Marked Facial Weakness, Ptosis, and Hanging Jaw: A Case with RYR1-Related Congenital Centronuclear Myopathy

AbstractCongenital myopathies are an expanding spectrum of neuromuscular disorders with early infantile or childhood onset hypotonia and slowly or nonprogressive skeletal muscle weakness. RYR1-related myopathies are the most common and frequently diagnosed class of congenital myopathies. Malignant hyperthermia susceptibility and central core disease are autosomal dominant or de novo RYR1 disorder, whereas multiminicore, congenital fiber type disproportion and centronuclear myopathy are autosomal recessive RYR1 disorders. The presence of ptosis, ophthalmoparesis, facial, and proximal muscles weakness, with the presence of dusty cores and multiple internal nuclei on muscle biopsy are clues to the diagnosis. We describe an 18-year-old male, who presented with early infantile onset ptosis, ophthalmoplegia, myopathic facies, hanging lower jaw, and proximal muscle weakness confirmed as an RYR1-related congenital centronuclear myopathy on genetic analysis and muscle biopsy.

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Molecular basis of impaired muscle function in a mouse model of congenital myopathy due to compound heterozygous RYR1 mutations

The Journal of General Physiology ◽

10.1085/jgp.2021ecc26 ◽

2021 ◽

Vol 154 (9) ◽

Author(s):

Alexis Ruizl ◽

Jan Eckhardt ◽

Susan Treves ◽

Francesco Zorzato

Keyword(s):

Mouse Model ◽

Malignant Hyperthermia ◽

Muscle Weakness ◽

Muscle Function ◽

Fiber Type ◽

Neuromuscular Disorders ◽

Extraocular Muscles ◽

Malignant Hyperthermia Susceptibility ◽

Compound Heterozygous ◽

Feeding Difficulties

Congenital myopathies (CM) are a group of early-onset, genetically diverse muscle disorders of variable severity with characteristic muscle biopsy findings. Mutations in RYR1, the gene encoding the RYR1, are the most common genetic cause, responsible for ∼30% of all human CM. They are linked to the pharmacogenetic disorder malignant hyperthermia susceptibility and to various disease phenotypes, including central core disease (which is primarily dominantly inherited), multiminicore disease (which is predominantly recessively inherited), some forms of centronuclear myopathy and congenital fiber-type disproportion (which can be either dominantly or recessively inherited), and King–Denborough syndrome (a CM characterized by skeletal abnormalities, dysmorphic features, and malignant hyperthermia susceptibility). The recessive forms of RYR1-linked CM are more severe, affecting children at birth and, in addition to profound muscle weakness, may also affect facial and extraocular muscles and cause skeletal deformities and feeding difficulties. To study the mechanism leading to the profound muscle weakness characterized by recessive RYR1-CM, we created transgenic mice knocked in for the compound heterozygous RYR1 p.Q1970fsX16+p.A4329D mutations (double knock-in mouse, or DKI) identified in a severely affected child. The in vivo and ex vivo physiological functions of fast twitch, slow twitch, and extraocular muscles were severely impaired in DKI mice; in addition, the mutations were accompanied by a >50% decrease in RYR1 protein in all muscles examined, as well as changes in the expression of many proteins important for muscle function and chromatin structure. Muscle ultrastructure was disorganized, with fewer CRU and mitochondria and presence of cores. MyHC-EO, the superfast and ocular-muscle−specific myosin heavy isoform, was almost undetectable in EOMs from DKI mutant mice. Thus, the DKI mouse model faithfully recapitulates the human disease and could be exploited for preclinical studies aimed at developing therapeutic strategies to treat neuromuscular disorders linked to recessive RYR1 mutations.

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THE SPECTRUM OF CONGENITAL MYOPATHIES IN ROMANIA – A PATHOLOGICAL RETROSPECTIVE STUDY

Romanian Journal of Neurology ◽

10.37897/rjn.2015.4.7 ◽

2015 ◽

Vol 14 (4) ◽

pp. 225-234

Author(s):

Alexandra Eugenia Bastian ◽

◽

Vlad Mageriu ◽

Emilia Manole ◽

◽

...

Keyword(s):

Muscle Biopsy ◽

Fiber Type ◽

Molecular Genetic ◽

Laboratory Data ◽

Diagnostic Algorithm ◽

University Hospital ◽

Morphological Data ◽

Motor Deficit ◽

Congenital Myopathies ◽

Muscle Biopsies

Objectives. Congenital myopathies (CM) are a highly heterogeneous group of disorders with genetic cause, characterized by motor deficit and weakness usually manifesting in the neonatal period, with slowly progressive or non-progressive course and affecting both sexes. MC classification has undergone many changes over time, and in recent years molecular genetic studies have enabled identification of novel genes and mutations, thus increasing the diagnostic complexity. We wanted to study the incidence and morphological features of the CM cases diagnosed by muscle biopsy in the Pathology Department of Colentina University Hospital over a period of 10 years (09.2005- 09.2015). Materials and methods. We retrospectively reviewed all the muscle biopsies diagnosed with different types of CM. Muscle biopsies were performed and specifically processed using routine and special stains on cryosections, semithin and ultrathin sections for ultrastructural examination. In all the cases we reassessed the clinical and laboratory data. Results. From a number of 1,530 peripheral nerve and muscle biopsies performed and analyzed in the 10 years period we diagnosed CM in 15 cases, representing 1.03% of the total. Of these, five were “central core myopathies”, five centronuclear/myotubular myopathies, one case of nemaline myopathy, one case of “reducing body myopathy” and three cases with congenital fiber type disproportion. Reassessment of morphological data in the clinical context allowed us to identify numerous overlaps between subtypes both in the clinical and pathological picture. Conclusions. The reduced number of MC identified in our country suggests that these diseases are probably underdiagnosed or diagnosed late, requiring a better understanding of the various clinical and pathological particularities. In the accurate diagnostic algorithm, muscle biopsy remains essential to establish the type of CM and thus to direct genetic tests.

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Centronuclear myopathy: histopathological aspects in ten patients with chilfhood onset

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x1998000100001 ◽

1998 ◽

Vol 56 (1) ◽

pp. 01-08 ◽

Cited By ~ 2

Author(s):

EDMAR ZANOTELI ◽

ACARY SOUZA BULLE OLIVEIRA ◽

BEATRIZ HITOMI KIYOMOTO ◽

BENY SCHMIDT ◽

ALBERTO ALAIN GABBAI

Keyword(s):

Ultrastructural Study ◽

Fiber Type ◽

Signs And Symptoms ◽

Congenital Myopathy ◽

Great Variability ◽

Type I ◽

Centronuclear Myopathy ◽

Adult Onset ◽

Childhood Onset

Centronuclear myopathy is a rare congenital myopathy. According to the period of onset of signs and symptoms and the degree of muscular involvement three clinical forms are distinguished: severe neonatal; childhood onset; and adult onset. We describe herein the muscle biopsy findings of ten patients with the childhood onset form of the disease including three cases with ultrastructural study. The biopsies disclosed increased nuclear centralization that varied from 25 to 90% of the fibers, type 1 predominance, great variability in fiber diameters, involvement in the internal fiber's architecture, and focal areas of myofilament disorganization. The main histopathologic differential diagnoses included type I fiber predominance, congenital fiber type disproportion, and myotonic dystrophy. The histologic abnormalities in centronuclear myopathy may be due to an arrest of maturation on the fetal myotubular stage. The cause of this arrest remains elusive.

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Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature

Skeletal Muscle ◽

10.1186/s13395-020-00243-4 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Tokunbor A. Lawal ◽

Joshua J. Todd ◽

Jessica W. Witherspoon ◽

Carsten G. Bönnemann ◽

James J. Dowling ◽

...

Keyword(s):

Malignant Hyperthermia ◽

Ryanodine Receptor ◽

Calcium Release ◽

Fiber Type ◽

Neuromuscular Disorders ◽

Malignant Hyperthermia Susceptibility ◽

Adult Onset ◽

Calcium Release Channel ◽

Release Channel ◽

Disease Spectrum

AbstractThe RYR1 gene, which encodes the sarcoplasmic reticulum calcium release channel or type 1 ryanodine receptor (RyR1) of skeletal muscle, was sequenced in 1988 and RYR1 variations that impair calcium homeostasis and increase susceptibility to malignant hyperthermia were first identified in 1991. Since then, RYR1-related myopathies (RYR1-RM) have been described as rare, histopathologically and clinically heterogeneous, and slowly progressive neuromuscular disorders. RYR1 variants can lead to dysfunctional RyR1-mediated calcium release, malignant hyperthermia susceptibility, elevated oxidative stress, deleterious post-translational modifications, and decreased RyR1 expression. RYR1-RM-affected individuals can present with delayed motor milestones, contractures, scoliosis, ophthalmoplegia, and respiratory insufficiency.Historically, RYR1-RM-affected individuals were diagnosed based on morphologic features observed in muscle biopsies including central cores, cores and rods, central nuclei, fiber type disproportion, and multi-minicores. However, these histopathologic features are not always specific to RYR1-RM and often change over time. As additional phenotypes were associated with RYR1 variations (including King-Denborough syndrome, exercise-induced rhabdomyolysis, lethal multiple pterygium syndrome, adult-onset distal myopathy, atypical periodic paralysis with or without myalgia, mild calf-predominant myopathy, and dusty core disease) the overlap among diagnostic categories is ever increasing. With the continuing emergence of new clinical subtypes along the RYR1 disease spectrum and reports of adult-onset phenotypes, nuanced nomenclatures have been reported (RYR1- [related, related congenital, congenital] myopathies). In this narrative review, we provide historical highlights of RYR1 research, accounts of the main diagnostic disease subtypes and propose RYR1-related disorders (RYR1-RD) as a unified nomenclature to describe this complex and evolving disease spectrum.

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Myriocin prevents muscle ceramide accumulation but not muscle fiber atrophy during short-term mechanical unloading

Journal of Applied Physiology ◽

10.1152/japplphysiol.00720.2015 ◽

2016 ◽

Vol 120 (2) ◽

pp. 178-187 ◽

Cited By ~ 13

Author(s):

Erwann Salaun ◽

Luz Lefeuvre-Orfila ◽

Thibault Cavey ◽

Brice Martin ◽

Bruno Turlin ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Muscle Weakness ◽

Muscle Atrophy ◽

De Novo ◽

Fiber Diameter ◽

Sphingolipid Metabolism ◽

Skeletal Muscle Atrophy ◽

De Novo Synthesis ◽

Skeletal Muscle Weakness

Bedridden patients in intensive care unit or after surgery intervention commonly develop skeletal muscle weakness. The latter is promoted by a variety of prolonged hospitalization-associated conditions. Muscle disuse is the most ubiquitous and contributes to rapid skeletal muscle atrophy and progressive functional strength reduction. Disuse causes a reduction in fatty acid oxidation, leading to its accumulation in skeletal muscle. We hypothesized that muscle fatty acid accumulation could stimulate ceramide synthesis and promote skeletal muscle weakness. Therefore, the present study was designed to determine the effects of sphingolipid metabolism on skeletal muscle atrophy induced by 7 days of disuse. For this purpose, male Wistar rats were treated with myriocin, an inhibitor of de novo synthesis of ceramides, and subjected to hindlimb unloading (HU) for 7 days. Soleus muscles were assayed for fiber diameter, ceramide levels, protein degradation, and apoptosis signaling. Serum and liver were removed to evaluate the potential hepatoxicity of myriocin treatment. We found that HU increases content of saturated C16:0 and C18:0 ceramides and decreases soleus muscle weight and fiber diameter. HU increased the level of polyubiquitinated proteins and induced apoptosis in skeletal muscle. Despite a prevention of C16:0 and C18:0 muscle accumulation, myriocin treatment did not prevent skeletal muscle atrophy and concomitant induction of apoptosis and proteolysis. Moreover, myriocin treatment increased serum transaminases and induced hepatocyte necrosis. These data highlight that inhibition of de novo synthesis of ceramides during immobilization is not an efficient strategy to prevent skeletal muscle atrophy and exerts adverse effects like hepatotoxicity.

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Expanding the phenotype of de novo SLC25A4-linked mitochondrial disease to include mild myopathy

Neurology Genetics ◽

10.1212/nxg.0000000000000256 ◽

2018 ◽

Vol 4 (4) ◽

pp. e256 ◽

Cited By ~ 6

Author(s):

Martin S. King ◽

Kyle Thompson ◽

Sila Hopton ◽

Langping He ◽

Edmund R.S. Kunji ◽

...

Keyword(s):

Lactococcus Lactis ◽

Muscle Biopsy ◽

Complex I ◽

Mitochondrial Myopathy ◽

De Novo ◽

Membrane Vesicles ◽

Adenosine Diphosphate ◽

Childhood Onset ◽

Expression Levels ◽

Protein Levels

ObjectiveTo determine the disease relevance of a novel de novo dominant variant in the SLC25A4 gene, encoding the muscle mitochondrial adenosine diphosphate (ADP)/adenosine triphosphate (ATP) carrier, identified in a child presenting with a previously unreported phenotype of mild childhood-onset myopathy.MethodsImmunohistochemical and western blot analysis of the patient's muscle tissue were used to assay for the evidence of mitochondrial myopathy and for complex I–V protein levels. To determine the effect of a putative pathogenic p.Lys33Gln variant on ADP/ATP transport, the mutant protein was expressed in Lactococcus lactis and its transport activity was assessed with fused membrane vesicles.ResultsOur data demonstrate that the heterozygous c.97A>T (p.Lys33Gln) SLC25A4 variant is associated with classic muscle biopsy findings of mitochondrial myopathy (cytochrome c oxidase [COX]-deficient and ragged blue fibers), significantly impaired ADP/ATP transport in Lactococcus lactis and decreased complex I, III, and IV protein levels in patient's skeletal muscle. Nonetheless, the expression levels of the total ADP/ATP carrier (AAC) content in the muscle biopsy was largely unaffected.ConclusionsThis report further expands the clinical phenotype of de novo dominant SLC25A4 mutations to a childhood-onset, mild skeletal myopathy, without evidence of previously reported clinical features associated with SLC25A4-associated disease, such as cardiomyopathy, encephalopathy or ophthalmoplegia. The most likely reason for the milder disease phenotype is that the overall AAC expression levels were not affected, meaning that expression of the wild-type allele and other isoforms may in part have compensated for the impaired mutant variant.

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De novo TRPV4 Leu619Pro variant causes a new channelopathy characterised by giant cell lesions of the jaws and skull, skeletal abnormalities and polyneuropathy

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107427 ◽

2021 ◽

pp. jmedgenet-2020-107427

Author(s):

Aviel Ragamin ◽

Carolina C Gomes ◽

Karen Bindels-de Heus ◽

Renata Sandoval ◽

Angelia V Bassenden ◽

...

Keyword(s):

Giant Cell ◽

De Novo ◽

Neuromuscular Disorders ◽

Somatic Mosaicism ◽

Ion Leakage ◽

Gain Of Function ◽

Therapeutic Modalities ◽

Organ Systems ◽

Heterozygous Variant ◽

Systemic Disorder

BackgroundPathogenic germline variants in Transient Receptor Potential Vanilloid 4 Cation Channel (TRPV4) lead to channelopathies, which are phenotypically diverse and heterogeneous disorders grossly divided in neuromuscular disorders and skeletal dysplasia. We recently reported in sporadic giant cell lesions of the jaws (GCLJs) novel, somatic, heterozygous, gain-of-function mutations in TRPV4, at Met713.MethodsHere we report two unrelated women with a de novo germline p.Leu619Pro TRPV4 variant and an overlapping systemic disorder affecting all organs individually described in TRPV4 channelopathies.ResultsFrom an early age, both patients had several lesions of the nervous system including progressive polyneuropathy, and multiple aggressive giant cell-rich lesions of the jaws and craniofacial/skull bones, and other skeletal lesions. One patient had a relatively milder disease phenotype possibly due to postzygotic somatic mosaicism. Indeed, the TRPV4 p.Leu619Pro variant was present at a lower frequency (variant allele frequency (VAF)=21.6%) than expected for a heterozygous variant as seen in the other proband, and showed variable regional frequency in the GCLJ (VAF ranging from 42% to 10%). In silico structural analysis suggests that the gain-of-function p.Leu619Pro alters the ion channel activity leading to constitutive ion leakage.ConclusionOur findings define a novel polysystemic syndrome due to germline TRPV4 p.Leu619Pro and further extend the spectrum of TRPV4 channelopathies. They further highlight the convergence of TRPV4 mutations on different organ systems leading to complex phenotypes which are further mitigated by possible post-zygotic mosaicism. Treatment of this disorder is challenging, and surgical intervention of the GCLJ worsens the lesions, suggesting the future use of MEK inhibitors and TRPV4 antagonists as therapeutic modalities for unmet clinical needs.

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Sleep Exacerbations and Facial Twitching: Diagnostic Clues for ADCY5-Related Dyskinesias

Neuropediatrics ◽

10.1055/s-0040-1721685 ◽

2020 ◽

Author(s):

Margherita Nosadini ◽

Gianluca D'Onofrio ◽

Maria Federica Pelizza ◽

Concetta Luisi ◽

Davide Padrin ◽

...

Keyword(s):

Movement Disorder ◽

Developmental Delay ◽

De Novo ◽

Brain Magnetic Resonance Imaging ◽

Neurological Impairment ◽

De Novo Mutation ◽

Oligoclonal Bands ◽

Emotional Stimuli ◽

Childhood Onset ◽

Ataxic Gait

Abstract Background Mutations in the adenylate cyclase 5 (ADCY5) gene are associated with childhood-onset paroxysmal dyskinesia. Methods We report a new video-documented case of pediatric ADCY5-related dyskinesia with de novo ADCY5 mutation. Results A boy born to nonconsanguineous parents after an uneventful pregnancy had developmental delay and hypotonia. At the age of 7 months, he presented with paroxysmal jerky–choreic–dystonic involuntary movements in wakefulness involving limbs, trunk, and face, exacerbated by emotional stimuli. These episodes gradually worsened in duration and frequency: at the age of 2.5 years, they occurred up to six times per day, and appeared also during sleep in prolonged bouts; the boy also had basal choreoathetoid–dystonic movements, hyperactivity, paraparetic–ataxic gait, generalized hypotonia with brisk tendon reflexes, drooling, and language delay with intellectual disability. Brain magnetic resonance imaging, electroencephalogram, electromyogram, eye review, metabolic investigations, oligoclonal bands, and autoantibodies were normal. Extensive genetic testing had not let to a diagnosis, until a heterozygous de novo mutation c.1252C > T (p.Arg418Trp) was identified in the ADCY5 gene. Clonazepam had partial effectiveness. The boy walked at the age of 3.5 years. At the age of 5 years, the paroxysmal movement disorder has slightly improved. Conclusion ADCY5 mutations should be considered among the differential diagnoses of early-onset paroxysmal choreic–athetosic–myoclonic–dystonic movement disorder involving limbs, trunk, and face, in patients with global neurological impairment with hypotonia and developmental delay. Facial dyskinesias and exacerbation by drowsiness/sleep and emotional stimuli are important clues that may allow a timely recognition of the disorder and avoidance of unnecessary diagnostic investigations.

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