Muscle magnetic resonance characterization of STIM1 tubular aggregate myopathy using unsupervised learning.

PURPOSE: Congenital myopathies are a heterogeneous group of diseases affecting the skeletal muscles and characterized by high clinical, genetic, and histological variability. Magnetic Resonance (MR) is a valuable tool for the assessment of involved muscles (i.e., fatty replacement and oedema) and disease progression. Machine Learning is becoming increasingly applied for diagnostic purposes, but to our knowledge, Self-Organizing Maps (SOMs) have never been used for the identification of the patterns in these diseases. The aim of this study is to evaluate if SOMs may discriminate between muscles with fatty replacement (S), oedema (E) or neither (N). METHODS: MR studies of a family affected by tubular aggregates myopathy (TAM) with the histologically proven autosomal dominant mutation of the STIM1 gene, were examined: for each patient, in two MR assessments (i.e., t0 and t1, the latter after 5 years), fifty-three muscles were evaluated for muscular fatty replacement on the T1w images, and for oedema on the STIR images, for reference. Sixty radiomic features were collected from each muscle at t0 and t1 MR assessment using 3DSlicer software, in order to obtain data from images. A SOM was created to analyze all datasets using three clusters (i.e., 0, 1 and 2) and results were compared with radiological evaluation. RESULTS: Six patients with TAM STIM1-mutation were included. At t0 MR assessments, all patients showed widespread fatty replacement that intensifies at t1, while oedema mainly affected the muscles of the legs and appears stable at follow-up. All muscles with oedema showed fatty replacement, too. At t0 SOM grid clustering shows almost all N muscles in Cluster 0 and most of the E muscles in Cluster 1; at t1 almost all E muscles appear in Cluster 1. CONCLUSION: Our unsupervised learning model appears to be able to recognize muscles altered by the presence of edema and fatty replacement.

A novel recessive mutation affecting DNAJB6a causes myofibrillar myopathy.

Mutations in the DNAJB6 gene have been identified as rare causes of myofibrillar myopathies. However, the underlying pathophysiologica mechanisms remain elusive. DNAJB6 has two known isoforms, including the nuclear isoform DNAJB6a and the cytoplasmic isoform DNAJB6b, which was thought to be the pathogenic isoform. Here, we report a novel recessive mutation c.695_699del (p. Val 232 Gly fs*7) in the DNAJB6 gene, associated with an apparently recessively inherited late onset distal myofibrillar myopathy in a Chinese family. Notably, the novel mutation localizes to exon 9 and uniquely encodes DNAJB6a. We further identified that this mutation decreases the mRNA and protein levels of DNAJB6a and results in an age-dependent recessive toxic effect on skeletal muscle in knock-in mice. Moreover, the mutant DNAJB6a showed a dose-dependent anti-aggregation effect on polyglutamine-containing proteins in vitro. Taking together, these findings reveal the pathogenic role of DNAJB6a insufficiency in myofibrillar myopathies and expand upon the molecular spectrum of DNAJB6 mutations.

Congenital myopathies: an update.

Congenital myopathies comprise a clinical, histopathological, and genetic heterogeneous group of rare hereditary muscle diseases that are defined by architectural abnormalities in the muscle fibres. They are subdivided by the predominant structural pathological change on muscle biopsy, resulting in five subgroups: (1) core myopathies; (2) nemaline myopathies; (3) centronuclear myopathies; (4) congenital fibre type disproportion myopathy; and (5) myosin storage myopathy. Besides the clinical features, muscle biopsy, muscle imaging, and genetic analyses are essential in the diagnosis of congenital myopathies. Using next-generation sequencing techniques, a large number of new genes are being identified as the cause of congenital myopathies as well as new mutations in known genes, broadening the phenotype-genotype spectrum of congenital myopathies. Management is performed by a multidisciplinary team specialized in neuromuscular disorders, where the (paediatric) neurologist has an essential role. To date, only supportive treatment is available, but novel pathomechanisms are being discovered and gene therapies are being explored. WHAT THIS PAPER ADDS: Many new genes are being identified in congenital myopathies, broadening the phenotype-genotype spectrum. Management is performed by a multidisciplinary team specialized in neuromuscular disorders.

MIOPATÍAS CONGÉNITAS: UNA ACTUALIZACIÓN: Las miopatías congénitas comprenden un grupo clínico heterogéneo, histopatológico y genético de enfermedades musculares hereditarias raras que se definen por anormalidades arquitectónicas en las fibras musculares. Se subdividen por el cambio patológico estructural predominante en la biopsia muscular, lo que resulta en cinco subgrupos: (1) miopatías núcleo, (2) miopatías nemalinas, (3) miopatías centronucleares, (4) miopatía de desproporción del tipo de fibra congénita y (5) miopatía de almacenamiento de miosina. Además de las características clínicas, la biopsia muscular, las imágenes musculares y los análisis genéticos son esenciales en el diagnóstico de las miopatías congénitas. Utilizando técnicas de secuenciación de última generación, se está identificando un gran número de genes nuevos como la causa de las miopatías congénitas, así como nuevas mutaciones en genes conocidos, ampliando el espectro fenotipo-genotipo de las miopatías congénitas. El manejo es realizado por un equipo multidisciplinario especializado en trastornos neuromusculares, donde el neurólogo (pediátrico) tiene un papel esencial. Hasta la fecha, solo se dispone de tratamiento de apoyo, pero se están descubriendo nuevos mecanismos patológicos y se están explorando las terapias genéticas.

MIOPATIAS CONGÊNITAS: UMA ATUALIZAÇÃO: Miopatias congênitas compreendem um grupo clínico, histopatológico e genético heterogêneo de doenças musculares raras hereditárias, definidas por anormalidades na arquitetura das fibras musculares. Elas são subdivididas pela mudança estutural patológica predominante na biópsia muscular, resultado em cinco subgrupos: (1) miopatias do tipo core, (2) miopatias nemalínicas, (3) miopatias centronucleares, (4) miopatias por disproporção congênita do tipo de fibra, (5) miopatia por armazenamento de miosina. Além dos aspectos clínicos, biópsia muscular, imagem muscular, e análise genética são essenciais para o diagnóstico de miopatias congênitas. Com o uso de técnicas de sequenciamento de última geração, um grande número de genes está sendo identificado como causa de miopatias congênitas, assim como novas mutações em genes conhecidos, ampliando o espectro fenótipo-genótico das miopatias congênitas. O manejo é realizado por uma equipe multidisciplinar especializada em desordens neuromusculares, em que o neurologista pediátrico tem papel essencial. Até o momento, apenas tratamento de apoio está disponível, mas novos patomecanismos estão sendo descobertos e terapias gênicas estão sendo exploradas.

FHL1-related clinical, muscle MRI and genetic features in six Chinese patients with reducing body myopathy.

Reducing body myopathy is a rare X-linked myopathy characterized by the presence of reducing bodies. The causative gene has been identified as FHL1. We presented with the clinical, muscle magnetic resonance imaging and genetic features of 6 unrelated Chinese patients with reducing body myopathy. We divided the patients into 2 groups according to their age at onset. In addition to limb muscle weakness, pronounced axial muscle involvement was a striking feature common to both groups. Muscle magnetic resonance imaging revealed fatty infiltration predominantly in the postero-medial muscles of the thigh and the soleus muscle of the calf, sparing the gluteus and sartorius muscles. Muscle pathology demonstrated the muscle fibres with reducing bodies distributed in small groups. Genetic analysis revealed FHL1 hemizygote variants in the 6 patients, including 4 novel and 2 reported variants. These variants were located in the LIM2 domain of FHL1 in 4 patients, but 2 located in the LIM4 domain. To the best of our knowledge, this is the first report of reducing body myopathy in the Chinese population. Our findings expand the genetic spectrum of reducing body myopathy.

Recessive mutations in proximal I-band of TTN gene cause severe congenital multi-minicore disease without cardiac involvement.

Titin, encoded by the gene TTN, is one of the main sarcomere components. It is involved in not only maintaining the structure of cardiac and skeletal muscles, but also in their development, extensibility, elasticity, and signaling events. Congenital titinopathy increasingly appears an important and common form of axial predominant congenital myopathy. The pathophysiological role of TTN in congenital titinopathy and pediatric heart diseases is yet to be explored. Here, we delineate the phenotype of two female siblings who developed severe congenital multi-minicore disease without cardiac involvement. Genetic investigation by whole exome sequencing demonstrated compound heterozygous TTN mutations (c.15496+1G>A, p.5166_5258del; c.18597_18598insC, p.Thr6200Hisfs*15), corresponding to the Ig domain of the proximal I-band. Aberrant splicing causing exon skipping was verified by in vitro minigene analysis. Our results suggest that TTN mutations affecting the Ig domain of the proximal I-band may be a cause of severe congenital defect in skeletal muscles without severe cardiac involvement, thereby providing evidence for the hypothesis that congenital titinopathy patients carrying biallelic N2BA only mutations are at lower cardiac risk than those with other combinations of mutations. Meanwhile, this study confirm the hypothesis on recessive truncating variants of TTN experimentally and thus support earlier reported genotype-phenotype correlations.

Myoimaging in Congenital Myopathies.

There is a great clinical and genetic heterogeneity in congenital myopathies. Myo-MRI with pattern recognition has become a first-line complementary tool in clinical practice for this group of diseases. For diagnostic purposes, whole-body imaging techniques are preferred when involvement is axial or diffuse, as in most congenital myopathies, because of involvement of the tongue, masticator, neck or trunk muscles. Myo-MRI is widely used to identify abnormalities in muscle signal, volume or texture. Recognizable profiles or patterns have been identified in many of these genetic myopathies. The role of the radiologist is crucial in order to adapt the Myo-MRI protocols to the age of the patient and several clinical situations. Myo-MRI in children with congenital myopathies is a very demanding technique with a balance between acceptable time of examination and sufficient spatial resolution in order to detect subtle changes. Technical evolutions combining qualitative and quantitative analysis are useful to follow disease progression overtime. Outcome measures are expected to play a role in natural history description as well as in future therapeutic trials. Genetic diagnosis and interpretation of next generation sequencing results could be greatly influenced by statistical analysis with tools such as algorithms as well as graphical representations using heatmaps.

The Use of Muscle Ultrasound in the Diagnosis and Differential Diagnosis of Congenital Disorders of Muscle in the Age of Next Generation Genetics.

Congenital disorders of muscle most importantly encompass the congenital muscular dystrophies as well as the congenital myopathies. With the broader availability of next generation genetic testing there has been an expansion of phenotypes and genotypes, while the very large genes such as titin, nebulin, and RYR1 have also become accessible to complete sequencing. This development has had considerable diagnostic power while at the same time also creating challenges in the interpretation of the many variants of uncertain significance that will need a solid clinical plausibility test, based on "deep" phenotyping, taking into account clinical, extended clinical, histological, and physiological data. One tool in this context is imaging of skeletal muscle, including by ultrasound. Muscle ultrasound is a useful, noninvasive, child-friendly technique for visualizing normal and pathological skeletal muscle. By virtue of its different mode of image acquisition compared to muscle MRI, it allows for the assessment of different and often earlier changes, also circumventing the need for sedation. Herein we highlight the important role of muscle ultrasound as a diagnostic tool and an extension of the physical exam in the work-up of congenital onset muscle disease, presenting various relevant clinical scenarios. We show how muscle ultrasound can confirm or refute skeletal muscle involvement and yield information about the nature of the involvement (myopathic vs neurogenic). Muscle ultrasound can also guide the appropriate next diagnostic steps and recognize diagnostically important qualitative patterns to help confirm or refute genetic considerations raised by next generation sequencing. We illustrate specific muscle ultrasound involvement patterns, which constitute accessible diagnostic hints and show that muscle ultrasound, in conjunction with the clinical phenotype, the histological appearance of the muscle biopsy (when available), and the ascertained genotype, can be a very powerful tool in integrating all available information into a final accurate and precise diagnosis in the age of next generation sequencing.

An autopsy case of peliosis hepatis with X-linked myotubular myopathy.

This report describes the autopsy case of a 4-year-old boy who died from hepatic hemorrhage and rupture caused by peliosis hepatis with X-linked myotubular myopathy. Peliosis hepatis is characterized by multiple blood-filled cavities of various sizes in the liver, which occurs in chronic wasting disease or with the use of specific drugs. X-linked myotubular myopathy is one of the most serious types of congenital myopathies, in which an affected male infant typically presents with severe hypotonia and respiratory distress immediately after birth. Although each disorder is rare, 12 cases of pediatric peliosis hepatis associated with X-linked myotubular myopathy have been reported, including our case. Peliosis hepatis should be considered as a cause of hepatic hemorrhage despite its low incidence, and it requires adequate gross and histological investigation for correct diagnosis.

[A case of hyperkalemic periodic paralysis presenting progressive myopathy with tubular aggregates].

A 33-year-old man admitted to our hospital for the evaluation of progressive muscular atrophy of his left lower leg. From his childhood, he had suffered from transient attacks of limb paralysis and myalgia lasting about 1 hour. At age 30, the muscle weakness and atrophy of his left lower leg emerged and progressed gradually. Muscle MR images showed atrophy and fat replacement in left lower leg, and muscle biopsy revealed tubular aggregates (TA). Genetic analysis showed heterozygous c.2111C>T/p.T704M missense mutation of SCN4A gene, which causes hyperkalemic periodic paralysis (HyperPP). Although HyperPP is rare, it is quite critical for clinicians to recognize that the patients of HyperPP often present progressive myopathy. We emphasize the importance of paying attention to progressive myopathy and discuss the pathological mechanism of myopathy through this case report.

Characterization and genetic diagnosis of centronuclear myopathies in seven Chinese patients.

Centronuclear myopathies (CNMs) are a group of clinically and genetically heterogeneous muscle disorders. Here, we report a cohort of seven CNM patients with their clinical, histological, and morphological features. In addition, using the next-generation sequencing (NGS) technique (5/7 patients), we identified small indels: intronic, exonic, and missense mutations in MTM1, DNM2, and RYR1 genes. Further genetic studies revealed skewed X-chromosome inactivation in two female patients carrying MTM1 mutations. Based on the results of genetic analysis, these seven patients were classified as (1) X-linked recessive myotubular myopathy (patients 1-3) with MTM1 mutations and mild phenotype, (2) the autosomal dominant CNM (patients 4-6) with DNM2 mutations, and (3) the autosomal recessive CNM (patient 7) with RYR1 mutations. In all patients, histological findings featured a high proportion of fibers with central nuclei. Radial arrangement of the sarcoplasmic strands was observed in DNM2-CNM and RYR1-CNM patients. Muscle magnetic resonance imaging (MRI) revealed a proximal pattern of involvement presented in both MTM1-CNM and RYR1-CNM patients. A distal pattern of involvement was present in DNM2-CNM patients. Our findings thereby identified a number of novel features that expand the reported clinicopathological phenotype of CNMs in China.

New variant of necklace fibres display peculiar lysosomal structures and mitophagy.

Here, we describe a new variant of necklace fibres with specific myopathological features that have not been described thus far. They were observed in two patients, from two independent families with identical DNM2 (dynamin 2) mutation (c.1106 G > A (p.Arg369Gln)), displaying mildly heterogeneous clinical phenotypes. The variant is characterized by lysosomal inclusions, arranged in a necklace pattern, containing homogenous material, devoid of myonuclei. The so-called necklace region has a certain characteristic distance to the sarcolemma. Electron microscopy, including three dimensional reconstructions of serial section images highlights their ultrastructural properties and relation to neighbouring organelles. This new pattern is compared to the previously reported patterns in muscle biopsies containing necklace fibres associated with MTM1- and DNM2-mutations.

BAG3 mutation in a patient with atypical phenotypes of myofibrillar myopathy and Charcot-Marie-Tooth disease.

Bcl2-associated athanogene 3 (BAG3) mutations have been reported to cause the myofibrillar myopathy (MFM) which shows progressive limb muscle weakness, respiratory failure, and cardiomyopathy. Myopathy patients with BAG3 mutation are very rare. We described a patient showing atypical phenotypes. We aimed to find the genetic cause of Korean patients with sensory motor polyneuropathy, myopathy and rigid spine. We performed whole exome sequencing (WES) with 423 patients with sensory motor polyneuropathy. We found BAG3 mutation in one patient with neuropathy, myopathy and rigid spine syndrome, and performed electrophysiological study, whole body MRI and muscle biopsy on the patient. A de novo heterozygous p.Pro209Leu (c.626C>T) mutation in BAG3 was identified in a female myopathy. She first noticed a gait disturbance and spinal rigidity at the age of 11, and serum creatine kinase levels were elevated ninefolds than normal. She showed an axonal sensory-motor polyneuropathy like Charcot-Marie-Tooth disease (CMT), myopathy, rigid spine and respiratory dysfunction; however, she did not show any cardiomyopathy, which is a common symptom in BAG3 mutation. Lower limb MRI and whole spine MRI showed bilateral symmetric fatty atrophy of muscles at the lower limb and paraspinal muscles. When we track traceable MRI 1 year later, the muscle damage progressed slowly. As far as our knowledge, this is the first Korean patient with BAG3 mutation. We described a BAG3 mutation patient with atypical phenotype of CMT and myopathy, and those are expected to broaden the clinical spectrum of the disease and help to diagnose it.

A Roma founder BIN1 mutation causes a novel phenotype of centronuclear myopathy with rigid spine.

OBJECTIVE: To describe a large series of BIN1 patients, in which a novel founder mutation in the Roma population of southern Spain has been identified. METHODS: Patients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for BIN1 mutations. Clinical, histologic, radiologic, and genetic features were analyzed. RESULTS: Eighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both BIN1 variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other BIN1 mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma. CONCLUSION: We have identified a BIN1 founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain.

Novel phenotypic variant in the MYH7 spectrum due to a stop-loss mutation in the C-terminal region: a case report.

BACKGROUND: Defects of the slow myosin heavy chain isoform coding MYH7 gene primarily cause skeletal myopathies including Laing Distal Myopathy, Myosin Storage Myopathy and are also responsible for cardiomyopathies. Scapuloperoneal and limb-girdle muscle weakness, congenital fiber type disproportion, multi-minicore disease were also reported in connection of MYH7. Pathogeneses of the defects in the head and proximal rod region of the protein are well described. However, the C-terminal mutations of the MYH7 gene are less known. Moreover, only two articles describe the phenotypic impact of the elongated mature protein product caused by termination signal loss. CASE PRESENTATION: Here we present a male patient with an unusual phenotypic variant of early-onset and predominant involvement of neck muscles with muscle biopsy indicating myopathy and sarcoplasmic storage material. Cardiomyopathic involvements could not be observed. Sequencing of MYH7 gene revealed a stop-loss mutation on the 3-prime end of the rod region, which causes the elongation of the mature protein. CONCLUSIONS: The elongated protein likely disrupts the functions of the sarcomere by multiple functional abnormalities. This elongation could also affect the thick filament degradation leading to protein deposition and accumulation in the sarcomere, resulting in the severe myopathy of certain axial muscles. The phenotypic expression of the detected novel MYH7 genotype could strengthen and further expand our knowledge about mutations affecting the structure of MyHCI by termination signal loss in the MYH7 gene.

Common and variable clinical, histological, and imaging findings of recessive RYR1-related centronuclear myopathy patients.

Mutations in RYR1 give rise to diverse skeletal muscle phenotypes, ranging from classical central core disease to susceptibility to malignant hyperthermia. Next-generation sequencing has recently shown that RYR1 is implicated in a wide variety of additional myopathies, including centronuclear myopathy. In this work, we established an international cohort of 21 patients from 18 families with autosomal recessive RYR1-related centronuclear myopathy, to better define the clinical, imaging, and histological spectrum of this disorder. Early onset of symptoms with hypotonia, motor developmental delay, proximal muscle weakness, and a stable course were common clinical features in the cohort. Ptosis and/or ophthalmoparesis, facial weakness, thoracic deformities, and spinal involvement were also frequent but variable. A common imaging pattern consisted of selective involvement of the vastus lateralis, adductor magnus, and biceps brachii in comparison to adjacent muscles. In addition to a variable prominence of central nuclei, muscle biopsy from 20 patients showed type 1 fiber predominance and a wide range of intermyofibrillary architecture abnormalities. All families harbored compound heterozygous mutations, most commonly a truncating mutation combined with a missense mutation. This work expands the phenotypic characterization of patients with recessive RYR1-related centronuclear myopathy by highlighting common and variable clinical, histological, and imaging findings in these patients.

Insights from genotype-phenotype correlations by novel SPEG mutations causing centronuclear myopathy.

Centronuclear myopathies (CNM) are a clinically and genetically heterogeneous group of congenital myopathies, defined histologically by increased number of fibres with centrally located nuclei, and type I fibre predominance in muscle biopsy. Myotubular myopathy, the X-linked form of CNM caused by mutations in the phosphoinositide phosphatase MTM1, is histologically characteristic since muscle fibres resemble myotubes. Here we present two unrelated patients with CNM and typical myotubular fibres in the muscle biopsy caused by mutations in striated muscle preferentially expressed protein kinase (SPEG). Next generation sequencing revealed novel biallelic homozygous mutations in SPEG in both cases. Patient 1 showed the c.1627_1628insA (p.Thr544Aspfs*48) mutation and patient 2 the c.9586C>T (p.Arg3196*) mutation. The clinical phenotype was distinctive in the two patients since patient 2 developed a dilated cardiomyopathy with milder myopathy features, while patient 1 showed only myopathic features without cardiac involvement. These findings expand the genotype-phenotype correlations after the initial report. Additionally, we describe whole body muscle MRI of patient 2 and we argue on the different SPEG isoforms in skeletal muscle and heart as the possible explanation leading to variable phenotypes of SPEG mutations.

[Centronuclear myopathy: clinical characteristics and MRI image features of oral and maxillofacial region].

Objective: To provide biomechnical basis for orthodontics of centronuclear myopathy (CNM) patients, we studied the oral and maxillofacial clinical features and MRI image manifestations to explore application of MRI to objective evaluation the affected facial muscles. Methods: The study consisted of 8 patients who were diagnosed as CNM (CNM group) and 20 healthy volunteers (control group). Their medical information were gathered and then we examined the ptosis situation and the facial index calculation of them. To measure the maximal hight of palate and the width of palate, patients and volunteers were made impressions. We also checked their maximum bite force with occlusion pressure tester. And they took lateral cephalometric radiographs to measure mandibular plane-Frankfort horizontal plane angle (MP-FH). At last, they were taken oral and maxillofacial region MRI to observe the affected situation of masseter muscle, medial pterygoid muscle and lateral pterygoid muscle. Results: Six patients were ptosis; 6 patients had inverse V-shaped mouth; 3 patients were difficulty in swallowing; 4 patients were anterior open bites; 4 patients were mouth breathing; 7 patients liked to eat soft foods. Morphological facial index ([91.3±0.5]%), MP-FH (34.9°±2.0°) of CNM group were greater than the control group, male maximal hight of palate ([19.0±0.2] mm), female maximal hight of palate ([18.0±0.6] mm) of CNM group were greater than the control group (P<0.05). Male width of palate ([34.5±0.8] mm), female width of palate ([33.4±1.0] mm), male maximum bite force ([464.3±78.2] N), female maximum bite force ([320.7±13.8] N), maximal opening of mouth ([3.4±0.3] cm) of CNM group were less than the control group (P<0.05). And these had significant difference compared with the control group (P<0.05). In MRI examination, there were 7 patients' masseter muscles, 4 patients' medial pterygoid muscles and 6 patients' lateral pterygoid muscles to atrophy asymmetrically. These three pieces of muscular fatty infiltration were inordinately, focused on Grade 0 to 4 and the both sides were similar. Conclusions: CNM patients with long and thin face, high palatine arches and low bite force together were the biomechanical basis of the maxillofacial deformities. MRI can clearly show the affected masseter muscle, medial pterygoid muscle, lateral pterygoid muscle, and can serve as an objective examination method for the evaluation of facial muscles. It can be worth of clinical popularization and application.

Homozygosity of the Dominant Myotilin c.179C>T (p.Ser60Phe) Mutation Causes a More Severe and Proximal Muscular Dystrophy.

Most myotilinopathy patients present with a dominant late onset distal phenotype and myofibrillar pathology, although the first MYOT mutation in a family reported to have LGMD phenotype. We report here a French family affected with a late onset proximal and distal muscle weakness and myofibrillar myopathy on muscle pathology, in which the siblings known to be clinically affected were homozygous for the c.179C>T (p.Ser60Phe) myotilin gene mutation. One subjectively asymptomatic member of the family was heterozygous for this mutation. This is the first report of a family with patients being homozygous for a known dominant MYOT mutation. Dominant negative mutations are generally considered not to cause a more severe disease in homozygosity, but our data clearly demonstrate the existence of dominant MYOT mutations with a possible dose effect causing a more severe disease phenotype in homozygosity in the spectrum of myofibrillar myopathies (MFM).