Progressive supranuclear palsy (ORPHA:683)
A rare late-onset neurodegenerative disease characterized by ocular motor dysfunction, postural instability, akinesia-rigidity, and cognitive dysfunction.
Epidemiology
Estimates of prevalence of progressive supranuclear palsy (PSP) range between 1/13,000-34,000. It mainly affects adults older than 50 years of age.
Clinical description
PSP usually manifests during the sixth or seventh decade of life. Five clinical variants have been described with clinicopathological correlations. Classical PSP (Richardson's syndrome) is the most common clinical variant and manifests with slowing of vertical saccadic eye movements, falls due to postural instability, axial akinetic-rigid syndrome, and cognitive impairment. Progressively patients develop other problems such as problems in speech and eventually a supranuclear gaze palsy and difficulties in swallowing. PSP with predominant Parkinsonism (PSP-P) is characterized by prominent early parkinsonism (tremor, limb bradykinesia, axial and limb rigidity) rather than falls and cognitive change. Over the years, patients ultimately develop clinical features characteristic of classical PSP. PSP with progressive gait freezing (PSP-PGF) is characterized by progressive freezing of gait, speech and writing early in the disease course. Later, axial rigidity, and facial immobility can occur, and supranuclear downgaze paresis may emerge after a decade. PSP with predominant corticobasal syndrome (PSP-CBS) is characterized by progressive apraxia/cortical sensory loss and limb rigidity/bradykinesia dystonia/myoclonus. PSP with predominant speech/language disorder (PSP-SL) is characterized by speech anomalies (apraxia of speech, agrammatism, nonfluent/agrammatic variant of primary progressive aphasia). Motor symptoms appear later in the course of the disease. PSP with predominant frontal presentation (PSP-F) presents with frontal cognitive/behavioral symptoms. Other variant manifestations of PSP include PSP with predominant ocular motor dysfunction (PSP-OM), PSP with predominant postural instability (PSP-PI), and PSP with predominant frontal presentation (PSP-F).
Etiology
PSP is a 4R tauopathy composed of a preponderance of four-repeat (exon 10 positive) tau isoforms and a characteristic biochemical profile (doublet tau 64 and tau 69). The MAPT H1-clade specific sub-haplotype, H1c, is a risk factor for this disease. PSP is also characterized by deficits in several neurotransmitter systems (e.g., dopaminergic, cholinergic, GABAergic). The factors that initiate tau-neurodegeneration are unknown.
Diagnostic methods
Diagnosis is based on the clinical picture and neuropsychological evaluation. On autopsy, PSP is characterized neuropathologically by neuronal loss and gliosis with tau-immunoreactive astrocytic plaques and neurofibrillary tangles in the brainstem and basal ganglia more than in cerebral cortex and cerebellum. Differences in the anatomical distribution of accumulation of phosphorylated tau protein correlate with the clinical variants.
Differential diagnosis
Differential diagnosis includes Parkinson disease and other atypical parkinsonian disorders (APD) such as multiple system atrophy and corticobasal degeneration. Similar eye movement abnormalities can occur in Niemann-Pick disease type C and Whipple disease.
Genetic counseling
PSP is a sporadic, non-hereditary disease.
Management and treatment
There is no treatment curing the disease. Some drugs, depending on the clinical variant, reduce morbidity and improve quality of life (e.g., levodopa responsiveness of patients with PSP-Parkinsonism). Amantadine may improve gait freezing, coenzyme Q10 may positively affect motor and cognitive dysfunction, and other anticholinergic medications occasionally improve voice and speech disturbance.
Prognosis
Progressively, patients become wheel-chair dependent due to the frequent falls. Difficulties in breathing and swallowing, and infections are the main causes of death, generally 6-12 years after onset of the disease.

                            Last update: 
                            November 2021


                            - Expert reviewer(s): 
                            Pr Günter HÖGLINGER | ERN-RND*


                                * European Reference Network