Genetics and Pathogenesis of Dystonia Thomsen, Mirja; Lange, Lara M; Zech, Michael ...
Annual review of pathology,
01/2024, Letnik:
19, Številka:
1
Journal Article
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Dystonia is a clinically and genetically highly heterogeneous neurological disorder characterized by abnormal movements and postures caused by involuntary sustained or intermittent muscle ...contractions. A number of groundbreaking genetic and molecular insights have recently been gained. While they enable genetic testing and counseling, their translation into new therapies is still limited. However, we are beginning to understand shared pathophysiological pathways and molecular mechanisms. It has become clear that dystonia results from a dysfunctional network involving the basal ganglia, cerebellum, thalamus, and cortex. On the molecular level, more than a handful of, often intertwined, pathways have been linked to pathogenic variants in dystonia genes, including gene transcription during neurodevelopment (e.g.,
KMT2B
,
THAP1
), calcium homeostasis (e.g.,
ANO3
,
HPCA
), striatal dopamine signaling (e.g.,
GNAL
), endoplasmic reticulum stress response (e.g.,
EIF2AK2
,
PRKRA
,
TOR1A
), autophagy (e.g.,
VPS16
), and others. Thus, different forms of dystonia can be molecularly grouped, which may facilitate treatment development in the future.
The Monogenic Network of the Global Parkinson's Genetics Program (GP2) aims to create an efficient infrastructure to accelerate the identification of novel genetic causes of Parkinson's disease (PD) ...and to improve our understanding of already identified genetic causes, such as reduced penetrance and variable clinical expressivity of known disease-causing variants. We aim to perform short- and long-read whole-genome sequencing for up to 10,000 patients with parkinsonism. Important features of this project are global involvement and focusing on historically underrepresented populations.
Paroxysmal dyskinesias (PxD) are rare movement disorders with characteristic episodes of involuntary mixed hyperkinetic movements. Scientific efforts and technical advances in molecular genetics have ...led to the discovery of a variety of genes associated with PxD; however, clinical and genetic information of rarely affected genes or infrequent variants is often limited. In our case series, we present two individuals with PxD including one with classical paroxysmal kinesigenic dyskinesia, who carry new likely pathogenic
variants in
(p.Gly396Val and p.Gly396Arg). The gene has only recently been discovered to be causative for familial paroxysmal kinesigenic dyskinesia. We also provide genetic evidence for pathogenicity of two newly identified disease-causing variants in
(p.Met96Thr and p.Leu231Pro) leading to paroxysmal exercise-induced dyskinesia. Since clinical information of carriers of variants in known disease-causing genes is often scarce, we encourage to share clinical data of individuals with rare or novel (likely) pathogenic variants to improve disease understanding.
The Capiru Formation records supracrustal metassedimentary rocks within the Southern Ribeira Belt. These rocks underwent heterogeneous deformation and metamorphism, resulting in an incomplete ...greenschist facies paragenesis. They are tectonically interbedded with strata that exhibit well-preserved primary structures. In the Morro Grande synform region, there is a continuous 150 m outcrop of metadolomites with preserved sedimentary records and was described in a stratigraphic profile (1:500) subsequently detailed (1:50). Dolomite, minor amounts of quartz, traces of ilite, graphite and zircon constitute the mineral assembly, defined by XRD, petrography and SEM-EDS. Distinct preserved facies are recognized by morphostructures: (1) lamina (parallel, discontinuous, crenulated); (2) stromatolites (homogeneous columnar, club-shaped, conical conophyton-like, pseudocolumnar, parallel-branching, divergent-branching, delicate-branching); (3) thrombolite (rugous) and (4) flat pebble conglomerate. Single-isotope data revials different microbial patterns, particularly in stromatolites (−1.57 to −0.40‰ δ13C; −8.21 to - 3.94‰ δ18O) and lamina (−1.89 to 1.29‰ δ13C; −7.32 to −3.55‰ δ18O). Facies associations suggest a shallow sea with a regressive trend. Tectonofacies are characterized by massive, venulated or brecciated carbonates. Chemostratigraphic profile is divided into two major intervals. At the bottom, the first does not exhibit a specific isotopic trend and can be subdivided in heterogeneous post-deformation venulas (Unit I, −1.75 to 0.40 δ13C; −2.34 to −8.16 δ18O), thrombolythic signals (Unit II, −1.43 to 0.40‰ δ13C; −6.35 to −4.11‰ δ18O), and facies variation, mainly supratidal (Unit III, 1.89 to 1.29‰ δ13C, −7.32 to −3.31‰ δ18O). Upwads in the profile, the second interval consists of microbial facies, displaying a more uniform signature with depleted values of δ13C and δ18O along with a slight enrichment marking the transition from intratidal to supratidal environments (Unit IV; −1.32 to −0.81‰ δ13C; - 8.17 to −6.25‰ δ18O) and supratidal lagoons (Unit V; −1.35 to −0.41‰ δ13C; −8.20 to −5.49‰ δ18O). Preserved EPS, graphite, and ilite confirm low-grade metamorphism, with clumped isotope thermometry temperatures ranging from 206.07 to 307.58 °C. Calcite is secondary, filling porosity and present in recrystallized facies. Isotopic signature of recrystallized facies differs from microbial ones, with the most depleted values (−2.16‰ δ13C; −14.02‰ δ18O) and lower formation temperature (122.29 ± 7.07 °C), indicating a late restricted event. This dolomitic succestion within Capiru Formation provides evidence of a shallow marine paleoenvironment with diverse microbial activity during its deposition.
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•Overview of a poorly studied Capiru Formation carbonate sequence.•Carbonate facies and associations of a 150 m preserved neoproterozoic microbial sequence.•Morphological, isotopic and chemical characterization of preserved facies.•Paleoenvironmental depositional model proposal for Rio Branco unit.
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