the study was conducted at the copenhagen neuromuscular center , rigshospitalet , denmark , in collaboration with the danish national rehabilitation centre for neuromuscular diseases .
one hundred nineteen patients registered with a diagnosis of cm aged older than 5 years were invited .
the age limit of 5 years was chosen , as the functional tests used were not validated for younger patients and because we wanted to focus on older cms .
all participants completed questionnaires concerning symptoms and medical history . a neurologist ( n.w . ) and a physiotherapist ( u.w . ) examined all patients .
muscle strength was evaluated using a transformed 11-point medical research council ( mrc ) scale ( 010 ) .
after initial evaluation , participants with phenotypic characteristics atypical for cm ( adult onset , fast progression , creatine kinase 600 u / l , dystrophy as the main histologic finding , or alternative disease explanation ) were excluded .
participants with a cm phenotype , but other genetic etiology , were excluded in the course of the genetic evaluation .
the study was approved by the local ethics committee ( protocol h - c-2009 - 017 ) , and all participants or their parents provided informed consent .
all participants were tested sequentially for mutations in skeletal muscle alpha actin 1 ( acta1 ) and tropomyosin 2 + 3 ( tpm2 + 3 ) genes , as no definite histologic or clinical phenotypes are established for these genes , and the tests were readily available .
core histology ( central core disease [ ccd ] ) elicited testing of the ryanodine receptor 1 ( ryr1 ) gene and the selenoprotein 1 ( sepn1 ) gene .
cnm or pronounced ophthalmoplegia leads to assessment of the genes dynamin 2 ( dnm2 ) , myotubularin 1 ( mtm1 ) , amphiphysin ( bin1 ) , and ryr1 .
rigid spine patients went through sepn1 testing . pronounced contractures led to the investigation of collagen vi genes ( not considered cm by the authors ) .
the remaining unclassified patients were examined for aberrations in neb and ryr1 , and if no mutations were found , exome sequencing was performed in the majority ( broad institute , boston or nijmegen university , holland ) with subsequent assessment of genes involved in myopathy .
the exons and flanking sequences of acta ( nm_001100.3 ) , tpm2 ( nm_003289.3 ) , and tpm3 ( nm_152263.2 ) were pcr amplified and sanger sequenced using bigdye v1.1 on an abi3130 sequencer .
the neb ( nm_004543.4 ) and ryr1 ( nm_000540.2 ) genes were sequenced using a custom ampliseq targeting approach on an ion pgm ( thermo fisher ) . areas with low ( < 30x ) or missing coverage were sanger sequenced .
the study was approved by the local ethics committee ( protocol h - c-2009 - 017 ) , and all participants or their parents provided informed consent .
all participants were tested sequentially for mutations in skeletal muscle alpha actin 1 ( acta1 ) and tropomyosin 2 + 3 ( tpm2 + 3 ) genes , as no definite histologic or clinical phenotypes are established for these genes , and the tests were readily available .
core histology ( central core disease [ ccd ] ) elicited testing of the ryanodine receptor 1 ( ryr1 ) gene and the selenoprotein 1 ( sepn1 ) gene .
cnm or pronounced ophthalmoplegia leads to assessment of the genes dynamin 2 ( dnm2 ) , myotubularin 1 ( mtm1 ) , amphiphysin ( bin1 ) , and ryr1 .
pronounced contractures led to the investigation of collagen vi genes ( not considered cm by the authors ) .
the remaining unclassified patients were examined for aberrations in neb and ryr1 , and if no mutations were found , exome sequencing was performed in the majority ( broad institute , boston or nijmegen university , holland ) with subsequent assessment of genes involved in myopathy .
dna was isolated from blood . the exons and flanking sequences of acta ( nm_001100.3 ) , tpm2 ( nm_003289.3 ) , and tpm3 ( nm_152263.2 ) were pcr amplified and sanger sequenced using bigdye v1.1 on an abi3130 sequencer .
the neb ( nm_004543.4 ) and ryr1 ( nm_000540.2 ) genes were sequenced using a custom ampliseq targeting approach on an ion pgm ( thermo fisher ) . areas with low ( < 30x ) or missing coverage were sanger sequenced .
twenty - five were excluded , leaving a total of 82 in the study . of the excluded , 14 displayed a phenotype inconsistent with cm ; 3 of these were subsequently confirmed with limb - girdle muscular dystrophy , type 1c ( lgmd1c ) , lgmd2l , and lgmd2a .
eleven had a phenotype compatible with cm , but an alternative genetic etiology was identified in 10 , and dna was missing in 1 ( figure 1 ) .
acta1 = skeletal muscle -actin 1 ; ad = autosomal dominant ; ar = autosomal recessive ; ck = creatine kinase ; cms = congenital myasthenic syndrome ; des = desmin ; dnm2 = dynamin 2 ; dok7 = downstream - of - kinase 7 myasthenic syndrome ; lgmd = limb - girdle muscular dystrophy ; mtm1 = myotubularin 1 ; neb = nebulin ; rapsn = receptor - associated protein of the synapse myasthenic syndrome ; ryr1 = ryanodine receptor 1 ; scn4a = sodium channel 4a ; sepn1 = selenoprotein 1 ; tpm2/3 = tropomyosin 2/3 ; ttn = titin . * of these 6 , 1 had lgmd2l , 1 lgmd2a , and 1 lgmd1c .
forty - one had specific histology ; 14 ( 17% ) had cores ( 3 multimini core disease ) , 15 ( 18% ) had cnm , and 12 ( 15% ) nemaline myopathy ( nm ) .
the remaining 41 had more unspecific histology ; 27 ( 33% ) had congenital fiber - type disproportion ( cftd ) or type i predominance ( t1 ) , and 14 ( 17% ) had unspecific myopathic biopsies . in 2 , biopsy material was unavailable ( table 1 ) .
histologic findings vs genotype a genetic diagnosis was reached in 46 ( 56.1% ) ( tables 1 and 2 ) .
eighteen had mutations in ryr1 ( 22.0% ) ( 13 heterozygous and 5 compound heterozygous ) , 6 had mutations in dnm2 , and 6 in neb .
three or less had mutations in acta1 , tpm2 , tpm 3 , mtm1 , sepn1 , scn4a , or ttn genes ( tables 1 and 3 ) .
twenty - one participants had a particular clinical / histologic phenotype leading to a genetic diagnosis .
twenty - five patients had no clinical or histologic clues , and genetic etiology was identified by single gene testing in 20 and by whole - exome sequencing ( wes ) in 5 ; 3 with recessive ryr1 mutations , 1 with mutation in ttn , and 1 with mutation in scn4a .
chance of identifying genetic etiology according to histology characteristics of patients with or without genetic diagnosis the diagnostic yield was highly dependent on histologic findings ( table 2 ) ; if only participants with cores , cnm , or nm were evaluated , a genetic etiology was identified in 83% .
if cftd / t1 were included , the number decreased to 63% . a genetic etiology was identified in 3/14 ( 21% ) with unspecific histology , 9/27 ( 33% ) with cftd / t1 , 12/12 ( 100% ) with nm , 9/14 ( 64% ) with cores , and 13/15 ( 87% ) of participants with cnm .
the 10 participants with a phenotype compatible with cm , but alternative genetic etiology had collagen myopathy , desminopathy , or congenital myasthenic syndrome ( cms ) ( figure 1 ) .
seven of 10 had unspecific or cftd histology , whereas the remaining 3 had more specific histology : one with desminopathy had cores , another with desminopathy had rods , and one collagen vi had centronuclear changes ( table 2 ) .
the age of genetically unresolved ( 27.8  16.7 ) and resolved ( 28.0  14.6 ) patients was identical .
the genetically unresolved had generally more unspecific histology and were less severely affected ( tables 2 and 3 ) .
a total of 48 different mutations were identified of which 31 were listed in the human gene mutation database ( hgmd ) or clinvar as pathogenic .
the remaining 17 were absent from the hgmd or clinvar and to our knowledge have not been associated with disease before .
twelve of these were identified in recessively inherited disorder ; 8 were predicted to result in premature stop codons or frameshifts and 4 were missense mutations .
the 4 missense mutations were identified in sepn1 , ryr1 , and scn4a , respectively , where mutations very often are missense and were predicted to be potentially pathogenic by sift , polyphen2 , align - gvgd , and mutationtaster in silico prediction softwares and were absent from the exac database compiling information of more than 120,000 alleles ( exac.broadinstitute.org ) , and from a danish control cohort of 2000 wes .
of the 4 variants , 2 were identified along with a known pathogenic mutation , whereas the remaining 2 were identified in sepn1 in a patient with a clear clinical presentation of a selenoprotein deficiency . where family members were available ,
the remaining 5 novel variants were all missense variants in ryr1 located in the well - known hot - spot region for the dominantly inherited ryr1 disorder . from the detailed muscle examination
, some patterns of weakness could be recognized for particular genotypes ( table 3 , figure 2 ) .
the acta1 patients were generally very weak in proximal , distal , and respiratory muscles , although 1 adult patient did not follow this pattern .
by contrast , the tpm2/3 patients had few mrc measurements below 7 , but despite this had the same decrease in respiratory function as the acta1 patients .
neb patients typically had preferential affection of the shoulder girdle and pronounced ankle dorsiflexor weakness with mrc of just 12 , but comparatively mild respiratory involvement .
as expected , dominant and recessive ryr1 patients differed in severity , with recessive patients being more severely affected .
the mtm1 patients were more severely affected than the others , but hand function was relatively better than that in the acta1 patients .
the respiratory involvement in the mtm1 and sepn1 patients exceeded that in all other groups .
contractures were not prevalent , but were noted in some neb , ryr1 , dnm2 , mtm1 , ttn , and sepn1 patients ( table 3 ) .
average time of walking ability was calculated in groups with more than 3 patients and exceeded the world health organization  defined normal limit of 18 months in patients with mutations in acta1 ( 30 months ) , tpm2/3 ( 20 months ) , and ryr1 ( 21 months , 2 never walked ) , whereas patients with mutations in neb ( 15 months ) and dnm2 ( 14 months ) fell within normal development .
four patients ( a genetically unresolved participant aged 26 years , 1 dnm2 patient aged 69 , an ryr1 patient aged 55 years , and a ttn patients aged 13 years ) died during the study period from 2009 until now . for medical research council ( mrc ) ;
information on work history was available in 42 of the 46 genetically verified cases ; 36 attended school or worked part or full time .
no participant had clinical evidence of cardiac involvement , and ecg performed in nearly all participants was unremarkable .
twenty - five were excluded , leaving a total of 82 in the study . of the excluded , 14 displayed a phenotype inconsistent with cm ; 3 of these were subsequently confirmed with limb - girdle muscular dystrophy , type 1c ( lgmd1c ) , lgmd2l , and lgmd2a .
eleven had a phenotype compatible with cm , but an alternative genetic etiology was identified in 10 , and dna was missing in 1 ( figure 1 ) .
acta1 = skeletal muscle -actin 1 ; ad = autosomal dominant ; ar = autosomal recessive ; ck = creatine kinase ; cms = congenital myasthenic syndrome ; des = desmin ; dnm2 = dynamin 2 ; dok7 = downstream - of - kinase 7 myasthenic syndrome ; lgmd = limb - girdle muscular dystrophy ; mtm1 = myotubularin 1 ; neb = nebulin ; rapsn = receptor - associated protein of the synapse myasthenic syndrome ; ryr1 = ryanodine receptor 1 ; scn4a = sodium channel 4a ; sepn1 = selenoprotein 1 ; tpm2/3 = tropomyosin 2/3 ; ttn = titin . * of these 6 , 1 had lgmd2l , 1 lgmd2a , and 1 lgmd1c .
forty - one had specific histology ; 14 ( 17% ) had cores ( 3 multimini core disease ) , 15 ( 18% ) had cnm , and 12 ( 15% ) nemaline myopathy ( nm ) .
the remaining 41 had more unspecific histology ; 27 ( 33% ) had congenital fiber - type disproportion ( cftd ) or type i predominance ( t1 ) , and 14 ( 17% ) had unspecific myopathic biopsies . in 2 ,
a genetic diagnosis was reached in 46 ( 56.1% ) ( tables 1 and 2 ) . eighteen had mutations in ryr1 ( 22.0% ) ( 13 heterozygous and 5 compound heterozygous ) , 6 had mutations in dnm2 , and 6 in neb .
three or less had mutations in acta1 , tpm2 , tpm 3 , mtm1 , sepn1 , scn4a , or ttn genes ( tables 1 and 3 ) .
twenty - one participants had a particular clinical / histologic phenotype leading to a genetic diagnosis .
twenty - five patients had no clinical or histologic clues , and genetic etiology was identified by single gene testing in 20 and by whole - exome sequencing ( wes ) in 5 ; 3 with recessive ryr1 mutations , 1 with mutation in ttn , and 1 with mutation in scn4a .
chance of identifying genetic etiology according to histology characteristics of patients with or without genetic diagnosis the diagnostic yield was highly dependent on histologic findings ( table 2 ) ; if only participants with cores , cnm , or nm were evaluated , a genetic etiology was identified in 83% .
a genetic etiology was identified in 3/14 ( 21% ) with unspecific histology , 9/27 ( 33% ) with cftd / t1 , 12/12 ( 100% ) with nm , 9/14 ( 64% ) with cores , and 13/15 ( 87% ) of participants with cnm .
the 10 participants with a phenotype compatible with cm , but alternative genetic etiology had collagen myopathy , desminopathy , or congenital myasthenic syndrome ( cms ) ( figure 1 ) .
seven of 10 had unspecific or cftd histology , whereas the remaining 3 had more specific histology : one with desminopathy had cores , another with desminopathy had rods , and one collagen vi had centronuclear changes ( table 2 ) .
the age of genetically unresolved ( 27.8  16.7 ) and resolved ( 28.0  14.6 ) patients was identical .
the genetically unresolved had generally more unspecific histology and were less severely affected ( tables 2 and 3 ) .
a total of 48 different mutations were identified of which 31 were listed in the human gene mutation database ( hgmd ) or clinvar as pathogenic . the remaining 17 were absent from the hgmd or clinvar and to our knowledge have not been associated with disease before .
twelve of these were identified in recessively inherited disorder ; 8 were predicted to result in premature stop codons or frameshifts and 4 were missense mutations .
the 4 missense mutations were identified in sepn1 , ryr1 , and scn4a , respectively , where mutations very often are missense and were predicted to be potentially pathogenic by sift , polyphen2 , align - gvgd , and mutationtaster in silico prediction softwares and were absent from the exac database compiling information of more than 120,000 alleles ( exac.broadinstitute.org ) , and from a danish control cohort of 2000 wes .
of the 4 variants , 2 were identified along with a known pathogenic mutation , whereas the remaining 2 were identified in sepn1 in a patient with a clear clinical presentation of a selenoprotein deficiency . where family members were available ,
the remaining 5 novel variants were all missense variants in ryr1 located in the well - known hot - spot region for the dominantly inherited ryr1 disorder .
from the detailed muscle examination , some patterns of weakness could be recognized for particular genotypes ( table 3 , figure 2 ) .
the acta1 patients were generally very weak in proximal , distal , and respiratory muscles , although 1 adult patient did not follow this pattern .
by contrast , the tpm2/3 patients had few mrc measurements below 7 , but despite this had the same decrease in respiratory function as the acta1 patients .
neb patients typically had preferential affection of the shoulder girdle and pronounced ankle dorsiflexor weakness with mrc of just 12 , but comparatively mild respiratory involvement .
as expected , dominant and recessive ryr1 patients differed in severity , with recessive patients being more severely affected .
the mtm1 patients were more severely affected than the others , but hand function was relatively better than that in the acta1 patients .
the respiratory involvement in the mtm1 and sepn1 patients exceeded that in all other groups .
contractures were not prevalent , but were noted in some neb , ryr1 , dnm2 , mtm1 , ttn , and sepn1 patients ( table 3 ) .
average time of walking ability was calculated in groups with more than 3 patients and exceeded the world health organization  defined normal limit of 18 months in patients with mutations in acta1 ( 30 months ) , tpm2/3 ( 20 months ) , and ryr1 ( 21 months , 2 never walked ) , whereas patients with mutations in neb ( 15 months ) and dnm2 ( 14 months ) fell within normal development .
four patients ( a genetically unresolved participant aged 26 years , 1 dnm2 patient aged 69 , an ryr1 patient aged 55 years , and a ttn patients aged 13 years ) died during the study period from 2009 until now . for medical research council ( mrc ) ; gray bars left side , black bars right side . bottom : forced vital capacity ( fvc ) in percentage of expected normal values .
information on work history was available in 42 of the 46 genetically verified cases ; 36 attended school or worked part or full time .
no participant had clinical evidence of cardiac involvement , and ecg performed in nearly all participants was unremarkable .
as only survivors from the early childhood were included , the information gathered is helpful for health care personal caring for older children and adults because existing knowledge has been obtained preferentially from pediatric cohorts .
the study is also a prospective , national study of phenotypes and genotypes in cm .
therefore , unlike previous retrospective studies , the study is less affected by selection bias and strengthened by a systematic data collection by just 1 neurologist and physiotherapist .
the report presents new data on national prevalence , distribution of histologic subtypes and genotypes , and expands the description of phenotypic characteristics .
this is lower than most previous studies , which determined the prevalence by chart reviews or databases to about 4:100,000 and focused on the pediatric population .
the exclusion of children not surviving to 5 years in our study could account for some of the discrepancy .
a previous study reported that 12% of their patients with cm died before the age of 6 years .
patients with mutations in those genes may therefore be underrepresented in our material if extrapolated to a general population .
the total prevalence , however , is probably not much influenced by this , as we , compared to previous studies , have included more elderly persons and in that way  compensate  for the lack of young children .
another explanation for our lower prevalence estimate could be that the prospective evaluation in our study may have eliminated more wrongly diagnosed patients .
this is , however , probably not the main explanation for the discrepancy , as most of the studies were very thorough in the attempt to avoid misdiagnosis .
alternatively , our very stringent inclusion criteria may have omitted a few cms with atypical features like high creatine kinase .
of the 15 excluded cases because of atypical features , however , 10 had definitely not cm , as alternative etiologies were identified or they turned out to be asymptomatic family members .
citizens in denmark are easily traceable , as they are centrally registered , and therefore , the lower prevalence in our study is not likely caused by problems in identifying patients .
a number of inherited muscle diseases , such as some limb - girdle muscular dystrophies and myotonic dystrophy type 2 , differ markedly in prevalence in denmark vs other countries , and this could also be the case for cms . in support of this , cm has the same low prevalence in northern england ( 1.37:100,000 , including bethlem myopathy with a prevalence of 0.77 ) as in denmark , where the genetic influence from historic viking invasions is great .
a london - based study observed a different pattern of histology , as the majority of their patients had ccd , whereas histologic findings of cores , cnm , nm , and cftd / t1 were more evenly distributed among our patients .
this difference in histology also points to a different genetic background and supports that not only the prevalence but also the genetic make - up of cm varies among geographic regions . concurring with this hypothesis , the genetic etiology in the london - based study was very different from ours .
they found ryr1 mutations in 59% and dnm2 in 0% of their cms , whereas ryr1 mutations were observed in 22% of our cases and dnm2 mutation in 7.3% .
the difference in ryr1 mutations in our population is probably not explained by different age distribution , as ryr1 patients usually survive past early childhood .
the dnm2 patients , however , are relatively mildly affected and may go unrecognized for years , which would make them underrepresented in a very young population .
this discrepancy , however , could relate to differences in testing strategies , where we sequenced all nonrepetitive coding sequences of neb , whereas only a single frequent deletion was assessed in the previous study . also , the genetic background may influence the distribution of genetic etiology .
two recent studies ( same group ) describing retrospective data in mostly pediatric patients reported the genetic cause in 67%79% . our lower diagnostic rate can partly be explained by methods of selecting patients , as we included many patients with unspecific myopathic biopsies and that subgroup only had a genetic etiology identified in 21% of cases . leaving the patients with unspecific myopathic histology out , we found a genetic etiology in 63% if cftd / t1 was included , and 83% without cftd / t1 .
differences in the success rate of identifying genetic etiology are therefore most likely caused by differences in histology among the included cohorts .
an alternative explanation might be that our patients were older than those in previous studies and that those who die before age 5 years often have mutations in acta1 or mtm1 , which are relatively easy to identify .
the chance of identifying genetic etiology was highly dependent on histology . a much higher percentage with a 
specific  histology like cores , nm , or cnm had a genetic etiology identified . in the subgroup with confirmed cm and nm , genetic etiology was identified in 100% . however , the specificity of cm is not 100% , as 1 patient with desmin mutation also had nm .
nm in patients with desmin mutations has only been reported in a few cases , but was attributed to the known protein accumulation in desminopathy .
 specific histology  for cm , however , was only found in 3/10 patients with a phenotype compatible with cm , but with alternative genetic diagnoses ( cms , desminopathy , colvi , or xii ) . a patient with selenoprotein deficiency had nemaline bodies in 2 muscle fibers .
although this might be an incidental finding , this patient was grouped together with the nms .
the detailed physical examination performed in this study suggests some new clinical clues to the genetic etiology . in the genetically resolved nemaline / cftd / t1 group ,
however , in contrast to the neb patients , patients affected by tpm2 and 3 aberrations had a disproportionately higher respiratory affection , and half of the neb patients had almost paralytic ankle dorsiflexion coexisting with mrc 78 in proximal muscles and a relatively preserved hand function . the preferential weakness of ankle dorsiflexors in some neb patients is well established . the only patient with combined cftd and pronounced ophthalmoplegia had recessive ryr1 disease .
the recessive ryr1 patients also exhibited a marked proximal - distal gradient in weakness , which was shared by the mtm1 patients , but the mtm1 patients had a much more noticeable respiratory affection .
severe ophthalmoplegia was , in agreement with a recent consensus statement , exclusively observed with recessive ryr1 , dnm2 , and mtm1 mutations .
ccd was almost synonymous with dominant ryr1 mutations , and these patients had much the same extremity affection as sepn1 patients , and both groups had a tendency to scoliosis .
the sepn1 patients , however , had much more respiratory and axial involvement as known for this condition .
mutations in dnm2 lead to cnm with ptosis and a lower extremity distal affection in all cases , but otherwise a relatively mild phenotype .
although these clinical clues are not 100% consistent , we believe that they contribute importantly when planning a genetic test strategy or interpreting test results .
ten patients were initially judged to have a phenotype compatible with cm , but turned out to have mutation in a gene not strictly belonging to the genes recognized as genes inducing cm ; 3 had mutations in the collagen vi gene , 3 in the collagen xii gene , 2 in the desmin gene , and 2 had cms .
the delineation of cm is not generally agreed upon , but we have , in line with others , chosen not to include collagen myopathies , as they typically have a progressive course and more contractures than other cms .
on follow - up , the widespread contractures in the 3 collagen vi patients led to the identification of mutations in the collagen vi genes , and in the patients with desmin mutations , the course showed to be much more progressive than was the impression at the initial visit . hence , in retrospect , the collagen vi myopathies and the desmin patients should not have been included .
by contrast , there were no red flags in the phenotype of the collagen xii patients and the patients with cmss .
the prevalence would not have been significantly different if these patients were included , as the total patient number compared to the complete population is still very small .
in contrast to most previous studies , we included many adult patients with very early - onset weakness .
we confirmed that for the majority , the disease course is nonprogressive and many patients are still engaged in an active work life .
taken together , this study adds new knowledge about the geographic variation in prevalence , distribution of subtypes , and clinical characteristics in an older population with cm that may influence strategies for diagnostic testing and counseling of patients .
nanna witting : study concept and design , acquisition of data , analysis and interpretation of data , and drafting of manuscript .
ulla werlauff : study concept and design , acquisition of data , analysis and interpretation of data , and critical revision of manuscript for intellectual content .
morten duno : acquisition of data , analysis and interpretation of data , and critical revision of manuscript for intellectual content .
john vissing : study concept and design , analysis and interpretation of data , and critical revision of manuscript for intellectual content .
dr . witting received research support from the danish council for independent research in medical sciences , the augustinus foundation , the jascha foundation , the novo nordisk foundation , and the gangsted foundation .
vissing has received research support , travel support , and speaker honoraria from genzyme / sanofi and ultragenyx pharmaceuticals ; has served on the editorial boards of neuromuscular disorders and the journal of neuromuscular diseases ; has received research support from atyr pharma , the danish medical research council , the augustinus foundation , the novo nordisk foundation , and the lundbeck foundation ; and has acted as a consultant on advisory boards for genzyme / sanofi , lundbeck , ultragenyx pharmaceuticals , novo nordisk , atyr pharma , sarepta , and alexion pharmaceuticals within the last 3 years .
 objective : congenital myopathy as a nosologic entity has long been recognized , but knowledge of overall and subtype prevalence and phenotype - genotype relationship is scarce , especially in the adult population.methods:a national cohort of 107 patients 5 years diagnosed with congenital myopathy were prospectively assessed clinically , histologically , and genetically.results:twenty-five patients were excluded because of atypical features or alternative etiologies . 
 the remaining 82 were on average 28 years old . 
 histologic examination revealed 14 ( 17% ) with core disease , 15 ( 18% ) centronuclear myopathy , 12 ( 15% ) nemaline rods , 27 ( 33% ) congenital fiber - type disproportion or type i predominance , and 14 ( 17% ) nonspecific myopathic changes . 
 genetic etiology was identified in 46 patients ( 56.1% ) ; 22.0% were heterozygous or compound heterozygous for mutations in ryr1 , 7.3% had dnm2 mutations , and 7.3% neb mutations . 
 less than 5% had mutations in acta1 , tpm2/3 , mtm1 , ttn , sepn1 , or sc4na . 
 a genetic cause was established in 83% with specific histology ( cores / rods / centronuclear myopathy ) vs 29% with unspecific histology . 
 the detailed clinical examination found gene - dependent discrepancies in the pattern of muscle affection and walking ability . 
 although walking ability was delayed in patients with acta1 , tpm2/3 , and ryr1 mutations , it was within normal limits in patients with neb and dnm2 mutations.conclusions:we found that overall , genetic and histologic prevalence of congenital myopathy in denmark differs from previous retrospective reports . 
 less ryr1 and more dnm2 and neb mutations and less core histology were present in our cohort . 
 these differences may be explained by our prospective design , the older cohort of patients , and by differences in genetic background . 