Uncommon yet impactful — case-based reflections on rare neurologic disorders

Rare diseases (RDs) are a heterogeneous group of disorders defined by their low prevalence - affecting fewer than 1 in 2,000 individuals in Europe and fewer than 200,000 people in the US. Although individually uncommon, rare diseases collectively impact an estimated 263 to 446 million people worldwide. Early recognition and diagnosis remain major challenges, particularly in neurology, where overlapping phenotypes and limited awareness often delay appropriate management. We present 3 illustrative case studies highlighting the diagnostic and therapeutic complexities associated with rare neurologic disorders. The first case describes a patient with CSF1R-related disorder; diagnosis was significantly delayed due to initial misattribution of symptoms to traumatic brain injury. This delay ultimately precluded timely intervention with disease-modifying therapies such as hematopoietic stem cell transplantation. The second case involves a patient with frontotemporal dementia and parkinsonism linked to chromosome 17 with a pathogenic c.837T>G, p.N279K variant in the MAPT gene, also known as pallidopontonigral degeneration. Although a strong family history facilitated early diagnosis, the case underscores the broader challenges of managing hereditary neurodegenerative diseases within affected families. The third case presents an exceptionally rare scenario of dual pathogenic mutations in ATXN3 and ATXN8OS, resulting in concurrent diagnoses of spinocerebellar ataxia types 3 and 8. This case exemplifies the clinical ambiguity and interpretive difficulty posed by co-occurring rare variants with overlapping symptomatology. Collectively, these 3 cases emphasize the importance of accurate, timely diagnosis to avoid unnecessary testing in rare neurologic diseases. Timely recognition enables access to emerging personalized therapies and support systems.