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SPG7 with parkinsonism responsive to levodopa and dopaminergic deficit
Parkinsonism and Related Disorders xxx (2017) 1e3
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Correspondence
SPG7 with parkinsonism responsive to levodopa and dopaminergic deficit a b s t r a c t Keywords: Ataxia Parkinsonism Hereditary spastic paraplegias
We report a 55-year-old woman with a long history of a gait disturbance that was followed by dysarthria and urinary incontinence. She underwent brain MRI, SPECT with TRODAT imaging and whole-exome sequencing, revealing the diagnosis of SPG7. She developed parkinsonism responsive to levodopa, expanding the phenotype of complex SPG7. © 2017 Published by Elsevier Ltd.
Dear Editor, Spastic paraplegia type 7 (SPG7, [MIM #607259]) is one of the most common subtypes of autosomal recessive hereditary spastic paraplegias (SPG), accounting for 5%e12% of autosomal recessive cases and up to 7% of sporadic adult onset mutations [1]. The SPG7 gene comprises 17 exons on chromosome region 16q24.3 and encodes the protein paraplegin, a mitochondrial metalloprotease [1]. The disease onset is predominantly in adulthood (third or fourth decade), but a wide range between ages 10 and 77 has been described [2]. Patients may present with a pure spastic paraplegia phenotype (with or without impaired vibration sense and sphincter disturbances) or a predominantly spastic-ataxic complex phenotype [2]. Complexity is usually based on a concomitant cerebellar ataxia which is experienced among most patients (>60%) and may even be or become more pronounced than the spastic paraplegia. In addition, other features that had been already described in the complex phenotype are: dysphagia, subtle cognitive impairment, optic atrophy, strabismus, supranuclear oculomotor palsy, decreased hearing, scoliosis, amyotrophy and/or sensorimotor neuropathy [2]. A 55-year-old woman presented with a 15-year history of a slowly progressive gait disturbance. For the last nine years, symptoms progressed and dysarthria, urinary incontinence and lowerlimb stiffness ensued. She reported no other medical comorbities, except for glucose intolerance. She was not under medications or illicit drugs. Parents were non-consanguineous, and family history was remarkable since a younger sister had a similar disease. Neurological examination revealed spastic paraparesis with mild cerebellar ataxia, dysarthria and ophthalmoparesis. In addition, patient had marked hypomimia and symmetric bradykinesia, rigidity and postural instability (Video 1). Brain MRI showed mild cerebellar atrophy. Cervical MRI was normal as well as a PET-CT scan. Nerve conduction studies/needle electroneuromyography and cerebrospinal fluid biochemistry were normal. Routine serum biochemistry and serum levels of vitamins B12 and E,
homocysteine, ceruloplasmin, VDRL, HIV, HTLV and rheumatological studies were normal. Patient underwent whole-exome sequencing which revealed 2 variants in the SPG7 gene: a pathogenic missense variant c.1529C>T and a novel missense variant c.2069C>T. The first variant has been already described as pathogenic (HGMD: CM085726). We also believe that the variant c.2069C>T is deleterious because it has not been previously reported in genomic databases (ExAC, 1000 Genomes), is located in a highly conserved region and predicted to be pathogenic according to multiple in silico algorithms (www.mutationtaster.org, SIFT and Polyphen2). In addition, it segregates with the phenotype, since her affected sister also had the same compound heterozygous genotype. Of note, her sister was recently diagnosed with a pure SPG7 phenotype and did not have parkinsonism. Patient was started on levodopa 300mg/day titrated up to 700 mg/day with successful control of her bradykinesia, and improvement in global movements and gait. Unified Parkinson's Disease Rating ScalePart III was 26 points at first evaluation, and 14 points three weeks after levodopa use. Brain SPECT imaging with TRODAT-1 revealed bilateral reduced uptake at the putamen (Fig. 1), when compared with a healthy subject. Patient was diagnosed with a complex phenotype of SPG7 with levodopa responsive parkinsonism. Supplementary video related to this article can be found at https://doi.org/10.1016/j.parkreldis.2017.12.004. In the largest series of patients with SPG7, the overall clinical phenotype is characterized by slowly progressive spastic paraparesis, variable degrees of cerebellar ataxia, ophthalmoplegia and optic atrophy [3]. Cerebellar ataxia was present in 57% of the patients, and in some of them the cerebellar syndrome was the presenting or more dominating disease feature. Usually, these patients may be included in the group of spastic ataxias. Cerebellar atrophy on brain MRI is the most frequent neuroimaging finding in complex SPG7 cases. Dystonia, ptosis and severe intellectual disability have been also described [3]. One study demonstrated that SPG7 was a major cause of unexplained ataxia presenting in mid-adult life,
https://doi.org/10.1016/j.parkreldis.2017.12.004 1353-8020/© 2017 Published by Elsevier Ltd.
Please cite this article in press as: J.L. Pedroso, et al., SPG7 with parkinsonism responsive to levodopa and dopaminergic deficit, Parkinsonism and Related Disorders (2017), https://doi.org/10.1016/j.parkreldis.2017.12.004
2
Correspondence / Parkinsonism and Related Disorders xxx (2017) 1e3
Fig. 1. (A) Brain SPECT with 99m Tc TRODAT-1 in a healthy subject with the same age of our patient shows a normal dopaminergic uptake in the striatum (white arrows); (B) Brain MRI in a control subject demonstrates normal bilateral hyperintense signal in the topography of the nigrossome 1 (white arrows); (C) Brain SPECT with 99m Tc TRODAT-1 in our patient with SPG7 and parkinsonism shows bilateral decreased binding in the caudate and putamen, revealing a pre-synaptic dopaminergic pathway damage (white arrows); (D) Brain MRI of our SPG7 patient discloses absence of the bilateral normal hyperintense signal in the topography of the nigrossome 1, suggesting a dopaminergic pathway dysfunction.
especially when associated with pyramidal signs and ocular findings (nystagmus, ophthalmoparesis or slow saccades) [4]. Parkinsonism responsive to levodopa has been already described in several patients with spastic paraplegia type 11 (SPG11) [5]. These patients also presented with reduced dopaminergic binding on SPECT with TRODAT, demonstrating a presynaptic dopaminergic pathway damage, similar to our patient with SPG7. In one single article, authors reported parkinsonism in a patient with SPG7, however this should be viewed with caution due to the concurrent use of neuroleptics [3]. The current observation provides clear evidence that SPG patients may present with a more widespread brain involvement, besides the pyramidal tracts. One might postulate that our patient have concomitant Parkinson's disease, but the symmetrical findings combined with a symmetric reduced dopaminergic binding on SPECT with TRODAT do not support this hypothesis. In conclusion, this report demonstrates that, although rare, parkinsonism responsive to levodopa may occur in SPG7. Conflicts of interest We have no conflict of interest. Financial disclosure We have nothing to disclose. Ethical statement Full consent was obtained from the patient for the case report publication. Authors' roles 1. Case report project: A. Conception, B. Organization, C. Execution;
2. Genetic testing: A. Conception, B. Execution; 3. Manuscript: A. Writing of the first draft, B. Review and Critique. Pedroso, JL: 1A, 1B, 1C, 3A, 3B (Nothing to disclose). Vale, TC: 1A, 1B, 1C, 3A, 3B (Nothing to disclose). Bueno, FL: 1A, 1B, 1C (Nothing to disclose). Marussi VHR: 2A, 2B, 3B (Nothing to disclose). Amaral, LLF: 1A, 1B, 1C (Nothing to disclose). França Jr MC: 2A, 2B, 3B (Nothing to disclose). Barsottini, OG: 1A, 3A, 3B (Nothing to disclose). References [1] F. Brugman, H. Scheffer, J.H. Wokke, et al., Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes, Neurology 71 (2008) 1500e1505. [2] T. Warnecke, T. Duning, A. Schwan, H. Lohmann, J.T. Epplen, P. Young, A novel form of autosomal recessive hereditary spastic paraplegia caused by a new SPG7 mutation, Neurology 69 (2007) 368e375. [3] K.L. van Gassen, C.D. van der Heijden, S.T. de Bot, et al., Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort, Brain 135 (2012) 2994e3004. [4] G. Pfeffer, A. Pyle, H. Griffin, et al., SPG7 are a common cause of undiagnosed ataxia, Neurology 84 (2015) 1174e1177. [5] M. Anheim, C. Lagier-Tourenne, G. Stevanin, et al., SPG11 spastic paraplegia. A new cause of juvenile parkinsonism, J. Neurol. 256 (2009) 104e108.
Luiz Pedroso*,1 Jose ~o Paulo, Sao Department of Neurology, Universidade Federal de Sa Paulo, SP, Brazil Thiago Cardoso Vale1 Department of Internal Medicine, Universidade Federal de Juiz de Fora, MG, Brazil Fabiana Lucas Bueno Samaritano Hospital, Division of Nuclear Medicine, Sao Paulo, SP, Brazil zaro Luís Faria do Amaral Victor Hugo Rocha Marussi, La Medimagem, Benefic^ encia Portuguesa, Sao Paulo, SP, Brazil
Please cite this article in press as: J.L. Pedroso, et al., SPG7 with parkinsonism responsive to levodopa and dopaminergic deficit, Parkinsonism and Related Disorders (2017), https://doi.org/10.1016/j.parkreldis.2017.12.004
Correspondence / Parkinsonism and Related Disorders xxx (2017) 1e3
Marcondes C. França Jr. Department of Neurology, Universidade de Campinas, Campinas, SP, Brazil Orlando G. Barsottini ~o Paulo, Sao Department of Neurology, Universidade Federal de Sa Paulo, SP, Brazil
1
*
3
Corresponding author. Rua Botucatu 740, 04023-900, Sao Paulo, SP, Brazil. E-mail address: [email protected] (J.L. Pedroso). 4 September 2017
These authors contributed equally to this work.
Please cite this article in press as: J.L. Pedroso, et al., SPG7 with parkinsonism responsive to levodopa and dopaminergic deficit, Parkinsonism and Related Disorders (2017), https://doi.org/10.1016/j.parkreldis.2017.12.004
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Correspondence
SPG7 with parkinsonism responsive to levodopa and dopaminergic deficit a b s t r a c t Keywords: Ataxia Parkinsonism Hereditary spastic paraplegias
We report a 55-year-old woman with a long history of a gait disturbance that was followed by dysarthria and urinary incontinence. She underwent brain MRI, SPECT with TRODAT imaging and whole-exome sequencing, revealing the diagnosis of SPG7. She developed parkinsonism responsive to levodopa, expanding the phenotype of complex SPG7. © 2017 Published by Elsevier Ltd.
Dear Editor, Spastic paraplegia type 7 (SPG7, [MIM #607259]) is one of the most common subtypes of autosomal recessive hereditary spastic paraplegias (SPG), accounting for 5%e12% of autosomal recessive cases and up to 7% of sporadic adult onset mutations [1]. The SPG7 gene comprises 17 exons on chromosome region 16q24.3 and encodes the protein paraplegin, a mitochondrial metalloprotease [1]. The disease onset is predominantly in adulthood (third or fourth decade), but a wide range between ages 10 and 77 has been described [2]. Patients may present with a pure spastic paraplegia phenotype (with or without impaired vibration sense and sphincter disturbances) or a predominantly spastic-ataxic complex phenotype [2]. Complexity is usually based on a concomitant cerebellar ataxia which is experienced among most patients (>60%) and may even be or become more pronounced than the spastic paraplegia. In addition, other features that had been already described in the complex phenotype are: dysphagia, subtle cognitive impairment, optic atrophy, strabismus, supranuclear oculomotor palsy, decreased hearing, scoliosis, amyotrophy and/or sensorimotor neuropathy [2]. A 55-year-old woman presented with a 15-year history of a slowly progressive gait disturbance. For the last nine years, symptoms progressed and dysarthria, urinary incontinence and lowerlimb stiffness ensued. She reported no other medical comorbities, except for glucose intolerance. She was not under medications or illicit drugs. Parents were non-consanguineous, and family history was remarkable since a younger sister had a similar disease. Neurological examination revealed spastic paraparesis with mild cerebellar ataxia, dysarthria and ophthalmoparesis. In addition, patient had marked hypomimia and symmetric bradykinesia, rigidity and postural instability (Video 1). Brain MRI showed mild cerebellar atrophy. Cervical MRI was normal as well as a PET-CT scan. Nerve conduction studies/needle electroneuromyography and cerebrospinal fluid biochemistry were normal. Routine serum biochemistry and serum levels of vitamins B12 and E,
homocysteine, ceruloplasmin, VDRL, HIV, HTLV and rheumatological studies were normal. Patient underwent whole-exome sequencing which revealed 2 variants in the SPG7 gene: a pathogenic missense variant c.1529C>T and a novel missense variant c.2069C>T. The first variant has been already described as pathogenic (HGMD: CM085726). We also believe that the variant c.2069C>T is deleterious because it has not been previously reported in genomic databases (ExAC, 1000 Genomes), is located in a highly conserved region and predicted to be pathogenic according to multiple in silico algorithms (www.mutationtaster.org, SIFT and Polyphen2). In addition, it segregates with the phenotype, since her affected sister also had the same compound heterozygous genotype. Of note, her sister was recently diagnosed with a pure SPG7 phenotype and did not have parkinsonism. Patient was started on levodopa 300mg/day titrated up to 700 mg/day with successful control of her bradykinesia, and improvement in global movements and gait. Unified Parkinson's Disease Rating ScalePart III was 26 points at first evaluation, and 14 points three weeks after levodopa use. Brain SPECT imaging with TRODAT-1 revealed bilateral reduced uptake at the putamen (Fig. 1), when compared with a healthy subject. Patient was diagnosed with a complex phenotype of SPG7 with levodopa responsive parkinsonism. Supplementary video related to this article can be found at https://doi.org/10.1016/j.parkreldis.2017.12.004. In the largest series of patients with SPG7, the overall clinical phenotype is characterized by slowly progressive spastic paraparesis, variable degrees of cerebellar ataxia, ophthalmoplegia and optic atrophy [3]. Cerebellar ataxia was present in 57% of the patients, and in some of them the cerebellar syndrome was the presenting or more dominating disease feature. Usually, these patients may be included in the group of spastic ataxias. Cerebellar atrophy on brain MRI is the most frequent neuroimaging finding in complex SPG7 cases. Dystonia, ptosis and severe intellectual disability have been also described [3]. One study demonstrated that SPG7 was a major cause of unexplained ataxia presenting in mid-adult life,
https://doi.org/10.1016/j.parkreldis.2017.12.004 1353-8020/© 2017 Published by Elsevier Ltd.
Please cite this article in press as: J.L. Pedroso, et al., SPG7 with parkinsonism responsive to levodopa and dopaminergic deficit, Parkinsonism and Related Disorders (2017), https://doi.org/10.1016/j.parkreldis.2017.12.004
2
Correspondence / Parkinsonism and Related Disorders xxx (2017) 1e3
Fig. 1. (A) Brain SPECT with 99m Tc TRODAT-1 in a healthy subject with the same age of our patient shows a normal dopaminergic uptake in the striatum (white arrows); (B) Brain MRI in a control subject demonstrates normal bilateral hyperintense signal in the topography of the nigrossome 1 (white arrows); (C) Brain SPECT with 99m Tc TRODAT-1 in our patient with SPG7 and parkinsonism shows bilateral decreased binding in the caudate and putamen, revealing a pre-synaptic dopaminergic pathway damage (white arrows); (D) Brain MRI of our SPG7 patient discloses absence of the bilateral normal hyperintense signal in the topography of the nigrossome 1, suggesting a dopaminergic pathway dysfunction.
especially when associated with pyramidal signs and ocular findings (nystagmus, ophthalmoparesis or slow saccades) [4]. Parkinsonism responsive to levodopa has been already described in several patients with spastic paraplegia type 11 (SPG11) [5]. These patients also presented with reduced dopaminergic binding on SPECT with TRODAT, demonstrating a presynaptic dopaminergic pathway damage, similar to our patient with SPG7. In one single article, authors reported parkinsonism in a patient with SPG7, however this should be viewed with caution due to the concurrent use of neuroleptics [3]. The current observation provides clear evidence that SPG patients may present with a more widespread brain involvement, besides the pyramidal tracts. One might postulate that our patient have concomitant Parkinson's disease, but the symmetrical findings combined with a symmetric reduced dopaminergic binding on SPECT with TRODAT do not support this hypothesis. In conclusion, this report demonstrates that, although rare, parkinsonism responsive to levodopa may occur in SPG7. Conflicts of interest We have no conflict of interest. Financial disclosure We have nothing to disclose. Ethical statement Full consent was obtained from the patient for the case report publication. Authors' roles 1. Case report project: A. Conception, B. Organization, C. Execution;
2. Genetic testing: A. Conception, B. Execution; 3. Manuscript: A. Writing of the first draft, B. Review and Critique. Pedroso, JL: 1A, 1B, 1C, 3A, 3B (Nothing to disclose). Vale, TC: 1A, 1B, 1C, 3A, 3B (Nothing to disclose). Bueno, FL: 1A, 1B, 1C (Nothing to disclose). Marussi VHR: 2A, 2B, 3B (Nothing to disclose). Amaral, LLF: 1A, 1B, 1C (Nothing to disclose). França Jr MC: 2A, 2B, 3B (Nothing to disclose). Barsottini, OG: 1A, 3A, 3B (Nothing to disclose). References [1] F. Brugman, H. Scheffer, J.H. Wokke, et al., Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes, Neurology 71 (2008) 1500e1505. [2] T. Warnecke, T. Duning, A. Schwan, H. Lohmann, J.T. Epplen, P. Young, A novel form of autosomal recessive hereditary spastic paraplegia caused by a new SPG7 mutation, Neurology 69 (2007) 368e375. [3] K.L. van Gassen, C.D. van der Heijden, S.T. de Bot, et al., Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort, Brain 135 (2012) 2994e3004. [4] G. Pfeffer, A. Pyle, H. Griffin, et al., SPG7 are a common cause of undiagnosed ataxia, Neurology 84 (2015) 1174e1177. [5] M. Anheim, C. Lagier-Tourenne, G. Stevanin, et al., SPG11 spastic paraplegia. A new cause of juvenile parkinsonism, J. Neurol. 256 (2009) 104e108.
Luiz Pedroso*,1 Jose ~o Paulo, Sao Department of Neurology, Universidade Federal de Sa Paulo, SP, Brazil Thiago Cardoso Vale1 Department of Internal Medicine, Universidade Federal de Juiz de Fora, MG, Brazil Fabiana Lucas Bueno Samaritano Hospital, Division of Nuclear Medicine, Sao Paulo, SP, Brazil zaro Luís Faria do Amaral Victor Hugo Rocha Marussi, La Medimagem, Benefic^ encia Portuguesa, Sao Paulo, SP, Brazil
Please cite this article in press as: J.L. Pedroso, et al., SPG7 with parkinsonism responsive to levodopa and dopaminergic deficit, Parkinsonism and Related Disorders (2017), https://doi.org/10.1016/j.parkreldis.2017.12.004
Correspondence / Parkinsonism and Related Disorders xxx (2017) 1e3
Marcondes C. França Jr. Department of Neurology, Universidade de Campinas, Campinas, SP, Brazil Orlando G. Barsottini ~o Paulo, Sao Department of Neurology, Universidade Federal de Sa Paulo, SP, Brazil
1
*
3
Corresponding author. Rua Botucatu 740, 04023-900, Sao Paulo, SP, Brazil. E-mail address: [email protected] (J.L. Pedroso). 4 September 2017
These authors contributed equally to this work.
Please cite this article in press as: J.L. Pedroso, et al., SPG7 with parkinsonism responsive to levodopa and dopaminergic deficit, Parkinsonism and Related Disorders (2017), https://doi.org/10.1016/j.parkreldis.2017.12.004