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Brain Advance Access first published online on June 23, 2004
This version published online on June 29, 2004
Brain, doi:10.1093/brain/awh216
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Received September 16, 2003
Revised April 20, 2004
Accepted April 23, 2004

Article

A non-DM1, non-DM2 multisystem myotonic disorder with frontotemporal dementia: phenotype and suggestive mapping of the DM3 locus to chromosome 15q21-24

Isabelle Le Ber 1, Maria Martinez 2, Dominique Campion 3, Annie Laquerrière 4, Christine Bétard 5, Guillaume Bassez 6, Carol Girard 1, Pascale Saugier-Veber 3, Gregory Raux 3, Nicolas Sergeant 7, Patrick Magnier 8, Thierry Maisonobe 9, Bruno Eymard 10, Charles Duyckaerts 11, André Delacourte 7, Thierry Frebourg 12, Didier Hannequin 13*

1 Département de Neurologie, Centre Hospitalo-Universitaire Charles Nicolle, Rouen, France
2 INSERM EMI 0006, Evry, France
3 INSERM U614 IRFMP, Faculté de Médecine et de Pharmacie, Rouen, France
4 Département de Neuropathologie, Centre Hospitalo-Universitaire Charles Nicolle, Rouen, France
5 Centre National de Génotypage, Evry, France
6 Service d'Histologie, Hôpital Henri Mondor, Créteil, France
7 INSERM U422, Groupe VCDN, Lille, France
8 Service d'Explorations Neurophysiologiques, Centre Hospitalo-Universitaire Charles Nicolle, Rouen, France
9 Service d'Explorations Neurophysiologiques, Paris
10 Institut de Myologie, Hôpital de la Salpêtrière, Paris
11 Laboratoire de Neuropathologie Escourolle and INSERM U289, Hôpital de la Salpêtrière, Paris
12 Service de Génétique Médicale, Centre Hospitalo-Universitaire Charles Nicolle, Rouen, France; INSERM U614 IRFMP, Faculté de Médecine et de Pharmacie, Rouen, France
13 Département de Neurologie, Centre Hospitalo-Universitaire Charles Nicolle, Rouen, France; Service de Génétique Médicale, Centre Hospitalo-Universitaire Charles Nicolle, Rouen, France; INSERM U614 IRFMP, Faculté de Médecine et de Pharmacie, Rouen, France

* To whom correspondence should be addressed. E-mail: Didier.Hannequin{at}chu-rouen.fr.


  Abstract

Summary The majority of proximal myotonic myopathy syndromes reported so far have been related to the myotonic dystrophy (DM) type 2 (DM2) mutation, an expanded (CCTG)n repeat in the ZNF9 gene. Here, we describe the phenotype and the histological features in muscle and brain of the first large pedigree with a non-myotonic dystrophy type 1 (DM1) non-DM2 multisystem myotonic disorder associated with severe frontotemporal dementia. Thirty individuals from three generations underwent detailed neurological, neuro-psychological, electrophysiological, brain imaging and molecular analyses. Ten of them had proximal muscle weakness at onset, clinical/electrical myotonia and DM-type cataracts. The mean age at onset was 46.7 ± 12.6 years (range: 32-69). Dementia was observed later in the course of the disease. On muscle biopsies, rare nuclear clumps, rimmed vacuoles and small angulated type 1 and type 2 fibres were seen early in the disease. They were replaced by fibrous adipose tissue at later stages. Immunohistochemical analysis of myosin heavy chain isoforms showed no selective fibre type atrophy--both type 1 and type 2 fibres being affected. Cortical atrophy without white matter lesions was seen on brain MRI. A brain single photon emission computed tomography (SPECT) study revealed marked frontotemporal hypoperfusion. Post-mortem examination of the brains of two patients showing prominent frontotemporal spongiosis, neuronal loss and rare neuronal and glial tau inclusions suggested frontotemporal dementia. Western blot analyses of the tau protein showed a triplet of isoforms (60, 64 and 69 kDa) in neocortical areas, and a doublet (64 and 69 kDa) in subcortical areas that distinguish our myotonic disorder from other's myotonic dystrophies. Molecular analyses failed to detect a repeat expansion in the DMPK and ZNF9 genes excluding both DM1 and DM2, whereas a genome-wide linkage analysis strongly suggested a linkage to chromosome 15q21-24. This previously unreported multisystem myotonic disorder including findings resembling DM1, DM2 and frontotemporal dementia provides further evidence of the clinical and genetic heterogeneity of the myotonic dystrophies. We propose to designate this disease myotonic dystrophy type 3, DM3.

Keywords: myotonic dystrophy; DM1; PROMM/DM2; DM3; frontotemporal dementia.
The following items in this paper have been updated: Figure 1; the legend for Table 1; the legend for Table 2.
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