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• W2970587489 abstract "•To get an accurate picture of the distribution of patients worldwide.•To get an accurate picture of the clinical presentation of patients worldwide.•To propose a series of actions regarding clinical readiness for calpainopathies. Eighteen researchers and clinicians and two representatives of patient organizations (Associazione Italiana Calpaina 3, Italy and Coalition to Cure Calpain3, USA), from 9 countries (France, Germany, Italy, Denmark, Spain, UK, Japan, Brazil and USA), met in Naarden, The Netherlands, from 15–17 September, 2017 to discuss clinical trial readiness for limb-girdle muscular dystrophy type 2A (LGMD2A; OMIM 253600), also classically referred to as calpainopathy. LGMD2A is due to mutations in the CAPN3 gene encoding a calcium-dependent cysteine protease named calpain 3 [[1]Richard I. Broux O. Allamand V. Fougerousse F. Chiannilkulchai N. Bourg N. et al.Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A.Cell. 1995; 81: 27-40Abstract Full Text PDF PubMed Scopus (862) Google Scholar]. This disease is characterized by slowly progressive muscle weakness affecting selectively the musculature of both girdles. There is no effective treatment for this disease to date. The emergence of novel therapeutic approaches in the field, such as gene therapy, has prompted a much awaited discussion among physicians and researchers about the readiness for clinical trials in calpainopathy. Michel Fardeau elaborated on the fascinating saga that led to the identification of the CAPN3 gene, from the very first clinical and pathological descriptions made by Erb in Germany to the molecular elucidation of the disease in 1995. The term itself of limb-girdle muscular dystrophy (LGMD), actually coined during World War II and popularized by Walton and Nattrass in 1954, remains hotly debated even nowadays. In the late 70s, Michel Fardeau had the opportunity to revisit Erb's concept of juvenile-onset muscular dystrophy thanks to a genetically isolated population called the ‘Petits Blancs des Hauts’ located in the Reunion Island, an overseas French territory in the Indian Ocean. Collecting clinical data and processing of DNA samples led to a first mapping to chromosome 15. Additional samples collected notably in the Amish communities of the USA and other countries (Brazil), via reverse genetics, made the identification of the CAPN3 gene possible at Genethon while clearly pinpointing the genetic heterogeneity of LGMD. Nowadays, calpainopathy remains the most frequent form of LGMD in the majority of countries with reported prevalence between 10 and 70 per million inhabitants [2Urtasun M. Saenz A. Roudaut C. Poza J.J. Urtizberea J.A. Cobo A.M. et al.Limb-girdle muscular dystrophy in Guipúzcoa (Basque Country, Spain).Brain. 1998; 121 (Epub 1998/10/08): 1735-1747Crossref PubMed Scopus (135) Google Scholar, 3Fanin M. Nascimbeni A.C. Fulizio L. Angelini C. The frequency of limb girdle muscular dystrophy 2A in northeastern Italy.Neuromuscul disor. 2005; 15 (Epub 2005/02/24): 218-224Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 4Fardeau M. Hillaire D. Mignard C. Feingold N. Feingold J. Mignard D. et al.Juvenile limb-girdle muscular dystrophy. Clinical, histopathological and genetic data from a small community living in the Reunion Island.Brain. 1996; 119 (Epub 1996/02/01): 295-308Crossref PubMed Scopus (162) Google Scholar]. Andoni Urtizberea gave an overview of what is currently known of calpainopathy, mainly from a clinical perspective. Thanks to a contribution from Lopez de Munain, (San Sebastian, Spain) and based on his personal experience, he reviewed the classical and non-classical clinical presentations of calpainopathy. Calpainopathy is sometimes capable of mimicking many other neuromuscular disorders such as, inflammatory myopathies (eosinophilic myositis) or metabolic myopathies. A growing number of benign cases are now also being reported. The recent discovery of an autosomal dominant form of calpainopathy adds to the clinical spectrum of calpainopathies. The existence of several founder mutations was highlighted as well as some degree of clinical heterogeneity even in families belonging to supposedly homogeneous genetic isolates. The fact that the NGS is nowadays substantially changing diagnostic algorithms was also addressed. Better knowledge of these clinical variants also matters in the context of future trials. Yasuko Ono (Japan) presented a review of current knowledge on the calpain family and the regulation and function of calpain 3 (Fig. 1). Calpain 3 is a member of the calpain family of non-lysosomal calcium-activated cysteine proteases. Although some isoforms were identified in lens and brain, the classical full-length form of CAPN3 is primarily expressed in skeletal muscle [[5]Sorimachi H. Imajoh-Ohmi S. Emori Y. Kawasaki H. Ohno S. Minami Y. et al.Molecular cloning of a novel mammalian calcium-dependent protease distinct from both m- and mu-types. Specific expression of the mRNA in skeletal muscle.J Biol Chem. 1989; 264 (Epub 1989/11/25): 20106-20111Abstract Full Text PDF PubMed Google Scholar]. Of note, the expression in the heart is at least 100 times lower than in skeletal muscle with a level that varies among species [6Herasse M. Ono Y. Fougerousse F. Kimura E. Stockholm D. Beley C. et al.Expression and functional characteristics of calpain 3 isoforms generated through tissue-specific transcriptional and posttranscriptional events.Mol Cell Biol. 1999; 19 (Epub 1999/05/18): 4047-4055Crossref PubMed Scopus (109) Google Scholar, 7Fougerousse F. Anderson L.V. Delezoide A.L. Suel L. Durand M. Beckmann J.S. Calpain3 expression during human cardiogenesis.Neuromuscul disor. 2000; 10 (Epub 2000/06/06): 251-256Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. In muscle, the enzyme is present as a dormant enzyme probably through interaction with one of its partner, the giant protein titin [8Sorimachi H. Kinbara K. Kimura S. Takahashi M. Ishiura S. Sasagawa N. et al.Muscle-specific calpain, p94, responsible for limb girdle muscular dystrophy type 2A, associates with connectin through IS2, a p94-specific sequence.J Biol Chem. 1995; 270 (Epub 1995/12/29): 31158-31162Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, 9Kinbara K. Sorimachi H. Ishiura S. Suzuki K. Muscle-specific calpain, p94, interacts with the extreme C-terminal region of connectin, a unique region flanked by two immunoglobulin C2 motifs.Arch Biochem Biophys. 1997; 342 (Epub 1997/06/01): 99-107Crossref PubMed Scopus (93) Google Scholar]. It was shown that calpain 3 self-activates by autolysis through the removal of an internal peptide to free the catalytic site for substrate accessibility [10Taveau M. Bourg N. Sillon G. Roudaut C. Bartoli M. Richard I. Calpain 3 is activated through autolysis within the active site and lyses sarcomeric and sarcolemmal components.Mol Cell Biol. 2003; 23 (Epub 2003/12/04): 9127-9135Crossref PubMed Scopus (124) Google Scholar, 11Garcia Diaz B.E. Gauthier S. Davies P.L. Ca2+ dependency of calpain 3 (p94) activation.Biochemistry. 2006; 45 (Epub 2006/03/15): 3714-3722Crossref PubMed Scopus (43) Google Scholar]. Although autolysis might be involved in the activation process of calpain 3, not all LGMD2A mutant proteins lose their autolytic activity. As one of recently identified modes of calpain 3 functions, intermolecular complementation for restoring protease activity after autolysis provides a new aspect in the effect of pathogenic mutations [[12]Ono Y. Shindo M. Doi N. Kitamura F. Gregorio C.C. Sorimachi H. The N- and C-terminal autolytic fragments of CAPN3/p94/calpain-3 restore proteolytic activity by intermolecular complementation.Proc Natl Acad Sci USA. 2014; 111 (Epub 2014/12/17): E5527-E5536Crossref PubMed Scopus (24) Google Scholar]. The precise function(s) of calpain3 and the mechanism by which it causes LGMD2A are not fully understood although several evidences pinpoint a role in cytoskeleton remodelling [13Duguez S. Bartoli M. Richard I. Calpain 3: a key regulator of the sarcomere?.FEBS J. 2006; 273: 3427-3436Crossref PubMed Scopus (100) Google Scholar, 14Kramerova I. Kudryashova E. Venkatraman G. Spencer M.J. Calpain 3 participates in sarcomere remodeling by acting upstream of the ubiquitin-proteasome pathway.Hum Mol Genet. 2007; 16 (Epub 2007/05/02): 1006Crossref PubMed Scopus (9) Google Scholar, 15Ojima K. Kawabata Y. Nakao H. Nakao K. Doi N. Kitamura F. et al.Dynamic distribution of muscle-specific calpain in mice has a key role in physical-stress adaptation and is impaired in muscular dystrophy.J Clin Invest. 2010; 120 (Epub 2010/07/02): 2672-2683Crossref PubMed Scopus (81) Google Scholar]. As an example of research investigating calpain 3 role in muscles, Amets Saenz (Spain) presented a study of the muscle cell protein turnover in myotubes of LGMD2A patients aiming at shedding some light on the pathophysiological mechanisms in LGMD2A and identifying therapeutic targets that may stop muscle degeneration [[16]Saenz A. Azpitarte M. Armananzas R. Leturcq F. Alzualde A. Inza I. et al.Gene expression profiling in limb-girdle muscular dystrophy 2A.PLoS ONE. 2008; 3 (Epub 2008/11/19; e3750)Crossref Scopus (36) Google Scholar]. LGMD2A patients' mature myotubes showed deficit in the transition from the transmembrane integrin β1A isoform to the β1D isoform which is seen under normal physiological conditions during myoblast fusion and muscle fibre maturation. They observed that Frizzled (FRZB), a protein of the Wnt pathway, regulates integrin β1D expression and that its silencing increases integrin β1D expression to levels similar to those in controls, suggesting that silencing FRZB may rescue the normal expression of proteins involved in the fusion process in LGMD2A. This could suggest that the Wnt pathway could represent a therapeutic option for LGMD2A, in addition to other pathways that have been proposed as potential targets [14Kramerova I. Kudryashova E. Venkatraman G. Spencer M.J. Calpain 3 participates in sarcomere remodeling by acting upstream of the ubiquitin-proteasome pathway.Hum Mol Genet. 2007; 16 (Epub 2007/05/02): 1006Crossref PubMed Scopus (9) Google Scholar, 17Baghdiguian S. Martin M. Richard I. Pons F. Astier C. Bourg N. et al.Calpain 3 deficiency is associated with myonuclear apoptosis and profound perturbation of the IkappaB alpha/NF-kappaB pathway in limb-girdle muscular dystrophy type 2A.Nat Med. 1999; 5 (Epub 1999/05/06): 503-511Crossref PubMed Scopus (0) Google Scholar, 18Laure L. Daniele N. Suel L. Marchand S. Aubert S. Bourg N. et al.A new pathway encompassing calpain 3 and its newly identified substrate cardiac ankyrin repeat protein is involved in the regulation of the nuclear factor-kappa B pathway in skeletal muscle.FEBS J. 2010; 277 (Epub 2010/09/24): 4322-4337Crossref PubMed Scopus (34) Google Scholar, 19Kramerova I. Kudryashova E. Ermolova N. Saenz A. Jaka O. Lopez de Munain A. et al.Impaired calcium calmodulin kinase signaling and muscle adaptation response in the absence of calpain 3.Hum Mol Genet. 2012; 21 (Epub 2012/04/17): 3193-3204Crossref PubMed Scopus (35) Google Scholar, 20Yalvac M.E. Amornvit J. Braganza C. Chen L. Hussain S.A. Shontz K.M. et al.Impaired regeneration in calpain-3 null muscle is associated with perturbations in mTORC1 signaling and defective mitochondrial biogenesis.Skelet Muscle. 2017; 7 (Epub 2017/12/16): 27Crossref PubMed Scopus (24) Google Scholar]. Bruno Eymard (Paris) presented the French experience on Calpainopathy. Overall, 231 cases of calpainopathy are registered in the French reference centre database with a mean age of onset around 13 years. In the two French genetic laboratories performing molecular diagnosis of calpainopathy, respectively in Paris (Dr. F Leturcq, Cochin hospital) and Marseille (Dr. M Krahn, La Timone hospital), 96 index cases with two calpain gene mutations have been identified between 2012 and 2016. The proportion of calpainopathy is around 20% of the all genetically tested LGMDs. Although the disease begins in most of patients during early adolescence, the age at onset is variable from early childhood to middle adulthood. These data are similar to these obtained in smaller series reported in 1996 and in 2016 [21Fardeau M. Eymard B. Mignard C. Tome F.M. Richard I. Beckmann J.S. Chromosome 15-linked limb-girdle muscular dystrophy: clinical phenotypes in Reunion Island and French metropolitan communities.Neuromuscul disor. 1996; 6 (Epub 1996/12/01): 447-453Abstract Full Text PDF PubMed Scopus (73) Google Scholar, 22Richard I. Hogrel J.Y. Stockholm D. Payan C.A. Fougerousse F. Eymard B. et al.Natural history of LGMD2A for delineating outcome measures in clinical trials.Ann Clin Transl Neurol. 2016; 3 (Epub 2016/04/16): 248-265Crossref PubMed Scopus (34) Google Scholar]. The disease course is always progressive, with worsening of weakness in both girdles, resulting in functional degradation. In a recently published series including 20 French patients, with age at inclusion ranging from 19 to 65 years (mean age of 42 years), followed at the Institute of Myology (Paris) for a natural history survey, 52% of patients were non-ambulant and 14% required a cane or walker aid [[22]Richard I. Hogrel J.Y. Stockholm D. Payan C.A. Fougerousse F. Eymard B. et al.Natural history of LGMD2A for delineating outcome measures in clinical trials.Ann Clin Transl Neurol. 2016; 3 (Epub 2016/04/16): 248-265Crossref PubMed Scopus (34) Google Scholar]. In the same report, 30 patients from Reunion Island and 35 patients from the Spanish-Basque population were also described: the age at onset and severity were similar in the 3 groups. In this study, as in our previous experience [[21]Fardeau M. Eymard B. Mignard C. Tome F.M. Richard I. Beckmann J.S. Chromosome 15-linked limb-girdle muscular dystrophy: clinical phenotypes in Reunion Island and French metropolitan communities.Neuromuscul disor. 1996; 6 (Epub 1996/12/01): 447-453Abstract Full Text PDF PubMed Scopus (73) Google Scholar], the clinical pattern was homogeneous with both girdle involvement, major involvement of serratus anterior with scapular winging, gluteus maximus and medius, selective posterior compartment of thigh hamstrings and adductors [[22]Richard I. Hogrel J.Y. Stockholm D. Payan C.A. Fougerousse F. Eymard B. et al.Natural history of LGMD2A for delineating outcome measures in clinical trials.Ann Clin Transl Neurol. 2016; 3 (Epub 2016/04/16): 248-265Crossref PubMed Scopus (34) Google Scholar]. Beside the classical presentation, it is possible to observe variations in the phenotype. For example, in one patient followed at the Institute of Myology, classified as retractile calpainopathy, contractures were prominent, affecting elbows and hips. No heart involvement was found in this patient and respiratory involvement was generally moderate. In nine patients with calpain gene mutations, followed at the Institute of Myology, calpain expression assayed by Western blot, was normal or minimally reduced. Interestingly, all patients but one was woman and age at onset was late from age of 18 years to 47 years, mean 32.1 years. Only 2 of 9 were non-ambulant, after a long duration, respectively 24 and 32 years. Andoni Urtizberea presented in detail an observational study of clinical manifestations and disease progression where a total of 85 genetically confirmed LGMD2A patients, aged 14–65 years, were recruited in three centres located in metropolitan France (Institute of Myology Paris), in Spain (San Sebastian), and on the Reunion Island (Saint-Pierre). They were followed up every 6 months for 2 years and a subgroup was assessed annually thereafter for two more years. Data collected for all patients included clinical history, blood parameters, muscle strength assessed by manual muscle testing (MMT) and quantitative muscle testing, functional scores, and pulmonary and cardiac functions. In addition, CT scans of the lower limbs were performed in a subgroup of patients (Fig. 2). This study confirms the clinical description of a slowly progressive disorder with onset in the first or second decade of life with some degree of variability related to gender and mutation type. The null mutations lead to a more severe phenotype while compound heterozygote patients are the least affected. Muscle weakness is remarkably symmetrical and predominant in the axial muscles of the trunk and proximal muscles of the lower limb. There was a high correlation between the weakness at individual muscle level as assessed by MMT and the loss of density in CT scan analysis. All the generated data will help to determine the endpoints for further clinical studies. Alicia Alonso-Jiménez and Jordi Diaz-Manera (Spain) reviewed and presented the data on calpainopathy patients in Spain. Spanish patients are followed up in several different centres. Although there are at this moment five Neuromuscular Disorders Units recognized as reference centres by the Spanish Ministry of Health (three in Barcelona, one in Valencia and one in Sevilla), the genetic study of the CAPN3 gene is performed in a single public centre located in San Sebastian-Donostia. The Spanish Neuromuscular Disorders registry (NMD-ES) contains at this moment clinical and genetic data of 83 calpainopathy patients. Thirty-six (43%) of these patients are women. The mean age at onset of symptoms in this cohort is 12.4 years old. At last visit, 97% of the patients had muscle weakness involving lower limbs more severely than upper limbs. Scapular winging was found in 64% of the patients. Up to 70% of the patients were non-ambulant while only 10% of the patients were able to walk independently without any help. The most common mutation detected in this cohort is the p.Arg788Ser-fs14* (present in 59% of the patients), which is usually known as the “Basque mutation” due to its high prevalence in patients from the Basque country. Other frequent mutations are the p.Gly222Arg (present in 10% of the cohort) and the p.Arg748Gln (present in 6% of the cohort). Michela Guglieri (UK) described a cohort of 56 LGMD2A UK patients, followed up at the John Walton Muscular Dystrophy Research Centre (JWMDRC) in Newcastle, UK. LGMD2A represents 21% of the total LGMD population followed up at the JWMDRC, which is in line with previously reported incidence studies. Patients were equally distributed between males and females (29 vs. 27); mean age was 38 years (range 14–83 years). Approximately 50% of the cases reported onset of muscle symptoms between the age of 10 and 20 years with however a wide range (4–60 years). Mean time at loss of ambulation was 12 years after disease onset (SD: 11 years). Early onset cases seemed to have a more severe course and earlier loss of ambulation while none of the seven patients with a late disease onset (>40 years) a wheelchair (age 50–83 years). Respiratory impairment was observed and correlates with the severity of skeletal muscle involvement; however even when detected, it was usually mild or moderate [Forced Vital Capacity (FVC) between 40% and 80% of predicted value]. None of the patients showed cardiac involvement. Homozygous or compound heterozygous mutations were confirmed in all patients, except two patients in whom only one mutation was identified (Multiplex ligation-dependent probe amplification studies are ongoing). Maggie Walter discussed a German cohort of 35 calpainopathy patients and reported on age of onset, disease duration, status of ambulation, creatine kinase (CK) levels, MRI findings, type of mutation, along with clinical and genetic heterogeneity. Mean onset was usually during adolescence, varying between 2 and 50 years of age; loss of independent ambulation occurred between 15 and 25 years after clinical onset. There was faster progression in patients with juvenile onset, similarly to the UK cohort. Most frequent mutations were c.550delA and c.1468C>T (p.Arg49Trp). The median age of symptom onset for patients with 2 null alleles (predicting loss of CAPN3 open reading frame and thus absence of calpain protein) was lower than in patients with one or zero null alleles. MRI findings showed that while mutations in genes encoding proteins of the Dystrophin Associated Complex (dystrophin and sarcoglycans) predominantly affect the anterior thigh muscles, proteins with enzyme function (calpain 3 and FKRP) predominantly involve the posterior thigh muscles. However, during the course of the disease, the anterior compartment becomes equally affected in calpainopathy. Of note, in contrast to severe MRI changes, some patients are able to walk well in their forties. Claudio Semplicini pointed out that LGMD2A represents the most frequent LGMD in Italy [23Fanin M. Nascimbeni A.C. Aurino S. Tasca E. Pegoraro E. Nigro V. et al.Frequency of LGMD gene mutations in Italian patients with distinct clinical phenotypes.Neurology. 2009; 72 (Epub 2009/04/22): 1432-1435Crossref PubMed Scopus (77) Google Scholar, 24Magri F. Nigro V. Angelini C. Mongini T. Mora M. Moroni I. et al.The Italian limb girdle muscular dystrophy registry: relative frequency, clinical features, and differential diagnosis.Muscle Nerve. 2017; 55 (Epub 2016/10/30): 55-68Crossref PubMed Scopus (59) Google Scholar], with an estimated prevalence of 1:105,000 in the North-East of the country [[3]Fanin M. Nascimbeni A.C. Fulizio L. Angelini C. The frequency of limb girdle muscular dystrophy 2A in northeastern Italy.Neuromuscul disor. 2005; 15 (Epub 2005/02/24): 218-224Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. He reviewed the data of 49 LGMD2A patients (age 8–68 years) from three centres (Padova, Milano and Bosisio Parini) included in a cross-sectional clinical evaluation protocol. Natural history data were collected, different motor function tests were performed [i.e. 6-minute walking test (6MWT), Performance of Upper Limb (PUL), North-Star Ambulatory Assessment (NSAA), and grip strength, timed tests] as well as cardiac and respiratory function evaluations. Psychometric Tests of Individual Neuromuscular Quality of Life (INQoL) and impact of fatigue (Fatigue Severity Scale) were also included. Motor function was correlated with age (young better than old), sex (females better than males), residual protein on Western Blot (presence better than absence) and number of frameshift/null alleles (0 better than 1 and 2). Specific mutations are associated with peculiar phenotypes, such as mutations in exon 11, recurrent in the Venice area, that are associated with a relatively late onset and loss of ambulation, a marked weakness of biceps brachii and a normal expression of CAPN3 on WB (autocatalytic defect) [[25]Fanin M. Nascimbeni A.C. Fulizio L. Trevisan C.P. Meznaric-Petrusa M. Angelini C. Loss of calpain-3 autocatalytic activity in LGMD2A patients with normal protein expression.Am J Pathol. 2003; 163 (Epub 2003/10/28): 1929-1936Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar]. NSAA, timed tests and proximal items of PUL seem, in the Italian cohort, the most clinically meaningful tests for future clinical trials. The collection of longitudinal data will help in better defining the disease evolution and clinic–molecular heterogeneity. Mariz Vainzof (Brazil) highlighted that Brazilian families with LGMD2A included families studied since 1990, when they also contributed to the identification of the CAPN3 gene. Since then, patients have been screened through protein and/or DNA analyses, first by individual gene screening and nowadays using NGS, at the Human Genome and Stem Cell Research Center, a reference centre for neuromuscular diseases in Brazil. LGMD2A was appointed as the more common form in Brazil, corresponding to about 32% of the LGMD cases. Genetic results observed in 63 patients, from 57 unrelated families were presented. A total of 31 different mutations were identified, with six newly described ones that include five non-sense mutations. Consanguinity in these families was very high (72%), with even two families presenting an autosomal dominant-like transmission. Some of the most common mutations in Europe and USA were also the more frequent in Brazil, such as the p.Arg788Serfs*14 (Basque mutation) and p.Arg110* mutations. The correlation of type of mutation and the protein was positive, with non-sense mutations showing total absence of the protein while some mutations were compatible with the presence of some calpain 3 protein in the muscle. Interestingly, some specific mutations, such as p.Lys254del and p.Arg490Trp showed the presence of almost normal calpain 3 in the muscle. Finally, using the Brazilian 80 plus bank of controls [[26]Naslavsky M.S. Yamamoto G.L. de Almeida T.F. Ezquina S.A.M. Sunaga D.Y. Pho N. et al.Exomic variants of an elderly cohort of Brazilians in the ABraOM database.Hum Mutat. 2017; 38 (Epub 2017/03/24): 751-763Crossref PubMed Scopus (144) Google Scholar], it was estimated that the frequency of LGMD2A pathogenic mutation described in ClinVar, a public database of the relationship between human variations and phenotypes (https://www.ncbi.nlm.nih.gov/clinvar/), represents a proportion of 1/90 heterozygous, and 1/32000 affected LGMD2A in the Brazilian population. Vincent Carson reported the case of the Amish community where a funder effect was reported for calpainopathies. He presented the history of installation of this community in the US, leading to two main settlements in Pennsylvania and Indiana through migration from Germany and from Switzerland. The homozygous Amish mutation is present in the population from Northern Indiana. Of note, this mutation was also identified in two patients in Europe. John Vissing presented the dominantly inherited form of calpainopathy, which was reported as a new form of calpainopathy in 2016 [[27]Vissing J. Barresi R. Witting N. Van Ghelue M. Gammelgaard L. Bindoff L.A. et al.A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy.Brain. 2016; 139 (Epub 2016/06/05): 2154-2163Crossref PubMed Scopus (65) Google Scholar]. Likely, the mechanism of disease is quite similar to the recessive form, as calpain 3 expression is also severely down-regulated in the dominant form, which could be due to a dominant negative effect of the mutant protein on the wild-type protein from the healthy allele. This means that all single CAPN3 variants cannot cause a dominant form of LGMD; only those that result in production of an aberrant protein that can polymerize with or otherwise disturb the wild-type protein. Unlike some cases of LGMD2A, where calpain 3 is lost completely, some wild-type protein is always present in the dominant form, albeit in severely reduced levels. Maybe for this reason, the phenotype of dominant calpainopathy is milder than the recessive form [[27]Vissing J. Barresi R. Witting N. Van Ghelue M. Gammelgaard L. Bindoff L.A. et al.A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy.Brain. 2016; 139 (Epub 2016/06/05): 2154-2163Crossref PubMed Scopus (65) Google Scholar]. The pattern of muscle affection closely resembles that in the recessive form, but in the dominant form, onset of disease is later (34 years vs. 16 years in LGMD2A) and the muscle weakness is milder. Also, plasma CK levels are not always elevated, which is almost always the case in LGMD2A. Future clinical investigations should be aimed at identifying new dominant cases, which may in some cases go unnoticed because of the milder nature of the disease. Vissing presented such a new condition related to a c.1715G>C missense mutation in CAPN3. As with the 10 dominantly inherited families reported with the same c.643_663del21 mutation in CAPN3, the disease in the three generations of the c.1715G>C mutation family showed loss of calpain 3 in muscle, variable muscle affection in generations with muscle affection similar to LGMD2A, and exome sequencing could not identify any other cause of the disease. In looking for dominantly inherited cases of calpainopathy, the clinician should look for; 1) segregation of a new CAPN3 variant with the disease, 2) calpain 3 loss on Western blot, 3) a phenotype which resembles LGMD2A, just milder, 4) and discard other diagnostic possibilities, by for instance, whole-exome sequencing. In conclusion, it appears that, in most countries, LGMD2A is usually the most frequent form of LGMD. Most of the patients present a classical clinical phenotype with a significant, selective involvement of the posterior compartment of the thigh. The disease course is usually slow but with a possible correlation between an early onset and a higher severity. Respiratory function may be compromised in a proportion of patients. Cardiac issues are rarely observed and are probably coincidental. Although it seems to be rarely severe in LGMD2A, assessment and monitoring of respiratory function should be part of the standards of care. Unusual presentations of calpainopathy with pseudo-metabolic or prominent joint contractures, benign hyperCKemia or non-conventional mode of transmission (autosomal dominant) have been presented and discussed. Genetic diagnosis for calpainopathies has been available on a routine basis using Sanger sequencing since early after the initial identification of CAPN3 in LGMD2A in 1995 [[1]Richard I. Broux O. Allamand V. Fougerousse F. Chiannilkulchai N. Bourg N. et al.Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A.Cell. 1995; 81: 27-40Abstract Full Text PDF PubMed Scopus (862) Google Scholar]. It is now available mainly using Next Generation Sequencing (NGS), including CAPN3 analysis within different strategies (for example gene-panel analyses including all known LGMD genes, or all known myopathy genes; Whole-Exome Sequencing; etc.). As for many other genes causing muscular dystrophies, CAPN3 has a large mu" @default.
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• W2970587489 title "233rd ENMC International Workshop:" @default.
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