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Table of Contents    
Year : 2017  |  Volume : 65  |  Issue : 5  |  Page : 1141-1142

Novel c.775_781dup,p(Thr261fs) mutation in SPG 7 gene in a patient with hereditary spastic paraparesis

1 Department of Neurology, Plymouth Hospital NHS Trust, United Kingdom
2 Clinical Scientist, Liverpool Women NHS Foundation Trust, United Kingdom
3 Department of Neurology, Hermitage Medical Clinic, Ireland

Date of Web Publication6-Sep-2017

Correspondence Address:
Shakya Bhattacharjee
Flat 96. 21, Plymbridge Lane, PL68AX
United Kingdom
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/neuroindia.NI_96_17

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How to cite this article:
Bhattacharjee S, Stinton V, Cairns D, Murray B. Novel c.775_781dup,p(Thr261fs) mutation in SPG 7 gene in a patient with hereditary spastic paraparesis. Neurol India 2017;65:1141-2

How to cite this URL:
Bhattacharjee S, Stinton V, Cairns D, Murray B. Novel c.775_781dup,p(Thr261fs) mutation in SPG 7 gene in a patient with hereditary spastic paraparesis. Neurol India [serial online] 2017 [cited 2022 Sep 25];65:1141-2. Available from: https://www.neurologyindia.com/text.asp?2017/65/5/1141/214102


A 61-year old gentleman with a history of ataxic gait for the last 40 years presented with further worsening of his gait in the last 4–5 years. He reported multiple falls due to poor balance. He denied any family history of similar problems. He had ophthalmoplegia on both lateral gaze with mild upgaze restriction, increased tone in both lower limbs, ankle clonus, extensor plantar reflexes bilaterally, ataxic gait, and intention tremor.

His blood examination for ataxia screening was negative. Magnetic resonance imaging showed mild cerebellar atrophy but with the entire spine being normal. His spinocerebellar ataxia (SCA) 1, 2, 3, 6 genes were negative. The next generation sequencing study of the hereditary spastic paraplegia gene panel (21) found him to be compound heterozygous for c.775_781dup, p(Thr261fs) frameshift mutation and c1529C>T, p.(Ala510Val) missense mutation in SPG-7 exons 6 and 11, respectively. These findings were confirmed by the conventional Sanger sequencing [Figure 1]. Though c1529C>T, p.(Ala510Val) mutation has been previously reported in hereditary spastic paraparesis type 7, to the best of our knowledge, c.775_781dup, p(Thr261fs) has not been previously reported in autosomal recessive hereditary spastic paraplegia due to SPG-7 mutation. As this previously unreported mutation c775_781dup, p.(Thr261fs) created a frameshift in SPG-7 gene, it is clearly pathogenic. However, we were unable to perform a full pedigree analysis as other family members refused testing. He was diagnosed with autosomal recessive spastic paraplegia due to c.775_781dup, p(Thr261fs), and c1529C>T, p.(Ala510Val) mutations in the SPG-7 gene.
Figure 1: Novel pathogenic SPG-7 c.775_781dup,p(Thr261fs) mutation

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The SPG-7 gene contributes to the occurrence of all hereditary spastic paraplegia (ARHSP) in less than 5% of patients; however, it can cause up to 18% of all undiagnosed ataxias.[1] Our patient demonstrated a novel pathogenic mutation in the SPG-7 gene. Sanchez Ferrero et al., reported 12 new mutations in the SPG-7 gene, of which 5 affected the paraplegin function.[2] Elleuch et al., reported 47 variations including 6 mutations and 27 polymorphisms. The pAla51oVal mutation was the most common mutation of the SPG-7 gene.[3]

The protein product of the SPG-7 gene, paraplegin, is involved in the maintenance of mitochondrial function by forming a part of the mitochondrial multimeric mAAA (matrix intermembrane ATPases associated with diverse cellular activities) protease complex. Paraplegin and AFG3L2 gene participate in the biogenesis and maintenance of mitochondrial respiratory chain complexes. The formation of m-AAA proteases with altered substrate specificities probably leads to axonal degeneration. The SPG-7 mutations enhance mitochondrial biogenesis in muscle and clonal expansion of mitochondrial DNA mutations, resulting in eye symptoms and myopathy.[4]

Often, the SPG-7 mutation presents with pure cerebellar ataxia at early stages. The SPG-7 mutation can, therefore, present as a pure and complex phenotype.[5] The complex phenotype shows clinical features such as optic nerve involvement, ophthalmoparesis, and peripheral neuropathy, in addition to features such as pyramidal tract signs and ataxia seen in the pure phenotype of spastic paraplegia.

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There are no conflicts of interest.

  References Top

Pfeffer G, Pyle A, Griffin H, Miller J, Wilson V, Turnbull L, et al. SPG 7 mutations are a common cause of undiagnosed ataxia. Neurology 2014; 84:1174-6.  Back to cited text no. 1
Sanchez-Ferrero E, Coto E, Beetz C, Gamez J, Corao AI, Diaz M, et al. SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V. Clin Genet 2013;83:257-62.  Back to cited text no. 2
Elleuch N, Depienne C, Benomar A, Hernandez MAO, Ferrer X, Fontaine B, et al. Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia. Neurology 2006; 66:654-9.  Back to cited text no. 3
Pfeffer G, Gorman GS, Griffin H, Kurzawa-Akanbi M, Blakely EL, Wilson I, et al. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance. Brain 2014; 137:1323-36.  Back to cited text no. 4
López E, Casasnovas C, Giménez J, Matilla-Dueñas A, Sánchez I, Volpini V. Characterization of Alu and recombination-associated motifs mediating a large homozygous SPG7 gene rearrangement causing hereditary spastic paraplegia. Neurogenetics 2015; 16:97-105.  Back to cited text no. 5


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