Cognitive deficits and CTG repeat expansion size in classical myotonic dystrophy type 1 (DM1)

Stefan Winblad, Christopher Lindberg, Stefan Hansen, Stefan Winblad, Christopher Lindberg, Stefan Hansen

Abstract

Background: This study was designed to investigate cognitive abilities and their correlations with CTG repeat expansion size in classical Myotonic dystrophy type 1 (DM1), given that earlier studies have indicated cognitive deficits, possibly correlating with blood CTG repeats expansion size.

Methods: A measurement of CTG repeat expansion in lymphocytes and an extensive neuropsychological examination was made in 47 patients (25 women and 22 men). Individual results in the examination were compared with normative data.

Results: A substantial proportion of patients with DM1 (> 40%) scored worse in comparison to normative collectives on tests measuring executive, arithmetic, attention, speed and visuospatial abilities. We found significant correlations between longer CTG repeat expansion size and lower results on most tests associated with these abilities. Furthermore, the association between executive (frontal) deficits and DM1 were strengthened when considering both test results and correlations with CTG repeat expansion size in lymphocytes.

Conclusion: This study showed deficits in several cognitive abilities when patients with DM1 are compared to normative collectives. Some of the neuropsychological tests associated with these abilities are correlated to CTG repeat expansion size in blood. These data highlight the importance of considering cognitive deficits when seeing patients with classical DM1 in clinical practice, but also the utility of using blood CTG repeat expansion size as a broad predictor of finding cognitive deficit in DM1.

Figures

Figure 1
Figure 1
Correlation between CTG repeats expansion size and total number of tests 1 SD < normative mean. Correlation between CTG repeats expansion size and total number of tests 1 SD < normative mean in patients with DM1 (P = < 0.05, rho = 0.30).

References

    1. Meola G. Myotonic dystrophies. Curr Opin Neurol. 2000;5:519–525. doi: 10.1097/00019052-200010000-00003.
    1. Brunner HG, Jennekens FGI, Smeets HJM, de Visser M, Winzen AR. Myotonic dystrophy (Steinerts disease) In: Emery AEH, editor. Diagnostic criteria for neuromuscular disorders. 2. London: Royal Society of Medicine Press; 1994. pp. 27–29.
    1. Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church C, Aburatani H, et al. Molecular basis of myotonic dystrophy: Expansion of a trinucleotid (CTG) repeat at the 3'end of a transcript encoding a protein kinase family member. Cell. 1992;68:799–808. doi: 10.1016/0092-8674(92)90154-5.
    1. Day JW, Ranum LP. RNA pathogenesis of the myotonic dystrophies. Neuromuscul Disord. 2005;1:5–16. doi: 10.1016/j.nmd.2004.09.012.
    1. Ashizawa T. Myotonic dystrophy as a brain disorder. Arch Neurol. 1998;3:291–293. doi: 10.1001/archneur.55.3.291.
    1. D'Angelo MG, Bresolin N. Report of the 95th European Neuromuscular Centre (ENMC) sponsored international workshop cognitive impairment in neuromuscular disorders, Naarden, The Netherlands, 13–15 July, 2001. Neuromuscul Disord. 2003;1:72–79. doi: 10.1016/S0960-8966(02)00155-4.
    1. Meola G, Sansone V, Perani D, Colleluori A, Cappa S, Cotelli M, et al. Reduced cerebral blood flow and impaired visual-spatial function in proximal myotonic dystrophy. Neurol. 1999;53:1042–1050.
    1. Meola G, Sansone V, Perani D, Collelouri A, Cappa S, Dragoni C, et al. Executive dysfunction and avoidant personality trait in myotonic dystrophy type 1 (DM-1) and in proximal myotonic dystrophy (PROMM/DM-2) Neuromuscul Disord. 2003;10:813–821. doi: 10.1016/S0960-8966(03)00137-8.
    1. Rubinsztein JS, Rubinsztein JC, McKenna PJ, Goodburn S, Holland AJ. Mild myotonic dystrophy is associated with memory impairment in the context of normal intelligence. J Med Genet. 1997;3:229–33.
    1. Damian MS, Bachmann G, Koch MC, Schilling G, Stoppler S, Dorndorf W. Brain disease and molecular analysis in myotonic dystrophy. Neuroreport. 1994;18:2549–2552.
    1. Winblad S, Lindberg C, Hansen S. Temperament and character in patients with classical myotonic dystrophy type 1 (DM-1) Neuromuscul Disord. 2005;15:287–292. doi: 10.1016/j.nmd.2004.12.003.
    1. Winblad S, Hellström P, Lindberg C, Hansen S. Facial emotion recognition in myotonic dystrophy type 1 correlates with CTG repeat expansion. J Neurol Neurosurg Psychiatry. 2006;2:219–223. doi: 10.1136/jnnp.2005.070763.
    1. Marchini C, Lonigro R, Veriello L, Pellizarri L, Bergonzi P, Damante G, et al. Correlations between individual clinical manifestations and CTG repeat amplification in myotonic dystrophy. Clin Genet. 2000;1:74–82. doi: 10.1034/j.1399-0004.2000.570112.x.
    1. Steyaert J, Umans S, Willekens D, Legius E, Pijkels E, de Die-Smulders C. A study of the cognitive and psychological profile in 16 children with congential or juvenile myotonic dystrophy. Clin Genet. 1997;3:135–41.
    1. Brooke MH. A clinician's view of neuromuscular diseases. 2. Baltimore: Williams & Willkins; 1986.
    1. Nordenskiöld U, Grimby G. Grip force in patients with rheumatoid arthritis and fibromyalgia and in healthy subjects. A study with the Grippit instrument. Scand J Rheumatol. 1993;22:14–19.
    1. Wechsler D. Wechsler Adult Intelligence Scale – Revised (WAIS-R) The Psychological Corporation. 1982.
    1. Tombaugh TN, Kozak J, Rees L. Normative data stratified by age and education for two measures of verbal fluency: FAS and animal naming. Arch Clin Neuropsychol. 1999;2:167–77. doi: 10.1016/S0887-6177(97)00095-4.
    1. Fastenau PS, Denburg NL, Hufford BJ. Adult norms for the Rey-Osterieth Complex Figure Test and for supplemental recognition and matching trials from the extended complex figure test. Clin Neuropsychol. 1999;1:30–47.
    1. Schmidt M. Rey Auditory Verbal Learning Test. A Handbook. Western Psychological Services. 1996.
    1. Tombaugh T. Trail Making Test A and B: normative data stratified by age and education. Arch Clin Neuropsychol. 2004;19:203–214. doi: 10.1016/S0887-6177(03)00039-8.
    1. Mitrushina M, Boone KB, Razani J, D'Elia LF. Handbook of normative data for neuropsychological assessment. New York: Oxford University Press; 2005. pp. 108–133.
    1. Grant DA, Berg EA, Nyman H. Wisconsin Card Sorting Test. WCST -revised and expanded. Psykologiförlaget. 1996.
    1. Modoni A, Silvestri G, Pomponi MG, Mangiola F, Tonali PA, Marra C. Characterization of the pattern of cognitive impairment in myotonic dystrophy type 1. Arch Neurol. 2004;61:1943–1947. doi: 10.1001/archneur.61.12.1943.
    1. Perini GI, Menegazzo E, Ermani M, Zara M, Gemma A, Feruzzi E, et al. Cognitive impairment and CTG (n) expansion in myotonic dystrophy patients. Biol Psychiatry. 1999;3:425–431. doi: 10.1016/S0006-3223(99)00016-5.
    1. Toga AW, Thompson PM. Genetics of brain structure and intelligence. Ann Rev Neurosci. 2005;28:1–23. doi: 10.1146/annurev.neuro.28.061604.135655.
    1. Bäckman L, Jones S, Berger AK, Laukka EJ, Small BJ. Multiple cognitive deficits during the transition to Alzheimer's disease. J Intern Med. 2004;3:195–204. doi: 10.1111/j.1365-2796.2004.01386.x.
    1. Martin GM. Genetic modulation of senescent phenotypes in Homo sapiens. Cell. 2005;4:523–532. doi: 10.1016/j.cell.2005.01.031.
    1. Wilson BA, Balleny H, Patterson K, Hodges JR. Myotonic dystrophy and progressive cognitive decline: a common condition or two separate problems. Cortex. 2006;1:113–121.
    1. Tuikka RA, Laaksonen RK, Somer HV. Cognitive function in myotonic dystrophy: a follow up study. Eur Neurol. 1993;6:436–441.
    1. Martorell L, Monckton DG, Gamez J, Baiget M. Complex patterns of male germline instability and somatic mosaicism in myotonic dystrophy type 1. Eur J Hum Genet. 2000;6:423–430. doi: 10.1038/sj.ejhg.5200478.
    1. Sergeant N, Sablonierre B, Schraen-Maschke S, Ghestem A, Maurage CA, Wattez A, et al. Dysregulation of human brain microtubule-associated mRNA mutation in myotonic dystrophy type 1. Hum Mol Genet. 2001;10:2143–55. doi: 10.1093/hmg/10.19.2143.
    1. Harper PS. Myotonic dystrophy. London PA: WB & Saunders; 2001.
    1. Jaspert A, Fashold R, Grehl H, Claus D. Myotonic dystrophy: correlation of clinical symptoms with size of the CTG trinucleotide repeat. J Neurol. 1995;2:99–104. doi: 10.1007/BF00887824.
    1. Turnpenny P, Clark C, Kelly K. Intelligence quotient profile in myotonic dystrophy, intergenerational deficit, and correlation with CTG amplification. J Med Genet. 1994;4:300–305.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera