A Five-Year Longitudinal Study in Facioscapolohumeral Muscular Dystrophy: Assessment of Variables Influencing Disease Progression

Background: Reduction of tandemly arrayed D4Z4 repeats is diagnostic for facioscapulohumeral muscular dystrophy (FSHD). However, various clinical phenotypes have been observed in carriers of this molecular lesion. Currently their natural history is obscure. Methods: A prospective observational cohort study is conducted to quantify disease progression over five-year follow-up (2013-2016) in246 carriers of D4Z4 reduced alleles DRA with 1-10 RU from the Italian National Registry for FSHD recruited between January 10th, 2007 and December 20th, 2011. Participants were subdivided in probands (141, males 84) and relatives (105, males 52). Muscle impairment was measured as FSHD score and disease progression as ΔFSHD score. Clinical phenotypes were assessed and categorized on the basis of the Comprehensive Clinical Evaluation Form (CCEF). Findings: The highest ΔFSHD score (1·7) was found in subjects with full FSHD phenotype (category A) or with complex/atypical diseases (category D); subjects with incomplete clinical phenotype (category B) had lower ΔFSHD score (0·6, p<0.0001). Of 97subjects with mild or no disability (FSHD score 0-2) at baseline 63 (64·9%) maintained the same FSHD score (ΔFSHD score 0); 79·1% of asymptomatic carriers (38/48)remained asymptomatic. Disease worsened in 79·4% (112/141) of probands versus 38·1% (40/105) of relatives and advanced more rapidly in probands compared to affected relatives (ΔFSHD score 2·3 versus 1·2). We found no differences in disease progression between the two sexes (p=0·151). Among different muscles investigated by MRC grading scale, tibialis anterior was affected the most (41·0% (101/246) of subjects) at baseline; in five years its strength diminished in 49·6% (70/141) of probands. Interpretation: CCEF categories have strong prognostic effect in carriers of DRA. Assessment of clinical phenotypes and family kinship are pivotal for the clinical management of DRA carrier and should guide eligibility criteria for clinical trials. Funding Statement: Telethon Italy GUP13012, AFM Telethon 16593, Regione Emilia Romagna RARER. Declaration of Interests: The authors report no competing interests. Ethics Approval Statement: The INRF database was approved by the local ethics committee of the contributing centers. Informed written consent was obtained from all study participants, in accordance with the ethical standards of the 1964 Declaration of Helsinki.