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Familial aggregation of white matter lesions in myotonic dystrophy type 1
Neuromuscular Disorders 18 (2008) 299–305 www.elsevier.com/locate/nmd
Familial aggregation of white matter lesions in myotonic dystrophy type 1 Alfonso Di Costanzo d,*, Lucio Santoro a, Mario de Cristofaro b, Fiore Manganelli a, Francesco Di Salle c, Gioacchino Tedeschi b b
a Department of Neurological Sciences, University ‘‘Federico II”, Via S. Pansini 5, 80131 Naples, Italy Department of Neurological Sciences, Second University of Naples, Piazza L. Miraglia 2, 80138 Naples, Italy c Department of Neurosciences, University of Pisa, via Roma 67, 56126 Pisa, Italy d Department of Health Sciences, University of Molise, Via Giovanni Paolo II, 86100 Campobasso, Italy
Received 28 October 2007; received in revised form 12 January 2008; accepted 30 January 2008
Abstract This study aimed to determine whether white matter lesions, previously described as a frequent feature in myotonic dystrophy type 1 (DM1), aggregate within DM1 families or are sporadic findings, and to explore the relationship between these lesions and clinical or genetic features. Brain MRI of 60 DM1 patients belonging to 22 families were evaluated and white matter lesions were rated according to a semiquantitative method. Presence and extent of lobar, temporal or periventricular lesions showed a significant association with the family history of lesions and the disease duration, and no association with the CTG repeat size. Furthermore, parent-offspring and sibling pairs showed a significant positive concordance for lesion severity. White matter lesions demonstrate familial aggregation in DM1 and no relationship with CTG repeat length. These findings suggest that other genetic causes and/or unknown environmental factors influence the occurrence and severity of lesions in patients carrying the DM1 genetic defect. Ó 2008 Elsevier B.V. All rights reserved. Keywords: Myotonic dystrophy; Magnetic resonance imaging; Brain; Cross-sectional studies
1. Introduction Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder with multisystemic clinical features involving the skeletal muscle, the heart, the eye, the endocrine system, the central and peripheral nervous systems, the smooth muscle, the bone and the skin [1,2]. The DM1 phenotype is highly variable ranging from the severe, often fatal, congenital form to the asymptomatic carrier of genetic defect [2]. It is caused by the expansion of a CTG repeat in the 30 untranslated region of a gene encoding for a protein kinase (DMPK) at DM1 locus on chromosome 19q13.3 [3–5].
*
Corresponding author. Tel.: +39 0874 404749; fax: +39 0874 404710. E-mail address: [email protected] (A. Di Costanzo).
0960-8966/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2008.01.008
Several pathogenic mechanisms have been proposed to explain the multisystemic nature and the variable expressivity of the symptoms in DM1 [2,6–8]. Substantial evidence has accumulated indicating that DMPK mRNA containing expanded CUG repeats is retained in nuclear inclusions and produces splicing abnormalities by perturbing the function of RNA-binding proteins. Indeed, disrupted mRNA alternative splicing in DM1 has been reported for several genes, and for the muscle-specific chloride channel (ClC-1) and insulin receptor, expression of the embryonic splicing pattern results in myotonia and insulin resistance, respectively, two characteristic features of the disease [7–10]. However, the causes of cerebral involvement are less well defined [8,11]. The variation between and within tissues (somatic mosaicism) and the expansion-biased (somatic instability) of CTG repeat size represent another mechanism implicated
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in the variable expression of disease [12,13]. However, the familial occurrence of abnormalities, such as cardiac conduction disturbances, mitral valve prolapse, pilomatrixomas, polyneuropathy, normal pressure hydrocephalus, dilatation of the urinary tract, intestinal pseudo-obstruction, subcortical-type dementia and left ventricular hypertrabeculation [14–17], and the familial similarities in muscular and cardiac involvement [18] suggest that other genetic mechanism or unknown environmental factors, or both might be implicated in DM1. Brain MRI of patients with DM1 can show findings ranging from no or minimal abnormalities to brain atrophy with large and severe white matter lesions [19–29]. In larger study populations, these lesions are found with a frequency ranging from 65% to 81% [21,22,25,26] and are significantly more common and severe in DM1 than in healthy controls [21,25,26]. This study was performed to determine whether white matter lesions aggregate within families or are sporadic findings in DM1, and to explore the relationship between these lesions and clinical or genetic features. 2. Patients and methods 2.1. Patients Sixty patients (30 men and 30 women) with noncongenital DM1 [2] belonging to 22 families with at least two affected first-degree relatives (Table 1) were included in the study. The diagnosis was based on clinical picture, family history and electromyography and supported by genetic analysis of leukocytes. The mean age ± SD was 38.3 ± 16.4 years (range, 10–76 years) and the duration of clinical symptoms varied from 0 (patients without complaints detected in family examinations) to 30 years. Twenty-nine patients acquired the disease by paternal and 25 by maternal transmission. The parents who could not be examined were considered affected on the basis of history or photographs; in 6 patients the affected parent could not be identified. The severity of muscular involvement was assessed by muscular impairment rating scale (MIRS) [30] and ranged from 1 (patients without clinical muscular impairment, diagnosed by genetic analysis) to 5 (patient with severe weakness, confined to wheelchair for short or long distances). No patient had history of cerebrovascular disease, multiple sclerosis, meningoencephalitis, hypoxic insult, head trauma causing unconsciousness, progressive dementia or other neurological illness that might explain the MRI findings. Either the patients or their parents gave the informed consent. 2.2. MRI evaluation Brain MRI included sagittal T1-weighted images with repetition times (TR) of 500 ms and echo times (TE) of 20 ms, and axial T2- and proton-density (PD)-weighted spin-echo images with TR of 2000 ms, TE1 of 40 ms and
TE2 of 100 ms. Slice thickness was 5 mm with 2-mm gap; field of view/matrix was 24 cm/192 256 for sagittal and 20 cm/160 192 for axial series. White matter lesions were identified as bright areas on both PD- and T2-weighted images. They were recorded as lobar (outside the periventricular and temporal regions), temporal or periventricular (abutting the ventricular lining) and scored according to a semiquantitative method [31]. The score was the sum of products between the number of lesions and the category indicating their size (1 < 0.5 cm; 2 = 0.5–1.0 cm; 3 = 1.0–1.5 cm; 4 = 1.5– 2.0 cm; 5 = 2.0–2.5 cm; 6 = 2.5–3.0 cm; 7 > 3.0 cm). The periventricular lesions were scored by measuring and summing their greatest thickness on PD-weighted images at the frontal and occipital horns (‘‘caps”) and at the body of the lateral ventricle (‘‘rims” or ‘‘bands”). Triangularshaped hyperintensities up to 1 cm in width and located anterolaterally to the frontal horns of the lateral ventricles were considered a normal finding and not scored. Two blinded experienced examiners independently evaluated the images and their results were compared. When they disagreed, a consensus reading was held to reach an unequivocal agreement. Inter- and intrarater reliabilities for total lesion scores, measured by intra-class correlation coefficient, were 0.83 and 0.87, respectively. 2.3. Genetic analysis The standard procedure consisted of DNA separation from leukocytes, digestion with NcoI and BamHI restriction enzymes, separation of DNA fragments by gel electrophoresis, transfer on to nylon membranes by Southern blotting, hybridization with DNA probe MDY1 and additional polymerase chain reaction using described primers [3]. The CTG repeat size was estimated at the point of the most heavily staining band or at the midpoint of the smear for very diffuse band. 2.4. Statistical analysis Data were analyzed using the SPSS (v 12.01) software package (SPSS Inc., Chicago, Illinois). The strength of association was measured by the chi-square test for categorical variables, such as sex, inheritance and family history (positive if at least one affected first-degree relative showed white matter lesions), and by the Spearman rank correlation coefficient for quantitative variables, such as age at scanning, age at onset, disease duration and CTG repeats. The group differences were evaluated by the Mann–Whitney U test. Stepwise multiple regression analysis (F to enter >3.84) was performed including lobar, temporal or periventricular lesion, or MIRS scores as dependent variables and sex, inheritance, family history (positive or negative for white matter lesions), age at scanning, age at onset, disease duration and CTG repeats as independent variables. The familial concordance (parent-offspring or sibling pairs) was carried out by
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Table 1 Clinical and MRI features of patients with myotonic dystrophy type 1 Family no.
Patient no./sex
Relationship
Age (years)
Duration (years)
Inheritancea
MIRSb
CTG repeatsc
1 1 1 2 2 3 3 4 4 5 5 6 6 6 7 7 8 8 8 9 9 9 10 10 11 11 12 12 12 12 13 13 13 14 14 14 15 15 16 16 16 17 17 17 18 18 19 19 20 20 20 21 21 21 22 22 22 22 22 22
1/m 2/m 3/f 4/m 5/m 6/m 7/m 8/m 9/m 10/f 11/f 12/m 13/f 14/f 15/f 16/f 17/m 18/f 19/f 20/m 21/f 22/f 23/m 24/f 25/f 26/m 27/m 28/f 29/f 30/f 31/m 32/m 33/f 34/f 35/f 36/f 37/m 38/f 39/f 40/m 41/m 42/f 43/m 44/m 45/f 46/f 47/f 48/m 49/m 50/f 51/m 52/m 53/m 54/f 55/f 56/m 57/f 58/m 59/m 60/f
Proband Parent Sibling Proband Parent Proband Parent Proband Offspring Proband Offspring Proband Sibling Parent Proband Sibling Proband Sibling Parent Proband Sibling Offspring Proband Offspring Proband Parent Proband Offspring Sibling Sibling Proband Parent Sibling Proband Offspring Sibling Proband Parent Proband Offspring Offspring Proband Sibling Parent Proband Sibling Sroband Sibling Proband Offspring Offspring Proband Parent Sibling Proband Sibling Sibling Sibling Sibling Sibling
27 54 24 39 76 21 58 43 16 53 18 39 29 67 32 22 35 33 57 60 44 22 45 13 43 66 39 10 35 41 23 56 20 43 18 47 35 56 65 42 28 24 24 54 59 45 12 18 46 10 16 27 65 34 41 47 44 46 43 50
6 14 0 2 0 9 30 10 2 9 2 26 0 0 6 1 13 14 23 17 24 8 12 0 10 20 10 1 15 6 6 0 2 22 3 20 15 10 7 22 16 10 12 0 26 22 1 0 16 0 3 8 20 4 21 9 22 0 0 0
p u p p p p u m p p m m m m p p m m p p p p p p p u m p m m p m p p m p m m m m m p p u u u m m p p p p p p m m m m m m
3 4 1 4 2 3 3 3 2 4 3 4 2 3 2 2 5 4 4 4 4 2 2 1 3 5 3 2 3 3 2 1 2 4 2 4 4 4 2 4 4 3 3 1 3 3 2 2 2 2 2 2 4 3 4 3 4 1 1 1
263 500 180 1230 56 250 173 210 650 1696 1230 405 255 405 463 430 2930 930 270 100 500 300 100 230 963
MIRS, muscular impairment rating scale [30]; WML, white matter lesion; L, lobar; T, temporal; PV, periventricular. a p, paternal; m, maternal; u, unknown. b Values are scores; see Methods section for details on scoring criteria. c Repeat numbers are estimated by the method reported in Genetic analysis section.
467 433 800 967 210 115 460 863 863 663 826 133 800 967 467 467 66 300 633 1480 830 60 60 60 625 210 625 563 96 930 63 60 56
WMLb L
T
PV
0 6 0 2 0 0 7 0 0 0 0 6 0 4 0 0 10 3 4 29 14 7 6 0 0 7 0 0 0 0 0 0 0 0 0 0 12 3 0 0 0 0 0 0 19 4 0 0 0 0 0 0 3 0 6 4 3 6 0 2
0 8 2 7 2 0 0 0 0 5 6 14 10 3 0 0 6 5 2 12 10 5 0 5 7 10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 8 9 0 0 0 0 0 2 3 2 8 2 6 0 0 0
0 1 0 2 2 0 2 0 0 0 0 4 0 4 0 0 2 0 2 6 6 3 0 0 2 4 0 0 0 0 0 0 0 0 0 0 0 2 4 3 2 0 0 0 6 2 0 0 0 0 0 0 3 0 2 0 1 0 0 0
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Cohen’s kappa coefficient for categorical variables, and intra-class correlation coefficient (random effect model) for quantitative variables. The significance level was set at p < 0.05. 3. Results White matter hyperintense lesions were found in 58.3% (35/60) of patients and 63.6% (14/22) of families, and were lobar in 38.3% (23/60) and 54.4% (12/22), temporal in 43.3% (26/60) and 50% (11/22) and periventricular in 36.6% (22/60) and 54.4% (12/22) (Table 1). The lobar and periventricular lesion scores showed a significant positive correlation with the age (rs P 0.48, p < 0.001) or disease duration (rs P 0.50, p < 0.001), while the temporal lesion scores showed a weak positive correlation only with the disease duration (rs = 0.30, p = 0.021). The chi-square test showed that lobar, temporal and periventricular lesions were significantly associated with the family history of lobar (v2 = 30.5, p < 0.001), temporal (v2 = 42.9, p < 0.001) and periventricular (v2 = 20.1, p < 0.001) lesions, respectively. The multiple regression analysis showed that lobar (r2 = 0.33, F = 12.1, p < 0.001) and temporal (r2 = 0.50, F = 25.5, p < 0.001) lesions remained significantly associated with the disease duration and the family history, and the periventricular lesions (r2 = 0.41, F = 11.1, p < 0.001) with the disease duration, the family history and the age at scanning. Parent-offspring pair comparisons showed more severe periventricular lesions in parent (Z = 2.3, p = 0.023), and earlier age at onset (Z = 5.7, p < 0.001) and longer CTG repeat length (Z = 2.7, p = 0.002) in offsprings. The analysis of concordance showed a significant positive concordance for periventricular (r = 0.66, p < 0.001), lobar (r = 0.32, p = 0.049) and temporal (r = 0.39, p = 0.022) lesion scores. Sibling pair comparisons showed no significant differences in age at onset and at scanning, disease duration, CTG repeat length, periventricular, lobar and temporal lesions, and MIRS scores (Z P1.32, p P 0.21). The analysis of concordance showed a positive concordance for periventricular (r = 0.57, p = 0.004), lobar (r = 0.57, p = 0.003) and temporal (r = 0.66, p < 0.001) lesion scores (Figs. 1 and 2). No relationship was found between the sex of patients or of affected parent and the MRI or clinical findings (Z P 2.0, p P 0.05). 4. Discussion Main, previously unreported findings in this study were the significant association with the family history (positive for white matter lesions) and the high concordance of lesion scores in DM1 first-degree relatives. In other words, the occurrence and severity of lobar, temporal and/or periventricular lesions in a DM1 patient appeared strictly linked to positivity of family history for the respective lesion types. Furthermore, parent and sibling, and sibling pairs presented a high similarity in the severity of lobar,
temporal and periventricular lesions. The finding of a familial aggregation of hyperintense lesions in DM1 is in disagreement with Censori et al. [21] who found no characteristic pattern of brain MRI abnormalities in members of the same families. However, these authors did not evaluate the strength of association with the family history and the familial concordance of white matter lesions. The occurrence and severity of white matter lesions resulted also linked to disease duration for lobar and temporal lesions, and to disease duration and aging for periventricular lesions, and not to age at onset, sex, inheritance and CTG repeat size. These findings are in accord with previous results [20,22,25,26] and in disagreement with others [21,22]. Bachmann et al. [22], in fact, reported a weak correlation between white matter involvement and CTG repeat size. The somatic mosaicism and the expansion-biased instability of the mutant alleles over the life span in DM1 [2,12] might explain the discordant results, considering that CTG repeat size was assessed on blood leukocytes and not on the brain. Furthermore, Censori et al. [21] reported a lack of relationship between lesion severity and disease duration. The marked variability of DM1 phenotype and the large variability of progression rate of disease [2] might explain the discrepant results. The familial aggregation of white matter lesions in DM1 suggests that other genetic factors, besides the abnormal elongation of CTG repeat, or environmental causes, or a combination of both modulate the white matter involvement in DM1. Although we did not find relationship between lesion scores and CTG repeat length, white matter lesions are more frequent and severe in DM1 patients than in general population [21,25,26]. Furthermore, DM2 patients can present hyperintense lesions similar to that of DM1 patients, with the exception of temporal lesions that are observed only in the latter [27]. These findings suggest that the presence of an abnormal CTG repeat length is essential for the occurrence of white matter lesions in DM1, especially for the temporal type. The misregulation of alternative splicing produced by the DM1 genetic defect involves three genes in the brain: microtubule-associated protein Tau (MAPT), N-methylD-aspartate receptor (NMDAR1) and amyloid precursor protein (APP) gene. The altered expression of the proteins encoded by these genes might cause the cerebral involvement in DM1 [8,11,32]. Tau, in particular, stabilizes the microtubules and modulates their dynamics, contributing directly or indirectly to key structural and regulatory cellular functions [33]. In DM1 brain, altered splicing of Tau transcripts involves exons 2/3 and 10, which results in the expression of the fetal isoform lacking the three possible inserts [32,34], and exon 6, which is brain-specific [35]. Tau isoforms might fail to provide the functions required in adult brain, disrupt the neuronal cytoskeleton and constitute the neurofibrillary tangles (NFT) described postmortem in specific areas of DM1 brains [34,36]. The toxicity of NFT and the loss of normal function of Tau have been implicated in the onset and progression of
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Fig. 1. T2- (A–C) and proton density- (D–F) weighted images showing white matter lesions (arrows) in both temporal poles of 3 DM1 relatives belonging to the family 9 (Table 1): (A and D) patient 20 (proband); (B and E) patient 21 (sister); (C and F) patient 22 (daughter).
Fig. 2. A–D T2- (top) and proton density- (bottom) weighted images showing a small lesion (arrows) in the white matter lateral to left trigone of 4 DM1 sibling belonging to the family 22 (Table 1): (A, E) patient 55; (B, F) patient 56; (C, G) patient 57; (D, H) patient 58. E–H White matter lesion (arrows) in the both temporal poles of patients 55 and 56, and in the right temporal pole of patient 57.
neurodegeneration [33]. White matter of DM1 brains shows abnormal Tau variants and RNA foci similar to that of gray matter, even if RNA foci were smaller and less intense in oligodendrocytes than in cortical neurons
[32,34]. Considering that neurons and oligodendrocytes can share common cytoskeletal pathologies [37], it is conceivable that Tau missplicing might contribute, at least in part, to the appearance of white matter lesions in DM1.
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However, the mechanism by which white matter is involved in some families and spared in others has to be elucidated. We suggest that another genetic defect might co-segregate with the DM1 defect in the families with the lesions. The observation that the CTG expansion in DM1 locus can co-segregate with other genetic defects [38,39] supports our hypothesis. Another possible explanation for the clustering of white matter lesions in DM1 is the occurrence of unknown environmental factors. A number of experiments on cultured human or rodent cells demonstrate that the rate of repeat expansion can be modified by exposure to a variety of defined chemicals [13]. Although translation from experimental setting to human investigation is not easy and does not allow for a definitive conclusion, these findings suggest that environmental modifiers shared by family members can affect the CTG repeat dynamics and produce the somatic instability that is thought to contribute toward the tissue specificity and progressive nature of the disturbances in DM1 [13]. In conclusion, a familial aggregation exists in the occurrence and severity of white matter lesions in DM1 patients, which appears independent of CTG repeat length. The findings suggest that genetic factors, in addition to CTG repeat expansion, or environmental factors, which may be similar in first-degree relatives, or a combination of both, modulate the white matter involvement in DM1. Prospective studies primarily designed to investigate on these unknown factors are warranted. References [1] The International Myotonic Dystrophy Consortium (IDMC). New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1). Neurology 2000; 54:1218-21. [2] Harper PS. Myotonic dystrophym. London: W.B. Saunders; 2001. [3] Brook JD, McCurrach ME, Harley HG, et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 30 end of a transcript encoding a protein kinase family member. Cell 1992;68:799–808. [4] Fu YH, Pizzuti Jr A, Fenwick RG, et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 1992;255:1256–8. [5] Mahadaven M, Tsilfidis C, Sabourin L, et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 30 untranslated region of the gene. Science 1992;255:1253–5. [6] Gennarelli M, Pavoni M, Amicucci P, et al. Reduction of the DMassociated homeo domain protein (DMAHP) mRNA in different brain areas of myotonic dystrophy patients. Neuromuscul Disord 1999;9:215–9. [7] Day JW, Ranum LP. RNA pathogenesis of the myotonic dystrophies. Neuromuscul Disord 2005;15:5–16. [8] de Leo´n MB, Cisneros B. Myotonic dystrophy 1 in the nervous system: from the clinic to molecular mechanisms. J Neurosci Res 2007;86:18–26. [9] Nezu Y, Kino Y, Sasagawa N, Nishino I, Ishiura S. Expression of MBNL and CELF mRNA transcripts in muscles with myotonic dystrophy. Neuromuscul Disord 2007;17:306–12. [10] Wheeler TM, Krym MC, Thornton CA. Ribonuclear foci at the neuromuscular junction in myotonic dystrophy type 1. Neuromuscul Disord 2007;17:242–7.
[11] Meola G, Sansone V. Cerebral involvement in myotonic dystrophies. Muscle Nerve 2007;36:294–306. [12] Mirkin SM. DNA structures, repeat expansions and human hereditary disorders. Curr Opin Struct Biol 2006;16:351–8. [13] Gomes-Pereira M, Moncktonb DG. Chemical modifiers of unstable expanded simple sequence repeats: what goes up, could come down. Mutat Res 2006;598:15–34. [14] Brunner HG, Hamel BCJ, Rieu P, Ho¨weler CJ, Peters FTM. Intestinal pseudo-obstruction in myotonic dystrophy. J Med Genet 1992;29:791–3. [15] Umeda Y, Ikeda U, Yamamoto J, et al. Myotonic dystrophy associated with QT prolongation and torsade de pointes. Clin Cardiol 1999;22:136–8. [16] Finsterer J, Sto¨llberger C, Kopsa W. Familial left ventricular hypertrabeculation in myotonic dystrophy type 1. Herz 2003;28:466–70. ´ o M, Campos Y, et al. Unusual [17] Seijo-Martı´nez M, Castro del Rı clinical findings and Complex III deficiency in a family with myotonic dystrophy. J Neurol Sci 2003;208:87–91. [18] Groh WJ, Lowe MR, Simmons Z, Bhakta D, Pascuzzi RM. Familial clustering of muscular and cardiac involvement in myotonic dystrophy type 1. Muscle Nerve 2005;31:719–24. [19] Chang L, Anderson T, Migneco OA, et al. Cerebral abnormalities in myotonic dystrophy. Cerebral blood flow, magnetic resonance imaging, and neuropsychological tests. Arch Neurol 1993;50:917–23. [20] Abe K, Fujimura H, Toyooka K, et al. Involvement of the central nervous system in myotonic dystrophy. J Neurol Sci 1994;27: 179–85. [21] Censori B, Provinciali L, Danni M, et al. Brain involvement in myotonic dystrophy: MRI features and their relationship to clinical and cognitive conditions. Acta Neurol Scand 1994;90:211–7. [22] Bachmann G, Damian MS, Koch M, Schilling G, Fach B, Sto¨ppler S. The clinical and genetic correlates of MRI findings in myotonic dystrophy. Neuroradiology 1996;38:629–35. [23] Ogata A, Terae S, Fujita M, Tashiro K. Anterior temporal white matter lesions in myotonic dystrophy with intellectual impairment: an MRI and neuropathological study. Neuroradiology 1998;40:411–5. [24] Martinello F, Piazza A, Pastorello E, Angelini C, Trevisan CP. Clinical and neuroimaging study of central nervous system in congenital myotonic dystrophy. J Neurol 1999;246:186–92. [25] Di Costanzo A, Di Salle F, Santoro L, Bonavita V, Tedeschi G. Brain MRI features of congenital- and adult-form myotonic dystrophy type 1: case-control study. Neuromuscul Disord 2002;12:476–83. [26] Di Costanzo A, Di Salle F, Santoro L, Tessitore A, Bonavita V, Tedeschi G. Pattern and significance of white matter abnormalities in myotonic dystrophy type 1: an MRI study. J Neurol 2002;249:1175–82. [27] Kornblum C, Reul J, Kress W, et al. Cranial magnetic resonance imaging in genetically proven myotonic dystrophy type 1 and 2. J Neurol 2004;251:710–4. [28] Kuo HC, Hsiao KM, Chen CJ, Hsieh YC, Huang CC. Brain magnetic resonance image changes in a family with congenital and classic myotonic dystrophy. Brain Dev 2005;27:291–6. [29] Giorgio A, Dotti MT, Battaglini M, et al. Cortical damage in brains of patients with adult-form of myotonic dystrophy type 1 and no or minimal MRI abnormalities. J Neurol 2006;11:1432–59. [30] Mathieu J, Boivin H, Meunier D, Gaudreault M, Be´gin P. Assessment of a disease-specific muscular impairment rating scale in myotonic dystrophy. Neurology 2001;56:336–40. [31] Scheltens P, Barkhof F, Leys D, et al. A semiquantitative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci 1993;114:7–12. [32] Jiang H, Mankodi A, Swanson MS, Moxley RT, Thornton CA. Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum Mol Genet 2004;13:3079–88. [33] Ballatore C, Lee VM-Y, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 2007;8:663–72.
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Familial aggregation of white matter lesions in myotonic dystrophy type 1 Alfonso Di Costanzo d,*, Lucio Santoro a, Mario de Cristofaro b, Fiore Manganelli a, Francesco Di Salle c, Gioacchino Tedeschi b b
a Department of Neurological Sciences, University ‘‘Federico II”, Via S. Pansini 5, 80131 Naples, Italy Department of Neurological Sciences, Second University of Naples, Piazza L. Miraglia 2, 80138 Naples, Italy c Department of Neurosciences, University of Pisa, via Roma 67, 56126 Pisa, Italy d Department of Health Sciences, University of Molise, Via Giovanni Paolo II, 86100 Campobasso, Italy
Received 28 October 2007; received in revised form 12 January 2008; accepted 30 January 2008
Abstract This study aimed to determine whether white matter lesions, previously described as a frequent feature in myotonic dystrophy type 1 (DM1), aggregate within DM1 families or are sporadic findings, and to explore the relationship between these lesions and clinical or genetic features. Brain MRI of 60 DM1 patients belonging to 22 families were evaluated and white matter lesions were rated according to a semiquantitative method. Presence and extent of lobar, temporal or periventricular lesions showed a significant association with the family history of lesions and the disease duration, and no association with the CTG repeat size. Furthermore, parent-offspring and sibling pairs showed a significant positive concordance for lesion severity. White matter lesions demonstrate familial aggregation in DM1 and no relationship with CTG repeat length. These findings suggest that other genetic causes and/or unknown environmental factors influence the occurrence and severity of lesions in patients carrying the DM1 genetic defect. Ó 2008 Elsevier B.V. All rights reserved. Keywords: Myotonic dystrophy; Magnetic resonance imaging; Brain; Cross-sectional studies
1. Introduction Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder with multisystemic clinical features involving the skeletal muscle, the heart, the eye, the endocrine system, the central and peripheral nervous systems, the smooth muscle, the bone and the skin [1,2]. The DM1 phenotype is highly variable ranging from the severe, often fatal, congenital form to the asymptomatic carrier of genetic defect [2]. It is caused by the expansion of a CTG repeat in the 30 untranslated region of a gene encoding for a protein kinase (DMPK) at DM1 locus on chromosome 19q13.3 [3–5].
*
Corresponding author. Tel.: +39 0874 404749; fax: +39 0874 404710. E-mail address: [email protected] (A. Di Costanzo).
0960-8966/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2008.01.008
Several pathogenic mechanisms have been proposed to explain the multisystemic nature and the variable expressivity of the symptoms in DM1 [2,6–8]. Substantial evidence has accumulated indicating that DMPK mRNA containing expanded CUG repeats is retained in nuclear inclusions and produces splicing abnormalities by perturbing the function of RNA-binding proteins. Indeed, disrupted mRNA alternative splicing in DM1 has been reported for several genes, and for the muscle-specific chloride channel (ClC-1) and insulin receptor, expression of the embryonic splicing pattern results in myotonia and insulin resistance, respectively, two characteristic features of the disease [7–10]. However, the causes of cerebral involvement are less well defined [8,11]. The variation between and within tissues (somatic mosaicism) and the expansion-biased (somatic instability) of CTG repeat size represent another mechanism implicated
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in the variable expression of disease [12,13]. However, the familial occurrence of abnormalities, such as cardiac conduction disturbances, mitral valve prolapse, pilomatrixomas, polyneuropathy, normal pressure hydrocephalus, dilatation of the urinary tract, intestinal pseudo-obstruction, subcortical-type dementia and left ventricular hypertrabeculation [14–17], and the familial similarities in muscular and cardiac involvement [18] suggest that other genetic mechanism or unknown environmental factors, or both might be implicated in DM1. Brain MRI of patients with DM1 can show findings ranging from no or minimal abnormalities to brain atrophy with large and severe white matter lesions [19–29]. In larger study populations, these lesions are found with a frequency ranging from 65% to 81% [21,22,25,26] and are significantly more common and severe in DM1 than in healthy controls [21,25,26]. This study was performed to determine whether white matter lesions aggregate within families or are sporadic findings in DM1, and to explore the relationship between these lesions and clinical or genetic features. 2. Patients and methods 2.1. Patients Sixty patients (30 men and 30 women) with noncongenital DM1 [2] belonging to 22 families with at least two affected first-degree relatives (Table 1) were included in the study. The diagnosis was based on clinical picture, family history and electromyography and supported by genetic analysis of leukocytes. The mean age ± SD was 38.3 ± 16.4 years (range, 10–76 years) and the duration of clinical symptoms varied from 0 (patients without complaints detected in family examinations) to 30 years. Twenty-nine patients acquired the disease by paternal and 25 by maternal transmission. The parents who could not be examined were considered affected on the basis of history or photographs; in 6 patients the affected parent could not be identified. The severity of muscular involvement was assessed by muscular impairment rating scale (MIRS) [30] and ranged from 1 (patients without clinical muscular impairment, diagnosed by genetic analysis) to 5 (patient with severe weakness, confined to wheelchair for short or long distances). No patient had history of cerebrovascular disease, multiple sclerosis, meningoencephalitis, hypoxic insult, head trauma causing unconsciousness, progressive dementia or other neurological illness that might explain the MRI findings. Either the patients or their parents gave the informed consent. 2.2. MRI evaluation Brain MRI included sagittal T1-weighted images with repetition times (TR) of 500 ms and echo times (TE) of 20 ms, and axial T2- and proton-density (PD)-weighted spin-echo images with TR of 2000 ms, TE1 of 40 ms and
TE2 of 100 ms. Slice thickness was 5 mm with 2-mm gap; field of view/matrix was 24 cm/192 256 for sagittal and 20 cm/160 192 for axial series. White matter lesions were identified as bright areas on both PD- and T2-weighted images. They were recorded as lobar (outside the periventricular and temporal regions), temporal or periventricular (abutting the ventricular lining) and scored according to a semiquantitative method [31]. The score was the sum of products between the number of lesions and the category indicating their size (1 < 0.5 cm; 2 = 0.5–1.0 cm; 3 = 1.0–1.5 cm; 4 = 1.5– 2.0 cm; 5 = 2.0–2.5 cm; 6 = 2.5–3.0 cm; 7 > 3.0 cm). The periventricular lesions were scored by measuring and summing their greatest thickness on PD-weighted images at the frontal and occipital horns (‘‘caps”) and at the body of the lateral ventricle (‘‘rims” or ‘‘bands”). Triangularshaped hyperintensities up to 1 cm in width and located anterolaterally to the frontal horns of the lateral ventricles were considered a normal finding and not scored. Two blinded experienced examiners independently evaluated the images and their results were compared. When they disagreed, a consensus reading was held to reach an unequivocal agreement. Inter- and intrarater reliabilities for total lesion scores, measured by intra-class correlation coefficient, were 0.83 and 0.87, respectively. 2.3. Genetic analysis The standard procedure consisted of DNA separation from leukocytes, digestion with NcoI and BamHI restriction enzymes, separation of DNA fragments by gel electrophoresis, transfer on to nylon membranes by Southern blotting, hybridization with DNA probe MDY1 and additional polymerase chain reaction using described primers [3]. The CTG repeat size was estimated at the point of the most heavily staining band or at the midpoint of the smear for very diffuse band. 2.4. Statistical analysis Data were analyzed using the SPSS (v 12.01) software package (SPSS Inc., Chicago, Illinois). The strength of association was measured by the chi-square test for categorical variables, such as sex, inheritance and family history (positive if at least one affected first-degree relative showed white matter lesions), and by the Spearman rank correlation coefficient for quantitative variables, such as age at scanning, age at onset, disease duration and CTG repeats. The group differences were evaluated by the Mann–Whitney U test. Stepwise multiple regression analysis (F to enter >3.84) was performed including lobar, temporal or periventricular lesion, or MIRS scores as dependent variables and sex, inheritance, family history (positive or negative for white matter lesions), age at scanning, age at onset, disease duration and CTG repeats as independent variables. The familial concordance (parent-offspring or sibling pairs) was carried out by
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Table 1 Clinical and MRI features of patients with myotonic dystrophy type 1 Family no.
Patient no./sex
Relationship
Age (years)
Duration (years)
Inheritancea
MIRSb
CTG repeatsc
1 1 1 2 2 3 3 4 4 5 5 6 6 6 7 7 8 8 8 9 9 9 10 10 11 11 12 12 12 12 13 13 13 14 14 14 15 15 16 16 16 17 17 17 18 18 19 19 20 20 20 21 21 21 22 22 22 22 22 22
1/m 2/m 3/f 4/m 5/m 6/m 7/m 8/m 9/m 10/f 11/f 12/m 13/f 14/f 15/f 16/f 17/m 18/f 19/f 20/m 21/f 22/f 23/m 24/f 25/f 26/m 27/m 28/f 29/f 30/f 31/m 32/m 33/f 34/f 35/f 36/f 37/m 38/f 39/f 40/m 41/m 42/f 43/m 44/m 45/f 46/f 47/f 48/m 49/m 50/f 51/m 52/m 53/m 54/f 55/f 56/m 57/f 58/m 59/m 60/f
Proband Parent Sibling Proband Parent Proband Parent Proband Offspring Proband Offspring Proband Sibling Parent Proband Sibling Proband Sibling Parent Proband Sibling Offspring Proband Offspring Proband Parent Proband Offspring Sibling Sibling Proband Parent Sibling Proband Offspring Sibling Proband Parent Proband Offspring Offspring Proband Sibling Parent Proband Sibling Sroband Sibling Proband Offspring Offspring Proband Parent Sibling Proband Sibling Sibling Sibling Sibling Sibling
27 54 24 39 76 21 58 43 16 53 18 39 29 67 32 22 35 33 57 60 44 22 45 13 43 66 39 10 35 41 23 56 20 43 18 47 35 56 65 42 28 24 24 54 59 45 12 18 46 10 16 27 65 34 41 47 44 46 43 50
6 14 0 2 0 9 30 10 2 9 2 26 0 0 6 1 13 14 23 17 24 8 12 0 10 20 10 1 15 6 6 0 2 22 3 20 15 10 7 22 16 10 12 0 26 22 1 0 16 0 3 8 20 4 21 9 22 0 0 0
p u p p p p u m p p m m m m p p m m p p p p p p p u m p m m p m p p m p m m m m m p p u u u m m p p p p p p m m m m m m
3 4 1 4 2 3 3 3 2 4 3 4 2 3 2 2 5 4 4 4 4 2 2 1 3 5 3 2 3 3 2 1 2 4 2 4 4 4 2 4 4 3 3 1 3 3 2 2 2 2 2 2 4 3 4 3 4 1 1 1
263 500 180 1230 56 250 173 210 650 1696 1230 405 255 405 463 430 2930 930 270 100 500 300 100 230 963
MIRS, muscular impairment rating scale [30]; WML, white matter lesion; L, lobar; T, temporal; PV, periventricular. a p, paternal; m, maternal; u, unknown. b Values are scores; see Methods section for details on scoring criteria. c Repeat numbers are estimated by the method reported in Genetic analysis section.
467 433 800 967 210 115 460 863 863 663 826 133 800 967 467 467 66 300 633 1480 830 60 60 60 625 210 625 563 96 930 63 60 56
WMLb L
T
PV
0 6 0 2 0 0 7 0 0 0 0 6 0 4 0 0 10 3 4 29 14 7 6 0 0 7 0 0 0 0 0 0 0 0 0 0 12 3 0 0 0 0 0 0 19 4 0 0 0 0 0 0 3 0 6 4 3 6 0 2
0 8 2 7 2 0 0 0 0 5 6 14 10 3 0 0 6 5 2 12 10 5 0 5 7 10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 8 9 0 0 0 0 0 2 3 2 8 2 6 0 0 0
0 1 0 2 2 0 2 0 0 0 0 4 0 4 0 0 2 0 2 6 6 3 0 0 2 4 0 0 0 0 0 0 0 0 0 0 0 2 4 3 2 0 0 0 6 2 0 0 0 0 0 0 3 0 2 0 1 0 0 0
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Cohen’s kappa coefficient for categorical variables, and intra-class correlation coefficient (random effect model) for quantitative variables. The significance level was set at p < 0.05. 3. Results White matter hyperintense lesions were found in 58.3% (35/60) of patients and 63.6% (14/22) of families, and were lobar in 38.3% (23/60) and 54.4% (12/22), temporal in 43.3% (26/60) and 50% (11/22) and periventricular in 36.6% (22/60) and 54.4% (12/22) (Table 1). The lobar and periventricular lesion scores showed a significant positive correlation with the age (rs P 0.48, p < 0.001) or disease duration (rs P 0.50, p < 0.001), while the temporal lesion scores showed a weak positive correlation only with the disease duration (rs = 0.30, p = 0.021). The chi-square test showed that lobar, temporal and periventricular lesions were significantly associated with the family history of lobar (v2 = 30.5, p < 0.001), temporal (v2 = 42.9, p < 0.001) and periventricular (v2 = 20.1, p < 0.001) lesions, respectively. The multiple regression analysis showed that lobar (r2 = 0.33, F = 12.1, p < 0.001) and temporal (r2 = 0.50, F = 25.5, p < 0.001) lesions remained significantly associated with the disease duration and the family history, and the periventricular lesions (r2 = 0.41, F = 11.1, p < 0.001) with the disease duration, the family history and the age at scanning. Parent-offspring pair comparisons showed more severe periventricular lesions in parent (Z = 2.3, p = 0.023), and earlier age at onset (Z = 5.7, p < 0.001) and longer CTG repeat length (Z = 2.7, p = 0.002) in offsprings. The analysis of concordance showed a significant positive concordance for periventricular (r = 0.66, p < 0.001), lobar (r = 0.32, p = 0.049) and temporal (r = 0.39, p = 0.022) lesion scores. Sibling pair comparisons showed no significant differences in age at onset and at scanning, disease duration, CTG repeat length, periventricular, lobar and temporal lesions, and MIRS scores (Z P1.32, p P 0.21). The analysis of concordance showed a positive concordance for periventricular (r = 0.57, p = 0.004), lobar (r = 0.57, p = 0.003) and temporal (r = 0.66, p < 0.001) lesion scores (Figs. 1 and 2). No relationship was found between the sex of patients or of affected parent and the MRI or clinical findings (Z P 2.0, p P 0.05). 4. Discussion Main, previously unreported findings in this study were the significant association with the family history (positive for white matter lesions) and the high concordance of lesion scores in DM1 first-degree relatives. In other words, the occurrence and severity of lobar, temporal and/or periventricular lesions in a DM1 patient appeared strictly linked to positivity of family history for the respective lesion types. Furthermore, parent and sibling, and sibling pairs presented a high similarity in the severity of lobar,
temporal and periventricular lesions. The finding of a familial aggregation of hyperintense lesions in DM1 is in disagreement with Censori et al. [21] who found no characteristic pattern of brain MRI abnormalities in members of the same families. However, these authors did not evaluate the strength of association with the family history and the familial concordance of white matter lesions. The occurrence and severity of white matter lesions resulted also linked to disease duration for lobar and temporal lesions, and to disease duration and aging for periventricular lesions, and not to age at onset, sex, inheritance and CTG repeat size. These findings are in accord with previous results [20,22,25,26] and in disagreement with others [21,22]. Bachmann et al. [22], in fact, reported a weak correlation between white matter involvement and CTG repeat size. The somatic mosaicism and the expansion-biased instability of the mutant alleles over the life span in DM1 [2,12] might explain the discordant results, considering that CTG repeat size was assessed on blood leukocytes and not on the brain. Furthermore, Censori et al. [21] reported a lack of relationship between lesion severity and disease duration. The marked variability of DM1 phenotype and the large variability of progression rate of disease [2] might explain the discrepant results. The familial aggregation of white matter lesions in DM1 suggests that other genetic factors, besides the abnormal elongation of CTG repeat, or environmental causes, or a combination of both modulate the white matter involvement in DM1. Although we did not find relationship between lesion scores and CTG repeat length, white matter lesions are more frequent and severe in DM1 patients than in general population [21,25,26]. Furthermore, DM2 patients can present hyperintense lesions similar to that of DM1 patients, with the exception of temporal lesions that are observed only in the latter [27]. These findings suggest that the presence of an abnormal CTG repeat length is essential for the occurrence of white matter lesions in DM1, especially for the temporal type. The misregulation of alternative splicing produced by the DM1 genetic defect involves three genes in the brain: microtubule-associated protein Tau (MAPT), N-methylD-aspartate receptor (NMDAR1) and amyloid precursor protein (APP) gene. The altered expression of the proteins encoded by these genes might cause the cerebral involvement in DM1 [8,11,32]. Tau, in particular, stabilizes the microtubules and modulates their dynamics, contributing directly or indirectly to key structural and regulatory cellular functions [33]. In DM1 brain, altered splicing of Tau transcripts involves exons 2/3 and 10, which results in the expression of the fetal isoform lacking the three possible inserts [32,34], and exon 6, which is brain-specific [35]. Tau isoforms might fail to provide the functions required in adult brain, disrupt the neuronal cytoskeleton and constitute the neurofibrillary tangles (NFT) described postmortem in specific areas of DM1 brains [34,36]. The toxicity of NFT and the loss of normal function of Tau have been implicated in the onset and progression of
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Fig. 1. T2- (A–C) and proton density- (D–F) weighted images showing white matter lesions (arrows) in both temporal poles of 3 DM1 relatives belonging to the family 9 (Table 1): (A and D) patient 20 (proband); (B and E) patient 21 (sister); (C and F) patient 22 (daughter).
Fig. 2. A–D T2- (top) and proton density- (bottom) weighted images showing a small lesion (arrows) in the white matter lateral to left trigone of 4 DM1 sibling belonging to the family 22 (Table 1): (A, E) patient 55; (B, F) patient 56; (C, G) patient 57; (D, H) patient 58. E–H White matter lesion (arrows) in the both temporal poles of patients 55 and 56, and in the right temporal pole of patient 57.
neurodegeneration [33]. White matter of DM1 brains shows abnormal Tau variants and RNA foci similar to that of gray matter, even if RNA foci were smaller and less intense in oligodendrocytes than in cortical neurons
[32,34]. Considering that neurons and oligodendrocytes can share common cytoskeletal pathologies [37], it is conceivable that Tau missplicing might contribute, at least in part, to the appearance of white matter lesions in DM1.
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However, the mechanism by which white matter is involved in some families and spared in others has to be elucidated. We suggest that another genetic defect might co-segregate with the DM1 defect in the families with the lesions. The observation that the CTG expansion in DM1 locus can co-segregate with other genetic defects [38,39] supports our hypothesis. Another possible explanation for the clustering of white matter lesions in DM1 is the occurrence of unknown environmental factors. A number of experiments on cultured human or rodent cells demonstrate that the rate of repeat expansion can be modified by exposure to a variety of defined chemicals [13]. Although translation from experimental setting to human investigation is not easy and does not allow for a definitive conclusion, these findings suggest that environmental modifiers shared by family members can affect the CTG repeat dynamics and produce the somatic instability that is thought to contribute toward the tissue specificity and progressive nature of the disturbances in DM1 [13]. In conclusion, a familial aggregation exists in the occurrence and severity of white matter lesions in DM1 patients, which appears independent of CTG repeat length. The findings suggest that genetic factors, in addition to CTG repeat expansion, or environmental factors, which may be similar in first-degree relatives, or a combination of both, modulate the white matter involvement in DM1. Prospective studies primarily designed to investigate on these unknown factors are warranted. References [1] The International Myotonic Dystrophy Consortium (IDMC). New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1). Neurology 2000; 54:1218-21. [2] Harper PS. Myotonic dystrophym. London: W.B. Saunders; 2001. [3] Brook JD, McCurrach ME, Harley HG, et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 30 end of a transcript encoding a protein kinase family member. Cell 1992;68:799–808. [4] Fu YH, Pizzuti Jr A, Fenwick RG, et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 1992;255:1256–8. [5] Mahadaven M, Tsilfidis C, Sabourin L, et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 30 untranslated region of the gene. Science 1992;255:1253–5. [6] Gennarelli M, Pavoni M, Amicucci P, et al. Reduction of the DMassociated homeo domain protein (DMAHP) mRNA in different brain areas of myotonic dystrophy patients. Neuromuscul Disord 1999;9:215–9. [7] Day JW, Ranum LP. RNA pathogenesis of the myotonic dystrophies. Neuromuscul Disord 2005;15:5–16. [8] de Leo´n MB, Cisneros B. Myotonic dystrophy 1 in the nervous system: from the clinic to molecular mechanisms. J Neurosci Res 2007;86:18–26. [9] Nezu Y, Kino Y, Sasagawa N, Nishino I, Ishiura S. Expression of MBNL and CELF mRNA transcripts in muscles with myotonic dystrophy. Neuromuscul Disord 2007;17:306–12. [10] Wheeler TM, Krym MC, Thornton CA. Ribonuclear foci at the neuromuscular junction in myotonic dystrophy type 1. Neuromuscul Disord 2007;17:242–7.
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