Second hit hypothesis in dystonia: Dysfunctional cross talk between neuroplasticity and environment?

Rauschenberger, Lisa; Knörr, Susanne; Pisani, Antonio; Hallett, Mark; Volkmann, Jens; Ip, Chi Wang

doi:10.1016/j.nbd.2021.105511

Cited by 19 publications

(13 citation statements)

References 163 publications

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“…Since in the family pedigree, the patient's father had passed away and her mother did not have either of the two variants while her daughter only had the mutation of c.1264G>A ( Figure 1 , Supplemental Figure 1 ), we supposed that c.1264G>A may be from the father and c.8965+9G>A may be de novo . Admittedly, for lacking the father's genetic information, we still did not rule out the possibility that other factors, such as environmental modifiers (e.g., perinatal adversities, drug abuse, infections, general anesthesia, or physical trauma) ( 6 , 24 ) and other variants in different genes, could co-segregate with identified compound heterozygous mutations and contribute to dystonia pathogenesis. In addition, it is noted that both variants were not in exon 41 that was inconsistent with Zech et al's report.…”

Section: Discussionmentioning

confidence: 99%

“…At present, the etiology and pathogenesis of dystonia remain largely unclear. The majority view is that dystonia is a neural network disorder, and specific gene variation may be one of the important causes underlying dystonia pathogenesis ( 3 – 6 ). With the rapid development of next-generation sequencing technology, more and more pathogenic genes have been discovered, providing perspectives for our in-depth understanding of dystonia development ( 7 – 10 ).…”

Section: Introductionmentioning

confidence: 99%

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A novel compound heterozygous mutation of COL6A3 in Chinese patients with isolated cervical dystonia

Dou

Zhou

et al. 2023

Front. Neurol.

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BackgroundThe etiology and pathogenesis of idiopathic dystonia remain obscure. Recent studies revealed that compound heterozygous mutations in collagen type VI alpha-3 gene COL6A3 may cause recessive isolated dystonia (DYT)-27. However, whether COL6A3 mutations are associated with Chinese patients with isolated dystonia is not yet reported.MethodsIn this study, 45 Chinese patients with isolated cervical dystonia were recruited, and their blood DNA samples were subjected to whole-exome sequencing. The potential causal variants of COL6A3 were identified based on the criteria of the American College of Medical Genetics and Genomics and by prediction software.ResultsAmong 45 isolated cervical dystonia patients, 18 patients (10 female patients and eight male patients) were found to have seven potential causal variants in the COL6A3 gene. Among these variants, a compound heterozygous mutation was found in one patient. One allele had a c.1264G>A mutation in exon 4 that resulted in an amino acid substitution of methionine for valine at codon 422 (p.Val422Met) and the other a c.8965+9G>A mutation involving a splicing change in exon 40. In addition, other five missense variants, including c.958G>A (p.Ala320Thr), c.1478T>C (p.Val493Ala), c.1597C>T (p.Arg533Cys), c.1762G>A (p.Asp588Asn), and c.4912G>A (p.Ala1638Thr), were identified as well.ConclusionWe identified a novel deleterious compound heterozygous mutation as well as five missense variants in the COL6A3 gene of Chinese patients with cervical dystonia. These findings may expand the spectrum of the COL6A3 genotype in isolated dystonia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel compound heterozygous mutation of COL6A3 in Chinese patients with isolated cervical dystonia

Dou

Zhou

et al. 2023

Front. Neurol.

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“…It is, therefore, possible that in some patients with PIMD, there are some pre-existing genetic risk factors ("first hit"), and certain peripheral trauma reduced the threshold of manifestation of PIMD ("second hit"). The "two-hit" hypothesis in the context of aberrant neuroplasticity and environmental factors (such as trauma) is elegantly described in a review article by Rauschenberger and colleagues [159].…”

Section: Possible Pathophysiologic Mechanismsmentioning

confidence: 99%

Peripherally-induced Movement Disorders: An Update

Lenka¹,

Jankovic

2023

Tremor and Other Hyperkinetic Movements

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Background: Peripherally-induced movement disorders (PIMD) should be considered when involuntary or abnormal movements emerge shortly after an injury to a body part. A close topographic and temporal association between peripheral injury and onset of the movement disorders is crucial to diagnosing PIMD. PIMD is under-recognized and often misdiagnosed as functional movement disorder, although both may co-exist. Given the considerable diagnostic, therapeutic, and psychosocial-legal challenges associated with PIMD, it is crucial to update the clinical and scientific information about this important movement disorder.Methods: A comprehensive PubMed search through a broad range of keywords and combinations was performed in February 2023 to identify relevant articles for this narrative review. Results:The spectrum of the phenomenology of PIMD is broad and it encompasses both hyperkinetic and hypokinetic movements. Hemifacial spasm is probably the most common PIMD. Others include dystonia, tremor, parkinsonism, myoclonus, painful leg moving toe syndrome, tics, polyminimyoclonus, and amputation stump dyskinesia. We also highlight conditions such as neuropathic tremor, pseudoathetosis, and MYBPC1associated myogenic tremor as examples of PIMD.Discussion: There is considerable heterogeneity among PIMD in terms of severity and nature of injury, natural course, association with pain, and response to treatment. As some patients may have co-existing functional movement disorder, neurologists should be able to differentiate the two disorders. While the exact pathophysiology remains elusive, aberrant central sensitization after peripheral stimuli and maladaptive plasticity in the sensorimotor cortex, on a background of genetic (two-hit hypothesis) or other predisposition, seem to play a role in the pathogenesis of PIMD.

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“…55 Alternatively, a compensation via endogenous protection factors may play a role. 55 The interplay between genetics and stressors may be especially detrimental in a defined time-window of neurodevelopment. This may explain the age-dependent susceptibility to develop a movement disorder phenotype as well as its specific manifestation (eg, dystonia or spastic paraplegia in childhoodvs.…”

Section: The Second Hit Paradigmmentioning

confidence: 99%

“…These peculiarities suggest a relevant role for extragenetic stressors in the pathophysiology of dystonia. According to the second‐hit hypothesis, the “first” genetic alteration underlies maladaptive synaptic plasticity and requires additional genetic or environmental factors to become clinically manifest 55 . Alternatively, a compensation via endogenous protection factors may play a role 55 .…”

Section: Mechanistic Insightsmentioning

confidence: 99%

Dystonia in ATP Synthase Defects: Reconnecting Mitochondria and Dopamine

Indelicato,

Boesch,

Mencacci

et al. 2023

Movement Disorders

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Four decades of research highlighted a significant role for mitochondrial dysfunction in the pathogenesis of movement disorders. A first milestone was set by the discovery that the neurotoxin N-methyl-4-phenylpyridinium (MPP + ), an apoptosis-inducing mitochondrial complex I inhibitor, induces parkinsonism by selectively damaging the substantia nigra. 1,2 This report sparked intensive investigations on the role of mitochondria in Parkinson's disease (PD), 3 fueled by the recognition of mitochondrial functions for several PD-associated genes. 2 Sequencing of the mitochondrial genome was completed in 1981. 4 Reports linking mitochondrial DNA (mtDNA) variants to neurological phenotypes rapidly followed. Notably, two early works identified dystonia as a prominent feature of distinct mitochondrial syndromes, 5,6 leading to the speculation that "movement disorders might have a mitochondrial etiology". 7 The association between mitochondrial diseases and various movement disorders has been confirmed by several case reports and few larger series. [8][9][10][11] Nonetheless, systematic explorations of the underlying pathophysiological mechanisms are scarce.Recently, independent studies elucidated a direct causal relationship between isolated dystonia and variants in genes encoding components of the mitochondrial ATP synthase (ATPase). 12,13 These remarkable findings encouraged us to reappraise the "mitochondria-movement disorder connection" 7 from a geneticsdriven perspective. We posit that mild energetic failure caused by specific ATPase variants may influence the synaptic activity of several nodes of the motor circuits involved in dystonia pathogenesis. ATPase activity modulation driven by other genetic or environmental stressors may play a role in the functional network alterations seen in more common idiopathic dystonias. Dystonia in Mitochondrial DiseasesUnique among the cellular organelles, mitochondria underlie a dual genomic control by both autochthonous mtDNA and the nuclear genome. 14,15 MtDNA encodes 13 subunits of the enzymatic complexes governing oxidative phosphorylation (OXPHOS) and 24 mitochondrial specific RNAs. 4 Further >1000 mitochondrial proteins are nuclear-encoded. 16 They are involved not only directly in OXPHOS, but also in respiratory chain-complex assembly, mtDNA replication, expression, and repair, as well as in other metabolic

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Second hit hypothesis in dystonia: Dysfunctional cross talk between neuroplasticity and environment?

Cited by 19 publications

References 163 publications

A novel compound heterozygous mutation of COL6A3 in Chinese patients with isolated cervical dystonia

A novel compound heterozygous mutation of COL6A3 in Chinese patients with isolated cervical dystonia

Peripherally-induced Movement Disorders: An Update

Dystonia in ATP Synthase Defects: Reconnecting Mitochondria and Dopamine

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