- Email: [email protected]
Brain white matter demyelinating lesions and amyotrophic lateral sclerosis in a patient with C9orf72 hexanucleotide repeat expansion
Author’s Accepted Manuscript Brain white matter demyelinating lesions and amyotrophic lateral sclerosis in a patient with C9orf72 hexanucleotide repeat expansion Miguel Oliveira Santos, Inês Caldeira, Marta Gromicho, Ana Pronto-Laborinho, Mamede de Carvalho www.elsevier.com/locate/msard
PII: DOI: Reference:
S2211-0348(17)30143-8 http://dx.doi.org/10.1016/j.msard.2017.06.010 MSARD589
To appear in: Multiple Sclerosis and Related Disorders Received date: 28 February 2017 Revised date: 11 June 2017 Accepted date: 19 June 2017 Cite this article as: Miguel Oliveira Santos, Inês Caldeira, Marta Gromicho, Ana Pronto-Laborinho and Mamede de Carvalho, Brain white matter demyelinating lesions and amyotrophic lateral sclerosis in a patient with C9orf72 hexanucleotide repeat expansion, Multiple Sclerosis and Related Disorders, http://dx.doi.org/10.1016/j.msard.2017.06.010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Brain white matter demyelinating lesions and amyotrophic lateral sclerosis in a patient with C9orf72 hexanucleotide repeat expansion.
Miguel Oliveira Santos1,2*, Inês Caldeira3, Marta Gromicho1, Ana Pronto-Laborinho1, Mamede de Carvalho1,2
1
Institute of Physiology Unit, Instituto de Medicina Molecular, Faculty of Medicine,
University of Lisbon, Portugal. 2
Department of Neurosciences and Mental Health, Hospital de Santa Maria, Centro
Hospitalar Lisboa Norte, Portugal. 3
Department of Neuroradiology. Hospital de Santa Maria, Centro Hospitalar Lisboa
Norte, Portugal. *
Corresponding Author. Miguel Oliveira Santos. Avenida Professor Egas Moniz
1649-035, Lisbon, Portugal. +351 964919683. [email protected]
Abstract A hexanucleotide repeat expansion in the C9orf72 gene is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. It has been described before four patients with multiple sclerosis (MS) and C9orf72-ALS. However, C9orf72 positivity is not associated with increased risk of MS. Inflammatory pathways related to NF-κB have been linked to ALS and MS, and appear to be important in C9orf72-ALS patients. A 42-year-old woman presented with progressive bulbar symptoms for 9 months. Neurological examination disclosed spastic dysarthria, atrophic tongue with fasciculations, brisk jaw and limb tendon reflexes, and bilateral Hoffman sign. Electrophysiological assessment confirmed ALS. Brain MRI revealed multiple and bilateral juxtacortical and periventricular
inflammatory changes, some with gadolinium-enhancement, configuring a probable MS-like pattern. CSF evaluation was unremarkable, with no oligoclonal bands. Visual and somatosensory evoked potentials were normal. Follow-up brain MRI 6 months later showed two new lesions in two relatively characteristic locations of MS, with no gadolinium-enhancement. Genetic screening revealed a C9orf72 expansion. As patient had no clinical manifestation of MS, a diagnosis of radiologically isolated syndrome was considered. We speculate that these demyelinating lesions might facilitate expressivity of C9orf72 expansion, through NF-κB activation. This plausible association may lead to the identification of a therapeutic target in this subgroup of C9orf72-ALS patients.
Keywords: Amyotrophic lateral sclerosis; Brain white matter demyelination; C9orf72 hexanucleotide repeat expansion; Frontotemporal lobar degeneration.
Introduction A GGGGCC hexanucleotide repeat expansion in the first intron of the C9orf72 gene is associated to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration.1,2 It represents the most common genetic abnormality both in familial (≈40.0%) and sporadic cases of ALS (5.0-7.0%), as well in frontotemporal dementia (≈40.0%).3 More recent studies have shown other possible clinical phenotypes related to C9orf72, in particular Parkinson’s disease, atypical parkinsonism (corticobasal degeneration syndrome and progressive supranuclear palsy)4,5 and Huntington disease phenocopies6, broadening its clinical spectrum. Based on clinical-pathological reports, a hypothetical association between multiple sclerosis (MS) and ALS has emerged.7-9 Regardless of whether neuroinflammation is
a cause or effect of the primary pathology, a cellular and molecular pathway leading to central axonal degeneration seems to be shared by both disorders.9,10 Two population-based studies in two distinctive geographic regions (Sweden11,12 and Iran10), suggest that relatives of MS patients are more likely to suffer from ALS, and additionally the same is also true for ALS patients regarding the risk of MS. Perhaps some families’ clusters have a common genetic background predisposing to both MS and ALS. In the light of these studies, we aim to describe and discuss a C9orf72-ALS patient with asymptomatic active brain demyelinating lesions.
Case Report A 42-year-old Caucasian woman presented with progressive speech slurring and swallowing difficulties for the previous 9 months. There were no sensory or limb motor symptoms and weight was stable. Past medical history was unremarkable, specifically she declined any previous episode of transitory neurological impairment, including visual symptoms. The patient’s grandfather had a history of no specified dementia, presenting it at unknown age. On examination, it was noticed severe spastic dysarthria, fasciculations were observed in the tongue that was slightly atrophic, jaw and limb deep tendon reflexes were very brisk, and bilateral Hoffman sign was disclosed. There was no wasting, fasciculations or muscle weakness in upper and lower extremities, but neck flexion was moderately weak. Sensory testing was normal (pinprick, light touch, postural or vibration sense). Patient neutral attitude towards her progressive disability raised suspicion of frontal dysfunction. Blood tests were unremarkable, including blood cells, sedimentation rate, angiotensin-converting enzyme, cryoglobulins and autoimmunity screening (antinuclear, anti-double stranded DNA, ANA screening, lupus anticoagulant, anti-
cardiolipin, anti-β2-glycoprotein-I, anti-neutrophil cytoplasmic and antitransglutaminase antibodies). Serology for HIV 1-2, hepatitis B-C virus, Lyme and syphilis (VDRL and TPHA) were negative. Nerve conduction studies were normal. Needle sampling identified chronic neurogenic changes in genioglossus and sternocleidomastoid muscles. Isolated fasciculation potentials were observed in hand muscles, without neurogenic changes. Respiratory function tests were normal. Brain MRI disclosed multiple and bilateral inflammatory lesions in the juxtacortical and periventricular white matter, and some of them showed gadolinium-enhancement, configuring a probable MS-like pattern (Figure 1A-F). A bilateral corticospinal tract high signal, according with clinical ALS diagnosis, was also noticed (Figure 2). There was no brain atrophy, corpus callosum involvement, microhaemorrhages or features of restricted diffusion. CSF analysis was normal, including neurotropic virus panel, and oligoclonal bands were absent. Visual and somatosensory evoked potentials revealed no abnormalities. Conventional neuropsychological assessment favoured a possible mild frontal dysfunction. A diagnosis of clinically possible ALS was made according to revised El Escorial Criteria (one region with lower and upper motor neuron signs).13 She was placed on riluzol 50 mg bid. She agreed to perform genetic testing that revealed pathological C9orf72 expansion. In the follow-up she developed progressive clinical signs of fronto-temporal dysfunction, widespread fasciculations and distal limb weakness, and moderate respiratory involvement over 12 months. A follow-up brain MRI 6 months later showed two new lesions in two different relatively characteristic sites of MS – callososeptal and juxtaventricular locations (Figure 3A-B). There were no gadolinium-enhancing lesions.
Discussion Although there is some strong evidence supporting an association between MS and C9orf72-ALS patients, the same is not valid for MS alone and C9orf72 expansions. Ismail et al.14, from a cohort of 650 ALS patients identified 5 with concurrent MS, and 4 of them had C9orf72 expansion. Nevertheless these latter authors14 and Fenoglio et al.15, screened 215 and 314 MS patients respectively, and the presence of C9orf72 expansion was negative. According to these results, it seems unlikely that C9orf72 plays a major role in MS pathophysiology, and probably other pathogenic mutations may still be missing. On the other hand Ismail et al.14, propose that the neuroprotective cytokine CXCL10 downregulation, observed only in C9orf72-ALS patients in comparison to non-C9orf72-ALS ones, may work as a catalyst in ALS development on the background of MS and its associated inflammatory pathways related to the transcription factor NF-κB. Our bulbar-onset C9orf72-ALS patient has active brain inflammatory changes that may be considered potentially consistent with MS, despite no previous identifiable MS symptoms, normal visual and somatosensory evoked potentials and negative CSF oligoclonal bands. Other possible causes, including neuropsychiatric systemic lupus erythematosus, phospholipid syndrome, ANCA-associated vasculitis, neurosarcoidosis and infectious disorders (HIV, neurosyphilis, neuroborreliosis) were also pondered, but additional relevant investigations were negative. In view of such results, we suggest that these incidental brain MRI findings may probably fit into the category of radiologically isolated syndrome.16 Despite being “clinically silent”, these active brain demyelinating lesions and their inherent inflammatory state may have contributed to ALS development by facilitating C9orf72 expansion penetrance
through mechanisms related to NF-κB activation, as previously described by Ismail et al.14 Perhaps C9orf72-ALS patients with any concurrent central nervous system demyelination may benefit from potential treatments that block these inflammatory pathways. Indeed more studies are needed to address this issue.
Funding This work was partially supported by OnWebDuals project (JPND-PS/0001/2013). This is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisation under the aegis of JPND - www.jpnd.eu: Germany, Bundesministerium für Bildung und Forschung (BMBF); Poland, Narodowe Centrum Badań i Rozwoju (NCBiR); Portugal, Fundação a Ciência e a Tecnologia (FCT); Sweden, Vetenskapsrådet (VR).
Declaration of interest The authors report no conflicts of interest.
Complying with ethics of experimentation All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
References 1.
DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded ggggcc hexanucleotide repeat in noncoding region of c9orf72 causes chromosome 9p-linked ftd and als. Neuron 2011;72:245-256.
2.
Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in c9orf72 is the cause of chromosome 9p21-linked als-ftd. Neuron 2011;72:257-268.
3.
Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, et al. Frequency of the c9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study. Lancet Neurol 2012;11:323-330.
4.
Lesage S, Le Ber I, Condroyer C, Broussolle E, Gabelle A, Thobois S, et al. C9orf72 repeat expansions are a rare genetic cause of parkinsonism. Brain 2013;136:385-391.
5.
Cannas A, Solla P, Borghero G, Floris GL, Chio A, Mascia MM, et al. C9orf72 intermediate repeat expansion in patients affected by atypical parkinsonian syndromes or parkinson's disease complicated by psychosis or dementia in a sardinian population. J Neurol 2015;262:2498-2503.
6.
Hensman Moss DJ, Poulter M, Beck J, Hehir J, Polke JM, Campbell T, et al. C9orf72 expansions are the most common genetic cause of huntington disease phenocopies. Neurology 2014;82:292-299.
7.
Hader WJ, Rpzdilsky B, Nair CP. The concurrence of multiple sclerosis and amyotrophic lateral sclerosis. Can J Neurol Sci 1986;13:66-69.
8.
Dynes GJ, Schwimer CJ, Staugaitis SM, Doyle JJ, Hays AP, Mitsumoto H. Amyotrophic lateral sclerosis with multiple sclerosis: A clinical and pathological report. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:349-353.
9.
Li G, Esiri MM, Ansorge O, DeLuca GC. Concurrent multiple sclerosis and amyotrophic lateral sclerosis: Where inflammation and neurodegeneration meet? J Neuroinflammation 2012;9:20.
10.
Etemadifar M, Abtahi SH, Akbari M, Maghzi AH. Multiple sclerosis and amyotrophic lateral sclerosis: Is there a link? Mult Scler 2012;18:902-904.
11.
Hemminki K, Li X, Sundquist J, Hillert J, Sundquist K. Risk for multiple sclerosis in relatives and spouses of patients diagnosed with autoimmune and related conditions. Neurogenetics 2009;10:5-11.
12.
Hemminki K, Li X, Sundquist J, Sundquist K. Familial risks for amyotrophic lateral sclerosis and autoimmune diseases. Neurogenetics 2009;10:111-116.
13.
Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron D. El escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:293-299.
14.
Ismail A, Cooper-Knock J, Highley JR, Milano A, Kirby J, Goodall E, et al. Concurrence of multiple sclerosis and amyotrophic lateral sclerosis in patients with hexanucleotide repeat expansions of c9orf72. J Neurol Neurosurg Psychiatry 2013;84:79-87.
15.
Fenoglio C, De Riz M, Villa C, Serpente M, Ridolfi E, Bonsi R, et al. C9orf72 repeat expansion not detected in patients with multiple sclerosis. Neurobiol Aging 2014;35:1213 e1211-1212.
16.
Labiano-Fontcuberta A, Benito-Leon J. Radiologically isolated syndrome: An update on a rare entity. Mult Scler 2016;22:1514-1521.
Figure 1 – Brain MRI. Axial FLAIR sequences (A, C and E) showed multiple and bilateral high signal lesions in juxtacortical and periventricular white matter. In T1 SE sequences (B, D and F) some of them had gadolinium-enhancement (white arrows) indicative of active disease.
Figure 2 – Brain MRI. Coronal T2 sequence revealed a bilateral corticospinal tract high signal, more pronounced on the right side (black arrows).
Figure 3 – Follow-up brain MRI 6 months later. Sagittal FLAIR sequences disclosed (white arrows) a new lesion involving the corpus callosum (A) and an additional one juxtaventricular to the right temporal horn (B). There were no gadolinium-enhancing lesions.
Highlights ·
A patient with C9orf72 gene expansion and an aggressive form of ALS.
·
MRI showed brain inflammatory lesions suggestive of asymptomatic MS.
·
These lesions may facilitate increased penetrance of the C9orf72 gene expansion.
Figure
Figure
Figure
PII: DOI: Reference:
S2211-0348(17)30143-8 http://dx.doi.org/10.1016/j.msard.2017.06.010 MSARD589
To appear in: Multiple Sclerosis and Related Disorders Received date: 28 February 2017 Revised date: 11 June 2017 Accepted date: 19 June 2017 Cite this article as: Miguel Oliveira Santos, Inês Caldeira, Marta Gromicho, Ana Pronto-Laborinho and Mamede de Carvalho, Brain white matter demyelinating lesions and amyotrophic lateral sclerosis in a patient with C9orf72 hexanucleotide repeat expansion, Multiple Sclerosis and Related Disorders, http://dx.doi.org/10.1016/j.msard.2017.06.010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Brain white matter demyelinating lesions and amyotrophic lateral sclerosis in a patient with C9orf72 hexanucleotide repeat expansion.
Miguel Oliveira Santos1,2*, Inês Caldeira3, Marta Gromicho1, Ana Pronto-Laborinho1, Mamede de Carvalho1,2
1
Institute of Physiology Unit, Instituto de Medicina Molecular, Faculty of Medicine,
University of Lisbon, Portugal. 2
Department of Neurosciences and Mental Health, Hospital de Santa Maria, Centro
Hospitalar Lisboa Norte, Portugal. 3
Department of Neuroradiology. Hospital de Santa Maria, Centro Hospitalar Lisboa
Norte, Portugal. *
Corresponding Author. Miguel Oliveira Santos. Avenida Professor Egas Moniz
1649-035, Lisbon, Portugal. +351 964919683. [email protected]
Abstract A hexanucleotide repeat expansion in the C9orf72 gene is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. It has been described before four patients with multiple sclerosis (MS) and C9orf72-ALS. However, C9orf72 positivity is not associated with increased risk of MS. Inflammatory pathways related to NF-κB have been linked to ALS and MS, and appear to be important in C9orf72-ALS patients. A 42-year-old woman presented with progressive bulbar symptoms for 9 months. Neurological examination disclosed spastic dysarthria, atrophic tongue with fasciculations, brisk jaw and limb tendon reflexes, and bilateral Hoffman sign. Electrophysiological assessment confirmed ALS. Brain MRI revealed multiple and bilateral juxtacortical and periventricular
inflammatory changes, some with gadolinium-enhancement, configuring a probable MS-like pattern. CSF evaluation was unremarkable, with no oligoclonal bands. Visual and somatosensory evoked potentials were normal. Follow-up brain MRI 6 months later showed two new lesions in two relatively characteristic locations of MS, with no gadolinium-enhancement. Genetic screening revealed a C9orf72 expansion. As patient had no clinical manifestation of MS, a diagnosis of radiologically isolated syndrome was considered. We speculate that these demyelinating lesions might facilitate expressivity of C9orf72 expansion, through NF-κB activation. This plausible association may lead to the identification of a therapeutic target in this subgroup of C9orf72-ALS patients.
Keywords: Amyotrophic lateral sclerosis; Brain white matter demyelination; C9orf72 hexanucleotide repeat expansion; Frontotemporal lobar degeneration.
Introduction A GGGGCC hexanucleotide repeat expansion in the first intron of the C9orf72 gene is associated to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration.1,2 It represents the most common genetic abnormality both in familial (≈40.0%) and sporadic cases of ALS (5.0-7.0%), as well in frontotemporal dementia (≈40.0%).3 More recent studies have shown other possible clinical phenotypes related to C9orf72, in particular Parkinson’s disease, atypical parkinsonism (corticobasal degeneration syndrome and progressive supranuclear palsy)4,5 and Huntington disease phenocopies6, broadening its clinical spectrum. Based on clinical-pathological reports, a hypothetical association between multiple sclerosis (MS) and ALS has emerged.7-9 Regardless of whether neuroinflammation is
a cause or effect of the primary pathology, a cellular and molecular pathway leading to central axonal degeneration seems to be shared by both disorders.9,10 Two population-based studies in two distinctive geographic regions (Sweden11,12 and Iran10), suggest that relatives of MS patients are more likely to suffer from ALS, and additionally the same is also true for ALS patients regarding the risk of MS. Perhaps some families’ clusters have a common genetic background predisposing to both MS and ALS. In the light of these studies, we aim to describe and discuss a C9orf72-ALS patient with asymptomatic active brain demyelinating lesions.
Case Report A 42-year-old Caucasian woman presented with progressive speech slurring and swallowing difficulties for the previous 9 months. There were no sensory or limb motor symptoms and weight was stable. Past medical history was unremarkable, specifically she declined any previous episode of transitory neurological impairment, including visual symptoms. The patient’s grandfather had a history of no specified dementia, presenting it at unknown age. On examination, it was noticed severe spastic dysarthria, fasciculations were observed in the tongue that was slightly atrophic, jaw and limb deep tendon reflexes were very brisk, and bilateral Hoffman sign was disclosed. There was no wasting, fasciculations or muscle weakness in upper and lower extremities, but neck flexion was moderately weak. Sensory testing was normal (pinprick, light touch, postural or vibration sense). Patient neutral attitude towards her progressive disability raised suspicion of frontal dysfunction. Blood tests were unremarkable, including blood cells, sedimentation rate, angiotensin-converting enzyme, cryoglobulins and autoimmunity screening (antinuclear, anti-double stranded DNA, ANA screening, lupus anticoagulant, anti-
cardiolipin, anti-β2-glycoprotein-I, anti-neutrophil cytoplasmic and antitransglutaminase antibodies). Serology for HIV 1-2, hepatitis B-C virus, Lyme and syphilis (VDRL and TPHA) were negative. Nerve conduction studies were normal. Needle sampling identified chronic neurogenic changes in genioglossus and sternocleidomastoid muscles. Isolated fasciculation potentials were observed in hand muscles, without neurogenic changes. Respiratory function tests were normal. Brain MRI disclosed multiple and bilateral inflammatory lesions in the juxtacortical and periventricular white matter, and some of them showed gadolinium-enhancement, configuring a probable MS-like pattern (Figure 1A-F). A bilateral corticospinal tract high signal, according with clinical ALS diagnosis, was also noticed (Figure 2). There was no brain atrophy, corpus callosum involvement, microhaemorrhages or features of restricted diffusion. CSF analysis was normal, including neurotropic virus panel, and oligoclonal bands were absent. Visual and somatosensory evoked potentials revealed no abnormalities. Conventional neuropsychological assessment favoured a possible mild frontal dysfunction. A diagnosis of clinically possible ALS was made according to revised El Escorial Criteria (one region with lower and upper motor neuron signs).13 She was placed on riluzol 50 mg bid. She agreed to perform genetic testing that revealed pathological C9orf72 expansion. In the follow-up she developed progressive clinical signs of fronto-temporal dysfunction, widespread fasciculations and distal limb weakness, and moderate respiratory involvement over 12 months. A follow-up brain MRI 6 months later showed two new lesions in two different relatively characteristic sites of MS – callososeptal and juxtaventricular locations (Figure 3A-B). There were no gadolinium-enhancing lesions.
Discussion Although there is some strong evidence supporting an association between MS and C9orf72-ALS patients, the same is not valid for MS alone and C9orf72 expansions. Ismail et al.14, from a cohort of 650 ALS patients identified 5 with concurrent MS, and 4 of them had C9orf72 expansion. Nevertheless these latter authors14 and Fenoglio et al.15, screened 215 and 314 MS patients respectively, and the presence of C9orf72 expansion was negative. According to these results, it seems unlikely that C9orf72 plays a major role in MS pathophysiology, and probably other pathogenic mutations may still be missing. On the other hand Ismail et al.14, propose that the neuroprotective cytokine CXCL10 downregulation, observed only in C9orf72-ALS patients in comparison to non-C9orf72-ALS ones, may work as a catalyst in ALS development on the background of MS and its associated inflammatory pathways related to the transcription factor NF-κB. Our bulbar-onset C9orf72-ALS patient has active brain inflammatory changes that may be considered potentially consistent with MS, despite no previous identifiable MS symptoms, normal visual and somatosensory evoked potentials and negative CSF oligoclonal bands. Other possible causes, including neuropsychiatric systemic lupus erythematosus, phospholipid syndrome, ANCA-associated vasculitis, neurosarcoidosis and infectious disorders (HIV, neurosyphilis, neuroborreliosis) were also pondered, but additional relevant investigations were negative. In view of such results, we suggest that these incidental brain MRI findings may probably fit into the category of radiologically isolated syndrome.16 Despite being “clinically silent”, these active brain demyelinating lesions and their inherent inflammatory state may have contributed to ALS development by facilitating C9orf72 expansion penetrance
through mechanisms related to NF-κB activation, as previously described by Ismail et al.14 Perhaps C9orf72-ALS patients with any concurrent central nervous system demyelination may benefit from potential treatments that block these inflammatory pathways. Indeed more studies are needed to address this issue.
Funding This work was partially supported by OnWebDuals project (JPND-PS/0001/2013). This is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisation under the aegis of JPND - www.jpnd.eu: Germany, Bundesministerium für Bildung und Forschung (BMBF); Poland, Narodowe Centrum Badań i Rozwoju (NCBiR); Portugal, Fundação a Ciência e a Tecnologia (FCT); Sweden, Vetenskapsrådet (VR).
Declaration of interest The authors report no conflicts of interest.
Complying with ethics of experimentation All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
References 1.
DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded ggggcc hexanucleotide repeat in noncoding region of c9orf72 causes chromosome 9p-linked ftd and als. Neuron 2011;72:245-256.
2.
Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in c9orf72 is the cause of chromosome 9p21-linked als-ftd. Neuron 2011;72:257-268.
3.
Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, et al. Frequency of the c9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study. Lancet Neurol 2012;11:323-330.
4.
Lesage S, Le Ber I, Condroyer C, Broussolle E, Gabelle A, Thobois S, et al. C9orf72 repeat expansions are a rare genetic cause of parkinsonism. Brain 2013;136:385-391.
5.
Cannas A, Solla P, Borghero G, Floris GL, Chio A, Mascia MM, et al. C9orf72 intermediate repeat expansion in patients affected by atypical parkinsonian syndromes or parkinson's disease complicated by psychosis or dementia in a sardinian population. J Neurol 2015;262:2498-2503.
6.
Hensman Moss DJ, Poulter M, Beck J, Hehir J, Polke JM, Campbell T, et al. C9orf72 expansions are the most common genetic cause of huntington disease phenocopies. Neurology 2014;82:292-299.
7.
Hader WJ, Rpzdilsky B, Nair CP. The concurrence of multiple sclerosis and amyotrophic lateral sclerosis. Can J Neurol Sci 1986;13:66-69.
8.
Dynes GJ, Schwimer CJ, Staugaitis SM, Doyle JJ, Hays AP, Mitsumoto H. Amyotrophic lateral sclerosis with multiple sclerosis: A clinical and pathological report. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:349-353.
9.
Li G, Esiri MM, Ansorge O, DeLuca GC. Concurrent multiple sclerosis and amyotrophic lateral sclerosis: Where inflammation and neurodegeneration meet? J Neuroinflammation 2012;9:20.
10.
Etemadifar M, Abtahi SH, Akbari M, Maghzi AH. Multiple sclerosis and amyotrophic lateral sclerosis: Is there a link? Mult Scler 2012;18:902-904.
11.
Hemminki K, Li X, Sundquist J, Hillert J, Sundquist K. Risk for multiple sclerosis in relatives and spouses of patients diagnosed with autoimmune and related conditions. Neurogenetics 2009;10:5-11.
12.
Hemminki K, Li X, Sundquist J, Sundquist K. Familial risks for amyotrophic lateral sclerosis and autoimmune diseases. Neurogenetics 2009;10:111-116.
13.
Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron D. El escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:293-299.
14.
Ismail A, Cooper-Knock J, Highley JR, Milano A, Kirby J, Goodall E, et al. Concurrence of multiple sclerosis and amyotrophic lateral sclerosis in patients with hexanucleotide repeat expansions of c9orf72. J Neurol Neurosurg Psychiatry 2013;84:79-87.
15.
Fenoglio C, De Riz M, Villa C, Serpente M, Ridolfi E, Bonsi R, et al. C9orf72 repeat expansion not detected in patients with multiple sclerosis. Neurobiol Aging 2014;35:1213 e1211-1212.
16.
Labiano-Fontcuberta A, Benito-Leon J. Radiologically isolated syndrome: An update on a rare entity. Mult Scler 2016;22:1514-1521.
Figure 1 – Brain MRI. Axial FLAIR sequences (A, C and E) showed multiple and bilateral high signal lesions in juxtacortical and periventricular white matter. In T1 SE sequences (B, D and F) some of them had gadolinium-enhancement (white arrows) indicative of active disease.
Figure 2 – Brain MRI. Coronal T2 sequence revealed a bilateral corticospinal tract high signal, more pronounced on the right side (black arrows).
Figure 3 – Follow-up brain MRI 6 months later. Sagittal FLAIR sequences disclosed (white arrows) a new lesion involving the corpus callosum (A) and an additional one juxtaventricular to the right temporal horn (B). There were no gadolinium-enhancing lesions.
Highlights ·
A patient with C9orf72 gene expansion and an aggressive form of ALS.
·
MRI showed brain inflammatory lesions suggestive of asymptomatic MS.
·
These lesions may facilitate increased penetrance of the C9orf72 gene expansion.
Figure
Figure
Figure