A novel form of autosomal recessive hereditary spastic paraplegia caused by a new SPG7 mutation

Ruhr-Universität Bochum, Bochum, North Rhine-Westphalia, Germany
Neurology (Impact Factor: 8.29). 08/2007; 69(4):368-75. DOI: 10.1212/01.wnl.0000266667.91074.fe
Source: PubMed


Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder characterized by progressive spastic paraparesis of the lower limbs.
To identify the genotype and characterize the phenotype in a family with a novel form of complicated autosomal recessive hereditary spastic paraparesis (ARHSP).
Six subjects of a Turkish family were examined by clinical evaluation, detailed neuropsychological testing, neurophysiologic studies, MRI, diffusion tensor imaging (DTI), and mutation analysis of SPG7 gene.
Three individuals were affected by a juvenile-onset form of complicated ARHSP due to the missense mutation c.2075G>C in exon 15 of the SPG7 gene in the homozygous state, substituting serine with threonine at codon 692. As additional clinical features, cerebellar syndrome, supranuclear palsy, and cognitive impairment, particularly disturbance of attention and executive functions, were found. MRI showed cerebellar atrophy and mild frontal cerebral atrophy. DTI revealed bilateral disturbance of white matter integrity in corticospinal tracts, frontal lobes, and the midbrain.
The new SPG7 gene mutation leads to a novel complicated autosomal recessive hereditary spastic paraparesis phenotype that widens the spectrum of different brain systems that are optionally affected in hereditary spastic paraplegia (HSP). In this novel phenotype, spastic paraparesis is related to cerebral damage of corticospinal tracts. Impairment of attention and executive functions is due to white matter loss in frontal lobes. Furthermore, supranuclear palsy is caused by white matter damage in the midbrain. This multisystem affection, which was detected by the use of diffusion tensor imaging, may reflect a mitochondrial dysfunction that contributes to the underlying pathogenesis of SPG7-HSP.

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    • "During the last few years, both dominant inheri- tance567and a wider phenotypic spectrum have been described. SPG7 is frequently associated with cerebellar involvement[8,9], as well as optic neuropa- thy[6], supranuclear palsy[10], ptosis and progressive external ophthalmoplegia (PEO). PEO is associated with mitochondrial disorders, especially where mutations in nuclear genes lead to multiple deletions in mitochondrial DNA, which is consistent with the role paraplegin is found to play in mitochondrial DNA maintenance[11,12]. "
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    ABSTRACT: Background and purpose: SPG7 is one of the most common forms of autosomal recessive hereditary spastic paraplegia. The phenotype has been shown to be heterogeneous, varying from a complex spastic ataxia to pure spastic paraplegia or pure ataxia. The aim of this study was to clinically and genetically characterize patients with SPG7 in Norway. Methods: Six Norwegian families with a clinical diagnosis of hereditary spastic paraplegia were diagnosed with SPG7 through Sanger sequencing and whole-exome sequencing. Haplotypes were established to identify a possible founder mutation. All patients were thoroughly examined and the clinical and molecular findings are described. Results: The core phenotype was spastic paraparesis with ataxia, bladder disturbances and progressive external ophthalmoplegia. The variant p.H701P was identified in homozygous state in one family and in compound heterozygous state in three families. Haplotype analysis of seven surrounding single nucleotide polymorphisms supports that this variant resides on a founder haplotype. Four of the families were compound heterozygous for the previously well-described p.A510V variant. Conclusion: SPG7 is a common subgroup of hereditary spinocerebellar disorders in Norway. The broad phenotype in the Norwegian SPG7 population illustrates the challenges with the traditional dichotomous classification of hereditary spinocerebellar disorders into hereditary spastic paraplegia or hereditary ataxia. A Norwegian founder mutation p.H701P was identified in four out of six families, making it a major cause of SPG7 in Norway.
    Full-text · Article · Jan 2016 · European Journal of Neurology
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    • "Hereditary spastic paraplegias (HSP) are a group of heterogeneous neurodegenerative disorders, which are clinically characterized by progressive spastic paralysis in the lower limbs [Depienne et al., 2007; Harding, 1983]. Mutations in the SPG7 gene (MIM 602783) cause an autosomal recessive (AR) form of HSP [Arnoldi et al., 2008; Brugman et al., 2008; Casari et al., 1998; Elleuch et al., 2006; McDermott et al., 2001; Tzoulis et al., 2008; Warnecke et al., 2007; Wilkinson et al., 2004]. The SPG7 gene codes for paraplegin, which contains an M41 metallopeptidase domain and an ATPase domain characteristic of the AAA family of ATPases [Langer, 2000]. "
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    ABSTRACT: An autosomal recessive form of hereditary spastic paraplegia (AR-HSP) is primarily caused by mutations in the SPG7 gene, which codes for paraplegin, a subunit of the hetero-oligomeric m-AAA protease in mitochondria. In the current study, sequencing of the SPG7 gene in the genomic DNA of 25 unrelated HSP individuals/families led to the identification of two HSP patients with compound heterozygous mutations (p.G349S/p.W583C and p.A510V/p.N739KfsX741) in the coding sequence of the SPG7 gene. We used a yeast complementation assay to evaluate the functional consequence of novel SPG7 sequence variants detected in the HSP patients. We assessed the proteolytic activity of hetero-oligomeric m-AAA proteases composed of paraplegin variant(s) and proteolytically inactive forms of AFG3L2 (AFG3L2(E575Q) or AFG3L2(K354A)) upon expression in m-AAA protease-deficient yeast cells. We demonstrate that the newly identified paraplegin variants perturb the proteolytic function of hetero-oligomeric m-AAA protease. Moreover, commonly occurring silent polymorphisms such as p.T503A and p.R688Q could be distinguished from mutations (p.G349S, p.W583C, p.A510V, and p.N739KfsX741) in our HSP cohort. The yeast complementation assay thus can serve as a reliable system to distinguish a pathogenic mutation from a silent polymorphism for any novel SPG7 sequence variant, which will facilitate the interpretation of genetic data for SPG7.
    Full-text · Article · May 2010 · Human Mutation
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    • "In symptomatic SPG gene mutation carriers, DTI has been used to assess the extent of white matter involvement within the CST and beyond (Dreha-Kulaczewski et al., 2006; Warnecke et al., 2007; Chen et al., 2008). DTI revealed an involvement of the corpus callosum, cerebellum and cingulum in two HSP patients with an autosomal recessive inherited mutation in the SPG11 gene. "
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    ABSTRACT: It is becoming increasingly clear that genetic variations account for a certain amount of variance in the acquisition and maintenance of different skills. Until now, several levels of genetic influences were examined, ranging from global heritability estimates down to the analysis of the contribution of single nucleotide polymorphisms (SNP) and variable number tandem repeats. In humans, the corticospinal motor system is essential to the acquisition of fine manual motor skills which require a finely tuned coordination of activity in distal forelimb muscles. Here we review recent brain mapping studies that have begun to explore the influence of functional genetic variation as well as mutations on function and structure of the human corticospinal motor system, and also the clinical implications of these studies. Transcranial magnetic stimulation of the primary motor hand area revealed a modulatory role of the common val66met polymorphism in the BDNF gene on corticospinal plasticity. Diffusion-sensitive magnetic resonance imaging has been employed to pinpoint subtle structural changes in corticospinal motor projections in individuals carrying a mutation in genes associated with motor neuron degeneration. These studies underscore the potential of non-invasive brain mapping techniques to characterize the genetic influence on the human corticospinal motor system.
    Full-text · Article · Mar 2009 · Neuroscience
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