Expanding the clinical, pathological and MRI phenotype of DNM2-related centronuclear myopathy.
Mutations in dynamin-2 (DNM2) cause autosomal dominant centronuclear myopathy (CNM). We report a series of 12 patients from eight families with CNM in whom we have identified a number of novel features that expand the reported clinicopathological phenotype. We identified two novel and five recurrent missense mutations in DNM2. Early clues to the diagnosis include relative weakness of neck flexors, external ophthalmoplegia and ptosis, although these are not present in all patients. Pes cavus was present in two patients, and in another two members of one family there was mild slowing of nerve conduction velocities. Whole-body MRI examination in two children and one adult revealed a similar pattern of involvement of selective muscles in head (lateral pterygoids), neck (extensors), trunk (paraspinal) and upper limbs (deep muscles of forearm). Findings in lower limbs and pelvic region were similar to that previously reported in adults with DNM2 mutations. Two patients presented with dystrophic changes as the predominant pathological feature on muscle biopsies; one of whom had a moderately raised creatine kinase, and both patients were initially diagnosed as congenital muscular dystrophy. DNM2 mutation analysis should be considered in patients with a suggestive clinical phenotype despite atypical histopathology, and MRI findings can be used to guide genetic testing. Subtle neuropathic features in some patients suggest an overlap with the DNM2 neuropathy phenotype. Missense mutations in the C-terminal region of the PH domain appear to be associated with a more severe clinical phenotype evident from infancy.
Susman
Rachel D
RD
The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, 2145, Sydney, NSW, Australia.
Quijano-Roy
Susana
S
Yang
Nan
N
Webster
Richard
R
Clarke
Nigel F
NF
Dowling
Jim
J
Kennerson
Marina
M
Nicholson
Garth
G
Biancalana
Valerie
V
Ilkovski
Biljana
B
Flanigan
Kevin M
KM
Arbuckle
Susan
S
Malladi
Chandra
C
Robinson
Phillip
P
Vucic
Steven
S
Mayer
Michèle
M
Romero
Norma B
NB
Urtizberea
Jon Andoni
JA
García-Bragado
Federico
F
Guicheney
Pascale
P
Bitoun
Marc
M
Carlier
Robert-Yves
RY
North
Kathryn N
KN
D000293:Adolescent; D000328:Adult; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D034285:Dynamin II / Q000235:genetics*; D005260:Female; D005530:Foot Deformities / Q000235:genetics / Q000473:pathology; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology* / Q000503:physiopathology; D020125:Mutation, Missense / Q000235:genetics; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D009431:Neural Conduction / Q000235:genetics; D010523:Peripheral Nervous System Diseases / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D010641:Phenotype; D017434:Protein Structure, Tertiary / Q000235:genetics
D005819:Genetic Markers; D034285:Dynamin II