Clinical features of facioscapulohumeral muscular dystrophy 2.
OBJECTIVE
In some 5% of patients with facioscapulohumeral muscular dystrophy (FSHD), no D4Z4 repeat contraction on chromosome 4q35 is observed. Such patients, termed patients with FSHD2, show loss of DNA methylation and heterochromatin markers at the D4Z4 repeat that are similar to patients with D4Z4 contractions (FSHD1). This commonality suggests that a change in D4Z4 chromatin structure unifies FSHD1 and FSHD2. The aim of our study was to critically evaluate the clinical features in patients with FSHD2 in order to establish whether these patients are phenotypically identical to FSHD1 and to establish the effects of the (epi-) genotype on the phenotype.


METHODS
This cross-sectional study studied 33 patients with FSHD2 from 27 families, the largest cohort described to date. All patients were clinically assessed using a standardized clinical evaluation form. Genotype analysis was performed by pulsed field gel electrophoresis and PCR; D4Z4 methylation was studied by methylation-sensitive Southern blot analysis.


RESULTS
FSHD2 is identical to FSHD1 in its clinical presentation. Notable differences include a higher incidence (67%) of sporadic cases and the absence of gender differences in disease severity in FSHD2. Overall, average disease severity in FSHD2 was similar to that reported in FSHD1 and was not influenced by D4Z4 repeat size. In FSHD2, a small effect of the degree of hypomethylation on disease severity was observed.


CONCLUSIONS
Clinically, patients with FSHD2 are indistinguishable from patients with FSHD1. The present data suggest that FSHD1 and FSHD2 are the result of the same pathophysiologic process.
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
J C
JC
de Greef
R J L F
RJ
Lemmers
P
P
Camaño
J W
JW
Day
S
S
Sacconi
M
M
Dunand
B G M
BG
van Engelen
S
S
Kiuru-Enari
G W
GW
Padberg
A L
AL
Rosa
C
C
Desnuelle
S
S
Spuler
M
M
Tarnopolsky
S L
SL
Venance
R R
RR
Frants
S M
SM
van der Maarel
R
R
Tawil
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002894:Chromosomes, Human, Pair 4; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D019175:DNA Methylation / Q000235:genetics; D042622:DNA Repeat Expansion / Q000235:genetics; D005192:Family Health; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D016601:RNA-Binding Proteins; D055815:Young Adult
C101270:FRG1 protein, human; C499414:FRG2 protein, human; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins