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T1-weighted skeletal muscle MRI of the lower limbs: (a) at thigh level, marked fatty infiltration and atrophy of the left long adductor (arrow); (b) at leg level, fatty infiltration of the medial head of the left gastrocnemius (arrow).
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We report the first case of a heterozygous T78M mutation in the caveolin-3 gene (CAV3) associated with rippling muscle disease and proximal myopathy. The patient displayed also bilateral winged scapula with limited abduction of upper arms and marked asymmetric atrophy of leg muscles shown by magnetic resonance imaging. Immunohistochemistry on the p...
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Context 1
... and leg muscle magnetic resonance imaging (MRI) revealed an asymmetric muscle pattern involve- ment, with marked fatty infiltration and atrophy of long adductor of the left thigh and medial head of the left gas- trocnemius (Fig. 3), mild signs of edema in thigh muscles (right femoral biceps and left gracile muscles) and in leg muscles (lateral head of the right gastrocnemius and bilat- eral tibial ...Citations
... An unusual high clinical severity may arise from the combination of borderline FSHD1 alleles with a secondary muscle disorder, this situation is often referred to as "double trouble." [24][25][26][27][28] This scenario could account for patients who exhibit atypical phenotypes or clinical variability within the same family. This might also explain some examples where the 4qA repeat array is even >10 U. Further research is required to understand this phenomenon. ...
The gold standard for facioscapulohumeral muscular dystrophy (FSHD) genetic diagnostic procedures was published in 2012. With the increasing complexity of the genetics of FSHD1 and 2, the increase of genetic testing centers, and the start of clinical trials for FSHD, it is crucial to provide an update on our knowledge of the genetic features of the FSHD loci and renew the international consensus on the molecular testing recommendations. To this end, members of the FSHD European Trial Network summarized the evidence presented during the 2022 ENMC meeting on Genetic diagnosis, clinical outcome measures, and biomarkers. The working group additionally invited genetic and clinical experts from the USA, India, Japan, Australia, South‐Africa, and Brazil to provide a global perspective. Six virtual meetings were organized to reach consensus on the minimal requirements for genetic confirmation of FSHD1 and FSHD2. Here, we present the clinical and genetic features of FSHD, specific features of FSHD1 and FSHD2, pros and cons of established and new technologies (Southern blot in combination with either linear or pulsed‐field gel electrophoresis, molecular combing, optical genome mapping, FSHD2 methylation analysis and FSHD2 genotyping), the possibilities and challenges of prenatal testing, including pre‐implantation genetic testing, and the minimal requirements and recommendations for genetic confirmation of FSHD1 and FSHD2. This consensus is expected to contribute to current clinical management and trial‐readiness for FSHD.
... Regarding the muscle pathology of caveolinopathy, routine stains usually reveal abnormal ndings with nonspeci c changes, such as disseminated atrophic bers, some bers with internal nuclei, foci of degeneration with necrosis and phagocytosis, proliferation of endomysial and perimysial connective tissue, and variation in ber size [31,32]. Furthermore, typical dystrophic changes with numerous endomysial in ammatory in ltration in the muscle bers have been rarely described [32,33]. Although most immunohistochemical studies demonstrated reduced immunoreaction of CAV3, a quarter of patients had normal expression of CAV3 along the surface of sarcolemma that may increase the probability of misdiagnosis for clinician [34]. ...
Background
Rippling muscle disease (RMD), one of the special clinical phenotypes of caveolinopathies, is characterized by muscle hyperexcitability causing by mutations in the CAV3 gene. Few data exist on muscle MRI in patients with RMD, frequently reported as normal.
Methods
Here, we describe a Han Chinese family with RMD. Whole exome sequencing (WES), muscle MRI, and tissue biopsy were performed in this study.
Results
The proband and his mother presented with RMD, which was initially noticed during their childhood or adolescence, accompanied with increased level of serum creatine kinase (CK). Biopsy specimen illustrated slight variation in fiber size and increased numbers of internal nuclei in the muscle fibers, without obvious atrophy. Muscle MRI of the thighs showed short-tau inversion recovery (STIR) hyperintensity without fatty replacement. WES identified a heterozygous missense mutation of c.80G>A (p.R27Q) in the CAV3 gene.
Conclusions
Our findings deepen our awareness of the muscle MRI and pathological features of hereditary RMD. Regarding muscle MRI, this study first reports STIR hyperintensity in the thighs, which may be linked with muscle oedema.
... Zarrouk-Mahjoub, 2016;Hodapp et al., 2006;Jones, McNamara, Longoni, et al., 2018;Katiyar, Davies, & Goel, 2020;Martin et al., 2014;Masciullo et al., 2013;Murakami, Kimura, Enomoto, et al., 2019;Polavarapu et al., 2019;Posey et al., 2016;Retterer et al., 2016;Ricci et al., 2012;Scarlato et al., 2015;Schreiber et al., 2013;Smith et al., 2019;Splinter et al., 2018;Trujillano et al., 2017;Vona et al., 2018). Complete diagnosis of these cases can pose a challenge as it can be difficult to ascertain if an atypical clinical feature could represent a novel phenotype of the primary condition or are due to a second genetic or acquired disease. ...
Reports of patients with concomitant diagnoses of two inherited genetic disorders, sometimes referred to as “double trouble,” have appeared intermittently in the medical literature. We report eight additional cases with dual diagnoses of two genetic conditions. All cases had a phenotype atypical for their primary diagnosis, leading to the search for a second genetic diagnosis. These cases highlight the importance of the history, physical examination and continued work‐up if the phenotype of the patient falls drastically outside what has been reported with their primary diagnosis. Some of the diagnoses of the patients presented here (e.g., Myotonic Dystrophy Type 1, fascioscapulohumeral muscular dystrophy) would not have been identified by genetic testing done on a next generation sequencing backbone (e.g., panel or exome sequencing). When the clinical picture is atypical or more severe than expected the possibility of a dual diagnosis (double trouble) should be considered. Identification of a second genetic condition can impact management and genetic counseling.
... These caveolae have an essential role in maintenance of sarcolemmal integrity, vesicular trafficking and signal transduction [44]. The p.Thr78Met CAV3 variant found in our patient has been repeatedly described in the literature as pathogenic, associated with many different phenotypes [43,[45][46][47][48][49][50][51][52][53][54]. ...
Inherited muscle disorders are caused by pathogenic changes in numerous genes. Herein, we aimed to investigate the etiology of muscle disease in 24 consecutive Greek patients with myopathy suspected to be genetic in origin, based on clinical presentation and laboratory and electrophysiological findings and absence of known acquired causes of myopathy. Of these, 16 patients (8 females, median 24 years-old, range 7 to 67 years-old) were diagnosed by Whole Exome Sequencing as suffering from a specific type of inherited muscle disorder. Specifically, we have identified causative variants in 6 limb-girdle muscular dystrophy genes (6 patients; ANO5, CAPN3, DYSF, ISPD, LAMA2, SGCA), 3 metabolic myopathy genes (4 patients; CPT2, ETFDH, GAA), 1 congenital myotonia gene (1 patient; CLCN1), 1 mitochondrial myopathy gene (1 patient; MT-TE) and 3 other myopathy-associated genes (4 patients; CAV3, LMNA, MYOT). In 6 additional family members affected by myopathy, we reached genetic diagnosis following identification of a causative variant in an index patient. In our patients, genetic diagnosis ended a lengthy diagnostic process and, in the case of Multiple acyl-CoA dehydrogenase deficiency and Pompe’s disease, it enabled specific treatment to be initiated. These results further expand the genotypic and phenotypic spectrum of inherited myopathies.
... Rippling muscle disease (RMD) is a rare autosomal-dominant disorder of skeletal muscle. It is characterized by signs of increased muscle irritability, such as percussion-induced rapid contraction (PIRC), percussion-induced muscle mounding (PIMM), and/or electrically silent muscle contractions (rippling muscle) [180]. Several mutations in Cav3 protein (Arg26Gln, Ala45Thr, Ala45Val, Asp27Glu, Pro28Leu, Pro28Thr, Val43Glu, Leu86Pro, Ala92Thr, and Pro104Leu) have been associated with RMD [12,18]. ...
... Several mutations in Cav3 protein (Arg26Gln, Ala45Thr, Ala45Val, Asp27Glu, Pro28Leu, Pro28Thr, Val43Glu, Leu86Pro, Ala92Thr, and Pro104Leu) have been associated with RMD [12,18]. Ricci et al. [180] have shown RMD and facioscapulohumeral dystrophy-like phenotypes in a patient carrying a heterozygous Cav3 T78M mutation and a D4Z4 partial deletion. Lo et al. [181] have reported RMD which was associated with reduced Cav3 levels, resulting in partial deficiency, or "mosaicism", of Cav3 localization in the absence of mutations in the Cav3 coding region. ...
Caveolae are the cholesterol-rich small invaginations of the plasma membrane present in many cell types including adipocytes, endothelial cells, epithelial cells, fibroblasts, smooth muscles, skeletal muscles and cardiac muscles. They serve as specialized platforms for many signaling molecules and regulate important cellular processes like energy metabolism, lipid metabolism, mitochondria homeostasis, and mechano-transduction. Caveolae can be internalized together with associated cargo. The caveolae-dependent endocytic pathway plays a role in the withdrawal of many plasma membrane components that can be sent for degradation or recycled back to the cell surface. Caveolae are formed by oligomerization of caveolin proteins. Caveolin-3 is a muscle-specific isoform, whose malfunction is associated with several diseases including diabetes, cancer, atherosclerosis, and cardiovascular diseases. Mutations in Caveolin-3 are known to cause muscular dystrophies that are collectively called caveolinopathies. Altered expression of Caveolin-3 is also observed in Duchenne’s muscular dystrophy, which is likely a part of the pathological process leading to muscle weakness. This review summarizes the major functions of Caveolin-3 in skeletal muscles and discusses its involvement in the pathology of muscular dystrophies.
... In some cases, it might be the simultaneous heterozygosity for a different and recessive myopathy, as suggested by many reports, in which the FSHD contractions are found in association with a second molecular variation. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] This possibility is also consistent with previous reports of expression changes of candidate proteins that were associated with FSHD in some families but were unchanged when other families were examined. It is also plausible that drugs or toxic agents might contribute to disease onset and clinical variability. ...
Importance
Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disorder, associated with the deletion of tandemly arrayed D4Z4 repetitive elements. The extensive use of molecular analysis of the D4Z4 locus for FSHD diagnosis has revealed wide clinical variability, suggesting that subgroups of patients exist among carriers of the D4Z4 reduced allele (DRA).
Objective
To investigate the clinical expression of FSHD in the genetic subgroup of carriers of a DRA with 7 to 8 repeat units (RUs).
Design, Setting, and Participants
This multicenter cross-sectional study included 422 carriers of DRA with 7 to 8 RUs (187 unrelated probands and 235 relatives) from a consecutive sample of 280 probands and 306 relatives from the Italian National Registry for FSHD collected between 2008 and 2016. Participants were evaluated by the Italian Clinical Network for FSHD, and all clinical and molecular data were collected in the Italian National Registry for FSHD database. Data analysis was conducted from January 2017 to June 2018.
Main Outcomes and Measures
The phenotypic classification of probands and relatives was obtained by applying the Comprehensive Clinical Evaluation Form which classifies patients in the 4 following categories: (1) participants presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) participants with muscle weakness limited to scapular girdle or facial muscles (category B, subcategories B1 and B2), (3) asymptomatic or healthy participants (category C, subcategories C1 and C2), and (4) participants with myopathic phenotypes presenting clinical features not consistent with FSHD canonical phenotype (category D, subcategories D1 and D2).
Results
A total of 187 probands (mean [SD] age at last neurological examination, 53.5 [15.2] years; 103 [55.1%] men) and 235 relatives (mean [SD] age at last neurologic examination, 45.1 [17.0] years; 104 [44.7%] men) with a DRA with 7 to 8 RUs and a molecular diagnosis of FSHD were evaluated. Of 187 probands, 99 (52.9%; 95% CI, 45.7%-60.1%) displayed the classic FSHD phenotype, whereas 86 (47.1%; 95% CI, 39.8%-54.3%) presented incomplete or atypical phenotypes. Of 235 carrier relatives from 106 unrelated families, 124 (52.8%; 95% CI, 46.4%-59.7%) had no motor impairment, whereas a small number (38 [16.2%; 95% CI, 9.8%-23.1%]) displayed the classic FSHD phenotype, and 73 (31.0%; 95% CI, 24.7%-38.0%) presented with incomplete or atypical phenotypes. In 37 of 106 families (34.9%; 95% CI, 25.9%-44.8%), the proband was the only participant presenting with a myopathic phenotype, while only 20 families (18.9%; 95% CI, 11.9%-27.6%) had a member with autosomal dominant FSHD.
Conclusions and Relevance
This study found large phenotypic variability associated with individuals carrying a DRA with 7 to 8 RUs, in contrast to the indication that a positive molecular test is the only determining aspect for FSHD diagnosis. These findings suggest that carriers of a DRA with 7 to 8 RUs constitute a genetic subgroup different from classic FSHD. Based on these results, it is recommended that clinicians use the Comprehensive Clinical Evaluation Form for clinical classification and, whenever possible, study the extended family to provide the most adequate clinical management and genetic counseling.
... In some cases, it might be the simultaneous heterozygosity for a different and recessive myopathy, as suggested by many reports, in which the FSHD contractions are found in association with a second molecular variation. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] This possibility is also consistent with previous reports of expression changes of candidate proteins that were associated with FSHD in some families but were unchanged when other families were examined. It is also plausible that drugs or toxic agents might contribute to disease onset and clinical variability. ...
IMPORTANCE Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disorder, associated with the deletion of tandemly arrayed D4Z4 repetitive elements. The extensive use of molecular analysis of the D4Z4 locus for FSHD diagnosis has revealed wide clinical variability, suggesting that subgroups of patients exist among carriers of the D4Z4 reduced allele (DRA). OBJECTIVE To investigate the clinical expression of FSHD in the genetic subgroup of carriers of a DRA with 7 to 8 repeat units (RUs). DESIGN, SETTING, AND PARTICIPANTS This multicenter cross-sectional study included 422 carriers of DRA with 7 to 8 RUs (187 unrelated probands and 235 relatives) from a consecutive sample of 280 probands and 306 relatives from the Italian National Registry for FSHD collected between 2008 and 2016. Participants were evaluated by the Italian Clinical Network for FSHD, and all clinical and molecular data were collected in the Italian National Registry for FSHD database. Data analysis was conducted from MAIN OUTCOMES AND MEASURES The phenotypic classification of probands and relatives was obtained by applying the Comprehensive Clinical Evaluation Form which classifies patients in the 4 following categories: (1) participants presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) participants with muscle weakness limited to scapular girdle or facial muscles (category B, subcategories B1 and B2), (3) asymptomatic or healthy participants (category C, subcategories C1 and C2), and (4) participants with myopathic phenotypes presenting clinical features not consistent with FSHD canonical phenotype (category D, subcategories D1 and D2). RESULTS A total of 187 probands (mean [SD] age at last neurological examination, 53.5 [15.2] years; 103 [55.1%] men) and 235 relatives (mean [SD] age at last neurologic examination, 45.1 [17.0] years; 104 [44.7%] men) with a DRA with 7 to 8 RUs and a molecular diagnosis of FSHD were evaluated. Of 187 probands, 99 (52.9%; 95% CI, 45.7%-60.1%) displayed the classic FSHD phenotype, whereas 86 (47.1%; 95% CI, 39.8%-54.3%) presented incomplete or atypical phenotypes. Of 235 carrier relatives from 106 unrelated families, 124 (52.8%; 95% CI, 46.4%-59.7%) had no motor impairment, whereas a small number (38 [16.2%; 95% CI, 9.8%-23.1%]) displayed the classic FSHD phenotype, and 73 (31.0%; 95% CI, 24.7%-38.0%) presented with incomplete or atypical phenotypes. In 37 of 106 families (34.9%; 95% CI, 25.9%-44.8%), the proband was the only participant presenting with a myopathic phenotype, while only 20 families (18.9%; 95% CI, 11.9%-27.6%) had a member with autosomal dominant FSHD. (continued) Key Points Question What are the phenotypes expressed among patients with facioscapulohumeral muscular dystrophy (FHSD) who are carriers of D4Z4 reduced allele with 7 to 8 repeat units? Findings In this cross-sectional study of 187 probands and 235 relatives who carry a D4Z4 reduced allele with 7 to 8 repeat units, 47.1% of probands did not have the classic FSHD phenotype, and 52.8% of the carrier relatives were nonpenetrant. In 106 families, 18.9% had a member with autosomal dominant FSHD, whereas in 34.9%, the proband was the only participant expressing a myopathic phenotype. Meaning The findings of this study suggest that knowledge of phenotypic variation in the expression of D4Z4 reduced allele with 7 to 8 repeat units in individuals with FSHD could be informative for clinical management and genetic counseling. Abstract (continued) CONCLUSIONS AND RELEVANCE This study found large phenotypic variability associated with individuals carrying a DRA with 7 to 8 RUs, in contrast to the indication that a positive molecular test is the only determining aspect for FSHD diagnosis. These findings suggest that carriers of a DRA with 7 to 8 RUs constitute a genetic subgroup different from classic FSHD. Based on these results, it is recommended that clinicians use the Comprehensive Clinical Evaluation Form for clinical classification and, whenever possible, study the extended family to provide the most adequate clinical management and genetic counseling.
... C митохондриальной миопатией (у одного больного) [41], миодистрофией Дюшенна (у одного больного) [41], миодистрофией Бекера [43] (у одного больного), с перонеальной мышечной атрофией Шарко-Мари (у матери и двух дочерей [44], с болезнью двигательного нейрона (у одного больного) [45], митохондриальной невропатией Лебера (у одного больного) [46], c миастенией (у одного больного) [47], a также с экстрамедулярной опухолью спинного мозга [48]. ...
Peculiarities of clinical picture and di9agnostics some muscular dystrophies
... However, D4Z4 contractions have also been reported in patients with atypical or overlapping symptoms, including SHD, [11] Duchenne muscular dystrophy [18] / Becker's muscular dystrophy (BMD), [19] limb-girdle muscular dystrophy (LGMD), [20] and caveolinopathy. [21] Interestingly, HPN was easily accompanied by muscular dystrophy or other syndromes, such as BMD [22] and dopamine beta-hydroxylase gene-related dysautonomia. [23] To date, the overlapping symptoms of HPN and FSHD have been reported in only four cases: only one patient had been genetically confirmed overlapping diagnoses of CMT1A and FSHD due to a PMP22 gene duplication and a 19 kb deletion of the D4Z4 locus, [8] while three cases did not proceed with the sequencing techniques, and the pathogenic mutation was unknown. ...
Background:
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by asymmetric muscular deficit of facial, shoulder-girdle muscles, and descending to lower limb muscles, but it exists in several extramuscular manifestations or overlapping syndromes. Herein, we report a "complex disease plus" patient with FSHD1, accompanied by peripheral neuropathy and myoclonic epilepsy.
Methods:
Standard clinical assessments, particular auxiliary examination, histological analysis, and molecular analysis were performed through the new Comprehensive Clinical Evaluation Form, pulsed-field gel electrophoresis-based Southern blot, Multiplex Ligation-dependent Probe Amplification (MLPA), whole exome sequencing (WES), and targeted methylation sequencing.
Results:
The patient presented with mild facial weakness, humeral poly-hill sign, scapular winging, peroneal weakness, drop foot, pes cavus, and myoclonic epilepsy. Furthermore, electrophysiology revealed severely demyelinated and axonal injury. The muscle and nerve biopsy revealed broadly fiber Type II grouping atrophy and myelinated nerve fibers that significantly decreased with thin myelinated fibers and onion bulbs changes. Generalized sharp and sharp-slow wave complexes on electroencephalography support the diagnosis toward myoclonic epilepsy. In addition, molecular testing demonstrated a co-segregated 20-kb 4q35-EcoRI fragment and permissive allele A, which corresponded with D4Z4 hypomethylation status in the family. Both the patient's mother and brother only presented the typical FSHD but lacked overlapping syndromes. However, no mutations for hereditary peripheral neuropathy and myoclonic epilepsy were discovered by MLPA and WES.
Conclusions:
The present study described a "tripe trouble" with FSHD, peripheral neuropathy, and myoclonic epilepsy, adding the spectrum of overlapping syndromes and contributing to the credible diagnosis of atypical phenotype. It would provide a direct clue on medical care and genetic counseling.
... В наблюдении G. Ricci и соавт. [17] лице-лопаточно-плечевая мышечная дистрофия сочеталась с редкой «болезнью пульсирующих мышц» (англ.: rippling muscle disease) -вариантом доминантной ПКМД, связанной с геном CAV3. ...
A rare case of two neuromuscular disorders in a 29-year-old female is presented: autosomal dominant hereditary motor and sensory neuropathy type 1A (HMSN1A) due to PMP22 duplication and autosomal recessive limb lumbo-muscular dystrophy type 2A (LGMD2A) produced by CAPN3 common mutation c.550delA and novel c.575C>G (p.Thr192Ser).Walking difficulties appeared in 27 years, the patient had signs of both disorders, more of LGMD, but was not disabled. HMSN1A was inherited from her father whose disease was not recognized earlier.
