A clinical case of a developmental disorder of the nervous system with involuntary movements associated with the spectrum of GNAO1-associated diseases

Nervous Developmental Disorder with Involuntary Movements (NEDIM) (OMIM 617493) is a rare movement disorder in children on the spectrum of GNAO1-associated movement disorders. With NEDIM, movement disorders appear in early childhood, progress and lead to disability. The disease is caused by pathogenic heterozygous variants in the GNAO1 gene and has an autosomal dominant mode of inheritance. The epidemiology of NEDIM has not yet been established. Clinical symptoms are extensive, ranging from severe motor and cognitive impairment with self-injurious behaviour and seizures to a mild phenotype of movement disorders without mental retardation and seizures. Some patients develop epilepsy. Hyperkinetic syndrome in most children is manifested with chorea, athetosis, dystonia, and ballism, affecting the muscles of the body, limbs and face. According to MRI, in some patients, gradually progressive atrophy of the brain substance is visualized. Currently, the disease has no developed pathogenetic methods of therapy. Treatment is symptomatic, including various drug regimens to reduce the severity of movement disorders and seizures. Management of nutrition of the patient and the prevention of secondary complications of movement disorders are also important. In foreign sources there is described the experience of using topiramate and teterabenazine, as well as deep brain stimulation (DBS), which demonstrate a good effect in the form of a significant reduction in the frequency of dystonic storms and the severity of motor disorders. The article presents a clinical case of diagnosis and treatment of a child with this disease, and also current trends in therapy.

Compliance with ethical standards. All photographs are published with the written consent of the child’s parents.

Contributions:
Kuzenkova L.M. — concept, writing, editing  the text;
Lyalina A.A. — writing, editing the text;
Zyryanova O.I. — writing, editing the text;
Yarosh M.A. — writing, editing the text;
Savostyanov K.V. — editing the text, molecular genetic examination;
Kanivets I.V. — the molecular genetic examination.
All co-authors are responsible for the integrity of all parts of the manuscript and approval of its final version.

Acknowledgements. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: November 11, 2022
Accepted: December 2, 2022
Published: January 15, 2023

1. Ananth A.L., Robichaux-Viehoever A., Kim Y.M., Hanson-Kahn A., Cox R., Enns G.M., et al. Clinical course of six children with GNAO1 mutations causing a severe and distinctive movement disorder. Pediat. Neurol. 2016; 59: 814. https://doi.org/10.1016/j.pediatrneurol.2016.02.018

2. Kulkarni N., Tang S., Bhardwaj R., Bernes S., Grebe T.A. Progressive movement disorder in brothers carrying a GNAO1 mutation responsive to deep brain stimulation. J. Child. Neurol. 2016; 31(2): 2114. https://doi.org/10.1177/0883073815587945

3. Saitsu H., Fukai R., Ben-Zeev B., Sakai Y., Mimaki M., Okamoto N., et al. Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay. Europ. J. Hum. Genet. 2016; 24(1): 12934. https://doi.org/10.1038/ejhg.2015.92

4. Schirinzi T., Garone G., Travaglini L., Vasco G., Galosi S., Rios L., et al. Phenomenology and clinical course of movement disorder in GNAO1 variants: Results from an analytical review. Parkinsonism Relat. Disord. 2019; 61: 1925. https://doi.org/10.1016/j.parkreldis.2018.11.019.

5. Guseva M.V. Epileptic encephalopathy type 17 in a young child. Rossiyskiy pediatricheskiy zhurnal. 2019; 22(5): 281–2. (in Russian)

6. Danti F.R., Galosi S., Romani M., Montomoli M., Carss K.J., Raymond F.L., et al. GNAO1 encephalopathy: broadening the phenotype and evaluating treatment and outcome. Neurol. Genet. 2017; 3(2): e143. https://doi.org/10.1212/nxg.0000000000000143

7. Menke L.A., Engelen M., Alders M., Odekerken V.J.J., Baas F., Cobben J.M. Recurrent GNAO1 mutations associated with developmental delay and a movement disorder. J. Child Neurol. 2016; 31(14): 1598601. https://doi.org/10.1177/0883073816666474

8. Schorling D.C., Dietel T., Evers C., Hinderhofer K., Korinthenberg R., Ezzo D., et al. Expanding phenotype of de novo mutations in GNAO1: Four new cases and review of literature. Neuropediatrics. 2017; 48(5): 3717. https://doi.org/10.1055/s-0037-1603977

9. Nakamura K., Kodera H., Akita T., Shiina M., Kato M., Hoshino H., et al. De Novo mutations in GNAO1, encoding a Galphao subunit of heterotrimeric G proteins, cause epileptic encephalopathy. Am. J. Hum. Genet. 2013; 93(3): 496505. https://doi.org/10.1016/j.ajhg.2013.07.014

10. Kelly M., Park M., Mihalek I., Rochtus A., Gramm M., Pérez-Palma E., et al. Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region. Epilepsia. 2019; 60(3): 40618. https://doi.org/10.1111/epi.14653

11. Feng H., Khalil S., Neubig R.R., Sidiropoulos C. A mechanistic review on GNAO1-associated movement disorder. Neurobiol. Dis. 2018; 116: 13141. https://doi.org/10.1016/j.nbd.2018.05.005

12. Sakamoto S., Monden Y., Fukai R., Miyake N., Saito H., Miyauchi A., et al. A case of severe movement disorder with GNAO1 mutation responsive to topiramate. Brain Dev. 2017; 39(5): 43943. https://doi.org/10.1016/j.braindev.2016.11.009

13. Akasaka M., Kamei A., Tanifuji S., Asami M., Ito J., Mizuma K., et al. GNAO1 mutation-related severe involuntary movements treated with gabapentin. Brain Dev. 2021; 43(4): 5769. https://doi.org/10.1016/j.braindev.2020.12.002

14. Bulica B. Novel GNO1 mutation in monozygotic twins responsive to DBS [abstract]. Mov. Disord. 2020; 35(Suppl. 1): S48.

15. Axeen E., Bell E., Robichaux Viehoever A., Schreiber J.M., Sidiropoulos C., Goodkin H.P. Results of the first GNAO1-related neurodevelopmental disorders caregiver survey. Pediatr. Neurol. 2021; 121: 2832. https://doi.org/10.1016/j.pediatrneurol.2021.05.005

16. Milovanova A.M., Pushkov A.A., Savostyanov K.V., Zrobok O.I., Vashurina T.V., Ananin P.V., et al. A study of genetic causes of congenital and infantile nephrotic syndrome in children of Russian Federation. Nefrologiya i dializ. 2021; 23(1): 57–72. https://doi.org/10.28996/2618-9801-2021-1-57-72 (in Russian)

17. Savostyanov K.V., Namazova-Baranova L.S., Basargina E.N., Vashakmadze N.D., Zhurkova N.V., Pushkov A.A., et al. The new genome variants in Russian children with genetically determined cardiomyopathies revealed with massive parallel sequencing. Vestnik Rossiyskoy akademii meditsinskikh nauk. 2017; 72(4): 242–53. https://doi.org/10.15690/vramn872 (in Russian)

18. Savostyanov K.V., Surkov A.N., Namazova-Baranova L.S., Zhanin I.S., Pushkov A.A., Basargina E.N., et al. Clinical application of massive parallel sequencing in molecular diagnostics of hereditary diseases of glycogen accumulation in the children population of the Russian Federation. Rossiyskiy pediatricheskiy zhurnal. 2017; 20(3): 132–9. https://doi.org/10.18821/1560-9561-2017-20-3-132-139 (in Russian)