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

Abstract

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.

Unique structural features of the mitochondrial AAA+ protease AFG3L2 reveal the molecular basis for activity in health and disease

“…In fact, single point mutations localized throughout the catalytic core of AFG3L2 are linked to multiple neurodegenerative disorders in humans that present with diverse pathologies and severity. The majority of identified AFG3L2 mutations are implicated in the autosomal dominant disease spinocerebellar ataxia type 28 (SCA28), primarily characterized by unbalanced standing, progressive gait and limb ataxia, and dysarthria, caused by degeneration of the cerebellum and its afferent and efferent connections [24][25][26][27][28][29][30][31][32] . An alternative heterozygous AFG3L2 point mutation has been causatively linked to a disorder called dominant optic atrophy (DOA), whereas homozygous individuals carrying rare mutations in AFG3L2 present neurodegenerative phenotypes distinct from those associated with either DOA or SCA28 [33][34][35][36] (Table S1).…”

Mice harbouring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity

“…We dwell on the complexities of the m-AAA structure, function and composition because it emerges that the majority of SCA28 patient mutations induce missense changes in AFG3L2 residues that participate in the formation of the proteolytic cleft. These missense mutations are mostly clustered in AFG3L2 exons 15 and 16 that form the protease domain: 654 Thr→Ile; 666 Met→Val/Arg/Thr; 671 Gly→Arg/Glu; 674 Ser→Leu; 689 Tyr→Asn/His; 691 Glu→Lys; 694 Ala→Glu; 700 Glu→Lys and 702 Arg→Gln (Almajan et al, 2012;Cagnoli et al, 2010;Di Bella et al, 2010;Edener et al, 2010;Lobbe et al, 2014;Szpisjak et al, 2017;Zuhlke et al, 2015). Confirmation of the importance of modifications in the proteolytic cleft for disease pathogenesis comes from the 432 Asn→Thr patient mutation: although encoded by exon 10, thus outside of the mutational hotspot, it modifies a cleft-facing residue from the ATPase aspect.…”

Expanding the clinical and genetic heterogeneity of SPAX5

“…More than 30 different AFG3L2 disease‐causing mutations have thus far been reported in over 80 SCA28 patients,11,12 whereas few SPAX5 families have been described 1,6,13. Interestingly, previously described patients with bi‐allelic mutations in AFG3L2 (Table 1) have severe phenotypes, including early‐onset spastic ataxia‐neuropathy syndrome or severe developmental delay and microcephaly, and often present progressive myoclonic epilepsy 1,13.…”