This study identifies a homozygous PTRHD1 (c.155G>A, p.Cys52Tyr) mutation in a family with early intellectual disability and later-onset atypical parkinsonism, expanding the clinical phenotype and showing widespread PTRHD1 expression in adult brain.

It implicates PTRHD1 as a rare monogenic contributor to neurodevelopmental and neurodegenerative phenotypes—valuable for genetic classification and hypothesis generation but of limited immediate translational or therapeutic relevance without mechanistic links to established Parkinson's pathways.

Five different homozygous PTRHD1 mutations, two of them in more than one family, have been reported as responsible for intellectual disability (ID) and parkinsonism. In all 10 families, onset of ID was early childhood, and in parkinsonism, later childhood to the fourth decade. We report on a family with four siblings presenting with mild to moderate ID and mildly ataxic gait without spasticity or hemiparesis that is not consistent with parkinsonism. The signs of parkinsonism such as bradykinesia, tremor, slow to response, dementia, and gait problems appeared in the fourth decade. There was no muscle rigidity and postural instability, but there were unusual features of exotropia, pectus excavatum, and prominent clavicles. Linkage analysis using SNP genotyping followed by exome sequencing led to the discovery of PTRHD1 c.155G>A (p.Cys52Tyr), already reported in an Iranian sibling pair. Our findings reveal that not all PTRHD1 mutations manifest with muscle rigidity and postural instability and confirm that gait problems may not be evident until towards the end of the fourth decade. Early onset behavioral problems in presented patients include attention deficit, hyperactivity, aggressive behavior and seclusion, apraxia of speech, stuttering, and somniloquy. Gait ataxia, exotropia, pectus excavatum, and prominent clavicles further widen the clinical phenotype. PTRHD1 is expressed in many organs, and we found widespread expression in the adult brain. The association of PTRHD1 dysfunction with both cognitive and motor phenotypes highlights the potential role of the protein in neurodevelopment and neurodegeneration.