Objective: To describe a clinical case and the results of genetic analysis in a patient with a combination of HGPPS1 and myoclonus-dystonia.

Background: Horizontal gaze palsy with progressive scoliosis (HGPPS1) is a rare autosomal recessive disorder caused by mutations in the ROBO3 gene. It is characterized by congenital absence of conjugated horizontal eye movements and early-onset scoliosis. The association of HGPPS1 with myoclonus-dystonia has not been previously reported in the literature.

Method: Longitudinal clinical observation, analysis of whole-genome sequencing data, brain MRI of the patient and a meta-analysis of 50 publications.

Results: In 2024, a female patient born in 2016 presented to the Republican Center for Movement Disorders and Botulinum therapy with complaints of progressive involuntary movements, retrocollis, truncal extension, and gait disturbance. Symptoms had been observed since early childhood. Family history: the older sister has a genetically confirmed diagnosis of HGPPS1 combined with tremor and retrocollis.

Neurological examination revealed horizontal gaze palsy, nystagmus, dysmetria on coordination testing, retrocollis, truncal torsion, dystonic posturing of the limbs, myoclonic hyperkinesias, and motor stereotypies.

Whole-genome sequencing identified two heterozygous variants in the ROBO3 gene resulting in a frameshift: a previously described pathogenic variant in exon 3 and a novel variant in exon 15.

Conclusion: This clinical observation illustrates a previously unreported phenotype caused by compound heterozygous mutations in the ROBO3 gene. In this patient and her sister, in addition to the classic manifestations of HGPPS1 syndrome, a pronounced dystonic syndrome with myoclonus was identified. In our opinion, the scoliosis also has a neurogenic origin and is associated with postural disturbance and truncal dystonia, resulting from disorganization of the corticospinal tracts. These findings warrant a reassessment of therapeutic and rehabilitation approaches.

Since most described cases pertain to the pediatric population, it is necessary to accumulate case series and to understand the spectrum of ROBO3-associated disorders in adults, as well as to conduct studies on the disease course in adult patients. The molecular mechanisms of pathogenicity of germline and somatic ROBO3 mutations remain a subject for further investigation.

References: 1. Chi-Wei Lin, et al. Horizontal gaze palsy with progressive scoliosis: a case report with magnetic resonance tractography and electrophysiological study. BMC Neurol. 2018;18(1):101. doi:10.1186/s12883-018-1081-9
2. Xavier C, et al. Horizontal Gaze Palsy and Progressive Scoliosis in Dizygotic Twins. Neuropediatrics. 2022;53(2):139-142. doi:10.1055/a-1736-7188

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MDS Abstracts - https://www.mdsabstracts.org/abstract/myoclonus-dystonia-as-a-phenotype-of-hgpps1-a-case-report/