Atypical parkinsonian disorders are a group of neurodegenerative diseases that share features with Parkinson's disease but typically have more rapid progression, earlier falls, and poorer response to dopaminergic medications. The main atypical parkinsonian disorders include Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), and Corticobasal Degeneration (CBD). While these diseases were historically considered sporadic, significant genetic contributions have been identified that provide insights into disease mechanisms and therapeutic targets. [@genomewide]
Genetic studies have revealed distinct genetic architectures for each atypical parkinsonian disorder: [@mashyam2022][@kumar2020]
Understanding these genetic variants is critical for: [@noveldctn1]
PSP is strongly associated with tau pathology. The MAPT gene H1 haplotype is the major genetic risk factor, increasing risk by 3-5x. Specific mutations like P301L cause familial PSP. [@kumar2020]
See: PSP Genetic Variants
MSA is characterized by alpha-synuclein pathology. Genetic variants in SNCA, GBA, and COQ2 contribute to disease risk.
See: MSA Genetic Variants
CBD shows both tau and TDP-43 pathology. MAPT H1 haplotype and specific mutations are the primary genetic risk factors.
See: CBD Genetic Variants
The MAPT gene encodes the tau protein, which is central to several atypical parkinsonian disorders. The H1 haplotype is a major risk factor for both PSP and CBD, increasing susceptibility by approximately 3-5 fold. Specific pathogenic mutations such as P301L, P301S, and R406W cause familial forms of PSP and CBD. These mutations alter tau's ability to bind microtubules and promote aggregation into neurofibrillary tangles. [@kumar2020]
SNCA mutations and multiplications are associated with MSA risk. The SNCA H1 haplotype is also a risk factor for PSP. Alpha-synuclein aggregates into glial cytoplasmic inclusions in MSA, distinguishing it from the Lewy bodies seen in PD.
GBA mutations, which cause Gaucher disease, are significant risk factors for both PD and MSA. Carriers of GBA mutations have a 5-10 fold increased risk of developing MSA. The mechanism involves lysosomal dysfunction and alpha-synuclein aggregation.
Variants in the COQ2 gene, which encodes Coenzyme Q10 biosynthesis protein, have been associated with MSA in Japanese populations. COQ2 variants may impair mitochondrial function and increase susceptibility to MSA.
DCTN1 variants are associated with Perry disease, an unusual autosomal dominant parkinsonism. The G71S mutation is the most common cause. Patients present with parkinsonism, psychiatric changes, and weight loss. [@noveldctn1]
PLA2G6-associated neurodegeneration (PLAN) can present with adult-onset parkinsonism. Phenotypes include dystonia-parkinsonism, iron accumulation, and corticobasal syndrome. [@pla2g6adult]
ATXN2 CAG repeat expansions are associated with spinocerebellar ataxia type 2 (SCA2) and are also implicated in ALS risk. Intermediate expansions may modify atypical parkinsonism phenotypes. [@atxn2expanding]
A landmark Spanish-Portuguese GWAS of 522 PSP cases identified a novel risk locus at NFASC/CNTN2 (rs12744678 C: OR=0.83, p=4.15×10⁻⁸). [@nfasc2025] This finding independently replicated eight known PSP risk variants across seven loci (MAPT, MOBP, EIF2AK3, STX6, SLCO1A2, DUSP10, and APOE). Enrichment analysis highlighted oligodendrocyte function and myelination as likely contributors to PSP pathogenesis, suggesting potential therapeutic avenues focused on modulating neuron-oligodendrocyte interactions.
The study also revealed reduced diagnostic specificity in clinically diagnosed atypical parkinsonian syndromes compared to histopathologically confirmed PSP cases, emphasizing the importance of genetic testing for accurate diagnosis.
Repeat expansions in NOTCH2NLC and FMR1 share clinical features with atypical parkinsonism, including parkinsonism and ataxia. [@notch2nlc2025] In a study of 252 patients with atypical parkinsonism (including MSA, PSP, CBS) and 341 asymptomatic individuals over 60 years old, NOTCH2NLC expansions (≥60 repeats) were identified in 6 patients (2.38%) versus 2 controls (0.58%, p=0.07). The findings suggest that NOTCH2NLC expansions can mimic PSP and MSA phenotypes, underscoring the need for genetic evaluation in cases of atypical parkinsonism.
Clonal hematopoiesis (CH), characterized by somatic mutations in hematopoietic stem cells, has emerged as a driver of brain pathology in aging. [@ch2025] Research demonstrated that monocyte-derived microglia (MoMg) progressively seed the brain of aging mice, accumulating in selected areas including the nigrostriatum and medulla—but not the frontal cortex. When carrying CH-associated mutations (e.g., DNMT3A R882H), these MoMg become pathogenic and promote motor deficits resembling atypical Parkinsonian disorders.
This finding has significant implications for understanding how age-related somatic mutations in blood cells may contribute to neurodegeneration, and suggests that targeting CH could represent a novel therapeutic strategy for atypical parkinsonian disorders.
Long-read sequencing has revealed pathogenic GAA repeat expansions in FGF14 as a contributor to Parkinson's disease phenotypes. [@fgf14pd2025] Given emerging evidence that repeat expansions in ataxia-associated genes like RFC1 can contribute to parkinsonism, this finding expands the genetic landscape of PD and atypical parkinsonian disorders.
Genetic testing for atypical parkinsonism variants is increasingly important for:
Understanding the genetic basis of atypical parkinsonism has led to several therapeutic approaches: