Karlien Mul

What's in a name? The clinical features of facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited and progressive muscle disorder. Although its name suggests otherwise, it comprises weakness of the facial, shoulder and upper arm muscles, and also of the trunk and leg muscles. Its severity and disease course vary greatly and mild or early FSHD can be difficult to recognise. Knowledge of its subtle signs and symptoms can lead directly to the correct diagnosis without diagnostic delay and without needing multiple diagnostic procedures. We give an overview of the signs and symptoms of FSHD in severe as well as in mild cases, to facilitate correct and instant recognition of this relatively common muscle disorder.

Adding quantitative muscle MRI to the FSHD clinical trial toolbox

Objective: To add quantitative muscle MRI to the clinical trial toolbox for facioscapulohumeral muscular dystrophy (FSHD) by correlating it to clinical outcome measures in a large cohort of genetically and clinically well-characterized patients with FSHD comprising the entire clinical spectrum. Methods: Quantitative MRI scans of leg muscles of 140 patients with FSHD1 and FSHD2 were assessed for fatty infiltration and TIRM hyperintensities and were correlated to multiple clinical outcome measures. Results: The mean fat fraction of the total leg musculature correlated highly with the motor function measure, FSHD clinical score, Ricci score, and 6-minute walking test (correlation coefficients −0.845, 0.835, 0.791, −0.701, respectively). Fat fraction per muscle group correlated well with corresponding muscle strength (correlation coefficients up to −0.82). The hamstring muscles, adductor muscles, rectus femoris, and gastrocnemius medialis were affected most frequently, also in early stage disease and in patients without leg muscle weakness. Muscle involvement was asymmetric in 20% of all muscle pairs and fatty infiltration within muscles showed a decrease from distal to proximal of 3.9%. TIRM hyperintense areas, suggesting inflammation, were found in 3.5% of all muscles, with and without fatty infiltration. Conclusions: We show a strong correlation between quantitative muscle MRI and clinical outcome measures. Muscle MRI is able to detect muscle pathology before clinical involvement of the leg muscles. This indicates that quantitative leg muscle MRI is a promising biomarker that captures disease severity and motor functioning and can thus be included in the FSHD trial toolbox.

Integrating clinical and genetic observations in facioscapulohumeral muscular dystrophy.

PURPOSE OF REVIEW This review gives an overview of the currently known key clinical and (epi)genetic aspects of facioscapulohumeral muscular dystrophy (FSHD) and provides perspectives to facilitate future research. RECENT FINDINGS Clinically, imaging studies have contributed to a detailed characterization of the FSHD phenotype, and a model is proposed with five stages of disease progression. A number of clinical trials have been conducted regarding exercise and diet aiming to reduce symptoms. Genetically, at least two different mechanisms (FSHD1 and FSHD2) lead to double homeobox 4 (DUX4) expression in skeletal myocytes, which is expected to be necessary for the disease. Disease severity is most likely determined by a combination of the D4Z4 repeat size and its epigenetic state. SUMMARY FSHD is one of the most common muscular dystrophies and is characterized by a typical distribution of muscle weakness. Progress has been made on clinical as well as on (epi)genetic aspects of the disease. Currently, there is no cure available for FSHD. For successful development of new treatments targeting the disease process, integration of clinical and pathogenetic knowledge is essential. A clinical trial toolbox that consists of patient registries, biomarkers and clinical outcome measures will be required to effectively conduct future clinical trials.

Lifetime endogenous estrogen exposure and disease severity in female patients with facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by large variability in disease severity, that is only partly explained by (epi)genetic factors. Clinical observations and recent in vitro work suggest a protective effect of estrogens in FSHD. The aims of this study were to assess whether the lifetime endogenous estrogen exposure contributes to the variability in disease severity in female patients, and whether female patients experience changes in disease progression during periods of hormonal changes. We calculated the lifetime endogenous estrogen exposure by subtracting periods with high progesterone levels (in which estrogens are counteracted) from the reproductive life span. Multiple linear regression in 85 patients did not show a contribution of the lifetime endogenous estrogen exposure to disease severity (B = 0.063, P-value = 0.517, ΔR2 = 0.003). The majority of women reported an unchanged rate of disease progression through periods of hormonal changes, like menarche, pregnancy or menopause. Women that noticed differences reported accelerations as well as decelerations. These results indicate that differences in estrogen exposure do not have a clinically relevant modifying effect on disease severity. However, a clinically relevant protective effect of greater differences in estrogen levels, or a protective effect caused by a more complex interplay with other reproductive hormones, cannot be ruled out.

Facioscapulohumeral muscular dystrophy as a genetic cause of pectus excavatum

extremity Asymmetrical weakness of shoulder girdle (shoulder abduction, anteflexion, endoand exorotation) Lower (Asymmetrical) weakness of foot dorsiflexors, knee flexors extremity and hip adductors Trunk (Asymmetrical) atrophy of m. pectoralis major Weakness of neck extension and flexion Abdominal muscle weakness with positive Beevor sign (upward movement of the umbilicus on flexing the neck) Lumbar hyperlordosis

FSHD type 2 and Bosma arhinia microphthalmia syndrome: Two faces of the same mutation

Objective To determine whether congenital arhinia/Bosma arhinia microphthalmia syndrome (BAMS) and facioscapulohumeral muscular dystrophy type 2 (FSHD2), 2 seemingly unrelated disorders both caused by heterozygous pathogenic missense variants in the SMCHD1 gene, might represent different ends of a broad single phenotypic spectrum associated with SMCHD1 dysfunction. Methods We examined and/or interviewed 14 patients with FSHD2 and 4 unaffected family members with N-terminal SMCHD1 pathogenic missense variants to identify BAMS subphenotypes. Results None of the patients with FSHD2 or family members demonstrated any congenital defects or dysmorphic features commonly found in patients with BAMS. One patient became anosmic after nasal surgery and one patient was hyposmic; one man was infertile (unknown cause) but reported normal pubertal development. Conclusion These data suggest that arhinia/BAMS and FSHD2 do not represent one phenotypic spectrum and that SMCHD1 pathogenic variants by themselves are insufficient to cause either of the 2 disorders. More likely, both arhinia/BAMS and FSHD2 are caused by complex oligogenic or multifactorial mechanisms that only partially overlap at the level of SMCHD1.

Quantitative muscle MRI and ultrasound for facioscapulohumeral muscular dystrophy: complementary imaging biomarkers

ObjectiveTo assess the overlap of and differences between quantitative muscle MRI and ultrasound in characterizing structural changes in leg muscles of facioscapulohumeral muscular dystrophy (FSHD) patients.MethodsWe performed quantitative MRI and quantitative ultrasound of ten leg muscles in 27 FSHD patients and assessed images, both quantitatively and visually, for fatty infiltration, fibrosis and edema.ResultsThe MRI fat fraction and ultrasound echogenicity z-score correlated strongly (CC 0.865, p < 0.05) and both correlated with clinical severity (MRI CC 0.828, ultrasound CC 0.767, p < 0.001). Ultrasound detected changes in muscle architecture in muscles that looked normal on MRI. MRI was better in detecting late stages of fatty infiltration and was more suitable to assess muscle edema. Correlations between quantitative and semi-quantitative scores were strong for MRI (CC 0.844–0.982, p < 0.05), and varied for ultrasound (CC 0.427–0.809, p = 0.026–p < 0.001).ConclusionsQuantitative muscle MRI and ultrasound are both promising imaging biomarkers for differentiating between degrees of structural muscle changes. As ultrasound is more sensitive to detect subtle structural changes and MRI is more accurate in end stage muscles and detecting edema, the techniques are complementary. Hence, the choice for a particular technique should be considered in light of the trial design.

Phenotype-genotype relations in facioscapulohumeral muscular dystrophy type 1

To determine how much of the clinical variability in facioscapulohumeral muscular dystrophy type 1 (FSHD1) can be explained by the D4Z4 repeat array size, D4Z4 methylation and familial factors, we included 152 carriers of an FSHD1 allele (23 single cases, 129 familial cases from 37 families) and performed state‐of‐the‐art genetic testing, extensive clinical evaluation and quantitative muscle MRI. Familial factors accounted for 50% of the variance in disease severity (FSHD clinical score). The explained variance by the D4Z4 repeat array size for disease severity was limited (approximately 10%), and varied per body region (facial muscles, upper and lower extremities approximately 30%, 15% and 3%, respectively). Unaffected gene carriers had longer repeat array sizes compared to symptomatic individuals (7.3 vs 6.0 units, P = 0.000) and slightly higher Delta1 methylation levels (D4Z4 methylation corrected for repeat size, 0.96 vs −2.46, P = 0.048).

Specific muscle strength is reduced in facioscapulohumeral dystrophy: An MRI based musculoskeletal analysis

The aim was to test whether strength per unit of muscle area (specific muscle strength) is affected in facioscapulohumeral dystrophy (FSHD) patients, as compared to healthy controls. Ten patients and ten healthy volunteers underwent an MRI examination and maximum voluntary isometric contraction measurements (MVICs) of the quadriceps muscles. Contractile muscle volume, as obtained from the MR images, was combined with the MVICs to calculate the physiological cross-sectional area (PCSA) and muscle strength using a musculoskeletal model. Subsequently, specific strength was calculated for each subject as muscle strength divided by total PCSA. FSHD patients had a reduced quadriceps muscle strength (median(1st quartile-3rd quartile): 2011 (905.4-2775) N vs. 5510 (4727-8321) N, p <0.001) and total PCSA (83.6 (62.3-124.8) cm2vs. 140.1(97.1-189.9) cm2, p = 0.015) compared to healthy controls. Furthermore, the specific strength of the quadriceps was significantly lower in patients compared to healthy controls (20.9 (14.7-24.0) N/cm2vs. 41.9 (38.3-49.0) N/cm2, p <0.001). Thus, even when correcting for atrophy and fatty infiltration, patients with FSHD generated less force per unit area of residual muscle tissue than healthy controls. Possible explanations include impaired force propagation due to fatty infiltration, reduced intrinsic force-generating capacity of the muscle fibers, or mitochondrial abnormalities leading to impaired energy metabolism.