Deep phenotyping of facioscapulohumeral muscular dystrophy type 2 by magnetic resonance imaging

Abstract

Background and purpose The aim was to define the radiological picture of facioscapulohumeral muscular dystrophy 2 (FSHD2) in comparison with FSHD1 and to explore correlations between imaging and clinical/molecular data. Methods Upper girdle and/or lower limb muscle magnetic resonance imaging scans of 34 molecularly confirmed FSHD2 patients from nine European neuromuscular centres were analysed. T1‐weighted and short‐tau inversion recovery (STIR) sequences were used to evaluate the global pattern and to assess the extent of fatty replacement and muscle oedema. Results The most frequently affected muscles were obliquus and transversus abdominis, semimembranosus, soleus and gluteus minimus in the lower limbs; trapezius, serratus anterior, latissimus dorsi and pectoralis major in the upper girdle. Iliopsoas, popliteus, obturator internus and tibialis posterior in the lower limbs and subscapularis, spinati, sternocleidomastoid and levator scapulae in the upper girdle were the most spared. Asymmetry and STIR hyperintensities were consistent features. The pattern of muscle involvement was similar to that of FSHD1, and the combined involvement of trapezius, abdominal and hamstring muscles, together with complete sparing of iliopsoas and subscapularis, was detected in 91% of patients. Peculiar differences were identified in a rostro‐caudal gradient, a predominant involvement of lower limb muscles compared to the upper girdle, and in the higher percentage of STIR hyperintensities in FSHD2. Conclusion This multicentre study defines the pattern of muscle involvement in FSHD2, providing useful information for diagnostics and clinical trial design. Both similarities and differences between FSHD1 and FSHD2 were detected, which is also relevant to better understand the pathogenic mechanisms underlying the FSHD‐related disease spectrum.

Facioscapulohumeral muscular dystrophy type 2: an update on the clinical, genetic, and molecular findings

“…Mair with T1-weighted and short-tau inversion recovery (STIR) sequences on MRI scans of the upper girdle and/or lower limb muscles, the overall pattern of disease was again similar to FSHD1. [96] Asymmetry and STIR hyperintensities were prominent features on MRI. [96] Intriguingly, peculiar differences could be identified radiologically in a rostrocaudal gradient for the two FSHD forms: disease involvement in the upper girdle muscles was comparable, but all lower limb muscles were significantly more affected in FSHD2, and the combined involvement of at least one abdominal and one hamstring muscle together with bilateral sparing of iliopsoas was more prevalent than in FSHD1.…”

“…[96] Asymmetry and STIR hyperintensities were prominent features on MRI. [96] Intriguingly, peculiar differences could be identified radiologically in a rostrocaudal gradient for the two FSHD forms: disease involvement in the upper girdle muscles was comparable, but all lower limb muscles were significantly more affected in FSHD2, and the combined involvement of at least one abdominal and one hamstring muscle together with bilateral sparing of iliopsoas was more prevalent than in FSHD1. [96] The patient population in Giacomucci et al contained a high proportion of patients with a pathogenic SMCHD1 mutation (32/34, the remaining 2 did not receive a genetic study; compared with 79-85% of FSHD2 patients in previous reports); [19,37] whether the higher frequency of lower limb involvement is specific to SMCHD1 mutation-positive FSHD2 or a common feature of FSHD2 should be investigated by similar radiological studies in the future.…”

“…[93,95] For example, Giacomucci et al have surmised, based on the discovery of the radiological disparity between FSHD1 and FSHD2, that SMCHD1 may play a part in the specific phenotype of FSHD2 due to the role of this gene in development and embryogenesis. [96] FSHD2 individuals almost universally show hypomethylation in the D4Z4 repeat arrays in their 4q and 10q chromosomes. While the hypomethylation of D4Z4 in FSHD shows a correlation with the reduction in D4Z4 repeat units [19] and a significantly reduced level of methylation is found in symptomatic FSHD patients in comparison to asymptomatic carriers, [97] the exact mechanism of methylation in the disease is yet unclear.…”

“…Symptoms and signs Weakness of the facial muscles, stabilisers of the shoulder, ankle dorsiflexors [103] Mostly indistinguishable from FSHD1; later age at onset, and dysphagia may be more common [40] Family Normal to elevated [40,106] EMG findings Changes consistent with mild myopathic in symptomatic muscles [103] A myogenic pattern [106] MR imaging of muscle Combined involvement of at least one abdominal and one hamstring muscle together with bilateral sparing of iliopsoas was more prevalent than in FSHD1 [96] Similar pattern of muscle involvement and asymmetry compared to FSHD1, although lower limb muscles may be more affected in FSHD2 [96] Muscle biopsy findings Typically, nonspecific, chronic myopathic changes [103] Variable muscle pathology, from normal to dystrophic changes [40,106] Abbreviations: CKcreatinine kinase; FSHDfacioscapulohumeral dystrophy; IU/Linternational units per litre; EMGelectromyography; MRmagnetic resonance.…”

247th ENMC International Workshop: Muscle magnetic resonance imaging - Implementing muscle MRI as a diagnostic tool for rare genetic myopathy cohorts. Hoofddorp, The Netherlands, September 2019

“…Giorgio Tasca, Italy, presented the recent experience of building patient cohorts for imaging, with particular regard to two large single center projects on facioscapulohumeral muscular dystrophy (FSHD) type 1 [53 , 54] and two multicenter projects dealing with sarcoglycanopathies [55] and FSHD type 2 [56] , developed in the context of the MYO-MRI COST Action (BM1304). He underlined the importance of studying sufficiently large cohorts to understand and characterize the full variability of phenotypes and severity in rare disorders.…”