Involvement of the central nervous system in myotonic dystrophy

doi:10.1016/0022-510X(94)90071-X

Journal of the Neurological Sciences

Volume 127, Issue 2, 20 December 1994, Pages 179-185

https://doi.org/10.1016/0022-510X(94)90071-X Get rights and content

Abstract

To investigate the etiological factors responsible for intellectual impairment and mood changes in patients with myotonic dystrophy (DM), we evaluated 14 patients with DM by means of neuropsychological evaluation and magnetic resonance images (MRI). There were significant differences between patients and controls in regard to the Barthel index, Zung's depression scale, attention, verbal fluency and digit span. All patients had ventricular enlargement and white matter abnormalities on MRI. However, the severity was variable and there was no difference in neuropsychological testing between patients with mild ventricular dilatation and those with severe dilatation. On the other hand, significant differences were present between patients with mild white matter lesions and those with severe white matter abnormalities in regard to verbal fluency and attention. Neuropathologic examination of an autopsied brain showed an increase in the interfascicular space of the white matter which produced pallor on myelin staining. The present findings suggested that the white matter abnormalities were the cause of cognitive impairment among patients with DM.

References (26)

R. Calderon
Myotonic dystrophy
a neglected cause of mental retardation
J. Pediatr.
(1966)
M.F. Folstein et al.
Mini-Mental State Examination: a practical method for grading the mental state of patients for clinician
J. Psychiat. Res.
(1975)
I.A. Awad et al.
Incidental subcortical lesions identified on magnetic resonance imaging in the elderly. I. Correlation with age and cerebrovascular risk factors
Stroke
(1986)
I.A. Awad et al.
Incidental subcortical lesions identified on magnetic resonance imaging in the elderly. II. Postmortem pathological correlations
Stroke
(1986)
T. Bird et al.
Cognitive and personality function in myotonic muscular dystrophy
J. Neurol. Neurosurg. Psychiat.
(1983)
W.G. Bradeley et al.
Patchy periventricular white matter lesions in the elderly: a common observation during NMR imaging
Noninvas. Med. Imaging
(1984)
L. Chang et al.
Cerebral abnormalities in myotonic dystrophy
Cerebral blood flow, magnetic resonance imaging, and neuropsychological tests
Arch. Neurol.
(1993)
J.L. Cummings et al.
Acquired and inherited disorders
K.H. Fischbeck
The mechanism of myotonic dystrophy
Ann Neurol.
(1994)
N. Hirono et al.
Spinocerebellar degeneration (SCD): cognitive disturbances
Acta Neurol. Scand.
(1985)

S.J. Huber et al.

Magnetic resonance imaging and clinical correlates of intellectual impairment in myotonic dystrophy

Arch. Neurol.

(1989)

W.R. Kinkel et al.

Subcortical arteriosclerotic encephalopathy (Binswanger's disease)

Computed tomographic, nuclear magnetic resonance, and clinical correlations

Arch. Neurol.

(1985)

J.R. Kirlwood

Atrophy, aging, and dementia

Cited by (72)

Lesion distribution and substrate of white matter damage in myotonic dystrophy type 1: Comparison with multiple sclerosis
2021, NeuroImage: Clinical
Citation Excerpt :
Finally, we isolated temporal lobe lesions in patients with DM1, with the aim to test whether their qMT parameters differ from those computed in the lesions detected in the rest of the brain. Based on the existing literature, we expected DM1 patients to have more white matter lesions than healthy controls, with evidence of demyelination (Abe et al., 1994; Mizukami et al., 1999). However, we hypothesised that the extent of demyelination would be lower in DM1 than MS. Finally, while the anterior temporal pole might be involved in progressive forms of MS, we did not expect anterior temporal lesions to be a prominent feature of patients with relapsing remitting MS, included in this study.
Myotonic Dystrophy type 1 (DM1) is an autosomal dominant condition caused by expansion of the CTG triplet repeats within the myotonic dystrophy protein of the kinase (DMPK) gene. The central nervous system is involved in the disease, with multiple symptoms including cognitive impairment. A typical feature of DM1 is the presence of widespread white matter (WM) lesions, whose total volume is associated with CTG triplet expansion. The aim of this study was to characterize the distribution and pathological substrate of these lesions as well as the normal appearing WM (NAWM) using quantitative magnetization transfer (qMT) MRI, and comparing data from DM1 patients with those from patients with multiple sclerosis (MS). Twenty-eight patients with DM1, 29 patients with relapsing-remitting MS, and 15 healthy controls had an MRI scan, including conventional and qMT imaging. The average pool size ratio (F), a proxy of myelination, was computed within lesions and NAWM for every participant. The lesion masks were warped into MNI space and lesion probability maps were obtained for each patient group. The lesion distribution, total lesion load and the tissue-specific mean F were compared between groups. The supratentorial distribution of lesions was similar in the 2 patient groups, although mean lesion volume was higher in MS than DM1. DM1 presented higher prevalence of anterior temporal lobe lesions, but none in the cerebellum and brainstem. Significantly reduced F values were found within DM1 lesions, suggesting a loss of myelin density. While F was reduced in the NAWM of MS patients, it did not differ between DM1 and controls. Our results provide further evidence for a need to compare histology and imaging using new MRI techniques in DM1 patients, in order to further our understanding of the underlying disease process contributing to WM disease.
White Matter Lesions Detected by Magnetic Resonance Imaging in Neonates and Children With Congenital Myotonic Dystrophy
2019, Pediatric Neurology
Congenital myotonic dystrophy (CDM1) is an autosomal dominant genetic disorder caused by abnormal cytosine-thymine-guanine trinucleotide repeat expansion that results in weakness and cognitive deficits. Studies detailing brain magnetic resonance imaging (MRI) findings in neonates and children with this condition are limited.
We evaluated the brain MRI findings in children, including neonates with CDM1, to assess the nature of central nervous system involvement and progression of MRI lesions over time.
The Cincinnati Children's Hospital neuromuscular disease database was used to identify 16 patients with CDM1 with genetically proven CDM1 who had undergone brain MRI. Hospital charts were reviewed to collect clinical information.
Ninety-four percent of patients had an abnormal MRI showing injury to the white matter. Nine patients underwent imaging before eight days of life, and eight of these patients showed signs of injury to the white matter. Three neonates had follow-up MRI scans, and all showed progression of injury. Seven patients had the first MRI between age 29 days and 22 years, and all had abnormalities involving the white matter. Two patients had additional congenital brain malformations, and one patient also harbored a mutation in CDKL5 with resultant epilepsy.
White matter abnormalities are found in patients with CDM1, even in the neonatal period. Many patients present with hypoxia and receive a diagnosis of hypoxic-ischemic encephalopathy and may even undergo therapeutic hypothermia. If MRI findings of white matter injury do not correlate with hypotonia and weakness, further evaluation for CDM1 should be considered.
Affective symptoms and apathy in myotonic dystrophy type 1 a systematic review and meta-analysis
2019, Journal of Affective Disorders
To gain insight into the prevalence of apathy, depression and anxiety symptoms in myotonic dystrophy type 1 (DM1) patients on the basis of a systematic review with a meta-analysis.
One author systematically searched and selected studies from Embase, Medline, PsychInfo and Web of Science (index periods up to August 2018). Data extraction and bias assessment were performed independently by two authors. We calculated (1) a weighted pooled prevalence and (2) weighted pooled standardized mean difference (Hedges’ g) from studies comparing DM1 patients to healthy and/or neuromuscular disease controls separately for symptoms of depression, anxiety and apathy.
The pooled prevalences of depression (26 studies, n = 1267 DM1 patients), anxiety (19 studies, n = 896) and apathy (5 studies, n = 428), were 18% (95%CI: 12–25), 16 (95%CI: 13–18) and 55% (95%CI: 50–60), respectively. Effect sizes (Hedges’ g) for depression, anxiety and apathy in DM1 patients compared to healthy controls were 1.04 (95%-CI: 0.71 to 1.37), 0.87 (95%-CI: 0.51 to 1.24) and 1.13 (95%-CI:0.54–1.71). Effect sizes for symptoms of depression, anxiety and apathy were 0.29 (95% CI: -0.12 to 0.70), 0.45 (95%-CI: –0.31 to 1.22) and 1.12 (95%-CI: 0.32–1.93) for DM1 patients versus neuromuscular disease controls. In most analyses, statistical heterogeneity was high.
Estimated pooled prevalences of clinically significant levels of symptoms of depression, anxiety and apathy in DM1 are 19, 17 and 55% respectively. Symptoms of depression and anxiety in DM1 may reflect reactive adjustment to progressive impairment and restricted participation similar to other chronic neuromuscular disease. The literature on the prevalence and severity of apathy, although a clinically relevant and characteristic symptom of DM1, is relatively scarce.
The cognitive profile of myotonic dystrophy type 1: A systematic review and meta-analysis
2017, Cortex
Citation Excerpt :
After deduplication, a total of 1864 articles underwent title and abstract screening (Fig. 1). We performed full-text evaluation of 127 studies, 39 of which were included, and one additional study was found via cross-referencing (Abe et al., 1994; Antonini et al., 2006; Caliandro et al., 2013; Censori, Danni, Del Pesce, & Provinciali, 1990; Chang et al., 1993; Colombo, Perini, Miotti, Armani, & Angelini, 1992; Gallais et al., 2015; Gaul et al., 2006; Hashimoto et al., 1995; Huber et al., 1989; Kleberg, Lindberg, & Winblad, 2014; Kobayakawa et al., 2012; Kobayakawa, Tsuruya, Takeda, Suzuki, & Kawamura, 2010; Malloy, Mishra, & Adler, 1990; Meola et al., 2003; Miaux et al., 1997; Minnerop et al., 2011; Palmer, Boone, Chang, Lee, & Black, 1994; Peric et al., 2014; Perini et al., 1989, 1999; Phillips, Steer, Soldan, Wiles, & Harper, 1999; Rubinsztein, Rubinsztein, McKenna, Goodburn, & Holland, 1997; Serra et al., 2014, 2015; Sinforiani, Mauri, Uggetti, & Sandrini, 1997; Sinforiani et al., 1991; Sistiaga et al., 2010; Stuss, Kates, & Poirier, 1987; Tanaka, Arai, Harada, Hozumi, & Hirata, 2012; Turnpenny, Clark, & Kelly, 1994; Van Spaendonck et al., 1995; Walker, Rosser, Mastaglia, & Walton, 1984; Weber et al., 2010; Winblad, Hellstrom, Lindberg, & Hansen, 2006; Woodward 3rd, Heaton, Simon, & Ringel, 1982; Wozniak et al., 2013; Wozniak, Mueller, Lim, Hemmy, & Day, 2014; Wozniak, Mueller, Ward, Lim, & Day, 2011; Zalonis et al., 2010). The main reasons for exclusion of 88 studies were absence of available full-text (n = 19), absence of a matched control group (n = 44), double reporting (n = 7) and the absence of reporting sufficient details for including that study in our meta-analysis (n = 14).
To examine the cognitive profile of patients with myotonic dystrophy type 1 (DM1) on the basis of a systematic review and meta-analysis of the literature.
Embase, Medline and PsycInfo were searched for studies reporting ≥1 neuropsychological test in both DM1 patients and healthy controls. Search, data extraction and risk of bias analysis were independently performed by two authors to minimize error. Neuropsychological tests were categorized into 12 cognitive domains and effect sizes (Hedges' g) were calculated for each domain and for tests administered in ≥5 studies.
DM1 participants demonstrated a significantly worse performance compared to controls in all cognitive domains. Effect sizes ranged from −.33 (small) for verbal memory to −1.01 (large) for visuospatial perception. Except for the domains global cognition, intelligence and social cognition, wide confidence intervals (CIs) were associated with moderate to marked statistical heterogeneity that necessitates careful interpretation of results. Out of the individual tests, the Rey–Osterrieth complex figure-copy (both non-verbal memory and visuoconstruction) showed consistent impairment with acceptable heterogeneity.
In DM1 patients, cognitive deficits may include a variable combination of global cognitive impairment with involvement across different domains, including social cognition, memory and visuospatial functioning. Although DM1 is a heterogeneous disorder, our study shows that meta-analysis is feasible, contributes to the understanding of brain involvement and may direct bedside testing. The protocol for this study has been registered in PROSPERO (International prospective register of systematic reviews) under ID: 42016037415.
A genetic systemic disease: Clinical description of type 1 myotonic dystrophy in adults
2012, Revue de Medecine Interne
La dystrophie myotonique (myopathie de Steinert) est une maladie génétique de transmission autosomique dominante, caractérisée par une expansion anormale de triplets nucléotidiques (CTG) dans un exon d’une région non codante du gène DMPK. Les transcrits mutants contiennent une expansion de répétitions CUG qui entraîne des troubles de la biogénèse de multiples ARNm responsables d’atteintes d’organe multiples. Le tableau est dominé par une myopathie progressive et une myotonie affectant non seulement la musculature squelettique, mais aussi les muscles lisses et ainsi responsables de désordres digestifs, urinaires et utérins. Si le pronostic fonctionnel est lié au handicap moteur, le pronostic vital est dominé, d’une part, par les troubles rythmiques et de la conduction cardiaque, liés à une fibrose sous-endocardique progressive et, d’autre part, par des manifestations respiratoires complexes associant plus ou moins insuffisance respiratoire restrictive, troubles centraux de la commande respiratoire et syndrome d’apnées obstructives du sommeil. Cataracte, intolérance au glucose, troubles endocriniens, hypogammaglobulinémie liée à une augmentation du catabolisme des immunoglobulines G, hypersomnolence et, parfois, troubles cognitifs viennent compléter le tableau clinique. L’espérance de vie des patients est diminuée, les causes de décès étant actuellement dominées par les complications respiratoires, mais aussi cardiaques ; une fréquence anormale de certaines tumeurs semble exister. La dystrophie myotonique ne concerne donc pas seulement le neurologue, mais nécessite une prise en charge pluridisciplinaire impliquant au minimum rééducateur, cardiologue, pneumologue, où l’interniste peut trouver sa place tant dans le dépistage que dans la recherche et la prise en charge des complications.
Type 1 myotonic dystrophy is an autosomal dominant inherited disorder related to the expansion of a trinucleotide (CTG) repeat in the exon 15 in the 3′-untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. Mutant transcripts containing an expanded CUG repeat are retained in nuclear foci and cause numerous dysfunctions by interfering with biogenesis of other mRNAs. Prominent clinical features are progressive muscular weakness and myotonia, which affect skeletal muscles but also white muscles leading to digestive, urinary and obstetrical disorders. Functional prognosis correlates with motor handicap and vital prognosis is linked to cardiac rhythm disturbances and conduction defects due to progressive subendocardial fibrosis, and to complex respiratory dysfunctions, which associate restrictive lung disease, involvement of the central inspiratory pathway, and sleep apnea. Other clinical features are lens opacity, glucose intolerance, metabolic syndrome, several endocrine disorders (gonadal deficiency, hyperparathydoidism), or immunoglobulin deficiency due to immunoglobulin G hypercatabolism. Life expectancy is reduced in myotonic dystrophy, and death is mainly caused by respiratory complications, but also by cardiac arrhythmias. Moreover, an abnormal incidence of tumors has been reported. Therefore, myotonic dystrophy does not only concern neurologists but a multidisciplinary approach is necessary, including at least pneumologist, cardiologist, and physiotherapist. General internists should also be implicated, not only in the initial diagnosis step, but also in the diagnosis of complications and their treatments.
Mutant human embryonic stem cells reveal neurite and synapse formation defects in type 1 myotonic dystrophy
2011, Cell Stem Cell
Citation Excerpt :
This functional defect is associated with an abnormally low expression of two genes that belong to the SLITRK family. Extensive data exist showing the involvement of the CNS in DM1: psychological dysfunction, mental retardation, excessive daytime sleepiness, and neuropathological abnormalities (Abe et al., 1994; Damian et al., 2001; de León and Cisneros, 2008; Delaporte, 1998; Meola et al., 2003; Modoni et al., 2004; Park and Radtke, 1995; Sistiaga et al., 2010; Turnpenny et al., 1994). Potential defects in neuritogenesis and synaptogenesis have also been suggested.
Myotonic dystrophy type 1 (DM1) is a multisystem disorder affecting a variety of organs, including the central nervous system. By using neuronal progeny derived from human embryonic stem cells carrying the causal DM1 mutation, we have identified an early developmental defect in genes involved in neurite formation and the establishment of neuromuscular connections. Differential gene expression profiling and quantitative RT-PCR revealed decreased expression of two members of the SLITRK family in DM1 neural cells and in DM1 brain biopsies. In addition, DM1 motoneuron/muscle cell cocultures showed alterations that are consistent with the known role of SLITRK genes in neurite outgrowth, neuritogenesis, and synaptogenesis. Rescue and knockdown experiments suggested that the functional defects can be directly attributed to SLITRK misexpression. These neuropathological mechanisms may be clinically significant for the functional changes in neuromuscular connections associated with DM1.

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Research articleInvolvement of the central nervous system in myotonic dystrophy

Abstract

J. Pediatr.

J. Psychiat. Res.

Incidental subcortical lesions identified on magnetic resonance imaging in the elderly. I. Correlation with age and cerebrovascular risk factors

Stroke

Incidental subcortical lesions identified on magnetic resonance imaging in the elderly. II. Postmortem pathological correlations

Stroke

Cognitive and personality function in myotonic muscular dystrophy

J. Neurol. Neurosurg. Psychiat.

Patchy periventricular white matter lesions in the elderly: a common observation during NMR imaging

Noninvas. Med. Imaging

Cerebral abnormalities in myotonic dystrophy

Cerebral blood flow, magnetic resonance imaging, and neuropsychological tests

Arch. Neurol.

Acquired and inherited disorders

The mechanism of myotonic dystrophy

Ann Neurol.

Spinocerebellar degeneration (SCD): cognitive disturbances

Acta Neurol. Scand.

Magnetic resonance imaging and clinical correlates of intellectual impairment in myotonic dystrophy

Arch. Neurol.

Subcortical arteriosclerotic encephalopathy (Binswanger's disease)

Computed tomographic, nuclear magnetic resonance, and clinical correlations

Arch. Neurol.

Atrophy, aging, and dementia

Research article
Involvement of the central nervous system in myotonic dystrophy