title: A non-DM1, non-DM2 multisystem myotonic disorder with frontotemporal dementia: phenotype and suggestive mapping of the DM3 locus to chromosome 15q21-24.
abstract: 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, neuropsychological, 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.
authors.affiliation: Département de Neurologie, Centre Hospitalo-Universitaire Charles Nicolle, Rouen, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.forename: Annie
authors.initials: A
authors.lastname: Laquerrière
authors.forename: Christine
authors.initials: C
authors.lastname: Bétard
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bassez
authors.forename: Carol
authors.initials: C
authors.lastname: Girard
authors.forename: Pascale
authors.initials: P
authors.lastname: Saugier-Veber
authors.forename: Gregory
authors.initials: G
authors.lastname: Raux
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
authors.forename: Patrick
authors.initials: P
authors.lastname: Magnier
authors.forename: Thierry
authors.initials: T
authors.lastname: Maisonobe
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.forename: Charles
authors.initials: C
authors.lastname: Duyckaerts
authors.forename: André
authors.initials: A
authors.lastname: Delacourte
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D002874:Chromosome Mapping / Q000379:methods; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D003704:Dementia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018908:Muscle Weakness / Q000209:etiology / Q000235:genetics / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology; D018995:Myosin Heavy Chains / Q000032:analysis; D020967:Myotonic Disorders / Q000150:complications / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000235:genetics; D012744:Sex Ratio; D016875:tau Proteins / Q000032:analysis
chemical_list: C433227:CNBP protein, human; D016601:RNA-Binding Proteins; D016875:tau Proteins; D018995:Myosin Heavy Chains