows an isolated abnormality (arrows) involving the anterolateral aspect of the left frontal lobe, including the cortex and underlying white matter, with increased signal intensity on both T2 and FLAIR images. Histopathology, after surgical removal of the lesion, showed characteristics consistent with a diffuse astrocytoma (WHO grade 2). Patient 6: axial and coronal images show dilated lateral ventricles; the sagittal cut shows a thin corpus callosum. Patient 7: the first axial MRI at age 2 (V) is normal, but a follow-up study at age 16 (W) shows loss of brain volume in generalized distribution. No abnormalities in the brainstem and cerebellum are visible in the sagittal image at age 16 (X).