| Article Access Statistics|
| Viewed||446 |
| Printed||4 |
| Emailed||0 |
| PDF Downloaded||10 |
| Comments ||[Add] |
Click on image for details.
|Year : 2021 | Volume
| Issue : 4 | Page : 1051-1052
Early Onset Degenerative Parkinsonism – Consider SPG7 Mutation
Shakya Bhattacharjee, Muhammad Noushad, Martin Sadler
Department of Neurology, Plymouth Hospital NHS Trust, Plymouth, United Kingdom
|Date of Submission||25-Dec-2020|
|Date of Decision||21-Jul-2021|
|Date of Acceptance||28-May-2021|
|Date of Web Publication||2-Sep-2021|
Neurology, Plymouth Hospital NHS Trust, PL68DH, Plymouth
Source of Support: None, Conflict of Interest: None
A 43-year-old man presented with ataxia and stiffness of lower limbs for approximately last 10 years. The clinical examination revealed bilateral parkinsonism The magnetic resonance imaging of the brain and spine showed no structural abnormality to explain his symptoms. However, the dopamine transporter scan showed abnormal tracer uptake in both basal ganglia, suggestive of degenerative parkinsonism. The next generation sequencing of spastic paraparesis gene panel revealed probably pathogenic novel mutation in the SPG7 gene. Though the exact mechanism of parkinsonism in SPG 7 mutation is unclear, mitochondrial dysfunction and oxidative stress seem to play a key role. SPG7 mutation should be considered as a cause of early onset degenerative parkinsonism when no alternative explanation can be found.
Keywords: Hereditary, mutation, paraparesis, parkinsonism, spasticKey Message: SPG 7 mutation should be considered as a cause of degenerative parkinsonism.
|How to cite this article:|
Bhattacharjee S, Noushad M, Sadler M. Early Onset Degenerative Parkinsonism – Consider SPG7 Mutation. Neurol India 2021;69:1051-2
| » Case Report|| |
A 43-year-old gentleman presented with worsening ataxic gait and both lower limb stiffness for last 10 years. He had no family history of similar symptoms. He developed left-hand rest tremor and slowness of movement almost 7 years after the onset of gait disturbance. The examination revealed both lower limb spasticity, ataxic gait, left upper limb rest tremor but no limb bradykinesia. He developed bilateral resting hand tremor within next 1 year. The magnetic resonance imaging of the head and spine showed no major structural abnormalities. The nerve conduction study revealed no large fiber neuropathy. The dopamine transporter scan (DaT) showed bilaterally abnormal tracer uptake (right more than left), suggestive of degenerative Parkinsonism More Details [Supplementary Figure]. His spinocerebellar ataxia gene panel, Spastic Paraplegia 4 (SPAST) gene, Parkin, PTEN-induced kinase (PINK 1), and Friedrich's ataxia genetic testing showed no pathogenic mutation. The hereditary spastic paraparesis gene panel showed compound heterozygous SPG 7 mutation. He was compound heterozygous for c637C>T mutation in exon 5 and c. 1454_1462 del mutation in exon 11 of the SPG 7 gene, predicted to result in the pArg213* and pArg485_Gluc487del protein changes respectively [Figure 1]. The C637C>T pArg213* mutation was not described previously in literature, but as it resulted in nonsense-mediated decay or premature truncation of protein, so it was likely pathogenic. The c. 1454_1462 del.p (Arg485_Glu487del) was previously reported in homozygous and heterozygous state in HSP patents., He was diagnosed as hereditary spastic paraparesis type 7 with symmetric parkinsonism. His parkinsonism did not respond to levodopa but improved with Pramipexole. Unfortunately, his spasticity progressed and needed walking aids after few months.
|Figure 1: c637C>T mutation in exon 5 of the SPG 7 gene, predicted to result in the pArg213* (* means no mutation was detected on one of two alleles)|
Click here to view
| » Discussion|| |
Coarelli G., et al. observed that almost 7% of patient with pathogenic SPG 7 mutation showed parkinsonism within first 10 years of the disease. The same authors also noticed that when patients presented within 20 years of the onset, the prevalence of parkinsonism was only 4%. The genotype–phenotype correlation showed that the prevalence of parkinsonism in both homozygous and heterozygous missense mutation was 4–6%. However, recently Casa-Fages BDL., et al. reported parkinsonism in almost 20% of all SPG 7 patients. The authors found that half of those SPG 7 patients with parkinsonism responded to Levodopa. Pedroso JL, et al. described symmetric degenerative parkinsonism with two variants of the SPG 7 gene, the pathogenic missense variant c. 1529C>T and a novel possibly pathogenic missense variant c. 2069C>T. However, unlike our patient, their patient responded well to Levodopa 700 mg. Van Gassen KL, et al. reported parkinsonism in a patient with SPG7 mutation; however, this should be viewed with caution due to the concurrent use of neuroleptics in the patient. Our patient clearly had degenerative parkinsonism (confirmed by the DaT) along with a possibly pathogenic novel mutation.
The exact cause of parkinsonism in SPG 7 mutation is not clear, but mitochondrial dysfunction and oxidative stress seem to play a key role. SPG7 encodes paraplegin, a mitochondrial protein responsible for assembling ribosomes and eliminating nonfunctional proteins from the mitochondria. The SPG 7 also works as possible regulator of the mitochondrial permeability transition pore. The mutation of the SPG 7 gene triggers the accumulation of mitochondrial DNA (mt DNA) deletions mainly in the dopaminergic neurons of the substantia nigra. This mt DNA metabolism abnormality probably affects the basal ganglia.
| » Conclusion|| |
Clinicians need to consider SPG 7 mutation as a potential cause of early onset of parkinsonism.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Pfeffer G, Gorman GS, Griffin H, Kurzawa-Akanbi M, et al
. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance. Brain 2014 ;137:1323-36.
van Gassen KL, van der Heijden CD, de Bot ST, den Dunnen WF, van den Berg LH, VerschuurenBemelmans CC, et al
. Genotypephenotype correlations in spastic paraplegia type 7: A study in a large Dutch cohort. Brain 2012;135:29943004.
Coarelli G, Schule R, van de Warrenburg BPC, De Jonghe P, Ewenczyk C, Martinuzzi A, et al
. Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7. Neurology 2019;92:e2679-e2690.
De la Casa-Fages B, Fernández-Eulate G, Gamez J, Barahona-Hernando R, Morís G, García-Barcina M, et al
. Parkinsonism and spastic paraplegia type 7: expanding the spectrum of mitochondrial parkinsonism. Mov Disord 2019;34:1547-61
Pedroso JL, Vale TC, Bueno FL, Marussi VHR, Amaral LLFD, França MC Jr., et al
. SPG7 with parkinsonism responsive to levodopa and dopaminergic deficit. Parkinsonism Relat Disord 2018;47:88-90.