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|LETTER TO EDITOR
|Year : 2017 | Volume
| Issue : 5 | Page : 1141-1142
Novel c.775_781dup,p(Thr261fs) mutation in SPG 7 gene in a patient with hereditary spastic paraparesis
Shakya Bhattacharjee1, Victoria Stinton2, Diane Cairns2, Brian Murray3
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 Publication||6-Sep-2017|
Flat 96. 21, Plymbridge Lane, PL68AX
Source of Support: None, Conflict of Interest: None
|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 2020 Jan 20];65:1141-2. Available from: http://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.
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. 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. 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.
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.
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. 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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