A Novel Missense Mutation in AFG3L2 Associated with Late Onset and Slow Progression of Spinocerebellar Ataxia Type 28

Löbbe, Anna Mareike; Kang, Jin‐Ho; Hilker, Rüdiger; Hackstein, Holger; Müller, Ulrich; Nolte, Dagmar

doi:10.1007/s12031-013-0187-1

Cited by 22 publications

(24 citation statements)

References 11 publications

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“…The identified c.2011G>C nucleotide change is a novel variant determining the p.Gly671Arg alteration, which is pathogenic [8]. Table 2 demonstrates that the clinical phenotype of our patients is similar to that of the 82 earlier published SCA28 patients [6][7][8][10][11][12][13][14][15][16][17][18]. The lack of ophthalmoparesis, ptosis and slowing of saccades in our patients are the main differences, but these symptoms usually appear later in the course of the disease.…”

Section: Discussionsupporting

confidence: 69%

“…Reviewing the available data from the scientific literature, only 9 out of 82 were described to had some kind of cognitive abnormality, without further specification [6][7][8][10][11][12][13][14][15][16][17][18]. Despite some limitations, including low case number and the fact that neuropsychological tests are poor localizers of brain pathology, the cognitive investigation performed in this study revealed slight abnormalities which may indicate the importance of integrity of cerebellar functioning in intact prefrontal activity [42].…”

Section: Discussionmentioning

confidence: 98%

“…All SCA28 cases were identified in the Caucasian population, except for one patient from Africa reported in the literature [6][7][8][10][11][12][13][14][15][16][17][18]. There is a lack of thorough cognitive characterization of SCA28 patients in the literature.…”

Section: Introductionmentioning

confidence: 99%

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Neurocognitive Characterization of an SCA28 Family Caused by a Novel AFG3L2 Gene Mutation

et al. 2017

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Spinocerebellar ataxia 28 (SCA28) is an extremely rare, autosomal, dominantly inherited, juvenile onset, slowly progressive, gait and limb ataxia with frequent eye movement abnormalities and cerebellar atrophy. The causative gene of SCA28 is AFG3L2, located on the short arm of chromosome 18. In this paper we demonstrate the neurocognitive assessment of 5 affected patients in the first Hungarian SCA28 family. The identified c.2011G>Cheterozygous base pair change is a novel point mutation variation resulting in an already known p.Gly671Arg amino acid change. The previously described 82 SCA28 patients were compared with our patients and we found that the majority of clinical features, including early onset, slow progression, gait and limb ataxia, dysarthria and pyramidal symptoms are similar to the alterations characteristic of other SCA28 patients. Some ophthalmological manifestations, such as ptosis, ophthalmoparesis and slowing of saccades are not present in our patients. Since detailed psychological investigation was not performed previously in SCA28 patients, the following major neuropsychological functions were examined: phonological immediate memory, visuospatial immediate memory, working memory, executive functions, everyday memory functions including semantic memory, visual attention and speed of processing. The results of these assessments demonstrated slightly lower levels of performance in complex working memory, visuospatial memory, semantic memory and executive functions with some variation between subjects. These abnormalities may be the consequence of alterations in the cerebellar-prefrontal connection system.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 98%

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Neurocognitive Characterization of an SCA28 Family Caused by a Novel AFG3L2 Gene Mutation

et al. 2017

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“…This indicates that different mutations in various locations in the AFG3L2 gene may lead to different clinical phenotypes. Furthermore, the p.R468C mutation is located in exon 11, while all known ataxia-causing mutations, except one, are located in exons 15 and 16 of AFG3L2 (23,24) (Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

Colavito¹,

Maritan²,

Suppiej³

et al. 2017

Biomedical Reports

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Abstract.Autosomal dominant optic atrophy (DOA) is the most frequent form of hereditary optic atrophy, a disease presenting with considerable inter-and intra-familial clinical variability. Although a number of mutations in different genes are now known to cause DOA, many cases remain undiagnosed. In an attempt to identify the underlying genetic defect, whole exome sequencing was performed in a 19-year-old male that had been affected by isolated DOA since childhood. The exome sequencing revealed a pathogenic mutation (p.R468C, c.1402C>T) in the AFG3 like matrix AAA peptidase subunit 2 (AFG3L2) gene, a gene known to be associated with spinocerebellar ataxia. The patient did not show any signs other than DOA. Thus, the result demonstrates the possibility that mutations in the AFG3L2 gene may be a cause of isolated autosomal DOA. IntroductionAutosomal dominant optic atrophy (DOA) is a disorder that results from the degeneration of the optic nerve fibers (1). It is one of the most prevalent forms of inherited optic neuropathies, which are genetic conditions affecting the retinal ganglion cells whose axons constitute the optic nerve (2). DOA is an important cause of inherited visual failure and occurs equally among males and females (1). Its prevalence is estimated to be 1 per 30,000 worldwide with higher frequencies in Denmark (1 per 10,000) due to a founder effect (3). It is generally diagnosed during childhood and is characterized by loss of visual acuity, dyschromatopsia, visual field defects and optic nerve pallor with optic disc excavation (4).The majority of DOA cases (80%) are isolated (non-syndromic) while the remaining (20%) are syndromic (2). DOA that presents clinically as an isolated optic neuropathy is caused by mutations in OPA1, mitochondrial dynamin like GTPase (OPA1) (4), OPA3, outer mitochondrial membrane lipid metabolism regulator (OPA3; also associated with cataracts) (5), aconitase 2 (ACO2) (6) and transmembrane protein 126A (TMEM126A) (7) genes, while syndromic DOA forms show greater genetic heterogeneity (8). To date, 224 genes associated with optic atrophy are listed in the Human Phenotype Ontology (HPO) database, the majority presenting with neurological symptoms, such as ataxia, mental retardation and spastic paraplegia (9). Increasing evidence also indicates that other genes, in addition to yet unidentified genes, are involved (10). Yet, despite these advancements, more than half of DOA patients still await a genetic diagnosis (11). This shortcoming may be overcome using whole exome sequencing, which has the potential to define the molecular diagnosis of patients presenting with a negative result for mutations in the OPA1, OPA3, ACO2 and TMEM126A genes.In the current study, the exome of an Italian patient affected by isolated DOA was analyzed. By combining exome sequencing with phenotype-driven variant analysis, a heterozygous mutation was identified in the AFG3 like matrix AAA peptidase subunit 2 (AFG3L2) gene. Notably, the p.R468C (c.1402C>T) mutation was recently described in a family ex...

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“…Most of the disease-related alterations were mapped to the region encompassing the peptidase domain (amino acids residues 654 through 700) (Edener et al 2010; Cagnoli et al 2010; Löbbe et al 2014; Smets et al 2014; Zühlke et al 2015). A number of heterozygous, substrate recognition-perturbing mutations in AFG3L2 were associated with autosomal dominant spinocerebellar ataxia type 28 (SCA28) (Di Bella et al 2010).…”

Section: M-aaa Proteasementioning

confidence: 99%

Mitochondrial Quality Control Proteases in Neuronal Welfare

Levytskyy

Germany

Khalimonchuk

2016

J Neuroimmune Pharmacol

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The functional integrity of mitochondria is a critical determinant of neuronal health and compromised mitochondrial function is a commonly recognized factor that underlies a plethora of neurological and neurodegenerative diseases. Metabolic demands of neural cells require high bioenergetic outputs that are often associated with enhanced production of reactive oxygen species. Unopposed accumulation of these respiratory byproducts over time leads to oxidative damage and imbalanced protein homeostasis within mitochondrial subcompartments, which in turn may result in cellular demise. The post-mitotic nature of neurons and their vulnerability to these stress factors necessitate strict protein homeostatic control to prevent such scenarios. A series of evolutionarily conserved proteases is one of the central elements of mitochondrial quality control. These versatile proteolytic enzymes conduct a multitude of activities to preserve normal mitochondrial function during organelle biogenesis, metabolic remodeling and stress. In this review we discuss neuroprotective aspects of mitochondrial quality control proteases and neuropathological manifestations arising from defective proteolysis within the mitochondrion.

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A Novel Missense Mutation in AFG3L2 Associated with Late Onset and Slow Progression of Spinocerebellar Ataxia Type 28

Cited by 22 publications

References 11 publications

Neurocognitive Characterization of an SCA28 Family Caused by a Novel AFG3L2 Gene Mutation

Neurocognitive Characterization of an SCA28 Family Caused by a Novel AFG3L2 Gene Mutation

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

Mitochondrial Quality Control Proteases in Neuronal Welfare

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