Journal of Clinical Neuroscience 21 (2014) 1123–1126
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Correlation between distribution of muscle weakness, electrophysiological findings and CTG expansion in myotonic dystrophy Roya Khoshbakht a, Akbar Soltanzadeh a, Babak Zamani a, Siyamak Abdi a, Kourosh Gharagozli b, Kimia Kahrizi c, Rahem Khoshbakht d, Shahriar Nafissi a,⇑ a
Department of Neurology, Tehran University of Medical Sciences, Shariati Hospital, North Karegar Street, Tehran 14114, Iran Department of Neurology, Shahid Beheshti University of Medical Sciences, Tehran, Iran Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran d Department of Pathobiology, School of Veterinary Medicine, University of Shiraz, Iran b c
a r t i c l e
i n f o
Article history: Received 16 June 2012 Accepted 24 September 2013
Keywords: Clinical manifestation CTG expansion Exercise Myotonic dystrophy
a b s t r a c t Myotonic dystrophy type 1 (DM-1) is a multi-system disorder affecting the muscles, brain, cardiovascular system, endocrine system, eyes and skin. Diagnosis is made by clinical, electrodiagnostic and genetic studies. This study aimed to determine the correlation between CTG expansion and distribution of muscle weakness and clinical and electrophysiological findings. Genetically confirmed DM-1 patients presenting to Shariati Hospital between 2005 and 2011 were included in this study. Clinical, electrodiagnostic and genetic testing was performed and the correlation between CTG expansion and distribution of muscle weakness and clinical and electromyographic findings was studied. Thirty-three genetically confirmed DM-1 patients were enrolled. Myotonia, bifacial weakness and distal upper limb weakness were seen in all patients. Diabetes mellitus was found in one patient (3%), cardiac disturbance in eight (24.2%), cataracts in eight (24.2%), hypogonadism in five (15.2%), frontal baldness in 13 (39.4%), temporalis wasting in 14 (42.4%), temporomandibular joint disorder in seven (21.2%) and mental retardation in eight (24.2%). The mean number of CTG repeats, measured by Southern blot, was 8780 (range 500–15,833). A negative correlation was found between CTG expansion and age of onset. Temporalis wasting and mental retardation were positively correlated with CTG expansion. No relationship was found between weakness distribution, electromyographic findings, other systemic features and CTG expansion. In this study of DM-1 in Iran, we found a correlation between CTG expansion and age of onset, temporalis wasting and mental disability. No correlation between CTG expansion and electrodiagnostic and other clinical findings were detected. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Myotonic dystrophy (DM), with a prevalence of 1/8000, is one of the most common muscular dystrophies [1]. It is a multi-system disease that affects the muscles, brain, cardiovascular system, endocrine system, eyes and skin. The clinical presentation ranges from severe congenital hypotonia to mild adult onset weakness or even asymptomatic disease. Cardinal muscular features are myotonia, weakness and atrophy of distal and facial muscles [1]. The pattern of inheritance is autosomal dominant and the disease is a member of the trinucleotide expansion family. In myotonic dystrophy type 1 (DM-1) the CTG trinucleotide expansion occurs in an untranslated part of the dystrophia myotonica protein kinase gene on chromosome 19q 13.3 [2–4]. While normal individuals have 5 to 30 copies of CTG, the number of CTG repeats ⇑ Corresponding author. Tel.: +98 21 8490 2224; fax: +98 21 2288 4420. E-mail address: nafi[email protected] (S. Nafissi). 0967-5868/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2013.09.016
in DM-1 patients can be in the thousands [3–6]. The disease can present at an early age and can become more severe in subsequent generations in a family due to expansion of CTG repeats (anticipation phenomenon). Electrodiagnostic studies can aid in diagnosis of DM, including the short exercise test (SET). In this test, the amplitude of the compound muscle action potential (CMAP) of a distal muscle is recorded before and after 10 seconds of exercise, and the drop in CMAP amplitude is measured [8]. This study aimed to evaluate the relationship between the number of CTG repeats and pattern of muscular involvement and electromyographic (EMG) findings in DM-1 patients. 2. Materials and methods In a cross-sectional study, DM patients presenting to Shariati Hospital – a tertiary referral hospital affiliated to Tehran University of Medical Sciences – between 2005 and 2011 were evaluated. DM type 2 patients and patients without genetic confirmation were
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excluded from the study. DM-1 was confirmed in 33 patients using triplet primed polymerase chain reaction, and the number of CTG repeats was determined in 21 patients using Southern blot assay. All patients were clinically examined and muscle forces were recorded based on the Medical Research Council score. Shoulder abduction, elbow flexion, elbow extension, wrist extension, finger extension, flexor pollicis longus, flexor digitorum profundus, first dorsal interosseous, abductor pollicis brevis (APB), hip flexion, hip abduction, hip adduction, hip extension, knee flexion, knee extension, foot plantar flexion, foot dorsiflexion, neck flexion and extension were examined on both sides and scored. Thorough systemic investigation was performed in all patients looking for cataracts, cardiac involvement, diabetes mellitus, hypogonadism, sterility, frontal balding and mental retardation. Patients with a Wechsler Adult Intelligence Scale score lower than 70 were considered to have a low intelligence quotient (mentally retarded). Standard four limb EMG and nerve conduction studies were performed on all patients [13] and CMAP were recorded after the SET on APB [8]. APB CMAP amplitude was recorded before and after 10 seconds of exercise and the percentage of amplitude drop in this muscle was calculated. The data were analyzed using the Statistical Package for the Social Science (SPSS, Chicago, IL, USA). The relationship between CTG repeat number and CMAP decrement and age was analyzed with regression analysis. Spearman correlation was used to show the relationship between CTG expansion and muscle strength.
3. Results Of the 33 patients entered in the study, 19 were male (57.6%). The mean age of onset was 24.8 years ± standard deviation of 10.9 years (range 2–51). All 33 patients had myotonia and bifacial weakness; ptosis was detected in 25 (78.8%) and dysphagia in seven patients (21.2%). A family history of DM was present in 25 patients (75.8%). There were no data regarding the number of CTG repeats in other family members. Weakness of at least one distal upper limb muscle was found in all 33 patients (100%) and involvement of at least one distal lower limb muscle was detected in 23 patients (69.7%). At least one proximal muscle in upper and lower limbs was involved in 21 (63.6%) and 18 (54.5%) patients, respectively. In 19 patients (87.9%) neck flexors were weak while neck extensor weakness was seen in just 10 patients (30.5%). Systemic involvement was investigated and diabetes mellitus was found in one patient (3%), cardiac disturbance in eight patients (24.2%) (right bundle branch block 37.5%, mitral valve prolapse 25%, and diastolic dysfunction, septal hypokinesia, prolonged PQ and left bundle branch block all 12.5%), cataract in eight (24.2%), hypogonadism in five (15.2%), frontal baldness in 13 (39.4%), temporalis wasting in 14 (42.4%), temporomandibular joint dysfunction in seven (21.2%) and mental retardation in eight patients (24.2%) (Table 1). All patients in this study had EMG myotonic discharges in the distal muscles of the upper limbs. The mean decrement of CMAP amplitude after SET was 32.7 ± 22.7%, ranging from 0 to 83.5% (Table 2). Decrement of
Table 1 Clinical characteristics and CTG expansion in myotonic dystrophy patients #
CTG repeats
Sex
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
800 500 1000 12333 8400 13833 13500 13567 8833 7167 10833 15833 11833 10833 10567 6833 5150 9567 5333 8833 8833 NA NA NA NA NA NA NA NA NA NA NA NA
F F M F F M M M M F F F M F M M M M F M F F M M M F F F M M M M M
Age of symptom onset 28 20 30 21 37 2 18 14 37 51 24 15 9 20 22 37 31 20 20 15 34 24 22 11 19 36 32 20 50 21 24 18 38
Family history + + + + + + + + + + + + + + + + + + + + + + + + +
Cardiac disturbance
Cataract
Infertility
+ + + + + + + +
+ + + + + + + +
+ + + + +
Frontal balding + + + + + + + + + + + + +
MR
Temporalis wasting
Bifacial weakness
Dysphagia
TMJ dislocation
Ptosis
+ + + + + + + +
+ + + + + + + + + + + + + +
+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+ + + + + + +
+
+ + + + + + + + + + + + + + + + + + + + + + + + +
F = female, M = male, MR = mental retardation, NA = not available, TMJ = temporomandibular joint, + = present, = absent.
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R. Khoshbakht et al. / Journal of Clinical Neuroscience 21 (2014) 1123–1126 Table 2 CTG expansion, compound muscle action potentials, area decrement and muscle force of abductor pollicis brevis in myotonic dystrophy patients Patient
CTG repeats
CMAP amplitude decrement (%)
CMAP area decrement (%)
Disease duration (years)
APB forcea (0–5)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
800 500 1000 12333 8400 13833 13500 13567 8833 7167 10833 15833 11833 10833 10567 6833 5150 9567 5333 8833 8833 NA NA NA NA NA NA NA NA NA NA NA NA
6.6 56.5 28.7 .0 10.9 20 23 23.8 40.6 .0 8.4 35.7 45.8 58 27.2 43.9 44.8 30.7 7.5 25.5 .0 79.3 41.6 17.4 20 63.8 13.3 12.1 56 42.8 52.6 83.5 59.7
1.3 60.9 36.4 20.2 35.9 24.3 39.2 27.2 45.1 15.1 48.3 46.5 61.8 63.6 36.4 58.2 66.2 45.8 44.3 48.1 25.7 77.2 48.1 23.2 34.2 78.3 15.2 11.1 48.6 66.6 65.2 76.9 62.6
4 8 13 24 12 29 31 9 10 7 15 16 10 20 15 2 6 12 4 22 2 13 18 32 20 5 3 2 4 33 2 20 1
4 5 4 4 4 4 4 4 3 3 4 5 4 4 4 4 4 5 4 4 4 5 4 3 4 3 3 5 4 4 4 3 5
a Based on the Medical Research Council score. APB = abductor pollicis brevis, CMAP = compound muscle action potentials, NA = not available.
CMAP amplitude was 0–20% in 12 patients (36.4%) and more than 20% in 21 patients (63.6%). The number of CTG repeats was determined by Southern blot assay. The mean number of CTG repeats was 8780 ± 4353 (range 500–15,833). The correlation between CTG expansion and strength of different muscles was studied using the Spearman correlation test and no significant correlations were detected. Using regression analysis, no significant correlation was found between CMAP decrement after SET and CTG expansion in the APB muscle. The anticipation phenomenon was evaluated and a significant negative correlation was present between age of onset and CTG expansion (r = 0.001, p = 0.035) using regression analysis. Considering the systemic features of DM, only mental retardation and temporalis wasting had a positive correlation with CTG expansion (r = 0.443, p = 0.044 and r = 0.485, p = 0.026, respectively).
4. Discussion DM, a multi-system disease which used to be diagnosed clinically with some contribution from electrodiagnostic studies, is now diagnosed easily using a genetic study. Asymptomatic or minimally symptomatic patients are now diagnosed by measuring the number of CTG repeats [7]. Knowing the number of CTG repeats in a patient has been viewed as an important piece of information that could possibly prognosticate the severity of disease. Various studies have investigated the correlation between CTG expansion and clinical manifestations with some intriguing results reported [7,9–11]. Our study attempted to cast light on this problem. Muscle weakness was seen, in order of frequency in this study, in the distal
upper, distal lower, proximal upper and proximal lower limb muscles. All patients had distal upper limb muscle involvement, with deep finger flexors such as flexor pollicis longus being the most commonly involved (97%). Foot dorsiflexors were the most commonly involved muscles in the lower limbs (69%). These results are in agreement with other studies [7,9–11]. Mondelli et al. reported that 46% of their patients had peripheral nervous system involvement (polyneuropathy) and Pfeilsticker et al. reported this finding in 25.9% [11,12]. None of our 33 patients showed any sign of neuropathy on clinical examination or electrodiagnostic studies [12]. In the Pfeilsticker et al. series, seven out of 27 patients had polyneuropathy, and four of them were diabetic. Diabetes or some other underlying disease may have been the cause of polyneuropathy in some of these patients [11]. Some studies have shown a positive correlation between CTG expansion and clinical severity of DM [3,4]. Other studies did not confirm this correlation [7,10]. We did not find any correlation between severity of muscle weakness and CTG expansion. The small sample size might be an explanation for the lack of correlation [7]. Another explanation could be tissue heterogeneity for the expanded allele in DM as CTG expansion is seen more in muscles than in leukocytes; this theory has not been validated [14–17]. As has been shown in most previous studies, there was a negative correlation between CTG expansion and age of onset in our study [6,7,11,18,19]. Perini et al. and Marchini et al. found a direct relationship between mental disability and CTG expansion [19,20]. Our study showed the same correlation. The CTG expansion was larger in mentally retarded patients compared to patients with a normal intelligence quotient. Our study also showed that temporalis wasting was seen more often in patients with larger CTG
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expansions, which has not been reported in previous studies. Like other studies, no correlation between other systemic features and CTG expansion was detected [10,19]. CMAP decrement after SET, which is useful in differentiating proximal myotonic myopathy from DM-1, did not show any significant correlation with CTG expansion in our study [21,22]. In conclusion, to our knowledge this is the first report of clinical and electrophysiologic features of DM from Iran. We found a correlation between CTG expansion and age of onset, temporalis wasting and mental disability in DM patients. Further studies with a larger sample size are needed to delineate more correlations. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Harper PS. Myotonic dystrophy. 2nd ed. London: W.B. Saunders; 1989. [2] Timchenko LT, Caskey CT. Trinucleotide repeat disorders in humans: discussions of mechanisms and medical issues. FASEB J 1996;10:1589–97. [3] Mandel J-L. Human genetics. Breaking the rule of three. Nature 1997;386:767–9. [4] Mahdavan M, Tsilifidis C, Sabourin I, et al. Myotonic dystrophy mutation: an unstable CTG repeat in the three untranslated region of the gene. Science 1992;255:1253–5. [5] Fu YH, Pizzuti A, Fenwick Jr RG, et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 1992;255:1256–8. [6] 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. [7] Gourie-Devi M, Chaudhuri JR, Vasanth A, et al. Correlation of clinical profile of MD with CTG repeat in the myotonin protein kinase gene. Indian J Med Res 1998;107:187–96.
[8] Tan SV, Matthews E, Barber M, et al. Refined exercise testing can aid DNAbased diagnosis in muscle channelopathies. Ann Neurol 2011;69:328–40. [9] Hunter A, Tsilfidis C, Mettler G, et al. The correlation of age of onset with CTG trinucleotide repeat amplification in myotonic dystrophy. J Med Genet 1992;29:774–9. [10] Jaspert A, Fahsold R, Grehl H, et al. Myotonic dystrophy correlation of clinical symptoms with the size of the CTG trinucleotide repeat. J Neurol 1995;242:99–104. [11] Pfeilsticker BH, Bertuzzo CS, Nucci A. Electrophysiological evaluation in myotonic dystrophy. Correlation with CTG length expansion. Arq Neuropsiquiatr 2001;59:186–91. [12] Mondelli M, Rossi A, Malandrini A, et al. Axonal motor and sensory neuropathy in myotonic dystrophy. Acta Neurol Scand 1993;88:141–8. [13] Preston DC, Shapiro BE. Electromyography and neuromuscular disorders. 2nd ed. Philadelphia: Elsevier; 2005. [14] Janson G, Williams P, Coerwinkel M, et al. Gonosomal mosaicism in myotonic dystrophy patients: involvement of mitotic events in (CTG)n repeat variation and selection against extreme expansion in sperm. Am J Hum Genet 1994;54:575–85. [15] Thornton CA, Johnson K, Moxley 3rd RT. Myotonic dystrophy patients have larger CTG expansions in skeletal muscle than in leukocytes. Ann Neurol 1994;35:104–7. [16] Ishii S, Nishio T, Sunohara H, et al. Small increase in triplet repeat length of cerebellum from patients with myotonic dystrophy. Hum Genet 1996;98:138–40. [17] Harper PS, Harley HG, Reardon W, et al. Anticipation in myotonic dystrophy: new light on an old problem. Am J Hum Genet 1992;51:10–6. [18] Harley HG, Brook JD, Rundle SA, et al. Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature 1992;355:545–6. [19] Marchini C, Lonigro R, Verriello L, et al. Correlation between individual clinical manifestation and CTG repeat amplification in myotonic dystrophy. Clin Genet 2000;57:74–82. [20] Perini GI, Menegazzo E, Ermani M, et al. Cognitive impairment and (CTG)n expansion in myotonic dystrophy patients. Biol Psychiatry 1999;46:425–31. [21] Sander HW, Tavoulareas GP, Quinto CM, et al. The exercise test distinguishes proximal myotonic myopathy from myotonic dystrophy. Muscle Nerve 1997;20:235–7. [22] Michel P, Sternberg D, Jeannet PY, et al. Comparative efficacy of repetitive nerve stimulation, exercise, and cold in differentiating myotonic disorders. Muscle Nerve 2007;36:643–50.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Correlation between distribution of muscle weakness, electrophysiological findings and CTG expansion in myotonic dystrophy Roya Khoshbakht a, Akbar Soltanzadeh a, Babak Zamani a, Siyamak Abdi a, Kourosh Gharagozli b, Kimia Kahrizi c, Rahem Khoshbakht d, Shahriar Nafissi a,⇑ a
Department of Neurology, Tehran University of Medical Sciences, Shariati Hospital, North Karegar Street, Tehran 14114, Iran Department of Neurology, Shahid Beheshti University of Medical Sciences, Tehran, Iran Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran d Department of Pathobiology, School of Veterinary Medicine, University of Shiraz, Iran b c
a r t i c l e
i n f o
Article history: Received 16 June 2012 Accepted 24 September 2013
Keywords: Clinical manifestation CTG expansion Exercise Myotonic dystrophy
a b s t r a c t Myotonic dystrophy type 1 (DM-1) is a multi-system disorder affecting the muscles, brain, cardiovascular system, endocrine system, eyes and skin. Diagnosis is made by clinical, electrodiagnostic and genetic studies. This study aimed to determine the correlation between CTG expansion and distribution of muscle weakness and clinical and electrophysiological findings. Genetically confirmed DM-1 patients presenting to Shariati Hospital between 2005 and 2011 were included in this study. Clinical, electrodiagnostic and genetic testing was performed and the correlation between CTG expansion and distribution of muscle weakness and clinical and electromyographic findings was studied. Thirty-three genetically confirmed DM-1 patients were enrolled. Myotonia, bifacial weakness and distal upper limb weakness were seen in all patients. Diabetes mellitus was found in one patient (3%), cardiac disturbance in eight (24.2%), cataracts in eight (24.2%), hypogonadism in five (15.2%), frontal baldness in 13 (39.4%), temporalis wasting in 14 (42.4%), temporomandibular joint disorder in seven (21.2%) and mental retardation in eight (24.2%). The mean number of CTG repeats, measured by Southern blot, was 8780 (range 500–15,833). A negative correlation was found between CTG expansion and age of onset. Temporalis wasting and mental retardation were positively correlated with CTG expansion. No relationship was found between weakness distribution, electromyographic findings, other systemic features and CTG expansion. In this study of DM-1 in Iran, we found a correlation between CTG expansion and age of onset, temporalis wasting and mental disability. No correlation between CTG expansion and electrodiagnostic and other clinical findings were detected. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Myotonic dystrophy (DM), with a prevalence of 1/8000, is one of the most common muscular dystrophies [1]. It is a multi-system disease that affects the muscles, brain, cardiovascular system, endocrine system, eyes and skin. The clinical presentation ranges from severe congenital hypotonia to mild adult onset weakness or even asymptomatic disease. Cardinal muscular features are myotonia, weakness and atrophy of distal and facial muscles [1]. The pattern of inheritance is autosomal dominant and the disease is a member of the trinucleotide expansion family. In myotonic dystrophy type 1 (DM-1) the CTG trinucleotide expansion occurs in an untranslated part of the dystrophia myotonica protein kinase gene on chromosome 19q 13.3 [2–4]. While normal individuals have 5 to 30 copies of CTG, the number of CTG repeats ⇑ Corresponding author. Tel.: +98 21 8490 2224; fax: +98 21 2288 4420. E-mail address: nafi[email protected] (S. Nafissi). 0967-5868/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2013.09.016
in DM-1 patients can be in the thousands [3–6]. The disease can present at an early age and can become more severe in subsequent generations in a family due to expansion of CTG repeats (anticipation phenomenon). Electrodiagnostic studies can aid in diagnosis of DM, including the short exercise test (SET). In this test, the amplitude of the compound muscle action potential (CMAP) of a distal muscle is recorded before and after 10 seconds of exercise, and the drop in CMAP amplitude is measured [8]. This study aimed to evaluate the relationship between the number of CTG repeats and pattern of muscular involvement and electromyographic (EMG) findings in DM-1 patients. 2. Materials and methods In a cross-sectional study, DM patients presenting to Shariati Hospital – a tertiary referral hospital affiliated to Tehran University of Medical Sciences – between 2005 and 2011 were evaluated. DM type 2 patients and patients without genetic confirmation were
1124
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excluded from the study. DM-1 was confirmed in 33 patients using triplet primed polymerase chain reaction, and the number of CTG repeats was determined in 21 patients using Southern blot assay. All patients were clinically examined and muscle forces were recorded based on the Medical Research Council score. Shoulder abduction, elbow flexion, elbow extension, wrist extension, finger extension, flexor pollicis longus, flexor digitorum profundus, first dorsal interosseous, abductor pollicis brevis (APB), hip flexion, hip abduction, hip adduction, hip extension, knee flexion, knee extension, foot plantar flexion, foot dorsiflexion, neck flexion and extension were examined on both sides and scored. Thorough systemic investigation was performed in all patients looking for cataracts, cardiac involvement, diabetes mellitus, hypogonadism, sterility, frontal balding and mental retardation. Patients with a Wechsler Adult Intelligence Scale score lower than 70 were considered to have a low intelligence quotient (mentally retarded). Standard four limb EMG and nerve conduction studies were performed on all patients [13] and CMAP were recorded after the SET on APB [8]. APB CMAP amplitude was recorded before and after 10 seconds of exercise and the percentage of amplitude drop in this muscle was calculated. The data were analyzed using the Statistical Package for the Social Science (SPSS, Chicago, IL, USA). The relationship between CTG repeat number and CMAP decrement and age was analyzed with regression analysis. Spearman correlation was used to show the relationship between CTG expansion and muscle strength.
3. Results Of the 33 patients entered in the study, 19 were male (57.6%). The mean age of onset was 24.8 years ± standard deviation of 10.9 years (range 2–51). All 33 patients had myotonia and bifacial weakness; ptosis was detected in 25 (78.8%) and dysphagia in seven patients (21.2%). A family history of DM was present in 25 patients (75.8%). There were no data regarding the number of CTG repeats in other family members. Weakness of at least one distal upper limb muscle was found in all 33 patients (100%) and involvement of at least one distal lower limb muscle was detected in 23 patients (69.7%). At least one proximal muscle in upper and lower limbs was involved in 21 (63.6%) and 18 (54.5%) patients, respectively. In 19 patients (87.9%) neck flexors were weak while neck extensor weakness was seen in just 10 patients (30.5%). Systemic involvement was investigated and diabetes mellitus was found in one patient (3%), cardiac disturbance in eight patients (24.2%) (right bundle branch block 37.5%, mitral valve prolapse 25%, and diastolic dysfunction, septal hypokinesia, prolonged PQ and left bundle branch block all 12.5%), cataract in eight (24.2%), hypogonadism in five (15.2%), frontal baldness in 13 (39.4%), temporalis wasting in 14 (42.4%), temporomandibular joint dysfunction in seven (21.2%) and mental retardation in eight patients (24.2%) (Table 1). All patients in this study had EMG myotonic discharges in the distal muscles of the upper limbs. The mean decrement of CMAP amplitude after SET was 32.7 ± 22.7%, ranging from 0 to 83.5% (Table 2). Decrement of
Table 1 Clinical characteristics and CTG expansion in myotonic dystrophy patients #
CTG repeats
Sex
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
800 500 1000 12333 8400 13833 13500 13567 8833 7167 10833 15833 11833 10833 10567 6833 5150 9567 5333 8833 8833 NA NA NA NA NA NA NA NA NA NA NA NA
F F M F F M M M M F F F M F M M M M F M F F M M M F F F M M M M M
Age of symptom onset 28 20 30 21 37 2 18 14 37 51 24 15 9 20 22 37 31 20 20 15 34 24 22 11 19 36 32 20 50 21 24 18 38
Family history + + + + + + + + + + + + + + + + + + + + + + + + +
Cardiac disturbance
Cataract
Infertility
+ + + + + + + +
+ + + + + + + +
+ + + + +
Frontal balding + + + + + + + + + + + + +
MR
Temporalis wasting
Bifacial weakness
Dysphagia
TMJ dislocation
Ptosis
+ + + + + + + +
+ + + + + + + + + + + + + +
+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+ + + + + + +
+
+ + + + + + + + + + + + + + + + + + + + + + + + +
F = female, M = male, MR = mental retardation, NA = not available, TMJ = temporomandibular joint, + = present, = absent.
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R. Khoshbakht et al. / Journal of Clinical Neuroscience 21 (2014) 1123–1126 Table 2 CTG expansion, compound muscle action potentials, area decrement and muscle force of abductor pollicis brevis in myotonic dystrophy patients Patient
CTG repeats
CMAP amplitude decrement (%)
CMAP area decrement (%)
Disease duration (years)
APB forcea (0–5)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
800 500 1000 12333 8400 13833 13500 13567 8833 7167 10833 15833 11833 10833 10567 6833 5150 9567 5333 8833 8833 NA NA NA NA NA NA NA NA NA NA NA NA
6.6 56.5 28.7 .0 10.9 20 23 23.8 40.6 .0 8.4 35.7 45.8 58 27.2 43.9 44.8 30.7 7.5 25.5 .0 79.3 41.6 17.4 20 63.8 13.3 12.1 56 42.8 52.6 83.5 59.7
1.3 60.9 36.4 20.2 35.9 24.3 39.2 27.2 45.1 15.1 48.3 46.5 61.8 63.6 36.4 58.2 66.2 45.8 44.3 48.1 25.7 77.2 48.1 23.2 34.2 78.3 15.2 11.1 48.6 66.6 65.2 76.9 62.6
4 8 13 24 12 29 31 9 10 7 15 16 10 20 15 2 6 12 4 22 2 13 18 32 20 5 3 2 4 33 2 20 1
4 5 4 4 4 4 4 4 3 3 4 5 4 4 4 4 4 5 4 4 4 5 4 3 4 3 3 5 4 4 4 3 5
a Based on the Medical Research Council score. APB = abductor pollicis brevis, CMAP = compound muscle action potentials, NA = not available.
CMAP amplitude was 0–20% in 12 patients (36.4%) and more than 20% in 21 patients (63.6%). The number of CTG repeats was determined by Southern blot assay. The mean number of CTG repeats was 8780 ± 4353 (range 500–15,833). The correlation between CTG expansion and strength of different muscles was studied using the Spearman correlation test and no significant correlations were detected. Using regression analysis, no significant correlation was found between CMAP decrement after SET and CTG expansion in the APB muscle. The anticipation phenomenon was evaluated and a significant negative correlation was present between age of onset and CTG expansion (r = 0.001, p = 0.035) using regression analysis. Considering the systemic features of DM, only mental retardation and temporalis wasting had a positive correlation with CTG expansion (r = 0.443, p = 0.044 and r = 0.485, p = 0.026, respectively).
4. Discussion DM, a multi-system disease which used to be diagnosed clinically with some contribution from electrodiagnostic studies, is now diagnosed easily using a genetic study. Asymptomatic or minimally symptomatic patients are now diagnosed by measuring the number of CTG repeats [7]. Knowing the number of CTG repeats in a patient has been viewed as an important piece of information that could possibly prognosticate the severity of disease. Various studies have investigated the correlation between CTG expansion and clinical manifestations with some intriguing results reported [7,9–11]. Our study attempted to cast light on this problem. Muscle weakness was seen, in order of frequency in this study, in the distal
upper, distal lower, proximal upper and proximal lower limb muscles. All patients had distal upper limb muscle involvement, with deep finger flexors such as flexor pollicis longus being the most commonly involved (97%). Foot dorsiflexors were the most commonly involved muscles in the lower limbs (69%). These results are in agreement with other studies [7,9–11]. Mondelli et al. reported that 46% of their patients had peripheral nervous system involvement (polyneuropathy) and Pfeilsticker et al. reported this finding in 25.9% [11,12]. None of our 33 patients showed any sign of neuropathy on clinical examination or electrodiagnostic studies [12]. In the Pfeilsticker et al. series, seven out of 27 patients had polyneuropathy, and four of them were diabetic. Diabetes or some other underlying disease may have been the cause of polyneuropathy in some of these patients [11]. Some studies have shown a positive correlation between CTG expansion and clinical severity of DM [3,4]. Other studies did not confirm this correlation [7,10]. We did not find any correlation between severity of muscle weakness and CTG expansion. The small sample size might be an explanation for the lack of correlation [7]. Another explanation could be tissue heterogeneity for the expanded allele in DM as CTG expansion is seen more in muscles than in leukocytes; this theory has not been validated [14–17]. As has been shown in most previous studies, there was a negative correlation between CTG expansion and age of onset in our study [6,7,11,18,19]. Perini et al. and Marchini et al. found a direct relationship between mental disability and CTG expansion [19,20]. Our study showed the same correlation. The CTG expansion was larger in mentally retarded patients compared to patients with a normal intelligence quotient. Our study also showed that temporalis wasting was seen more often in patients with larger CTG
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expansions, which has not been reported in previous studies. Like other studies, no correlation between other systemic features and CTG expansion was detected [10,19]. CMAP decrement after SET, which is useful in differentiating proximal myotonic myopathy from DM-1, did not show any significant correlation with CTG expansion in our study [21,22]. In conclusion, to our knowledge this is the first report of clinical and electrophysiologic features of DM from Iran. We found a correlation between CTG expansion and age of onset, temporalis wasting and mental disability in DM patients. Further studies with a larger sample size are needed to delineate more correlations. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Harper PS. Myotonic dystrophy. 2nd ed. London: W.B. Saunders; 1989. [2] Timchenko LT, Caskey CT. Trinucleotide repeat disorders in humans: discussions of mechanisms and medical issues. FASEB J 1996;10:1589–97. [3] Mandel J-L. Human genetics. Breaking the rule of three. Nature 1997;386:767–9. [4] Mahdavan M, Tsilifidis C, Sabourin I, et al. Myotonic dystrophy mutation: an unstable CTG repeat in the three untranslated region of the gene. Science 1992;255:1253–5. [5] Fu YH, Pizzuti A, Fenwick Jr RG, et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 1992;255:1256–8. [6] 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. [7] Gourie-Devi M, Chaudhuri JR, Vasanth A, et al. Correlation of clinical profile of MD with CTG repeat in the myotonin protein kinase gene. Indian J Med Res 1998;107:187–96.
[8] Tan SV, Matthews E, Barber M, et al. Refined exercise testing can aid DNAbased diagnosis in muscle channelopathies. Ann Neurol 2011;69:328–40. [9] Hunter A, Tsilfidis C, Mettler G, et al. The correlation of age of onset with CTG trinucleotide repeat amplification in myotonic dystrophy. J Med Genet 1992;29:774–9. [10] Jaspert A, Fahsold R, Grehl H, et al. Myotonic dystrophy correlation of clinical symptoms with the size of the CTG trinucleotide repeat. J Neurol 1995;242:99–104. [11] Pfeilsticker BH, Bertuzzo CS, Nucci A. Electrophysiological evaluation in myotonic dystrophy. Correlation with CTG length expansion. Arq Neuropsiquiatr 2001;59:186–91. [12] Mondelli M, Rossi A, Malandrini A, et al. Axonal motor and sensory neuropathy in myotonic dystrophy. Acta Neurol Scand 1993;88:141–8. [13] Preston DC, Shapiro BE. Electromyography and neuromuscular disorders. 2nd ed. Philadelphia: Elsevier; 2005. [14] Janson G, Williams P, Coerwinkel M, et al. Gonosomal mosaicism in myotonic dystrophy patients: involvement of mitotic events in (CTG)n repeat variation and selection against extreme expansion in sperm. Am J Hum Genet 1994;54:575–85. [15] Thornton CA, Johnson K, Moxley 3rd RT. Myotonic dystrophy patients have larger CTG expansions in skeletal muscle than in leukocytes. Ann Neurol 1994;35:104–7. [16] Ishii S, Nishio T, Sunohara H, et al. Small increase in triplet repeat length of cerebellum from patients with myotonic dystrophy. Hum Genet 1996;98:138–40. [17] Harper PS, Harley HG, Reardon W, et al. Anticipation in myotonic dystrophy: new light on an old problem. Am J Hum Genet 1992;51:10–6. [18] Harley HG, Brook JD, Rundle SA, et al. Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature 1992;355:545–6. [19] Marchini C, Lonigro R, Verriello L, et al. Correlation between individual clinical manifestation and CTG repeat amplification in myotonic dystrophy. Clin Genet 2000;57:74–82. [20] Perini GI, Menegazzo E, Ermani M, et al. Cognitive impairment and (CTG)n expansion in myotonic dystrophy patients. Biol Psychiatry 1999;46:425–31. [21] Sander HW, Tavoulareas GP, Quinto CM, et al. The exercise test distinguishes proximal myotonic myopathy from myotonic dystrophy. Muscle Nerve 1997;20:235–7. [22] Michel P, Sternberg D, Jeannet PY, et al. Comparative efficacy of repetitive nerve stimulation, exercise, and cold in differentiating myotonic disorders. Muscle Nerve 2007;36:643–50.
