Genotype-Phenotype Correlations in Monogenic Parkinson Disease: A Review on Clinical and Molecular Findings

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.

Keywords: Juvenile parkinsonism; Parkinson's disease; early onset parkinsonism; monogenic; phenotype.

Figure 1

Genotype-phenotype correlation in monogenic Parkinsonian conditions. Central arrow: time of onset. Each colored bar represents a subset of conditions. (A) iPD-like, late-onset autosomal dominant Parkinsonisms. (B) Complicated autosomal dominant Parkinsonisms. (C) Genetic risk factor causing late-onset Parkinsonism. (D) Typical autosomal recessive early-onset Parkinsonisms. (E) Complicated autosomal recessive early onset Parkinsonisms. (F) Juvenile uncomplicated Parkinsonism. (G) Juvenile pallido-pyramidal syndromes. (H) Juvenile atypical Parkinsonisms.