Pallidal degenerations and related disorders: an update

Abstract

Neurodegenerative disorders involving preferentially the globus pallidus, its efferet and afferent circuits and/or related neuronal systems are rare. They include a variety of both familial and sporadic progressive movement disorders, clinically manifesting as choreoathetosis, dystonia, Parkinsonism, akinesia or myoclonus, often associated with seizures, mental impairment and motor or cerebellar symptoms. Based on the involved neuronal systems, this heterogenous group has been classified into several subgroups: "pure" pallidal atrophy (PPA) and extended forms, pallidonigral and pallidonigrospinal degeneration (PND, PNSD), pallidopyramidal syndrome (PPS), a highly debatable group, pallidopontonigral (PPND), nigrostriatal-pallidal-pyramidal degeneration (NSPPD) (Kufor-Rakeb syndrome /KRS), pallidoluysian degeneration (PLD), pallidoluysionigral degeneration (PLND), pallidoluysiodentate atrophy (PLDA), the more frequent dentatorubral-pallidoluysian atrophy (DRPLA), and other hereditary multisystem disorders affecting these systems, e.g., neuroferritinopathy (NF). Some of these syndromes are sporadic, others show autosomal recessive or dominant heredity, and for some specific gene mutations have been detected, e.g., ATP13A2/PARK9 (KRS), FTL1 or ATP13A2 (neuroferritinopathy), CAG triple expansions in gene ATN1 (DRPLA) or pA152T variant in MAPT gene (PNLD). One of the latter, and both PPND and DRPLA are particular subcortical 4-R tauopathies, related to progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and frontotemporal lobe degeneration-17 (FTLD-17), while others show additional 3-R and 4-R tauopathies or TDP-43 pathologies. The differential diagnosis includes a large variety of neurodegenerations ranging from Huntington and Joseph-Machado disease, tauopathies (PSP), torsion dystonia, multiple system atrophy, neurodegeneration with brain iron accumulation (NBIA), and other extrapyramidal disorders. Neuroimaging data and biological markers have been published for only few syndromes. In the presence of positive family histories, an early genetic counseling may be effective. The etiology of most phenotypes is unknown, and only for some pathogenic mechanisms, like polyglutamine-induced oxidative stress and autophagy in DRPLA, mitochondrial dysfunction induced by oxidative stress in KRS or ferrostasis/toxicity and protein aggregation in NF, have been discussed. Currently no disease-modifying therapy is available, and symptomatic treatment of hypo-, hyperkinetic, spastic or other symptoms may be helpful.

Keywords: Clinical features; Differential diagnosis; Genetics; Neuroimage findings; Neuropathology; Pallidal; Pallidoluysiodentate atrophy; Pallidonigral; Therapy.