A case report of SPG11 mutations in a Chinese ARHSP-TCC family
© The Author(s). 2016
Received: 5 December 2015
Accepted: 17 May 2016
Published: 3 June 2016
Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a complicated form of hereditary spastic paraplegia, characterized by progressive spastic paraplegia, weakness of the lower extremities and is usually accompanied by mental retardation. Mutations in the Spastic Paraplegia gene 11 (SPG11) account for a large proportion of ARHSP-TCC cases worldwide.
We describe a Chinese family with ARHSP-TCC. Two daughters of this family presented with a spastic gait and cognitive impairment. Brain imaging of the index patient revealed a thin corpus callosum. We performed detailed physical and auxiliary examinations and were able to exclude acquired causes of spastic paraplegia. To determine the causative mutation, we took a candidate gene approach and screened the coding sequence and some flanking intronic sequence of SPG11 by direct Sanger sequencing. We identified two novel compound heterozygous mutations in SPG11 in affected individuals (c.1551_1552delTT, p.Cys518SerfsTer39 and c.5867-1G > T (IVS30-1G > T), p.Thr1956ArgfsTer15). Bioinformatic analysis predicts that these mutations would lead to a loss of protein function due to the truncation of the SPG11 protein.
The results of this case report indicate a broader approach to include screening for SPG11 mutations in ARHSP-TCC patients. Our findings enrich the phenotypic spectrum of SPG11 mutations.
KeywordsAutosomal recessive hereditary spastic paraplegia with thin corpus callosum (ARHSP-TCC) SPG11 Gene mutation Heterozygous mutations
Hereditary spastic paraplegia (HSP) is a kind of neurodegenerative disease characterized by progressive weakness and spasticity of the lower limbs. Depending on the mode of inheritance, it can be classified as autosomal dominant, autosomal recessive or X-linked. In complicated forms, additional neurological signs, such as ataxia, mental retardation, epilepsy, peripheral neuropathies, are present . HSP with Thin Corpus Callosum (HSP-TCC) is one of the most common complicated forms of autosomal recessive hereditary spastic paraplegia (ARHSP). ARHSP-TCC is most commonly caused by mutations in the spastic paraplegia 11 (SPG11) gene . SPG11 maps to chromosome 15q21, encodes a 2443 amino acid protein, SPATACSIN, and is widely expressed in the nervous system, particularly in the neurons of the cerebellum and cerebral cortex . Here, we report a Chinese HSP-TCC non-consanguineous family whose affected family members possess two compound heterozygous mutations in SPG11. These results implicate a need for wider screening of SPG11 mutations in ARHSP-TCC patients.
Her sister (II-1) is a 33-year old female with a similar, but more severe clinical phenotype with an 18 year history of disease. She is bedridden and severely handicapped due to the disturbance in her gait. She has severe cognitive impairment and did not progress past an elementary school education.
We identified novel compound heterozygous mutations in SPG11 in a Chinese HSP-TCC family (c.1551_1552delTT and c.5867-1G > T (IVS30-1G > T)). Our patients presented with typical clinical symptoms of ARHSP-TCC which included spastic paraplegia, cognitive impairment, peripheral neuropathy and distal musle atrophy. Thinning of thoracic spinal cord in our index patient is likely the result of degeneration of long corticospinal tracts and is usually present in nearly all subtypes of the HSP, mostly at later disease stages [6, 7].
Mutations in SPG11 are found in the majority of reported complex ARHSP-TCC cases with TCC being the single best indicator for SPG11 . Another Chinese family with ARHSP-TCC was reported previously, the index patient presented with prominent intellectual disability rather than spasticity had different compound heterozygous mutations of SPG11 . For patients presenting with HSP-TCC, SPG11 should be screened initially once infectious causes are eliminated. Other SPG loci including SPG15, SPG35 and SPG48 should be considered if no mutations in SPG11 are discovered . Interestingly, mutations in SPG11 can also cause other disorders, such as juvenile amyotrophic lateral sclerosis (ALS5) , juvenile Parkinsonism , and autosomal recessive axonal Charcot-Marie-Tooth disease . Thus, SPG11 mutations have an wide phenotypic spectrum suggesting that additional care should be taken when examining HSP patients. In summary, we demonstrate the importance of screening the SPG11 gene in the ARHSP-TCC patients and have provided additional clinical phenotypes resulting from mutations in the SPG11 gene.
AR, autosomal recessive; CSF, cerebrospinal fluid; EMG, electromyography; HSP, hereditary spastic paraplegia; MMSE, mini-mental state examination; MoCA, Montreal cognitive assessment; MRI, magnetic resonance imaging; SPG, spastic paraplegia gene; TCC, thin corpus callosum.
The authors would like to thank the patients and their families, without their participation this work would not have been possible. The authors would like to acknowledge Tetsuo Ashizawa for his advice for result analysis.
This study was supported in part by the Research Fund of the China-Japan Friendship Hospital (2013-RC-3).
Study design and drafting of manuscript: LZ, YJ. Clinical study perform: YJ, JJ. Genetic analysis: KNM LZ. Acquisition, and interpretation of data: YJ, KNM LZ, JJ. Critical revision of the manuscript: KNM YJ, LZ. Obtained funding: YJ. All authors have read and approved the final manuscript.
The authors declare that they have no competing interests.
Ethics approval and consent to participate
The study protocol was reviewed and approved by the Ethics Committee (IRB) of China-Japan Friendship Hospital (2016-7-1). Written informed consent was obtained from the patient and her family for genetic analysis and publication of this case report.
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- Fink JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol. 2013;126:307–28.View ArticlePubMedPubMed CentralGoogle Scholar
- Stevanin G, Azzedine H, Denora P, Boukhris A, Tazie M, Lossos A, et al. Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration. Brain. 2008;131:772–84.View ArticlePubMedGoogle Scholar
- Paisan-Ruiz C, Dogu O, Yilmaz A, Houlden H, Singleton A. SPG11 mutations are common in familial cases of complicated hereditary spastic paraplegia (HSP). Neurology. 2008;70:1384–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Stevanin G, Santorelli FM, Azzedine H, Coutinho P, Chomilier J, Denora PS, et al. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet. 2007;39:366–72.View ArticlePubMedGoogle Scholar
- Samaranch L, Riverol M, Masdeu JC, Lorenzo E, Vidal-Taboada JM, Irigoyen J, et al. SPG11 compound mutations in spastic paraparesis with thin corpus callosum. Neurology. 2008;71:332–6.View ArticlePubMedGoogle Scholar
- Hourani R, El-Hajj T, Barada WH, Hourani M, Yamout BI. MR imaging findings in autosomal recessive hereditary spastic paraplegia. AJNR Am J Neuroradiol. 2009;30:936–40.View ArticlePubMedGoogle Scholar
- Sperfeld AD, Baumgartner A, Kassubek J. Magnetic resonance investigation of the upper spinal cord in pure and complicated hereditary spastic paraparesis. Eur Neurol. 2005;54:181–5.View ArticlePubMedGoogle Scholar
- Ma J, Xiong L, Chang Y, Jing X, Huang W, Hu B, et al. Novel mutations c.[5121_5122insAG] + [6859C > T] of the SPG11 gene associated with cerebellum hypometabolism in a Chinese case of hereditary spastic paraplegia with thin corpus callosum. Parkinsonism Relat Disord. 2014;20(2):256–9.View ArticlePubMedGoogle Scholar
- Pensato V, Castellotti B, Gellera C, Pareyson D, Ciano C, Nanetti L, et al. Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48. Brain. 2014;137:1907–20.View ArticlePubMedGoogle Scholar
- Orlacchio A, Babalini C, Borreca A, Patrono C, Massa R, Basaran S, et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain. 2010;133:591–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Anheim M, Lagier-Tourenne C, Stevanin G, Fleury M, Durr A, Namer IJ, et al. SPG11 spastic paraplegia. A new cause of juvenile parkinsonism. J Neurol. 2009;256:104–8.View ArticlePubMedGoogle Scholar
- Montecchiani C, Pedace L, Lo Giudice T, Casella A, Mearini M, Gaudiello F, et al. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. Brain. 2016;139:73–85.View ArticlePubMedGoogle Scholar