Reply to: “Clinical and Molecular Profiling in GNAO1 Permits Phenotype–Genotype Correlation”

Abstract

With great interest we read the recently published article by Lasa-Aranzasti et al on clinical and molecular profiling of GNAO1. The authors characterized the neurological phenotype and the molecular mechanisms caused by pathogenic Gɑo identified in a cohort of patients with GNAO1-related disorders. They provided functional data underlying the proposed developmental and epileptic encephalopathy 17 and neurodevelopmental disorder with involuntary movement phenotypes.¹ Their study also included 1 patient exhibiting a rather mild phenotype with hyperkinetic movements (generalized chorea, myoclonus, and dystonia) associated with mild intellectual disability. The underlying mutation (p.Ile344del) was located at the end of protein and led the authors to the conclusion that milder phenotypes are correlated with splicing variants, previously hypothesized haploinsufficiency based on loss of function,² or variants at the end of the protein.

We report on a 34-year-old patient, who was referred to our movement disorders clinic to assess a 2-year-earlier-developed propranolol-resistant, myoclonic head tremor in the context of a cerebral palsy, which was prediagnosed due to delayed development of speech at age 4, despite the lack of a clear perinatal event. There was no history of epileptic seizures. At age 12 a slowly progressing action tremor of his right hand occurred, leading him to write with his left hand. He graduated regularly from secondary school and worked in logistics and later in farming. He performed skiing, hiking, and swimming without restraints.

At 32 years the tremor of his right hand had worsened, and he developed a myoclonic head tremor.

Our neurological examination at age 34 revealed segmental dystonia with predominant cervical dystonia with phasic abnormal rotation mainly to the left, laryngeal dystonia of the adductor type, slight postural tremor of the hands, and writing tremor with dystonic posture leading to an inability to write. His gait was mainly unaffected, showing only a reduced arm swing (Video 1).

His cognitive functions were slightly decreased, scoring 24/30 on the Montreal Cognitive Assessment test.

Brain magnetic resonance at age 32 demonstrated a slightly asymmetric ventricular system without further abnormalities. His family history (parents and four siblings) was negative for movement disorders or epilepsy.

Regarding the rather atypical presentation for cerebral palsy, we performed a trio-exome analysis that revealed a heterozygous de novo missense variant in GNAO1 (NM_020988.3:c.4G > C,p.Gly2Arg), which was absent from control databases (in-house exomes, gnomAD version 4.0) and located in a highly mutation-constrained N-terminal region of GNAO1; the variant was classified as “likely pathogenic” according to American College of Medical Genetics and Genomics (ACMG), establishing the diagnosis of GNAO1-related dystonia with comparatively mild phenotype.

Although the consequence on protein function is unknown for the newly identified variant, our observation strengthens the proposition that missense amino-acid substitutions of GNAO1 at the start of the GNAO1 can also lead to less-severe clinical outcomes.³ Our report contributes to an expansion of the catalog of GNAO1 variation that produces attenuated clinical images with predominant dystonia, which may have important implications for better understanding of pathophysiology and future therapy development.

M.S. received a travel grant from Ipsen Pharma; T.M. received a travel grant from Merz Therapeutics GmbH; MZ acknowledges grant support from the EJP RD (EJP RD Joint Transnational Call 2022) and the German Federal Ministry of Education and Research (BMBF, Bonn, Germany), awarded to the project PreDYT (PREdictive biomarkers in DYsTonia, 01GM2302), and from the Federal Ministry of Education and Research (BMBF) and the Free State of Bavaria under the Excellence Strategy of the Federal Government and the Länder, as well as by the Technical University of Munich—Institute for Advanced Study. MZ's research is supported by a “Schlüsselprojekt” grant from the Else Kröner-Fresenius-Stiftung (2022_EKSE.185); B.H. received speaker honoraria from AbbVie and Ipsen Pharma.

(1) Research project: A. Clinical patient treatment and recruitment, B. Genetic analysis. (2) Manuscript preparation: A. Writing of the first draft, B. Review and critique.

M.S.: 1A, 2A, 2B

T.M.: 1A, 2B

M.Z.: 1B, 2B

B.H.: 1A, 2B