Postsynaptic movement disorders: clinical phenotypes, genotypes, and disease mechanisms

Abela, Lucia; Kurian, Manju A.

doi:10.1007/s10545-018-0205-0

Cited by 26 publications

(22 citation statements)

References 126 publications

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“…Severe axial involvement was noted in 7 of these 9 cases, being a potential clinical clue. Such a wide clinical spectrum is not surprising, given that other genes causing early onset dystonia are associated with a phenotypic continuum, ranging from pure dystonia to more complex presentations 2,33 . Moreover, our observations suggest an incomplete penetrance and variable expressivity for EIF2AK2 variants, as also frequently reported for variants causing other autosomal dominant forms of dystonia, including DYT‐TOR1A and DYT‐THAP1 1,2 .…”

Section: Discussionsupporting

confidence: 75%

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

Kuipers

Mandemakers

et al. 2020

Annals of Neurology

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Objective The study was undertaken to identify a monogenic cause of early onset, generalized dystonia. Methods Methods consisted of genome‐wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients. Results We identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR‐mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon‐inducible double‐stranded RNA‐dependent protein kinase activator A), the product of another gene causing monogenic dystonia. Interpretation We identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485–497

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Section: Discussionsupporting

confidence: 75%

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

Kuipers

Mandemakers

et al. 2020

Annals of Neurology

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“…This postsynaptic approach is described in this issue by Dr. Àlex Bayès (Bayés 2018;Bayés et al 2011) as a global overview and by Drs. Abela and Kurian (Abela and Kurian 2018) in the case of movement disorders.…”

Section: Iem Inborn Errors Of Metabolismmentioning

confidence: 99%

Synaptic metabolism and brain circuitries in inborn errors of metabolism

García‐Cazorla

Artuch

Bayés

2018

J of Inher Metab Disea

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Abbreviations IEM inborn errors of metabolismMore than 300 new inborn errors or metabolism (IEM) have been described during the last 5 years and most of them have major neurological symptoms (Ferreira et al. 2018;Saudubray and Garcia-Cazorla 2018). These disorders have changed paradigms transforming the concept and classification of IEM and are contributing enormously to our understanding of mechanisms in neurological diseases. A pioneer initiative in this direction was the description of the vast new group of complex lipid synthesis and remodelling defects that stands at the frontier between classical IEM and cellular neurobiology (Lamari et al. 2015). More recently, many defects affecting systems involved in intracellular vesiculation, trafficking, processing and quality control of complex molecules, such as protein folding and autophagy (Ebrahimi-Fakhari et al. 2016), have described a number of diseases with important repercussion in the brain.The -omics era is currently transforming neurology, and in particular child neurology, with the description of an increasing amount of new monogenic diseases. However, the pathophysiological approach to these disorders is mostly based on neuroanatomy, neurophysiology and the description of individual proteins. The role of metabolism, which strongly orchestrates neuronal function, has been mostly neglected in the study of brain disorders. On the other hand, the description of biological mechanisms of disease in the field of IEM has not fully considered the particularities of the nervous system. The human brain is a unique system that exhibits a complex architecture and a great diversity of functions and cellular types. Neurons are large and highly polarised cells consisting of axons and dendritic arborisations that communicate with each other through synaptic contacts, which are essential to their function. To integrate information within and between compartments, neurons need sophisticated transfer mechanisms, ensuring that necessary molecules are available in the right place at the right time. Metabolism is regulating these functions and appears to have specific properties at every single neuronal compartment. Metabolism has also specific rules depending on the specific subtype of nervous cell (different populations of neurons, glia, oligodendrocytes, microglia…). An important model of compartmentalised signalling and metabolism occurs at the synapse, which is the main topic of this special issue.The synapse is a highly specialised cell junction that connects a presynaptic transmitting neuron with a postsynaptic receiving neuron. Synapses connect more than one hundred billion neurons present in the human brain, and wire-select neurons into functional circuits, enabling the brain to process and transfer information (Südhof 2013). The concept of Bsynaptic metabolism^is introduced in this special issue and is the conducting wire of most of its articles; it could be defined as the specific chemical composition and metabolic functions occurring at the synapse. The presynapti...

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“…GNAO1 is severalfold more abundant than any other Gα protein in the CNS [11]. Neurons and neuroendocrine cells are the primary site of expression of the gene [19,13]. Known Gβγ partners of GNAO1 are encoded by GNB1 (as Gβ) and GNG2 (as Gγ) [20], though the existence of other partners is likely.…”

Section: Gtpase: Gnao1mentioning

confidence: 99%

“…The reason for the latter is that because GNAO1 inhibits its effector, the hyperactive GNAO1 means hyper-downregulated GABA signaling. Adding to the complexity of the pathway, GABA-ergic neurons expressing GNAO1 may themselves have an inhibitory role [13].…”

Section: Rationalizing the Phenotype Through Modeling The Signal Tranmentioning

confidence: 99%

“…It functions at the core of multiple neurotransmitter pathways, and is expressed in multiple types of neurons [11]. In particular, GNAO1 expresses profusely in the striatum, [12,13], Table S1, region of the brain responsible for the smooth transition between movement sequences [14]. Unsurprisingly then, GNAO1 pathogenic variants cause a spectrum of neurological phenotypes, roughly falling into two categories: movement disorders (MD) or epilepsy-related (E) phenotypes.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular map of GNAO1-related disease phenotypes and reactions to therapy

Mihalek

Waugh

M³

et al. 2017

Preprint

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The GNAO1 gene codes for the most commonly expressed Gα protein in the central nervous system. De novo GNAO1 variants cause complex early-onset neurological phenotypes, sometimes with distinct epilepsy or movement disorder manifestations, and sometimes with both manifestations in the same patient. G-protein coupled receptor (GPCR) signaling is among the best studied molecular interaction pathways in the human organism, which provides the input needed to quantitatively evaluate how mutations modify the GPCR signal. This in turn allows rational interpretation of distinct phenotypes arising from mutations in GNAO1. In this work we outline a model that enables understanding of clinical phenotypes at a molecular level and anticipating symptoms and treatment response for future patients. We show that apparently similar mutations in GNAO1 can lead to distinct phenotypes through distinct modulation of the incoming GPCR signal.

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Postsynaptic movement disorders: clinical phenotypes, genotypes, and disease mechanisms

Cited by 26 publications

References 126 publications

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

Synaptic metabolism and brain circuitries in inborn errors of metabolism

Molecular map of GNAO1-related disease phenotypes and reactions to therapy

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