Abstract
Parkinson disease (PD) is a complex neurodegenerative disorder, usually with multifactorial etiology. It is characterized by prominent movement disorders and non-motor symptoms. Movement disorders commonly include bradykinesia, rigidity, and resting tremor. Non-motor symptoms can include behavior disorders, sleep disturbances, hyposmia, cognitive impairment, and depression. A fraction of PD cases instead is due to Parkinsonian conditions with Mendelian inheritance. The study of the genetic causes of these phenotypes has shed light onto common pathogenetic mechanisms underlying Parkinsonian conditions. Monogenic Parkinsonisms can present autosomal dominant, autosomal recessive, or even X-linked inheritance patterns. Clinical presentations vary from forms indistinguishable from idiopathic PD to severe childhood-onset conditions with other neurological signs. We provided a comprehensive description of each condition, discussing current knowledge on genotype-phenotype correlations. Despite the broad clinical spectrum and the many genes involved, the phenotype appears to be related to the disrupted cell function and inheritance pattern, and several assumptions about genotype-phenotype correlations can be made. The interest in these assumptions is not merely speculative, in the light of novel promising targeted therapies currently under development.
Highlights
Parkinson disease (PD) is a complex, progressive, neurodegenerative disorder with worldwide incidence of 5–35 in 100,000 cases per year and prevalence reaching 2–4% at the age of 85
Pathogenic variants in LRRK2 and VPS35 are usually related to Parkinsonisms resembling typical PD, while alterations in SNCA are more frequently found in atypical forms
The increase in the LRRK2 kinase activity mainly compromises neuronal vesicular trafficking, through an aberrant excessive phosphorylation of Rab GTPases [48]. These findings have suggested that LRRK2 kinase inhibitors might be a therapeutic target in LRRK2-related PD for monogenic LRRK2related Parkinsonisms and for the more common iPD [49]
Summary
Parkinson disease (PD) is a complex, progressive, neurodegenerative disorder with worldwide incidence of 5–35 in 100,000 cases per year and prevalence reaching 2–4% at the age of 85. Clinical manifestations include motor signs (resting tremor, rigidity, bradykinesia, and postural instability) and non-motor features such as hyposmia, constipation, mood disorders, and rapid eye movement sleep behavior disorder (RBD), Monogenic Parkinson Disease: Genotype-Phenotype Correlations often preceding the motor signs. Parkinsonisms presenting as an iPD-like condition will be classified as “typical PD.”. Cases presenting complex phenotypes, featuring prominent additional neurological signs, such as dementia, spasticity, dystonia, and/or abnormal ocular movements, will be classified as “atypical PD.”. We will discuss the clinical presentation and genetic cause of each condition, with insights into underlying molecular pathology, to provide genotype–phenotype correlations. The phenotypes will be presented and discussed individually, based on transmission patterns and clinical features.
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