Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited myopathies in adults. It is associated with genetic and epigenetic deregulation of the D4Z4 locus on the sub-telomeric region of chromosome 4q35, resulting in abnormal expression of DUX4p. Type 1 FSHD (FSHD1) is the most common form of the disease and accounts for 95% of cases, while Type 2 FSHD (FSHD2) accounts for only 5% of all FSHD cases. FSHD1 and FSHD2 are closely related in terms of genetic and epigenetic foundations, pathophysiology and clinical manifestations. Although initially described as distinct entities based on their genetics, recent information suggests that both forms of myopathy may represent the opposite ends of a spectrum of molecular diseases in which alteration of the genetic and epigenetic factors that govern DUX4 suppression in skeletal muscle have a different impact in both forms of the disease. FSHD1 and FSHD2 are both associated with re-expression of DUX4 leading to muscle atrophy, but the genetics underlying this re-expression are different, depending on whether it is type 1 or type 2. For FSHD1, it is associated with a critical contraction of the D4Z4 region and the 4qA permissive allele, leading to the expression of DUX4. In contrast, FSHD2 is caused by the inheritance of two independent genetic variations. A heterozygous mutation, mainly located on the SMCHD1 (Structural Maintenance of Chromosome flexible Hinge Domain containing 1) gene, results in a loss of function of chromatin D4Z4 repressor. This mutation, combined with the 4qA allele bearing the DU4 polyadenylation site, makes this allele permissive for the expression of the DUX4 topical gene.
Therefore, because the two forms of FSHD are genetically distinct and very few patients have FSHD2, our knowledge of the impact of chromatin D4Z4 repressors, such as SMCHD1, or the progression and severity of the disease remains very limited. It is important to note that a lack of reliable biomarkers specific to the severity and progression of the disease may prevent the development of therapies to treat patients with FSHD2. This study will allow us to better understand the natural progression of FSHD2 over time, to assess the responsiveness of clinical outcome measures (COMs) and to identify and validate inflammatory serum biomarkers predicting the severity and progression of the disease.
Genetically confirmed FSHD2: pathogenic mutation in SMCHD1 gene and at least one D4Z4 4qA allele;
Age 18-75 years
Symptomatic limb weakness
Group ambulant patient with a RICCI score of 2 to 4
None
Single group
Validation of new COMs for FSHD2 patients
Diagnostic testMonitoring of commonly used and new COMs in FSHD2 patients
Minimal clinical importance of the Motor Function Measure-32 (MFM-32) from Baseline (V1) to 18 months (V3)
Within MFM-32, 32 terms will be evaluated to describe patient's motor functions and grouped into 3 sub-scores at baseline and 18 months: D1: standing position and transfer D2: axial and proximal motor function D3: distal motor function The MFM-32 ratings rely on the use of a 4-point Likert scale based on the subject's maximal abilities without assistance (0: cannot initiate the task or maintain the starting position; 1: performs the task partially; 2: performs the task incompletely or imperfectly;3: performs the task fully and normally.)
Change of the Italian Severity Score (FCS) from Baseline (V1) to 18 months (V3)
The Italian Severity Score (FCS) ranks weakness in the face, shoulders, arms, distal, and proximal lower extremities on a 15-points scale
Change of the Clinical Severity Score (CSS) from Baseline (V1) to 18 months (V3)
The Clinical Severity score (CSS) ranks weakness in the face, shoulders, arms, distal, and proximal lower extremities on a 10-points scale
Change of the Manual Muscle Testing (MMT) from Baseline (V1) to 18 months (V3)
The Manual Muscle Testing is a modified Medical Research Council 13-point and is used with standardized positions for each grade and each muscle following the recommendations of the FSH-DY Group. Shoulder abduction and flexion, elbow flexion and extension, wrist flexion and extension, fingers flexion and extension, hip flexion and abd/adduction, knee flexion and extension, ankle plantarflexion and dorsiflexion strength will be measured bilaterally
Change of the Hand-Held dynamometry (HHD) from Baseline (V1) to 18 months (V3)
Hand-Held dynamometry (HHD) assess the isometric muscle strength in both the upper and lower limbs bilaterally (global shoulder abduction and flexion, elbow flexion and extension, hip abduction, knee extension, ankle dorsiflexion isometric strength). The required equipment is a calibrated hand-held dynamometer (MicroFet). The patient has to push against the hand-held dynamometer 3 times as hard as he can for 3-5 seconds. The maximal value will be kept for further analysis.
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