Microtubule-associated protein tau gene mutations have been associated with different neurodegenerative diseases that share pathological changes with tau protein accumulation. Specifically, it has been associated with Alzheimer's disease, corticobasal degeneration, PSP, Pick disease, and argyrophilic grain disease. Between 0.6 and 14.3% of total PSP disease cases are due to MAPT mutations (3). Among GPSPS, mutations related to the MAPT gene appear to be the most frequent cause. The pattern of inheritance is autosomal dominant, penetrance is frequently complete, and there is usually variable expressivity, with different phenotypes observed for the same mutation. The most frequently reported mutation is IVS10+3 (35%). While dementia is generally a frequent feature in MAPT mutations (5, 6), among GPSPS, 51.1% presented with PSP-parkinsonism (PSP-P, 20–24%) or PSP-RS (11–18%) motor features, and 41.9% had frontal predominant cognitive symptoms at onset (PSP-F). Mutations related to a motor phenotype onset are R5L, L284R, S285R, delN296, N296N, and G303V, and those associated with cognitive symptoms at diagnosis are P301L, S305S, and IVS10+3. The mean age at presentation is 46.3 years (range 32–63 years). Upper and lower motor neuron involvement or denervation was observed in some cases for P301L and IVA10+3 mutations. As a differential clinical feature, visual grasping has been observed in N296N mutations, a sign associated with medial frontal lobe dysfunction leading to forced fixation and dependency of gaze on objects brought into the patient's field of view (7). On magnetic resonance imaging (MRI), MAPT mutations are generally associated with predominant and symmetric atrophy in the frontotemporal lobes, with paramagnetic accumulation in midbrain nuclei and white matter changes. Anterior temporal atrophy is symmetric and more marked than orbitofrontal and lateral prefrontal atrophy. Mutations in the splicing region usually lead to medial temporal lobe involvement and mutations in the coding regions affect the lateral temporal lobe. In ¹⁸fluorodeoxyglucose positron emission tomography (FDG-PET), the most common pattern is bilateral temporal hypometabolism (4). For GPSPS, this pattern of frontotemporal atrophy was found on computed tomography (CT) and MRI, as well as frontal hypometabolism on FDG-PET, but only for PSP-F presentations. MRI of cases with PSP-P showed mild and diffuse brain atrophy as the main pattern (8–25). In patients with a clinical diagnosis of PSP, in vivo hippocampal, basal ganglia, and midbrain retention of 18F-AV-1451 tau PET have been seen. Patients with MAPT S305N (SUVRs) and P301L mutations have shown lower levels of tau PET-specific standardized uptake value ratios (SUVRs) at the temporal poles than patients with mutations outside exon 10, and P301L mutations have shown lower levels of tau PET in the white matter (26, 27).

The GGGGCC hexanucleotide repeat expansion in the non-coding region of the first exon leads to haploinsufficiency (28) and additional unclear factors (29) that lead to neuronal dysfunction. This expansion is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (30, 31). The clinical spectrum has expanded in the last years, including genotype–phenotype associations to other neurodegenerative diseases such as PSP, corticobasal syndrome (CBS), Parkinson's disease (PD), multiple system atrophy, Huntington disease-like syndrome, and Creutzfeldt–Jakob disease (CJD) (31–34). Yet, its exact role in these neurodegenerative diseases remains largely unknown (35, 36). Up to 35% of patients with the C9orf72 gene expansion have parkinsonism (6) and 7% of patients with PSP syndrome, and a positive family history carries the C9orf72 gene expansion, representing the second-most frequent genetic mutation related to GPSPS after MAPT. For those patients with >30 repeats and PSP syndrome, the mean age at presentation was 64 years (range 40–79), and 12% of patients had a family history of neurodegenerative disease. The PSP-RS phenotype was present in the majority of these cases, and PSP-F was the second-most frequent phenotype. Family history following an autosomal dominant inheritance pattern, frequent hallucinations, and motor neuron disease may be differential findings in this entity. As in MAPT mutations, a symmetric atrophy of the anterior temporal lobe has been described, but it differs from MAPT in greater involvement of the cerebellum in combination with atrophy of the medial prefrontal, dorsolateral, and orbitofrontal cortex (4). Both cortical and midbrain atrophy as well as frontotemporal-predominant atrophy were observed in patients with GPSPS (37–40).

Kufor–Rakeb syndrome is an autosomal recessive disease due to ATP13A2 gene mutations, which has been related to levodopa-responsive juvenile parkinsonism with associated dyskinesias, supranuclear vertical gaze palsy, and prominent psychiatric symptoms (41). The mean age at the onset of the disease is 14.9 years (range 7.5–22 years). Although psychiatric symptoms are frequent, diagnosis is based on severe motor symptoms at onset, with PSP-P and PSP-RS being the most frequent phenotypes. A distinctive clinical feature present in all cases is the development of clinically relevant facial-faucial-finger mini-myoclonus, which are jerky movements in the perioral area, tongue, and fingers. Neuroimaging shows diffuse cerebral atrophy with cerebellar involvement in most patients, unrelated to the disease progression. Then, one patient showed bilateral striatal hypometabolism in FDG-PET and dopamine transporter single-photon emission computed tomography (DAT-SPECT) studies, consistent with nigrostriatal dopaminergic dysfunction (42, 43).

Niemann–Pick disease type C is a lysosomal disorder of autosomal recessive inheritance due to mutations in the NPC1 or NPC2 genes. In infantile forms, ataxia, dystonia, bulbar symptoms, epilepsy, gelastic cataplexy, and developmental delay predominate. Clinical symptoms in the adult onset presentations have a slower progression, but are characterized by severe cognitive and psychiatric disturbances (schizophrenia-like symptoms often refractory to treatment), ataxia, segmental dystonia with predominant facial and bibrachial involvement, vertical supranuclear gaze palsy (especially downward), and occasional bilateral leg spasticity (6, 44). Among the adolescent–adult cases reported that met clinical criteria for PSP, the most frequent phenotype at onset was PSP-F. These cases showed frontal predominant cortical atrophy on MRI, sometimes associated with corpus callosum atrophy. Those with predominant oculomotor symptoms were more likely to have brainstem and cerebellar atrophy, with relative sparing of cortical and subcortical areas (45). When patients with a PSP phenotype and additional symptoms that raise the suspicion of Niemann–Pick type C, screening with filipin staining is a good approach prior to genetic study.

Granulin precursor gene mutations have been mainly associated with Alzheimer's disease, FTD, CBS, progressive non-fluent aphasia, and cortical sensory symptoms (6, 46). Most mutations produce a stop codon resulting in haploinsufficiency. Mutations in the GRN gene, however, have been also found in patients with the PSP syndrome. The mean age at onset is around 60 years (range 63–68), and 50% of patients had a known family history of parkinsonism, PSP, or behavioral variant of frontotemporal dementia (bvFTD). Between 50 and 75% of patients with PSP syndrome and GRN mutation had an initial phenotype of PSP-F, and the remainder had PSP-SL and PSP-P phenotypes. As a differential clinical feature of GRN gene mutations, up to 25% of patients developed visual hallucinations and delusions. Orobuccal dyskinesias were common, although many reported patients had previous exposure to neuroleptics. The usual pattern of GRN mutations on MRI is different from MAPT mutations, following a distribution of asymmetric frontotemporal atrophy and additional involvement of the inferior parietal lobe. More specifically, patients with the 102delC mutation of GRN gene show more widespread frontal, temporal, and brainstem atrophy on MRI (47–51).

Mutations in the SYNJ1 gene, also known as the PARK20 gene, have been associated with monogenic parkinsonism with autosomal recessive inheritance and predominant postural instability (52), dystonia, cognitive impairment, and seizures (53). Some cases with PSP syndrome have been described, with a very early disease onset. Mean age is 24.7 years (range 21–28), with PSP-P being the most frequently reported phenotype. One case was associated with developmental delay, and in another two cases, levodopa-induced dyskinesias were frequent. Apart from one case showing cortical and midbrain atrophy, MRI has no specific abnormalities. Cortical and caudate hypometabolism was observed with FDG-PET, and DAT-SPECT showed a bilateral and severe nigrostriatal deficit (54–57).

The dynactin gene, DCTN1, has classically been associated with Perry syndrome, which is defined by parkinsonism, psychiatric symptoms, central hypoventilation, and bodyweight loss (58). Following the discovery of the gene, the clinical spectrum associated with mutations in DCTN1 has broadened to include FTD, motor neuron disease, and PSP syndrome (6, 59). Most reported cases (60–80%) had a PSP-P phenotype, and 20–40% had PSP-F. The mean age at presentation was 59.5 years (range 46–84), and all patients had family history of bvFTD, Perry syndrome, or PD. MRI findings were variable, ranging from mild diffuse atrophy to brainstem or predominant frontoparietal atrophy. Frontal hypoperfusion was also demonstrated in one case by SPECT (60–63).

Among the main genetic prion diseases due to mutations in the PRNP gene, genetic CJD, Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia are known. While the presentation can be heterogeneous, the most common features include dementia, psychiatric disturbances, myoclonus, ataxia, cortical blindness, extrapyramidal symptoms, and insomnia (64–66). Some families with PSP phenotype have been described, with PSP-P or PSP-F associated with initial psychiatric symptoms following PSP. The mean age at presentation was 52.9 years. All patients had ataxia and/or nystagmus. MRI showed heterogenous findings, such as non-specific white matter changes, cerebellar atrophy, basal ganglia iron deposition, and cortical ribbon hyperintense on DWI and FLAIR sequences (66–69). In patients with the PSP syndrome, a family history with autosomal dominant inheritance pattern is found.

Some monogenic diseases can mimic the PSP phenotype in early stages. In these cases, PSP syndrome is usually an incidental finding, and the disease course reveals other clinical features that allow the exclusion of the diagnosis (Table 2).