Deletion of <i>AFG3L2</i> associated with spinocerebellar ataxia type 28 in the context of multiple genomic anomalies

Myers, Kenneth A.; Warman‐Chardon, Jodi; Huang, Lijia; Boycott, Kym M.

doi:10.1002/ajmg.a.36771

Cited by 9 publications

(7 citation statements)

References 20 publications

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“…Furthermore, this 18p region also contains genes associated with late-onset diseases which have been reported in patients with 18p deletion, such as GNAL (Guanine nucleotide binding protein-G protein) related to dystonia-25 (DYT25) and AFG3L2 (AFG3-like-AAA-ATPase-2) related to spinocerebellar ataxia-28 (SCA28). Despite the young age of our patients, searching for early signs and symptoms of these diseases is essential to a better prognosis (Esposito et al 2014;Myers et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Intellectual, adaptive and behavioural characteristics in four patients with 18p deletion syndrome

Mello

Bueno

Benedetto

et al. 2018

J intellect Disabil Res

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Background The association of behavioural phenotype assessment with cytogenomic characterisation may provide a better comprehension of genotype–phenotype correlations in syndromes caused by chromosomal abnormalities, such as 18p deletion syndrome. Method We report on four Brazilian patients with 18p deletion syndrome characterised by cytogenomic techniques and detailed neuropsychological evaluation. Intellectual, adaptive and behavioural characteristics were assessed through the Wechsler's Scales, the Vineland‐II Scale and the Child Behaviour Checklist, respectively. Socio‐economic measures including main caretaker educational level and family income as defined by Brazilian criteria for social class classification were also collected to evaluate a possible contribution of environmental factors in neurocognitive variability. Results Two out of four patients showed intellectual disability (IQ < 70). Wechsler's scale results suggest that in our sample, interpretation of social situations based on observation of non‐verbal behaviour constitute a cognitive strength while judgement of social rules and language skills associated with word knowledge and verbal fluency may be a cognitive weakness. Concerning adaptive behaviour, motor and socialisation domains showed to better develop than communication and daily living skills on the Vineland‐II Scale. Only one patient presented internalising behavioural problems based on the Child Behaviour Checklist. Our results also suggested that socio‐economic status may contribute to overall patient development. Conclusion Our results suggest that some 18p deletion syndrome patients may present average intellectual performance and that the segment deletion size and some families' socio‐economic conditions may influence cognitive development.

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Section: Discussionmentioning

confidence: 99%

Intellectual, adaptive and behavioural characteristics in four patients with 18p deletion syndrome

Mello

Bueno

Benedetto

et al. 2018

J intellect Disabil Res

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“…The remainder of the breakpoints are scattered along the entirety of the short arm. Interestingly, there have been no reports of large interstitial deletions of 18p, though there have been some microdeletions reported [Myers et al, ]. Approximately half of the deletions, regardless of breakpoint location, occur on the maternal chromosome [Schaub et al, ].…”

Section: Molecular Characterizationmentioning

confidence: 99%

A review of 18p deletions

Hasi-Zogaj

Sebold

Heard³

et al. 2015

American J of Med Genetics Pt C

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Since 18p- was first described in 1963, much progress has been made in our understanding of this classic deletion condition. We have been able to establish a fairly complete picture of the phenotype when the deletion breakpoint occurs at the centromere, and we are working to establish the phenotypic effects when each gene on 18p is hemizygous. Our aim is to provide genotype-specific anticipatory guidance and recommendations to families with an 18p- diagnosis. In addition, establishing the molecular underpinnings of the condition will potentially suggest targets for molecular treatments. Thus, the next step is to establish the precise effects of specific gene deletions. As we look forward to deepening our understanding of 18p-, our focus will continue to be on the establishment of robust genotype-phenotype correlations and the penetrance of these phenotypes. We will continue to follow our 18p- cohort closely as they age to determine the presence or absence of some of these diagnoses, including spinocerebellar ataxia (SCA), facioscapulohumeral muscular dystrophy (FSHD), and dystonia. We will also continue to refine the critical regions for other phenotypes as we enroll additional (hopefully informative) participants into the research study and as the mechanisms of the genes in these regions are elucidated. Mouse models will also be developed to further our understanding of the effects of hemizygosity as well as to serve as models for treatment development.

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“…By contrast, the exon 10 mutation modifies the structure of the pore channel entry, in which substrates are pulled to be degraded ( Di Bella et al, 2010 ). In addition, two AFG3L2 gene deletions have been reported in SCA28 patients, one of the entire gene ( Myers et al, 2014 ), and one including exon 14 to exon 16 ( Smets et al, 2014 ), as well as one frame shift mutation in exon 15, deleting the last 144 amino acids ( Musova et al, 2014 ), ( Figure 4 ). Thus AFG3L2 haplo-insufficiency is one of the possible causes of SCA28.…”

Section: Introductionmentioning

confidence: 99%

A novel mutation of AFG3L2 might cause dominant optic atrophy in patients with mild intellectual disability

et al. 2015

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Dominant optic neuropathies causing fiber loss in the optic nerve are among the most frequent inherited mitochondrial diseases. In most genetically resolved cases, the disease is associated to a mutation in OPA1, which encodes an inner mitochondrial dynamin involved in network fusion, cristae structure and mitochondrial genome maintenance. OPA1 cleavage is regulated by two m-AAA proteases, SPG7 and AFG3L2, which are, respectively involved in Spastic Paraplegia 7 and Spino-Cerebellar Ataxia 28. Here, we identified a novel mutation c.1402C>T in AFG3L2, modifying the arginine 468 in cysteine in an evolutionary highly conserved arginine-finger motif, in a family with optic atrophy and mild intellectual disability. Ophthalmic examinations disclosed a loss of retinal nerve fibers on the temporal and nasal sides of the optic disk and a red–green dyschromatopsia. Thus, our results suggest that neuro-ophthalmological symptom as optic atrophy might be associated with AFG3L2 mutations, and should prompt the screening of this gene in patients with isolated and syndromic inherited optic neuropathies.

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Deletion of AFG3L2 associated with spinocerebellar ataxia type 28 in the context of multiple genomic anomalies

Cited by 9 publications

References 20 publications

Intellectual, adaptive and behavioural characteristics in four patients with 18p deletion syndrome

Intellectual, adaptive and behavioural characteristics in four patients with 18p deletion syndrome

A review of 18p deletions

A novel mutation of AFG3L2 might cause dominant optic atrophy in patients with mild intellectual disability

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