X‐Linked Parkinsonism: Phenotypic and Genetic Heterogeneity

Abstract

A BS TRACT: X-linked parkinsonism encompasses rare heterogeneous disorders mainly inherited as a recessive trait, therefore being more prevalent in males. Recent developments have revealed a complex underlying panorama, including a spectrum of disorders in which parkinsonism is variably associated with additional neurological and non-neurological signs. In particular, a childhoodonset encephalopathy with epilepsy and/or cognitive disability is the most common feature. Their genetic basis is also heterogeneous, with many causative genes and different mutation types ranging from "classical" coding variants to intronic repeat expansions. In this review, we provide an updated overview of the phenotypic and genetic spectrum of the most relevant X-linked parkinsonian syndromes, namely X-linked dystonia-parkinsonism (XDP, Lubag disease), fragile X-associated tremor/ataxia syndrome (FXTAS), beta-propeller protein-associated neurodegeneration (BPAN, NBIA/PARK-WDR45), Fabry disease, Waisman syndrome, methyl CpG-binding protein 2 (MeCP2) spectrum disorder, phosphoglycerate kinase-1 deficiency syndrome (PGK1) and X-linked parkinsonism and spasticity (XPDS). All clinical and radiological features reported in the literature have been reviewed. Epilepsy occasionally represents the symptom of onset, predating parkinsonism even by a few years; action tremor is another common feature along with akinetic-rigid parkinsonism. A focus on the genetic background and its pathophysiological implications is provided. The pathogenesis of these disorders ranges from well-defined metabolic alterations (PGK1) to non-specific lysosomal dysfunctions (XPDS) and vesicular trafficking alterations (Waisman syndrome). However, in other cases it still remains poorly defined. Recognition of the phenotypic and genetic heterogeneity of X-linked parkinsonism has important implications for diagnosis, management, and genetic counseling.

Parkinson's disease – genetic cause

“…Mutations in eight genetic loci ( TAF1, FMR1, RAB39B, WDR45, GLA, MeCP2, PGK1 and ATP6AP ) on the X chromosome were associated with the development of Parkinson's disease [77 ▪▪ ]. X-linked parkinsonism manifests at a young age (JOPD or EOPD), accompanied by many (atypical) features such as intellectual disability, psychiatric features, spasticity, seizures, myoclonus, dystonia, and have poor response to levodopa [77 ▪▪ ]. Most of the affected individuals are men; however, rarely, female carriers may present with a mild phenotype of pure Parkinson's disease with a good response to levodopa and no atypical features.…”

Genetic Architecture of Parkinson’s Disease

“…The disease phenotype and the mRNA level are influenced by the number of monomers (CCCCST)n in the VNTR repeat. This number varies from 34 to 52 and affects both the comparative severity of dystonia/parkinsonism and the age of clinical onset of the disease [68][69][70].…”

Genetic architecture of Parkinson’s disease subtypes – Review of the literature

“…Mutations in at least eight genetic loci ( TAF1, FMR1, RAB39B, WDR45 , GLA , MeCP2 , PGK1 , and ATP6AP) on the X chromosome were associated with the development of PD ( Di Lazzaro et al, 2021 ; Dulski et al, forthcoming ). Contrary to the autosomal monogenic forms, pathogenic variants on the X chromosome usually manifest at a young age (JOPD or EOPD), with parkinsonism accompanied by many (atypical) features including intellectual disability or early cognitive decline, psychiatric features, spasticity, seizures ( Di Lazzaro et al, 2021 ; Dulski et al, forthcoming ), myoclonus, dystonia, and usually display a poor response to dopaminergic treatment. Most of the affected individuals are males; however, rarely, female carriers may present with a mild phenotype of pure PD with a good response to levodopa and no atypical features ( Di Lazzaro et al, 2021 ; Dulski et al, forthcoming ).…”

“…Contrary to the autosomal monogenic forms, pathogenic variants on the X chromosome usually manifest at a young age (JOPD or EOPD), with parkinsonism accompanied by many (atypical) features including intellectual disability or early cognitive decline, psychiatric features, spasticity, seizures ( Di Lazzaro et al, 2021 ; Dulski et al, forthcoming ), myoclonus, dystonia, and usually display a poor response to dopaminergic treatment. Most of the affected individuals are males; however, rarely, female carriers may present with a mild phenotype of pure PD with a good response to levodopa and no atypical features ( Di Lazzaro et al, 2021 ; Dulski et al, forthcoming ). Based on previous studies, no conclusion regarding the most often associated PD subtypes can be drawn.…”