PSP-1 results from pathogenic variants in the MAPT gene on chromosome 17, which encodes microtubule-associated protein tau. The condition is inherited in an autosomal dominant manner, meaning a single pathogenic variant in one copy of MAPT is sufficient for disease development. MAPT mutations produce abnormal tau protein that accumulates as neurofibrillary tangles in neurons and astrocytic plaques in glial cells. PSP-1 represents one phenotypic expression of MAPT-related disease; the same gene is also associated with frontotemporal dementia and corticobasal syndrome depending on the specific variant and context. De novo pathogenic MAPT variants have been reported but are considered rare; most cases arise from a carrier parent. Penetrance is high, meaning most individuals carrying a pathogenic MAPT variant are expected to develop manifestations during their lifetime.

No formal consensus diagnostic criteria exist specifically for PSP-1, but published clinical diagnostic criteria for progressive supranuclear palsy (Richardson's syndrome) guide recognition. The diagnosis of MAPT-related PSP is established by identifying a heterozygous pathogenic variant in MAPT through molecular genetic testing, in the context of compatible clinical and imaging findings. Clinically, the disorder is suspected in individuals with progressive falls, postural instability, supranuclear gaze palsy, and a family history consistent with autosomal dominant inheritance. Brain MRI or CT may reveal atrophy of the frontal and temporal lobes, often symmetric but potentially asymmetric. Beta amyloid PET imaging assists in distinguishing the condition from Alzheimer disease, and fluorodeoxyglucose (FDG) PET may help differentiate from other causes of frontal lobe dementia. The overlapping clinical presentations with sporadic PSP, corticobasal syndrome, frontotemporal dementia, and Parkinson disease can complicate clinical recognition.

No FDA-approved disease-modifying therapy exists for PSP-1. Management is supportive, addressing the constellation of motor, communicative, and behavioral manifestations through a multidisciplinary approach. For parkinsonian features, a levodopa trial has been used, though most affected individuals do not show a significant clinical response, and psychiatric side effects of levodopa are a consideration. Psychiatric and behavioral manifestations, including affective disorders and disinhibition, have been addressed with selective serotonin reuptake inhibitors (SSRIs); atypical antipsychotics have been used as a temporary measure for severe agitation or psychosis refractory to SSRIs. Dysarthria is addressed through speech-language pathology evaluation, with augmentative communication devices as an option. Dysphagia management includes dietary modification and assessment of aspiration risk; gastrostomy may be considered in severe cases. Sialorrhea has been addressed with anticholinergic agents or salivary gland botulinum toxin injections. Physical and occupational therapy target mobility, fall prevention, and activities of daily living adaptation.

PSP-1 follows a relentlessly progressive course. Based on MAPT-related disease cohort data, mean disease duration is approximately 9.3 years from onset, though individual variation is substantial and durations exceeding 30 years have been observed. Mean age at death in affected individuals is approximately 58.5 years, with a range of 24 to 93 years. Motor impairment advances over time; some individuals become chairbound and others bedbound as the disease progresses. The condition is considered highly penetrant for individuals carrying a pathogenic MAPT variant.

The PSP-1 research landscape is active, with 34 current clinical trials. A Phase 3 study evaluating NIO752 (Novartis Pharmaceuticals, NCT07498426) is recruiting, with expected completion in 2031. UCB0107 has been evaluated in a Phase 1 long-term safety study (UCB Biopharma SRL, NCT04658199), currently in the active non-recruiting phase through 2027. An imaging differentiation study of parkinsonism is underway at the University of Florida (NCT05913687, active through 2027). The National Institute of Neurological Disorders and Stroke (NINDS) is conducting an observational study enrolling participants with PSP and related complex neurodegenerative conditions (NCT03225144, recruiting through 2027). The trial portfolio spans drug therapy, medical devices, and procedural approaches, with both academic and industry sponsors represented.