Early-onset parkinsonism with intellectual disability in an Italian family associated with a PTRHD1 variant

• First Italian family with early-onset parkinsonism and intellectual disability linked to PTRHD1 • Identification of a novel homozygous PTRHD1 nonsense variant (c.213C>A; p.Tyr71*) • Combined clinical, neuropsychological, and genetic characterization delineates a syndromic profile • Findings broaden the phenotypic and mutational landscape of PTRHD1-related parkinsonism • Results refine genotype–phenotype correlations and inform genetic testing in early-onset cases First Italian family with early-onset parkinsonism and intellectual disability linked to PTRHD1 Identification of a novel homozygous PTRHD1 nonsense variant (c.213C>A; p.Tyr71*) Combined clinical, neuropsychological, and genetic characterization delineates a syndromic profile Findings broaden the phenotypic and mutational landscape of PTRHD1-related parkinsonism Results refine genotype–phenotype correlations and inform genetic testing in early-onset cases Mutations in PTRHD1 have recently been implicated in autosomal recessive neurodevelopmental syndromes characterized by intellectual disability, and variably penetrant early-onset parkinsonism, mainly in consanguineous families of Middle Eastern or African origin. To describe the clinical and genetic findings of the first Italian family carrying a homozygous PTRHD1 nonsense mutation associated with early-onset parkinsonism and intellectual disability. A 45-gene Parkinson’s disease panel was analyzed by targeted next-generation sequencing in a proband, a 32-year-old female with moderate intellectual disability and early-onset parkinsonism. The analysis revealed a homozygous nonsense variant (c.213C>A, p.Tyr71*), segregating with severe intellectual disability and variably penetrant parkinsonian features in the proband’s paternal cousin and his father. This study expands the mutational and geographical spectrum of PTRHD1 -related disorders and reinforces the inclusion of PTRHD1 in genetic screening panels for early-onset parkinsonism, particularly in individuals with intellectual disability and evidence of autosomal recessive inheritance.