- Email: [email protected]
White matter hyperintensities in myotonic dystrophy type 2: Not always another expression of the disease
Accepted Manuscript
White matter hyperintensities in myotonic dystrophy type 2: not always another expression of the disease. M Karatzikou , C Bakirtzis , J Nikolaidis , D Parisis , N Grigoriadis PII: DOI: Reference:
S2211-0348(18)30197-4 10.1016/j.msard.2018.06.020 MSARD 875
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
20 February 2018 24 June 2018 28 June 2018
Please cite this article as: M Karatzikou , C Bakirtzis , J Nikolaidis , D Parisis , N Grigoriadis , White matter hyperintensities in myotonic dystrophy type 2: not always another expression of the disease., Multiple Sclerosis and Related Disorders (2018), doi: 10.1016/j.msard.2018.06.020
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 proof before it is published in its final 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.
ACCEPTED MANUSCRIPT Highlights Α rare case of concomitant multiple sclerosis in patient with myotonic dystrophy 2. White matter abnormalities a common feature of myotonic dystrophy 2. Differential diagnosis of CNS involvement in DM2 is challenging.
AC
CE
PT
ED
M
AN US
CR IP T
ACCEPTED MANUSCRIPT White matter hyperintensities in myotonic dystrophy type 2: not always another expression of the disease. M Karatzikou, C Bakirtzis, J Nikolaidis, D Parisis, N Grigoriadis Multiple Sclerosis Center, 2nd Department of Neurology, Aristotle University of Thessaloniki, Greece Corresponding author:
CR IP T
M Karatzikou
AN US
Multiple Sclerosis Center 2nd Department of Neurology AHEPA University Hospital Aristotle University of Thessaloniki 1 Stilp Kyriakidi str GR 54636 Thessaloniki, Central Macedonia, Greece ABSTRACT
INTRODUCTION
PT
ED
M
Myotonic dystrophy type 2(DM2), inherited in an autosomal, dominant manner, is clinically characterized by muscle weakness, variable myotonia, cataract and multiorgan involvement, including the Central Nervous System. Recent data from literature indicate a possible autoimmune susceptibility of patients with DM2, while white matter abnormalities are a common feature of the disease. We report herein the case of a 38-year old woman, with the rare co-existence of DM2 and MS and argue about the challenging differential diagnosis if CNS involvement is present in DM2 patients. Thus, is it another expression of a multisystem disorder or an unfortunate pure coincidence?
AC
CE
Myotonic dystrophy type 2(DM2) is an autosomal, dominant disorder that is clinically characterized by proximal weakness, variable myotonia and cataract. Recent data have indicated a high prevalence of autoantibodies and concomitant autoimmune diseases in DM2 patients, thus suggesting a possible autoimmune susceptibility. Involvement of Central Nervous System (CNS) has also been reported in DM2 and when present, differential diagnosis might be challenging. We present herein a case of concomitant multiple sclerosis (MS) in a patient with DM2.
CASE REPORT A 38-year old Greek woman, was first admitted to our clinic 5 years ago for further investigation of a transient episode of stuttering, which gradually subsided without treatment. MRI demonstrated multiple white matter high signal lesions on T2 and FLAIR images in periventricular and subcortical regions and an enhancing lesion at precentral gyrus.
ACCEPTED MANUSCRIPT
CR IP T
Neurological examination showed a mild weakness (MRC 4/5) of the proximal leg muscles and mild calf hypertrophy. Laboratory findings showed IgG hypogammaglobulinemia (352mg/dl). Cerebrospinal fluid (CSF) was acellular with normal protein and glucose. Oligoclonal bands were positive in CSF but not in serum (pattern 2). Further work-up for metabolic, immune-mediated and infectious disorders was normal. However, due to her phenotype and positive family history of proximal muscle weakness with suspected autosomal dominant pattern of inheritance, genetic testing was performed, confirming the diagnosis of DM2 with the detection of one allele with more than 75 repeats in intron 1 of CNBP gene (conventional and repeat primed PCR). Electromyography (EMG) study revealed mild myopathic changes of motor unit potentials but no myotonic discharges. At this time patient was discharged from hospital and was advised for close monitoring. At follow-up, one year later, the patient remained clinically stable. Follow –up brain MRI didn’t show new lesions or gadolinium enhancement (FIGURE 1).
PT
DISCUSSION
ED
M
AN US
Two years later, during puerperium, the patient experienced an episode of right-sided numbness that resolved within one week. Finally, she was readmitted to hospital due to unsteadiness, numbness in the left side of face and weakness and numbness in her right arm and leg. Clinical examination revealed dysarthria, bilateral limb ataxia more prominent on the right side and ipsilateral mild pyramidal weakness. Brain MRI disclosed a new enhancing lesion in the left side of the pons (FIGURE 2). CSF analysis was performed and once again findings were normal besides positive oligoclonal bands. Diagnostic workup was repeated, including serum anti-AQP4 and antiMOG antibodies but all findings were normal. She received a 5 days course of intravenous methylprednisolone and symptoms gradually resolved. At that time, patient was diagnosed with multiple sclerosis according to revised McDonald criteria and was advised to start disease modifying treatment.
AC
CE
Myotonic dystrophy type 2, originally referred to as proximal myotonic myopathy, is caused by a CCTG expansion in intron 1 of the zinc finger protein 9 on chromosome 3q21. RNAs carrying CCUG expansions are forming transcript aggregates in the nucleus, called foci, which interfere with proteins associated with RNA metabolism. Deregulation of protein steady state subsequently leads to mis splicing of many downstream target genes, which in part explains the multisystem involvement of disease. Regarding CNS, RNA foci are recognized widespread in various cell types. 1 CNS involvement in myotonic dystrophy 1 and 2 clinically manifests with mood disturbances, daytime sleepiness and a frontal dysexecutive syndrome, more pronounced in DM1.2Regarding brain MRI findings , studies with limited numbers of participants, reported white matter abnormalities in most of DM2 patients.3-5 Findings varied from mild, patchy, and asymmetrical subcortical and periventricular white matter lesions to large leukodystrophy- like white matter hyperintensities, while patients presented various neurological symptoms (dysmetria, unsteadiness, wrist rigidity). In overall, white matter abnormalities in DM2 were less frequent, extensive and diffuse compared with DM1 group.
ACCEPTED MANUSCRIPT
CR IP T
Our patient’s MRI demonstrated a WML- pattern that could resemble abnormalities as seen in patients with DM2. While, the most frequent MRI pattern in DM2 is that of a confluent periventricular white matter involvement, there have also been described cases with patchy, asymmetrical, periventricular and subcortical WML, with involvement in some cases of the infratentorial region (mainly with signal hyperintensities of the pons)3. However, after an extensive literature search, we could not find evidence of contrast enhancement of white matter hyperintensities in DM2. Moreover, there has not been documented a “relapsing remitting” form of CNS symptomatology, neither the persistent presence of CSF specific oligoclonal bands in DM2 patients. Clinical, laboratory and imaging characteristics of this patient direct the diagnosis toward a relapsing-remitting form of MS. To our knowledge, there are only two case reports in literature describing the coexistence of DM2 and MS. 6, 7
AN US
Autoimmune diseases and autoantibody formation has been reported in increased frequency among patients with DM2, an association whose mechanism is not clear.8 DM2 mutation could possibly affect function of immune system through RNA toxicity and the subsequent spliceopathy. A genetic linkage to autoimmune susceptibility might be another perspective. Repeat expansion within mRNA is considered the main but not the only pathogenic mechanism and may contribute to disease pathology by affecting the expression of neighboring genes. However, we recognize that the co-existence of MS and DM2 in our patient represents a pure coincidence, since no direct mechanisms of casualty can be identified. CONCLUSION
CE
PT
ED
M
Considered at first sight as muscle and heart disease, growing clinical, neuropsychological, imaging, and histopathological evidence demonstrate that myotonic dystrophy also affects the brain. However, despite the “multisystem nature” of DM2, unrelated brain disorders may occur and need to be considered. Clinicians should be aware of this, so that possible, treatable disorders will not remain undiagnosed.
AC
REFERENCES
1. Gourdon G., Meola G. Et al. Myotonic Dystrophies: State of the Art of New Therapeutic Developments for the CNS. Front Cell Neurosci. 2017; 11: 101 2. Scheider-Gold C, Bellenberg B. Cortical and Subcortical Grey and White Matter Atrophy in Myotonic Dystrophies Type 1 and 2 Is Associated with Cognitive Impairment, Depression and Daytime Sleepiness. PLoS One. 2015; 10(6): e0130352. 3. Kornblum C, Reul J et al. Cranial magnetic resonance imaging in genetically proven myotonic dystrophy type 1 and 2. J Neurol. 2004 Jun;251(6):710-4.
ACCEPTED MANUSCRIPT
4. Romeo V, Pegoraro E,Ferrati C,Squarzanti F et al,Brain involvement in myotonic dystrophies:neuroimaging and neuropsychological comparative study in DM1 and DM2. J Neurol 2010 ;257 (8):1246-55 5. Minnerop M, Weber B,Schoene-Bake JC,Roeske S et al .The beain in myotonic dystrophy 1 and 2 :evidence for a predominant white matter disease. Brain 2011 ;134(Pt 12):3530-46.
CR IP T
6. Ehler E, Novotna A. Myotonic dystrophy type 2 and multiple sclerosis: Case report. Clin Neurol Neurosurg. 2012 Dec;114(10):1358-60 7. Terrence CF, Myotonic dystrophy and multiple sclerosis.J Neurol 1976 ;213(4):305-8.
AN US
8. Tieleman AA, den Broeder AA et al. Strong association between myotonic dystrophy type 2 and autoimmune diseases. J Neurol Neurosurg Psychiatry. 2009 Nov;80(11):1293-5
M
Disclosures:
ED
All authors have nothing to disclose related to the submitted manuscript.
AC
CE
PT
Patient consent was obtained prior to submission of the manuscript.
ACCEPTED MANUSCRIPT
CE
PT
ED
M
AN US
CR IP T
FIGURE 1: FLAIR sequences 1 year prior to diagnosis, showing larger subcortical lesions and a normal pontine appearance.
AC
FIGURE 2: FLAIR sequences revealing subcortical, periventricular and pontine white matter lesions and post contrast T1-weighted sequence presenting enhancement of the pontine lesion (arrow).
AC
CE
PT
ED
M
AN US
CR IP T
ACCEPTED MANUSCRIPT
White matter hyperintensities in myotonic dystrophy type 2: not always another expression of the disease. M Karatzikou , C Bakirtzis , J Nikolaidis , D Parisis , N Grigoriadis PII: DOI: Reference:
S2211-0348(18)30197-4 10.1016/j.msard.2018.06.020 MSARD 875
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
20 February 2018 24 June 2018 28 June 2018
Please cite this article as: M Karatzikou , C Bakirtzis , J Nikolaidis , D Parisis , N Grigoriadis , White matter hyperintensities in myotonic dystrophy type 2: not always another expression of the disease., Multiple Sclerosis and Related Disorders (2018), doi: 10.1016/j.msard.2018.06.020
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 proof before it is published in its final 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.
ACCEPTED MANUSCRIPT Highlights Α rare case of concomitant multiple sclerosis in patient with myotonic dystrophy 2. White matter abnormalities a common feature of myotonic dystrophy 2. Differential diagnosis of CNS involvement in DM2 is challenging.
AC
CE
PT
ED
M
AN US
CR IP T
ACCEPTED MANUSCRIPT White matter hyperintensities in myotonic dystrophy type 2: not always another expression of the disease. M Karatzikou, C Bakirtzis, J Nikolaidis, D Parisis, N Grigoriadis Multiple Sclerosis Center, 2nd Department of Neurology, Aristotle University of Thessaloniki, Greece Corresponding author:
CR IP T
M Karatzikou
AN US
Multiple Sclerosis Center 2nd Department of Neurology AHEPA University Hospital Aristotle University of Thessaloniki 1 Stilp Kyriakidi str GR 54636 Thessaloniki, Central Macedonia, Greece ABSTRACT
INTRODUCTION
PT
ED
M
Myotonic dystrophy type 2(DM2), inherited in an autosomal, dominant manner, is clinically characterized by muscle weakness, variable myotonia, cataract and multiorgan involvement, including the Central Nervous System. Recent data from literature indicate a possible autoimmune susceptibility of patients with DM2, while white matter abnormalities are a common feature of the disease. We report herein the case of a 38-year old woman, with the rare co-existence of DM2 and MS and argue about the challenging differential diagnosis if CNS involvement is present in DM2 patients. Thus, is it another expression of a multisystem disorder or an unfortunate pure coincidence?
AC
CE
Myotonic dystrophy type 2(DM2) is an autosomal, dominant disorder that is clinically characterized by proximal weakness, variable myotonia and cataract. Recent data have indicated a high prevalence of autoantibodies and concomitant autoimmune diseases in DM2 patients, thus suggesting a possible autoimmune susceptibility. Involvement of Central Nervous System (CNS) has also been reported in DM2 and when present, differential diagnosis might be challenging. We present herein a case of concomitant multiple sclerosis (MS) in a patient with DM2.
CASE REPORT A 38-year old Greek woman, was first admitted to our clinic 5 years ago for further investigation of a transient episode of stuttering, which gradually subsided without treatment. MRI demonstrated multiple white matter high signal lesions on T2 and FLAIR images in periventricular and subcortical regions and an enhancing lesion at precentral gyrus.
ACCEPTED MANUSCRIPT
CR IP T
Neurological examination showed a mild weakness (MRC 4/5) of the proximal leg muscles and mild calf hypertrophy. Laboratory findings showed IgG hypogammaglobulinemia (352mg/dl). Cerebrospinal fluid (CSF) was acellular with normal protein and glucose. Oligoclonal bands were positive in CSF but not in serum (pattern 2). Further work-up for metabolic, immune-mediated and infectious disorders was normal. However, due to her phenotype and positive family history of proximal muscle weakness with suspected autosomal dominant pattern of inheritance, genetic testing was performed, confirming the diagnosis of DM2 with the detection of one allele with more than 75 repeats in intron 1 of CNBP gene (conventional and repeat primed PCR). Electromyography (EMG) study revealed mild myopathic changes of motor unit potentials but no myotonic discharges. At this time patient was discharged from hospital and was advised for close monitoring. At follow-up, one year later, the patient remained clinically stable. Follow –up brain MRI didn’t show new lesions or gadolinium enhancement (FIGURE 1).
PT
DISCUSSION
ED
M
AN US
Two years later, during puerperium, the patient experienced an episode of right-sided numbness that resolved within one week. Finally, she was readmitted to hospital due to unsteadiness, numbness in the left side of face and weakness and numbness in her right arm and leg. Clinical examination revealed dysarthria, bilateral limb ataxia more prominent on the right side and ipsilateral mild pyramidal weakness. Brain MRI disclosed a new enhancing lesion in the left side of the pons (FIGURE 2). CSF analysis was performed and once again findings were normal besides positive oligoclonal bands. Diagnostic workup was repeated, including serum anti-AQP4 and antiMOG antibodies but all findings were normal. She received a 5 days course of intravenous methylprednisolone and symptoms gradually resolved. At that time, patient was diagnosed with multiple sclerosis according to revised McDonald criteria and was advised to start disease modifying treatment.
AC
CE
Myotonic dystrophy type 2, originally referred to as proximal myotonic myopathy, is caused by a CCTG expansion in intron 1 of the zinc finger protein 9 on chromosome 3q21. RNAs carrying CCUG expansions are forming transcript aggregates in the nucleus, called foci, which interfere with proteins associated with RNA metabolism. Deregulation of protein steady state subsequently leads to mis splicing of many downstream target genes, which in part explains the multisystem involvement of disease. Regarding CNS, RNA foci are recognized widespread in various cell types. 1 CNS involvement in myotonic dystrophy 1 and 2 clinically manifests with mood disturbances, daytime sleepiness and a frontal dysexecutive syndrome, more pronounced in DM1.2Regarding brain MRI findings , studies with limited numbers of participants, reported white matter abnormalities in most of DM2 patients.3-5 Findings varied from mild, patchy, and asymmetrical subcortical and periventricular white matter lesions to large leukodystrophy- like white matter hyperintensities, while patients presented various neurological symptoms (dysmetria, unsteadiness, wrist rigidity). In overall, white matter abnormalities in DM2 were less frequent, extensive and diffuse compared with DM1 group.
ACCEPTED MANUSCRIPT
CR IP T
Our patient’s MRI demonstrated a WML- pattern that could resemble abnormalities as seen in patients with DM2. While, the most frequent MRI pattern in DM2 is that of a confluent periventricular white matter involvement, there have also been described cases with patchy, asymmetrical, periventricular and subcortical WML, with involvement in some cases of the infratentorial region (mainly with signal hyperintensities of the pons)3. However, after an extensive literature search, we could not find evidence of contrast enhancement of white matter hyperintensities in DM2. Moreover, there has not been documented a “relapsing remitting” form of CNS symptomatology, neither the persistent presence of CSF specific oligoclonal bands in DM2 patients. Clinical, laboratory and imaging characteristics of this patient direct the diagnosis toward a relapsing-remitting form of MS. To our knowledge, there are only two case reports in literature describing the coexistence of DM2 and MS. 6, 7
AN US
Autoimmune diseases and autoantibody formation has been reported in increased frequency among patients with DM2, an association whose mechanism is not clear.8 DM2 mutation could possibly affect function of immune system through RNA toxicity and the subsequent spliceopathy. A genetic linkage to autoimmune susceptibility might be another perspective. Repeat expansion within mRNA is considered the main but not the only pathogenic mechanism and may contribute to disease pathology by affecting the expression of neighboring genes. However, we recognize that the co-existence of MS and DM2 in our patient represents a pure coincidence, since no direct mechanisms of casualty can be identified. CONCLUSION
CE
PT
ED
M
Considered at first sight as muscle and heart disease, growing clinical, neuropsychological, imaging, and histopathological evidence demonstrate that myotonic dystrophy also affects the brain. However, despite the “multisystem nature” of DM2, unrelated brain disorders may occur and need to be considered. Clinicians should be aware of this, so that possible, treatable disorders will not remain undiagnosed.
AC
REFERENCES
1. Gourdon G., Meola G. Et al. Myotonic Dystrophies: State of the Art of New Therapeutic Developments for the CNS. Front Cell Neurosci. 2017; 11: 101 2. Scheider-Gold C, Bellenberg B. Cortical and Subcortical Grey and White Matter Atrophy in Myotonic Dystrophies Type 1 and 2 Is Associated with Cognitive Impairment, Depression and Daytime Sleepiness. PLoS One. 2015; 10(6): e0130352. 3. Kornblum C, Reul J et al. Cranial magnetic resonance imaging in genetically proven myotonic dystrophy type 1 and 2. J Neurol. 2004 Jun;251(6):710-4.
ACCEPTED MANUSCRIPT
4. Romeo V, Pegoraro E,Ferrati C,Squarzanti F et al,Brain involvement in myotonic dystrophies:neuroimaging and neuropsychological comparative study in DM1 and DM2. J Neurol 2010 ;257 (8):1246-55 5. Minnerop M, Weber B,Schoene-Bake JC,Roeske S et al .The beain in myotonic dystrophy 1 and 2 :evidence for a predominant white matter disease. Brain 2011 ;134(Pt 12):3530-46.
CR IP T
6. Ehler E, Novotna A. Myotonic dystrophy type 2 and multiple sclerosis: Case report. Clin Neurol Neurosurg. 2012 Dec;114(10):1358-60 7. Terrence CF, Myotonic dystrophy and multiple sclerosis.J Neurol 1976 ;213(4):305-8.
AN US
8. Tieleman AA, den Broeder AA et al. Strong association between myotonic dystrophy type 2 and autoimmune diseases. J Neurol Neurosurg Psychiatry. 2009 Nov;80(11):1293-5
M
Disclosures:
ED
All authors have nothing to disclose related to the submitted manuscript.
AC
CE
PT
Patient consent was obtained prior to submission of the manuscript.
ACCEPTED MANUSCRIPT
CE
PT
ED
M
AN US
CR IP T
FIGURE 1: FLAIR sequences 1 year prior to diagnosis, showing larger subcortical lesions and a normal pontine appearance.
AC
FIGURE 2: FLAIR sequences revealing subcortical, periventricular and pontine white matter lesions and post contrast T1-weighted sequence presenting enhancement of the pontine lesion (arrow).
AC
CE
PT
ED
M
AN US
CR IP T
ACCEPTED MANUSCRIPT