Multi-minicore Disease (MmD) is a recessively inherited neuromuscular disorder characterized by multiple cores on muscle biopsy and clinical features of a congenital myopathy. Prevalence is unknown. ...Marked clinical variability corresponds to genetic heterogeneity: the most instantly recognizable classic phenotype characterized by spinal rigidity, early scoliosis and respiratory impairment is due to recessive mutations in the selenoprotein N (SEPN1) gene, whereas recessive mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wider range of clinical features comprising external ophthalmoplegia, distal weakness and wasting or predominant hip girdle involvement resembling central core disease (CCD). In the latter forms, there may also be a histopathologic continuum with CCD due to dominant RYR1 mutations, reflecting the common genetic background. Pathogenetic mechanisms of RYR1-related MmD are currently not well understood, but likely to involve altered excitability and/or changes in calcium homeoestasis; calcium-binding motifs within the selenoprotein N protein also suggest a possible role in calcium handling. The diagnosis of MmD is based on the presence of suggestive clinical features and multiple cores on muscle biopsy; muscle MRI may aid genetic testing as patterns of selective muscle involvement are distinct depending on the genetic background. Mutational analysis of the RYR1 or the SEPN1 gene may provide genetic confirmation of the diagnosis. Management is mainly supportive and has to address the risk of marked respiratory impairment in SEPN1-related MmD and the possibility of malignant hyperthermia susceptibility in RYR1-related forms. In the majority of patients, weakness is static or only slowly progressive, with the degree of respiratory impairment being the most important prognostic factor.
The congenital myopathies are a group of early-onset, non-dystrophic neuromuscular conditions with characteristic muscle biopsy findings, variable severity and a stable or slowly progressive course. ...Pronounced weakness in axial and proximal muscle groups is a common feature, and involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects. Central core disease (CCD), multi-minicore disease (MmD), centronuclear myopathy (CNM) and nemaline myopathy were among the first congenital myopathies to be reported, and they still represent the main diagnostic categories. However, these entities seem to belong to a much wider phenotypic spectrum. To date, congenital myopathies have been attributed to mutations in over 20 genes, which encode proteins implicated in skeletal muscle Ca
homeostasis, excitation-contraction coupling, thin-thick filament assembly and interactions, and other mechanisms. RYR1 mutations are the most frequent genetic cause, and CCD and MmD are the most common subgroups. Next-generation sequencing has vastly improved mutation detection and has enabled the identification of novel genetic backgrounds. At present, management of congenital myopathies is largely supportive, although new therapeutic approaches are reaching the clinical trial stage.
Single gene disorders of the autophagy pathway are an emerging, novel and diverse group of multisystem diseases in children. Clinically, these disorders prominently affect the central nervous system ...at various stages of development, leading to brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration, among others. Frequent early and severe involvement of the central nervous system puts the paediatric neurologist, neurogeneticist, and neurometabolic specialist at the forefront of recognizing and treating these rare conditions. On a molecular level, mutations in key autophagy genes map to different stages of this highly conserved pathway and thus lead to impairment in isolation membrane (or phagophore) and autophagosome formation, maturation, or autophagosome-lysosome fusion. Here we discuss 'congenital disorders of autophagy' as an emerging subclass of inborn errors of metabolism by using the examples of six recently identified monogenic diseases: EPG5-related Vici syndrome, beta-propeller protein-associated neurodegeneration due to mutations in WDR45, SNX14-associated autosomal-recessive cerebellar ataxia and intellectual disability syndrome, and three forms of hereditary spastic paraplegia, SPG11, SPG15 and SPG49 caused by SPG11, ZFYVE26 and TECPR2 mutations, respectively. We also highlight associations between defective autophagy and other inborn errors of metabolism such as lysosomal storage diseases and neurodevelopmental diseases associated with the mTOR pathway, which may be included in the wider spectrum of autophagy-related diseases from a pathobiological point of view. By exploring these emerging themes in disease pathogenesis and underlying pathophysiological mechanisms, we discuss how congenital disorders of autophagy inform our understanding of the importance of this fascinating cellular pathway for central nervous system biology and disease. Finally, we review the concept of modulating autophagy as a therapeutic target and argue that congenital disorders of autophagy provide a unique genetic perspective on the possibilities and challenges of pathway-specific drug development.
Centronuclear myopathy (CNM) is an inherited neuromuscular disorder characterised by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy.The incidence of X-linked ...myotubular myopathy is estimated at 2/100000 male births but epidemiological data for other forms are not currently available.The clinical picture is highly variable. The X-linked form usually gives rise to a severe phenotype in males presenting at birth with marked weakness and hypotonia, external ophthalmoplegia and respiratory failure. Signs of antenatal onset comprise reduced foetal movements, polyhydramnios and thinning of the ribs on chest radiographs; birth asphyxia may be the present. Affected infants are often macrosomic, with length above the 90th centile and large head circumference. Testes are frequently undescended. Both autosomal-recessive (AR) and autosomal-dominant (AD) forms differ from the X-linked form regarding age at onset, severity, clinical characteristics and prognosis. In general, AD forms have a later onset and milder course than the X-linked form, and the AR form is intermediate in both respects.Mutations in the myotubularin (MTM1) gene on chromosome Xq28 have been identified in the majority of patients with the X-linked recessive form, whilst AD and AR forms have been associated with mutations in the dynamin 2 (DNM2) gene on chromosome 19p13.2 and the amphiphysin 2 (BIN1) gene on chromosome 2q14, respectively. Single cases with features of CNM have been associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the hJUMPY (MTMR14) genes.Diagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features; muscle magnetic resonance imaging may complement clinical assessment and inform genetic testing in cases with equivocal features. Genetic counselling should be offered to all patients and families in whom a diagnosis of CNM has been made.The main differential diagnoses include congenital myotonic dystrophy and other conditions with severe neonatal hypotonia.Management of CNM is mainly supportive, based on a multidisciplinary approach. Whereas the X-linked form due to MTM1 mutations is often fatal in infancy, dominant forms due to DNM2 mutations and some cases of the recessive BIN1-related form appear to be associated with an overall more favourable prognosis.
Centronuclear myopathies (CNMs) are a genetically heterogeneous group of inherited neuromuscular disorders characterized by clinical features of a congenital myopathy and abundant central nuclei as ...the most prominent histopathological feature. The most common forms of congenital myopathies with central nuclei have been attributed to X-linked recessive mutations in the MTM1 gene encoding myotubularin ("X-linked myotubular myopathy"), autosomal-dominant mutations in the DNM2 gene encoding dynamin-2 and the BIN1 gene encoding amphiphysin-2 (also named bridging integrator-1, BIN1, or SH3P9), and autosomal-recessive mutations in BIN1, the RYR1 gene encoding the skeletal muscle ryanodine receptor, and the TTN gene encoding titin. Models to study and rescue the affected cellular pathways are now available in yeast, C. elegans, drosophila, zebrafish, mouse, and dog. Defects in membrane trafficking have emerged as a key pathogenic mechanisms, with aberrant T-tubule formation, abnormalities of triadic assembly, and disturbance of the excitation-contraction machinery the main downstream effects studied to date. Abnormal autophagy has recently been recognized as another important collateral of defective membrane trafficking in different genetic forms of CNM, suggesting an intriguing link to primary disorders of defective autophagy with overlapping histopathological features. The following review will provide an overview of clinical, histopathological, and genetic aspects of the CNMs in the context of the key pathogenic mechanism, outline unresolved questions, and indicate promising future lines of enquiry.
The terminal stages of neuronal degeneration and death in neurodegenerative diseases remain elusive. Autophagy is an essential catabolic process frequently failing in neurodegeneration. Selective ...autophagy routes have recently emerged, including nucleophagy, defined as degradation of nuclear components by autophagy. Here, we show that, in a mouse model for the polyglutamine disease dentatorubral-pallidoluysian atrophy (DRPLA), progressive acquirement of an ataxic phenotype is linked to severe cerebellar cellular pathology, characterized by nuclear degeneration through nucleophagy-based LaminB1 degradation and excretion. We find that canonical autophagy is stalled in DRPLA mice and in human fibroblasts from patients of DRPLA. This is evidenced by accumulation of p62 and downregulation of LC3-I/II conversion as well as reduced Tfeb expression. Chronic autophagy blockage in several conditions, including DRPLA and Vici syndrome, an early-onset autolysosomal pathology, leads to the activation of alternative clearance pathways including Golgi membrane-associated and nucleophagy-based LaminB1 degradation and excretion. The combination of these alternative pathways and canonical autophagy blockade, results in dramatic nuclear pathology with disruption of the nuclear organization, bringing about terminal cell atrophy and degeneration. Thus, our findings identify a novel progressive mechanism for the terminal phases of neuronal cell degeneration and death in human neurodegenerative diseases and provide a link between autophagy block, activation of alternative pathways for degradation, and excretion of cellular components.
•Progressive stall in canonical autophagy in disease-specific areas in DRPLA•Chronic autophagy block activates alternative degradation pathways in vivo•Nucleophagy-associated LaminB1 accumulates in the cytoplasm and is then excreted
Golgi-mediated degradation and excretion of LaminB1 promote cell atrophy and death. Baron et al. demonstrate that a block in canonical autophagy signaling leads to activation of alternative clearance routes. Golgi-mediated degradation and excretion of nuclear LaminB1 finally result in terminal nuclear breakdown, cell atrophy, and death.
Carey Fineman Ziter Syndrome (CFZS) is a rare autosomal recessive disease caused by mutations in the MYMK locus which encodes the protein, myomaker. Myomaker is essential for fusion and concurrent ...myonuclei donation of muscle progenitors during growth and development. Strikingly, in humans, MYMK mutations appear to prompt myofiber hypertrophy but paradoxically, induce generalised muscle weakness. As the underlying cellular mechanisms remain unexplored, the present study aimed to gain insights by combining myofiber deep-phenotyping and proteomic profiling. Hence, we isolated individual muscle fibers from CFZS patients and performed mechanical, 3D morphological and proteomic analyses. Myofibers from CFZS patients were ~ 4x larger than controls and possessed ~ 2x more myonuclei than those from healthy subjects, leading to disproportionally larger myonuclear domain volumes. These greater myonuclear domain sizes were accompanied by smaller intrinsic cellular force generating-capacities in myofibers from CFZS patients than in control muscle cells. Our complementary proteomic analyses indicated remodelling in 233 proteins particularly those associated with cellular respiration. Overall, our findings suggest that myomaker is somewhat functional in CFZS patients, but the associated nuclear accretion may ultimately lead to non-functional hypertrophy and altered energy-related mechanisms in CFZS patients. All of these are likely contributors of the muscle weakness experienced by CFZS patients.
Introduction Narcolepsy with cataplexy and myasthenia gravis are both chronic neurological conditions causing symptoms of muscle weakness, often affecting facial muscles, and both attributed to an ...immune-mediated aetiology. Here we report an adolescent girl diagnosed with both conditions and discuss possible shared mechanisms and the diagnostic challenges presented by her case, to inform and aid clinicians managing children and young people with these rare conditions. Case A ten-year-old girl was referred o the paediatric sleep clinic with a two year history of excessive daytime sleepiness and cataplexy, featuring full loss of postural tone. She was subsequently found to have narcolepsy with cataplexy based on positive PSG (figure 1) & MSLT findings with supporting HLA-DQB1*06:02 result. She was managed with methylphenidate, and later venlafaxine, but experienced unsatisfactory symptom control. Two years later she represented to ophthalmology with ptosis and was subsequently found to have elevated acetylcholine receptor antibodies. She was referred to paediatric neurology and clinical examination demonstrated fatiguability consistent with myasthenia gravis and pyridostigmine was started with good effect. Abstract P17 Figure 1 Hypnogram generated from our patient‘s PSG demonstrating rapid sleep onset time (SOT), with first REM cycle arising from N1 Figure omitted. See PDF Discussion Interesting comparisons between both conditions can be drawn: both cause weakness that can affect facial muscles and cause ptosis and both can be worse as the day progresses for different reasons; both have an immune-mediated aetiology with myasthenia gravis well recognised as antibody-mediated and narcolepsy shown to have increased T-cell activity; both have documented association with other autoimmune disorders. Conclusion This case highlights an unusual presentation of two very rare conditions with both overlapping clinical features. Co-occurrence is incredibly rare, but caution and consideration of other differential diagnoses is advised if symptoms do not respond to treatment, or are not fully consistent with typical narcolepsy. The possible co-existence of other immune-mediated disorders should be borne in mind, with a low threshold to involve other expert professionals. References Wise MS, Lynch J. Narcolepsy in children. Semin. Pediatr. Neurol. 2001;8:198–206 Andlauer O, et al. Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency. JAMA Neurol. 2013;70:891–902 Drakatos P, et al. First rapid eye movement sleep periods and sleep-onset rapid eye movement periods in sleep-stage sequencing of hypersomnias. Sleep Med. 2013;14:897–901 Mignot E, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch. Neurol. 2002;59:1553–1562 Miyagawa T, Tokunaga K. Genetics of narcolepsy. Hum. Genome Var. 2019;6:4 Jayawant S. Myasthenia in children. (Mac Keith Press, 2020) Bassetti CLA, et al. European guideline and expert statements on the management of narcolepsy in adults and children. J. Sleep Res. 2021;30:e13387 Pensato U, Pizza F, Plazzi G. Myasthenic or cataplectic facies? Ice pack test response in paediatric type 1 narcolepsy. Sleep Med. 2021;87:20–21 El Sammak S, Cipriani V, Sahni A, Attarian H. Narcolepsy type 1 comorbid with myasthenia gravis: possible immunological link. J. Clin. Sleep Med. JCSM Off. Publ. Am. Acad. Sleep Med. 2022;18:1889–1890 Latorre D, et al. T cells in patients with narcolepsy target self-antigens of hypocretin neurons. Nature 2018;562:63–68 Giannoccaro MP, et al. Antibodies against hypocretin receptor 2 are rare in narcolepsy. Sleep 2017;40 Mart nez-Orozco FJ, et al. Narcolepsy with cataplexy and comorbid immunopathological diseases. J. Sleep Res. 2014;23:414–419 Aydinoz S, et al. Allergies and disease severity in childhood narcolepsy: preliminary findings. Sleep 2015;38:1981–1984 Barateau L, et al. Comorbidity between central disorders of hypersomnolence and immune-based disorders. Neurology 2017;88:93–100 Tajima Y, Yaguchi H, Mito Y. Non-motor comorbidity of Myasthenia Gravis: Myasthenia Gravis as a systemic immunological disorder involving non-motor systems. Intern. Med. Tokyo Jpn. 2019;58:1341–1347
Vici syndrome is a rare congenital multisystem disorder due to recessive mutations in the key autophagy regulator EPG5. Vici syndrome is characterized by agenesis of the corpus callosum, ...hypopigmentation, immunodeficiency, cataracts, and cardiomyopathy, with variable additional multisystem involvement. Here we report on a 5-year-old girl who presented with global developmental delay, seizures, callosal agenesis, cataracts, sensorineural hearing loss, hypopigmentation, and immunodeficiency with a low CD4 count and recurrent infections. EPG5 sequencing (prompted by suggestive clinical features) revealed a homozygous missense mutation, c.1007A>G (p.Gln336Arg). The patient was referred to our center for evaluation of nocturnal apnea. Overnight polysomnography showed severe central sleep apnea (CSA) with an overall apnea-hypopnea index of 100.5 events per hour of sleep (central apnea index of 97.5, mixed apnea index of 2, and obstructive hypopnea index of 1). The patient responded to bilevel positive airway pressure therapy with a backup rate with normalization of the apnea-hypopnea index and maintenance of oxygen saturation >90%. Despite successful control of the severe CSA, the patient was eventually started on nocturnal oxygen therapy due to excessive upper airway secretions and the high risk of possible aspiration with positive airway pressure therapy. This is the first report of EPG5-related Vici syndrome associated with CSA. We discuss the polysomnographic findings in our patient in the context of a brief literature review of the reported sleep abnormalities in Vici syndrome.
Purpose
Patients with neuromuscular disorders (NMDs) are at increased risk of perioperative complications. The objective of this scoping review was to examine emerging evidence from published ...studies, case reports, and review articles on anesthetic management of patients with NMDs, following the methodological frame for scoping reviews.
Sources
We searched PubMed and EMBASE for articles published between 1 January 2000 and 14 July 2021.
Principal findings
Three prospective and 21 retrospective studies on altered pharmacokinetics and pharmacodynamics of neuromuscular blocking agents (NMBA) in NMD patients were included. Furthermore, 168 case reports/series reporting 212 anesthetics in 197 patients were included. These studies showed that preanesthetic neuromuscular monitoring can be used for precise NMBA dosing in myasthenia gravis patients. Sugammadex was associated with fewer postoperative myasthenic crises. Perioperative complications were not associated with specific anesthetic agents. Case reports/series showed that in 32% (67/212) of anesthetics, at least one complication was reported. Unexpected intensive care unit admission was a frequently reported complication. Patients with a complicated disease course may have had a higher use of succinylcholine (unadjusted relative risk, 0.13; 95% confidence interval CI, 0.20 to 0.86) and volatile anesthetics (adjusted odds ratio OR, 0.38; 95% CI, 0.20 to 0.73;
P
= 0.004).
Conclusion
Evidence on the anesthetic management and perioperative complications of patients with NMDs is mainly based on small retrospective studies and case reports. Further clinical trials or large retrospective studies are required to investigate the choice of safe anesthetic agents. Main areas of interest are the potential benefits of neuromuscular monitoring and sugammadex and the risks possibly associated with volatile anesthetics and succinylcholine.
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