Early onset and slow progression of SCA28, a rare dominant ataxia in a large four-generation family with a novel AFG3L2 mutation

Edener, Ulf; Wöllner, Janine; Hehr, Ute; Kohl, Zacharias; Schilling, Stefan; Kreuz, Friedmar R.; Bauer, Peter; Bernard, Veronica; Gillessen‐Kaesbach, Gabriele; Zühlke, Christine

doi:10.1038/ejhg.2010.40

Cited by 56 publications

(44 citation statements)

References 8 publications

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“…All mutations so far reported in patients with SCA28 are located in one of these exons (Cagnoli et al, 2010;Di Bella et al, 2010;Edener et al, 2010).…”

Section: Sca28 Analysismentioning

confidence: 99%

“…Paraplegin assembles with the paralogous AFG3L2 protein (MIM 604581) to form the oligomeric mAAA protease complex involved in mitochondrial protein maturation and degradation (Leonhard et al, 2000;Nolden et al, 2005;Rugarli and Langer, 2006;Tatsuta and Langer, 2009). Interestingly, heterozygous mutations in the AFG3L2 gene are responsible for the autosomal dominant spinocerebellar ataxia SCA28, which is characterized by young adult onset, slowly progressive gait and limb ataxia, dysarthria, increased reflexes and ophthalmoparesis (Edener et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy

Klebe¹,

Depienne²,

Gerber³

et al. 2013

Basal Ganglia

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Mutations in the spastic paraplegia 7 (SPG7) gene encoding paraplegin are responsible for autosomal recessive hereditary spasticity. We screened 135 unrelated index cases, selected in five different settings: SPG7-positive patients detected during SPG31 analysis using SPG31/SPG7 multiplex ligation-dependent probe amplification (n = 7); previously reported ambiguous SPG7 cases (n = 5); patients carefully selected on the basis of their phenotype (spasticity of the lower limbs with cerebellar signs and/or cerebellar atrophy on magnetic resonance imaging/computer tomography scan and/or optic neuropathy and without other signs) (n = 24); patients with hereditary spastic paraparesis referred consecutively from attending neurologists and the national reference centre in a diagnostic setting (n = 98); and the index case of a four-generation family with autosomal dominant optic neuropathy but no spasticity linked to the SPG7 locus. We identified two SPG7 mutations in 23/134 spastic patients, 21% of the patients selected according to phenotype but only 8% of those referred directly. Our results confirm the pathogenicity of Ala510Val, which was the most frequent mutation in our series (65%) and segregated at the homozygous state with spastic paraparesis in a large family with autosomal recessive inheritance. All SPG7-positive patients tested had optic neuropathy or abnormalities revealed by optical coherence tomography, indicating that abnormalities in optical coherence tomography could be a clinical biomarker for SPG7 testing. In addition, the presence of late-onset very slowly progressive spastic gait (median age 39 years, range 18-52 years) associated with cerebellar ataxia (39%) or cerebellar atrophy (47%) constitute, with abnormal optical coherence tomography, key features pointing towards SPG7-testing. Interestingly, three relatives of patients with heterozygote SPG7 mutations had cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs, suggesting that SPG7 mutations at the heterozygous state might predispose to late-onset neurodegenerative disorders, mimicking autosomal dominant inheritance. Finally, a novel missense SPG7 mutation at the heterozygous state (Asp411Ala) was identified as the cause of autosomal dominant optic neuropathy in a large family, indicating that some SPG7 mutations can occasionally be dominantly inherited and be an uncommon cause of isolated optic neuropathy. Altogether, these results emphasize the clinical variability associated with SPG7 mutations, ranging from optic neuropathy to spastic paraplegia, and support the view that SPG7 screening should be carried out in both conditions.

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“…All mutations so far reported in patients with SCA28 are located in one of these exons (Cagnoli et al, 2010;Di Bella et al, 2010;Edener et al, 2010).…”

Section: Sca28 Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy

Klebe¹,

Depienne²,

Gerber³

et al. 2013

Basal Ganglia

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“…Several SCA28-causing missense mutations have been identified in the AFG3L2 gene (2)(3)(4). Moreover, homozygous mutations in AFG3L2 are responsible for a myoclonic epilepsy-ataxia-polyneuropathy syndrome of childhood (5).…”

Section: Introductionmentioning

confidence: 99%

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

Maltecca¹,

Baseggio²,

Consolato³

et al. 2014

J. Clin. Invest.

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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

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“…gene have been shown to be responsible for autosomaldominant spinocerebellar ataxia type 28, characterized by onset in young adulthood, slowly progressive gait and limb ataxia, increased reflexes, dysarthria and ophthalmoparesis (89,100,101). Patients harbouring homozygous AFG3L2 in vivo 31: 511-525 (2017) mutations present with a more severe phenotype including dystonia, oculomotor apraxia, and progressive myoclonic epilepsy (102), but not optic neuropathy.…”

Section: Afg3l2 Heterozygous Missense Mutations In the Afg3l2mentioning

confidence: 99%

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

Bagli

Zikou

Agnantis

et al. 2017

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Abstract. Inherited optic neuropathies are a genetically diverse group of disorders mainly characterized by visual loss and optic atrophy. Since the first recognition of Leber's hereditary optic neuropathy, several genetic defects altering primary mitochondrial respiration have been proposed to contribute to the development of syndromic and nonsyndromic optic neuropathies. Moreover, the genomics and imaging revolution in the past decade has increased diagnostic efficiency and accuracy, allowing recognition of a link between mitochondrial dynamics machinery and a broad range of inherited neurodegenerative diseases involving the optic nerve. Mutations of novel genes modifying mainly the balance between mitochondrial fusion and fission have been shown to lead to overlapping clinical phenotypes ranging from isolated optic atrophy to severe, sometimes lethal multisystem disorders, and are reviewed herein. Given the particular vulnerability of retinal ganglion cells to mitochondrial dysfunction, the accessibility of the eye as a part of the central nervous system and improvements in technical imaging concerning assessment of the retinal nerve fiber layer, optic nerve evaluation becomes critical -even in asymptomatic patients -for correct diagnosis, understanding and early treatment of these complex and enigmatic clinical entities.Mitochondria represent a tubular and branched membrane system playing a fundamental role in several cellular processes required for the development and maintenance of an organism, such as metabolism, apoptosis, ion buffering and autophagy (1-3). They reveal a high degree of interconnectivity and plasticity, mainly dictated by metabolic status and developmental stage (4) and, therefore, a constant state of mitochondrial network flux is fundamental. This dynamic state is achieved through mitochondrial dynamics, a complex machinery of highly conserved mechanisms, including mitochondrial fusion, fission, transport, interorganellar communication and mitochondrial quality control (i.e. mitophagy), tuned to a variety of signals and stimuli (5-7), and well-orchestrated by specific intracellular proteins.The morphology and intracellular distribution of mitochondria vary significantly between tissues and cell types, being enriched in areas of increased metabolic demand, such as neurons, especially the presynaptic and postsynaptic terminals (8). Accordingly, it is not surprising that the pathogenic mechanism of various neurodegenerative diseases is established through an underlying deficiency of mitochondrial energy metabolism (9). However, in recent years it has been shown that impairment of mitochondrial dynamics also leads to synaptic dysfunction, dendritic and axonal degeneration and consequently to neurodegeneration (10,11). In this respect, restoration of mitochondrial function has become, for some time now, the priority target of novel neuroprotective strategies (12).Mitochondrial membrane dynamics, and more specifically fission and fusion, are indispensable for mitochondrial distribution and hom...

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Early onset and slow progression of SCA28, a rare dominant ataxia in a large four-generation family with a novel AFG3L2 mutation

Cited by 56 publications

References 8 publications

Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy

Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

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