Case of Early-Onset Parkinson’s Disease in a Heterozygous Mutation Carrier of the ATP7B Gene

Ilyechova, Ekaterina Y.; Miliukhina, Irina; Karpenko, Marina N.; Orlov, Iurii A.; Puchkova, L. V.; Samsonov, Sergey A.

doi:10.3390/jpm9030041

Cited by 7 publications

(5 citation statements)

References 88 publications

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“…It is also interesting to highlight that two out of the three heterozygous carriers of PRKN mutations and three out of the six carriers of ATP7B variants had an early onset presentation of the disease, being diagnosed before 50 years of age ( Supplementary Table S1 ). These data are in agreement with previous observations [ 38 , 39 , 40 ].…”

Section: Discussionsupporting

confidence: 94%

Over-Mutated Mitochondrial, Lysosomal and TFEB-Regulated Genes in Parkinson’s Disease

Segur-Bailach

Ugarteburu

Tort

et al. 2022

JCM

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The association between Parkinson’s disease (PD) and mutations in genes involved in lysosomal and mitochondrial function has been previously reported. However, little is known about the involvement of other genes or cellular mechanisms. We aim to identify novel genetic associations to better understand the pathogenesis of PD. We performed WES in a cohort of 32 PD patients and 30 age-matched controls. We searched for rare variants in 1667 genes: PD-associated, related to lysosomal function and mitochondrial function and TFEB-regulated. When comparing the PD patient cohort with that of age matched controls, a statistically significant burden of rare variants in the previous group of genes were identified. In addition, the Z-score calculation, using the European population database (GnomAD), showed an over-representation of particular variants in 36 genes. Interestingly, 11 of these genes are implicated in mitochondrial function and 18 are TFEB-regulated genes. Our results suggest, for the first time, an involvement of TFEB-regulated genes in the genetic susceptibility to PD. This is remarkable as TFEB factor has been reported to be sequestered inside Lewy bodies, pointing to a role of TFEB in the pathogenesis of PD. Our data also reinforce the involvement of lysosomal and mitochondrial mechanisms in PD.

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Section: Discussionsupporting

confidence: 94%

Over-Mutated Mitochondrial, Lysosomal and TFEB-Regulated Genes in Parkinson’s Disease

Segur-Bailach

Ugarteburu

Tort

et al. 2022

JCM

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“…In WD, mixed dysarthria is often observed [ 83 ], but dystonic dysarthria associated with orofacial dystonia was also reported [ 84 ]. In ATP7B heterozygous mutation carriers dysarthria has been reported [ 85 ]. In our case, orofacial dystonia appeared late in the disease course.…”

Section: Discussionmentioning

confidence: 99%

A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes

Gawęda-Walerych

Sitek

Borczyk

et al. 2022

Genes

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Our aim was to analyze the phenotypic-genetic correlations in a patient diagnosed with early onset corticobasal syndrome with progressive non-fluent aphasia (CBS-PNFA), characterized by predominant apraxia of speech, accompanied by prominent right-sided upper-limb limb-kinetic apraxia, alien limb phenomenon, synkinesis, myoclonus, mild cortical sensory loss, and right-sided hemispatial neglect. Whole-exome sequencing (WES) identified rare single heterozygous variants in ATP7B (c.3207C>A), SORL1 (c.352G>A), SETX (c.2385_2387delAAA), and FOXP1 (c.1762G>A) genes. The functional analysis revealed that the deletion in the SETX gene changed the splicing pattern, which was accompanied by lower SETX mRNA levels in the patient’s fibroblasts, suggesting loss-of-function as the underlying mechanism. In addition, the patient’s fibroblasts demonstrated altered mitochondrial architecture with decreased connectivity, compared to the control individuals. This is the first association of the CBS-PNFA phenotype with the most common ATP7B pathogenic variant p.H1069Q, previously linked to Wilson’s disease, and early onset Parkinson’s disease. This study expands the complex clinical spectrum related to variants in well-known disease genes, such as ATP7B, SORL1, SETX, and FOXP1, corroborating the hypothesis of oligogenic inheritance. To date, the FOXP1 gene has been linked exclusively to neurodevelopmental speech disorders, while our study highlights its possible relevance for adult-onset progressive apraxia of speech, which guarantees further study.

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“…A similar case exhibiting the early onset of clinical PD symptoms in a heterozygous H1096Q mutation carrier was described in a cohort from Poland [ 137 ]. In Russia, another study reported a patient with early-onset PD and a novel mutation that led to the C1079G substitution of a conserved cysteine residue in the ATP7B nucleotide-binding domain [ 138 ]. In the latter case, the holo-Cp concentration level was at first within a normal range; however, during 8 years of observation, the holo-Cp concentration significantly decreased, while the non-ceruloplasmin copper level increased.…”

Section: Proofs For the Existence Of The Link Between Copper Dyshomeo...mentioning

confidence: 99%

“…Therefore, the meta-analysis emphasized that the concerted measurement of all indexes of copper status is required to establish a connection between PD and disorders in copper homeostasis, including measuring the concentrations of copper weakly associated with the Cp molecule [ 138 ].…”

Section: Updated Meta-analysis On the Significance Of The Link Betwee...mentioning

confidence: 99%

Abnormalities in Copper Status Associated with an Elevated Risk of Parkinson’s Phenotype Development

Karpenko,

Muruzheva,

Ilyechova

et al. 2023

Antioxidants

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In the last 15 years, among the many reasons given for the development of idiopathic forms of Parkinson’s disease (PD), copper imbalance has been identified as a factor, and PD is often referred to as a copper-mediated disorder. More than 640 papers have been devoted to the relationship between PD and copper status in the blood, which include the following markers: total copper concentration, enzymatic ceruloplasmin (Cp) concentration, Cp protein level, and non-ceruloplasmin copper level. Most studies measure only one of these markers. Therefore, the existence of a correlation between copper status and the development of PD is still debated. Based on data from the published literature, meta-analysis, and our own research, it is clear that there is a connection between the development of PD symptoms and the number of copper atoms, which are weakly associated with the ceruloplasmin molecule. In this work, the link between the risk of developing PD and various inborn errors related to copper metabolism, leading to decreased levels of oxidase ceruloplasmin in the circulation and cerebrospinal fluid, is discussed.

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Case of Early-Onset Parkinson’s Disease in a Heterozygous Mutation Carrier of the ATP7B Gene

Cited by 7 publications

References 88 publications

Over-Mutated Mitochondrial, Lysosomal and TFEB-Regulated Genes in Parkinson’s Disease

Over-Mutated Mitochondrial, Lysosomal and TFEB-Regulated Genes in Parkinson’s Disease

A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes

Abnormalities in Copper Status Associated with an Elevated Risk of Parkinson’s Phenotype Development

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