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Paroxysmal movement disorders include two groups of intermittent neurologic disorders: paroxysmal dyskinesia, in which episodes of involuntary hyperkinetic movements (mainly chorea and/or dystonia) occur with preserved consciousness, and episodic ataxias, which are characterized by discrete attacks of cerebellar dysfunction, sometimes associated with progressive ataxia. Since episodic ataxias are individually discussed in Chapter 8 of this volume, we herein provide a deep overview of phenotypic, genetic, pathophysiologic, diagnostic, and treatment aspects of paroxysmal dyskinesia, following the trigger-based nomenclature which distinguishes paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, and paroxysmal exercise-induced dyskinesia. Emerging paroxysmal dyskinesia not fulfilling the criteria for the above-mentioned subtypes will also be discussed. Phenotypic and genotypic overlap among paroxysmal movement disorders, epilepsy, and migraine have progressively emerged, thus shedding light on a shared pathophysiologic framework. Advances in our understanding of the pathomechanisms underlying paroxysmal movement disorders, which involve dysfunctions of ion channels, proteins associated with the vesical synaptic cycle machinery, and proteins involved in neuronal energy metabolism, point toward a discrete number of converging pathophysiologic pathways and may lay foundations for developing target-specific therapies.
Assuntos
Transtornos dos Movimentos , Humanos , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/terapia , Transtornos dos Movimentos/fisiopatologia , Coreia/diagnóstico , Coreia/terapia , Coreia/fisiopatologia , Coreia/genéticaRESUMO
BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive atypical parkinsonian condition that results in severe disability. There are few studies of PSP in patients of non-white European ancestry. OBJECTIVES: We aim to perform deep phenotyping in a South Asian PSP cohort to uncover possible ethnic differences in disease characteristics. METHODS: Consecutive PSP patients had their clinical records reviewed for clinical features operationalized in the Movement Disorder Society (MDS)-PSP diagnostic criteria and relevant investigations, including imaging and genetic tests. Clinical variables were summarized by descriptive statistics and Kaplan-Meier curves were generated for survival analysis. RESULTS: Twenty-seven patients, comprising Indians (78%), Pakistanis (11%) and Sri Lankans (11%) were included. Mean age of symptom onset was 63.8 ± 7.0 years and 22% of patients had an early age of onset (<60 years). The most common presenting symptom was parkinsonism (56%), followed by cognitive dysfunction (37%), falls (33%) and dysarthria (26%). The predominance types at final review were distributed across PSP-RS (67%), PSP-PGF (15%), PSP-P (15%) and PSP-F (4%). Atypical clinical features like cerebellar signs (33%), REM-sleep behavior disorder (RBD) (55%), visual hallucinations (22%), and a family history of parkinsonism (20%) were evident in a proportion of patients. CONCLUSIONS: We present a South Asian cohort of PSP patients with a higher than previously reported percentages of early-onset disease, family history and atypical clinical manifestations. These patients do not fit easily into the PSP phenotypes defined by the current MDS criteria. Dedicated clinicopathological and genetic tests are needed in this population to dissect the pathogenesis of clinically-defined PSP.
RESUMO
Nucleotide repeat expansions in the human genome are a well-known cause of neurological disease. In the past decade, advances in DNA sequencing technologies have led to a better understanding of the role of non-coding DNA, that is, the DNA that is not transcribed into proteins. These techniques have also enabled the identification of pathogenic non-coding repeat expansions that cause neurological disorders. Mounting evidence shows that adult patients with familial or sporadic presentations of epilepsy, cognitive dysfunction, myopathy, neuropathy, ataxia, or movement disorders can be carriers of non-coding repeat expansions. The description of the clinical, epidemiological, and molecular features of these recently identified non-coding repeat expansion disorders should guide clinicians in the diagnosis and management of these patients, and help in the genetic counselling for patients and their families.
Assuntos
Doenças do Sistema Nervoso , Humanos , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/diagnóstico , Diagnóstico Diferencial , Expansão das Repetições de DNA/genéticaRESUMO
Biallelic expansions of the AAGGG repeat in the replication factor C subunit 1 (RFC1) have recently been described to be responsible for cerebellar ataxia, peripheral neuropathy and vestibular areflexia syndrome. This genetic alteration has also allowed genetic classification in up to one-third of cases with idiopathic sensory neuropathy. Here, we screened a well-characterized cohort of inflammatory neuropathy patients for RFC1 repeat expansions to explore whether RFC1 was increased from background rates and possibly involved in the pathogenesis of inflammatory neuropathy. A total of 259 individuals with inflammatory neuropathy and 243 healthy controls were screened for the AAGGG repeat expansion using short-range flanking PCR and repeat-primed PCR. Cases without amplifiable PCR product on flanking PCR and positive repeat-primed PCR were also tested for the mostly non-pathogenic expansions of the AAAGG and AAAAG repeat units. None of the patients showed biallelic AAGGG expansion of RFC1, and their carrier frequency for AAGGG was comparable with controls [n = 27 (5.2%) and n = 23 (4.7%), respectively; P > 0.5]. Data suggest that the pathologic expansions of AAGGG repeats do not contribute to the development of inflammatory neuropathies nor lead to misdiagnosed cases. Accordingly, routine genetic screening for RFC1 repeat expansion is not indicated in this patient population.
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Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson's disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials.
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Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD and parkinsonism to perinatal lethality with neurological manifestations across 15 unrelated pedigrees with 22 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants impair mitochondrial membrane potential, dynamics and mitophagy in patient-derived fibroblasts. Additionally, we develop models of psmf1 knockdown Drosophila and Psmf1 conditional knockout mouse exhibiting age-dependent motor impairment, with diffuse gliosis in mice. These findings unequivocally link defective PSMF1 to early-onset PD and neurodegeneration and suggest mitochondrial dysfunction as a mechanistic contributor.