TY - JOUR
T1 - Facioscapulohumeral muscular dystrophy 1 patients participating in the UK FSHD registry can be subdivided into 4 patterns of self-reported symptoms
AU - Banerji, Christopher R.S.
AU - Cammish, Phillip
AU - Evangelista, Teresinha
AU - Zammit, Peter S.
AU - Straub, Volker
AU - Marini-Bettolo, Chiara
PY - 2020/4
Y1 - 2020/4
N2 - Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant incurable skeletal muscle disease. FSHD1 constitutes 95% of cases and is linked to truncation of the D4Z4 macrosatellite at 4q35. In most cases the condition initially presents with facial and proximal weakness of the upper limbs, but over the course of the disease involves lower limb and truncal muscles. Weakness is progressive and frequently asymmetric, which is a hallmark of the disease. Here we performed an analysis of 643 FSHD1 patients in the UK FSHD patient registry, investigating factors affecting rate of onset of 5 major FSHD symptoms: facial, periscapular, foot dorsiflexor, hip girdle weakness, and hearing loss. We found shorter D4Z4 repeat length associated with accelerated onset of each symptom. Furthermore, paternal inheritance of the pathogenic allele was associated with accelerated onset of foot dorsiflexor weakness, while pregnancy and carrying multiple children to term was associated with slower onset of all muscle symptoms. Lastly, we performed clustering analysis on age of onset of the 4 muscle symptoms across 222 patients. We identified 4 clinical presentations of FSHD1. A classical presentation (74%) and 3 facial sparing phenotypes: a mild presentation (5%) with later facial and periscapular involvement, an early shoulder presentation (10%) with accelerated periscapular weakness and an early foot presentation (9%) with accelerated foot dorsiflexor weakness. The mild presentation was associated with longer D4Z4 repeat lengths, while the early foot presentation had a female bias. We note, however that symptom progression differs significantly in these 4 clinical presentations independently of D4Z4 repeat length and gender, motivating investigation of further modifiers of FSHD1 severity.
AB - Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant incurable skeletal muscle disease. FSHD1 constitutes 95% of cases and is linked to truncation of the D4Z4 macrosatellite at 4q35. In most cases the condition initially presents with facial and proximal weakness of the upper limbs, but over the course of the disease involves lower limb and truncal muscles. Weakness is progressive and frequently asymmetric, which is a hallmark of the disease. Here we performed an analysis of 643 FSHD1 patients in the UK FSHD patient registry, investigating factors affecting rate of onset of 5 major FSHD symptoms: facial, periscapular, foot dorsiflexor, hip girdle weakness, and hearing loss. We found shorter D4Z4 repeat length associated with accelerated onset of each symptom. Furthermore, paternal inheritance of the pathogenic allele was associated with accelerated onset of foot dorsiflexor weakness, while pregnancy and carrying multiple children to term was associated with slower onset of all muscle symptoms. Lastly, we performed clustering analysis on age of onset of the 4 muscle symptoms across 222 patients. We identified 4 clinical presentations of FSHD1. A classical presentation (74%) and 3 facial sparing phenotypes: a mild presentation (5%) with later facial and periscapular involvement, an early shoulder presentation (10%) with accelerated periscapular weakness and an early foot presentation (9%) with accelerated foot dorsiflexor weakness. The mild presentation was associated with longer D4Z4 repeat lengths, while the early foot presentation had a female bias. We note, however that symptom progression differs significantly in these 4 clinical presentations independently of D4Z4 repeat length and gender, motivating investigation of further modifiers of FSHD1 severity.
KW - Clinical subgroup
KW - Facioscapulohumeral muscular dystrophy
KW - FSHD
KW - FSHD1
KW - Heterogeneity
KW - Patient registry
KW - Symptom onset
UR - http://www.scopus.com/inward/record.url?scp=85083435692&partnerID=8YFLogxK
U2 - 10.1016/j.nmd.2020.03.001
DO - 10.1016/j.nmd.2020.03.001
M3 - Article
AN - SCOPUS:85083435692
SN - 0960-8966
VL - 30
SP - 315
EP - 328
JO - Neuromuscular Disorders
JF - Neuromuscular Disorders
IS - 4
ER -