Partial deletion of
            <i>AFG3L2</i>
            causing spinocerebellar ataxia type 28

Smets, Katrien; Deconinck, Tine; Baets, Jonathan; Sieben, Anne; Martin, J. J.; Smouts, Iris; Wang, Shuaiyu; Taroni, Franco; Bella, Daniela Di; Hecke, Wim Van; Parizel, Paul M.; Jadoul, Christina; Potter, Robert De; Couvreur, Francine; Rugarli, Elena I.; Jonghe, Peter De

doi:10.1212/wnl.0000000000000491

Cited by 27 publications

(21 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

See 2 more Smart Citations

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

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

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

et al. 2017

View full text Add to dashboard Cite

show abstract

“…However, the coexpression of WT and mutant AFG3L2 is able to correct the respiratory defect for most of the mutations, indicating that haploinsufficiency is the disease-causing mechanism (2). Remarkably, a partial AFG3L2 deletion (exons [14][15][16] has been recently identified as the cause of SCA28 in 2 large Belgian families, and functional studies revealed a reduced number of m-AAA complexes in these patients, demonstrating that SCA28 is due to haploinsufficiency (15). Indeed, the Afg3l2-haploinsufficient mouse resembles the phenotype of SCA28 patients, showing a progressive decline in motor performance caused by dark degeneration of Purkinje cells (PC-DCD) (16).…”

Section: Introductionmentioning

confidence: 99%

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

Maltecca¹,

Baseggio²,

Consolato³

et al. 2014

J. Clin. Invest.

View full text Add to dashboard Cite

Spinocerebellar ataxia type 28 (SCA28) is a neurodegenerative disease caused by mutations of the mitochondrial protease AFG3L2. The SCA28 mouse model, which is haploinsufficient for Afg3l2, exhibits a progressive decline in motor function and displays dark degeneration of Purkinje cells (PC-DCD) of mitochondrial origin. Here, we determined that mitochondria in cultured Afg3l2-deficient PCs ineffectively buffer evoked Ca2+ peaks, resulting in enhanced cytoplasmic Ca2+ concentrations, which subsequently triggers PC-DCD. This Ca2+-handling defect is the result of negative synergism between mitochondrial depolarization and altered organelle trafficking to PC dendrites in Afg3l2-mutant cells. In SCA28 mice, partial genetic silencing of the metabotropic glutamate receptor mGluR1 decreased Ca2+ influx in PCs and reversed the ataxic phenotype. Moreover, administration of the β-lactam antibiotic ceftriaxone, which promotes synaptic glutamate clearance, thereby reducing Ca2+ influx, improved ataxia-associated phenotypes in SCA28 mice when given either prior to or after symptom onset. Together, the results of this study indicate that ineffective mitochondrial Ca2+ handling in PCs underlies SCA28 pathogenesis and suggest that strategies that lower glutamate stimulation of PCs should be further explored as a potential treatment for SCA28 patients

show abstract

“…In SCA28, missense mutations were traditionally described in exon 15 and 16 of AFG3L2 [49]. Recently, reports mentioned a deletion of exons 14-16 in two families with classical presentation [50], a deletion encompassing the entire gene in a patient with infancyonset global developmental delay [51], and a frameshift mutation leading to a premature stop codon associated with late-onset HCA and cognitive decline [52]. AFG3L2 was also recently involved in an AR syndrome comprised of spastic ataxia and neuropathy, SPAX5 [53].…”

Section: Novel Types Of Mutations/transmission In Previously Describementioning

confidence: 99%

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

2015

View full text Add to dashboard Cite

Hereditary cerebellar ataxias (HCAs) are clinically and genetically heterogeneous neurodegenerative disorders, characterised by a cerebellar syndrome and other neurological or non-neurological signs. So far, more than 20 genes have been described in autosomal dominant HCA; in autosomal recessive HCA, even more genes are involved, in often more complex phenotypes. Because of that complexity, the genetic diagnosis of these diseases is often based on the next-generation sequencing techniques. In this review paper, we discuss the major contributions that they have made to the genetic landscape of HCAs. Numerous novel genes have been identified; still more have recently been implicated in HCAs in addition to being responsible for other diseases. The phenotypic spectrum associated with a single gene constantly gains in complexity. Novel types of mutations or transmissions in known genes are regularly being identified. All these factors make genotype-phenotype correlations particularly difficult. Some but not all of this variability can be explained by different pathophysiological consequences (loss of function, gain of function, variable levels of haploinsufficiency). This also raises the question of modifier genes. Finally, we highlight some functional pathways that increasingly appear important in HCAs.

show abstract

Partial deletion of AFG3L2 causing spinocerebellar ataxia type 28

Cited by 27 publications

References 22 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

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

Contact Info

Product

Resources

About