Phenotypic Diversity in Stress-induced Childhood-Onset Neurodegeneration with Variable Ataxia and Seizures: Novel Associations with Parkinsonism, Icthyosis and Cataract.

Abstract

Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an exceptionally rare autosomal recessive neurodegenerative disorder. It is caused by biallelic inactivating variants in the ADP-ribosyl-serine hydrolase (ADPRS) gene that encodes for the enzyme ADP-ribosyl hydrolase3 (ARH3) involved in DNA repair. A distinctive feature of this condition is the exacerbation of clinical symptoms triggered by physical or emotional stress, as well as febrile illnesses. In this report, we describe three unrelated patients diagnosed with CONDSIAS, each having variable clinical phenotypes and responses to treatment. Patient 1 is a 26-year-old female with language delay, intellectual disability, and infrequent seizures in childhood. She later developed parkinsonism, truncal dystonia, ataxia, peripheral neuropathy, and neuropsychiatric symptoms in her second decade. Patient 2, an 8-year-old boy born to consanguineous parents, presented with infection-triggered episodic ataxia and ichthyosis. His elder sibling had suffered from progressive ataxia and succumbed to sudden death at the age of 8. Patient 3 is a 6-year-old girl who presented with progressive ataxia, myoclonus, oculomotor apraxia, and upward gaze palsy. Both patients 2 and 3 responded favourably to treatment with high-dose vitamin supplementation, while patient 1 showed stable disease progression without specific therapeutic intervention, suggesting spontaneous stabilization of her condition. Extra-neurological manifestations included ichthyosis in patients 1 and 2 and cataracts in patient 1. These three cases illustrate the heterogeneity in clinical presentation and prognosis of CONDSIAS, highlighting the occurrence of predominant extrapyramidal features and systemic involvement, thereby expanding the phenotypic spectrum beyond the typical manifestations of ataxia and seizures.