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This article presents two case reports of children with neurotransmitter disorders associated with dual pathology. The first case involves a girl who was initially misdiagnosed due to the presence of other genes within her chromosomal microdeletion. The second case involves a girl who was initially diagnosed with cerebral palsy but was later found to have sepiapterin reductase deficiency. The article emphasizes the importance of considering dual pathology and avoiding premature diagnostic closure in the diagnosis of neurotransmitter disorders. It also highlights the significance of recognizing red flags and conducting appropriate investigations for early intervention and maximizing treatment benefits. Treatment with levodopa and 5-hydroxytryptophan resulted in positive responses and improved long-term outcomes for both patients. [Extracted from the article]

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD and parkinsonism to perinatal lethality with neurological manifestations across 15 unrelated pedigrees with 22 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants impair mitochondrial membrane potential, dynamics and mitophagy in patient-derived fibroblasts. Additionally, we develop models of psmf1 knockdown Drosophila and Psmf1 conditional knockout mouse exhibiting age-dependent motor impairment, with diffuse gliosis in mice. These findings unequivocally link defective PSMF1 to early-onset PD and neurodegeneration and suggest mitochondrial dysfunction as a mechanistic contributor.