Muscular Dystrophy

Congenital Muscular Dystrophy

Emery-Dreifuss Muscular Dystrophy

Limb Girdle Muscular Dystrophy

Duchenne Muscular Dystrophy

Congenital Myopathy

Distal Myopathy

Myofibrillar Myopathy

Myotonic Syndromes

Congenital Myasthenic Syndrome

Periodic Paralysis

Malignant Hyperthermia

P H E N O T Y P E - B A S E D N E X T G E N E R A T I O N S E Q U E N C I N G F O R N E U R O M U S C U L A R D I S E A S E

A Phenotype-Based Next Generation Sequencing Approach

A T H E N A D I A G N O S T I C S

NEXTGEN TESTING

When your patient presents with symptoms ofmuscle disease, the specific cause is not alwaysclear. Using Next Generation Sequencing (NGS) touncover a genetic cause of disease may lead toanswers that direct the most appropriate treatment and care for your patient.

Athena Diagnostics® now offers NGS evaluations forneuromuscular disease arranged by clinicalphenotype, testing only the most relevant genes,which streamlines the diagnostic process and savestime and money.

By combining diagnostic technology, fast turnaround time, and Athena Insight™, Athena Diagnostics offers a uniquely powerfultoolset that can make an important difference in the care of your patient. It may also help predictthe risk of disease in family members.

Phenotype-based evaluations forneuromuscular disease can allowfor earlier diagnosis and treatment.

The More You Know, The More You Can Do

An accurate and early diagnosis can be essential for both evaluation and treatment because specific interventions are increasingly being recognized.

The Value of Genetic Testing • Provide a definitive diagnosis that helps guide

patient treatment and care decisions

• Save the patient and family from stressful,invasive, and expensive diagnostic procedureslike muscle biopsy

• Help counsel the patient and relativesconcerning possible recurrence risk

• Provide key genetic information for familyplanning

• Better understand the cause of disease with an increase in genotype-specific trials

Teresa Canney, Medical Technologist, Next Generation Sequencing

1. Phenotype-Guided Evaluations• Athena Diagnostics Neuromuscular Advanced Evaluations

are organized by phenotype, making test selection easy andavoiding costly and unnecessary testing.

• Evaluations are based on peer-reviewed published literature* to facilitate clinically-meaningful diagnostic and treatment decisions.

2. Fast, Cost-Efficient Testing with Powerful Proprietary Technology• Concordance with Sanger sequencing is achieved for excellent

sensitivity and specificity.

• Our hybridization-based enrichment technology allows removalof duplicate fragments, reducing amplification bias, providingexcellent allele balance, more confident variant calls, and better sensitivity.

• Regions with known pseudogenes or other sequence homology are sequenced at no additional charge using Sanger technology if interference with NGS accuracy is detected.

• Each evaluation is accomplished with one blood draw and a 6-week turnaround.

3. Athena Insight™, In-Depth Variant Interpretation and Reporting• Created by scientists and geneticists at Athena Diagnostics, Athena Insight™ incorporates a standardized,

evidence-based pathogenicity assessment/scoring process that stratifies variants based on the relativelikelihood of pathogenicity.

• Our team of variant scientists collaborate on evaluations to provide the best possible results and optimal analytic value.

• Assessments of variants are based on multiple independent types of evidence. This provides the confidenceof pathogenicity assessment from accumulated evidence in the medical literature, as well as variant databases.

• The clinician receives a complete synopsis and interpretation of findings with a determination of thelikelihood of variants being benign or pathogenic. Results are presented in clear, concise terms suitable for use during discussions with patients and family members.

• Over 19,000 pathogenicity assessments on more than 12,000 unique variants have been successfullyperformed to date, focused on genetic disorders in neurology, endocrinology, and nephrology. This allows amore accurate definition of the region of interest.

• In many cases, it is beneficial to test other family members to enhance interpretations of variants of unknown significance. Please call an Athena Diagnostics genetic counselor for details.

* Kaplan JC. The 2012 version of the gene table of monogenic neuromuscular disorders. Neuromuscular disorders : NMD 2011;21:833-61.

Phenotype-Based NGSDiagnostics

Fast, Cost-Efficient NGS Technology

In-DepthResults

Interpretation

ATHENADIAGNOSTICS

NEXTGENTESTING

Three Reasons Why Next Generation Sequencing fromAthena Diagnostics Can Make a Difference

Comprehensive Servicesthat Go Beyond Results

Genetic Counseling Services

Our team of genetic counselors is readily available toprovide in-depth information on the nature, inheritance, and implications of genetic test results.

• Genetic counseling can help the physician guide thepatient in making informed medical and personaldecisions for themselves and their family.

Pre-Authorization Services

Pre-authorization for in-network orders eases theworkload in your office.

Care360® The power and flexibility of this cloud-based, electronichealth record system developed by Quest Diagnosticsenables 24/7 access and greater efficiencies inmanaging lab orders and results.

• Place test orders, analyze results, and gain practice-wide insights quickly and easily.

• Save time and improve access to critical patient information.

Carol A. Hoffman, Ph.D., M.S., LGC Genetic Counselor

New Billing Solutions that Simplify Testing

Introducing the Athena Alliance Program

Athena Diagnostics is committed to providing testingthat makes a difference in patient care. As a part of that commitment, we are pleased to announce theAthena Alliance Program, a new solution dedicated tosimplifying the billing process for you and your patients.

Personalized Patient Services• Support from point of order, to specimen collection,

to determination of insurance coverage, submission,and appeals

• Regionally structured to provide local expertise• Decision support algorithms to order the most

useful testing for your patients

Financial Assistance• Income-based financial assistance is available to

patients in all 50 U.S. states regardless of insurance status.

Phenotype-Based Next Generation Sequencingfor Neuromuscular Disease

Neuromuscular Genes Tested

A T H E N A D I A G N O S T I C S

NEXTGEN TESTING

5501 5502 5503 5504 5505 5506 5507 5508 5511 5518 5519 5530Muscular Congenital Congenital Distal Myofibrillar Myotonic Periodic Malignant Congenital Emery- Limb Girdle DMDDystrophy Muscular Myopathy Myopathy Myopathy Syndromes Paralysis Hyper- Myasthenic Dreifuss Muscular Evaluation

Dystrophy thermia Syndrome* Muscular DystrophyDystrophy

ANO5 B3GALNT2 ACTA1 ANO5 BAG3 ATP2A1 CACNA1S RYR1 ARGN EMD ANO5 DMD††

CAPN3†† B3GNT1 BIN1 CAV3 CRYAB CAV3 SCN4A CACNA1S CHAT FHL1 CAPN3††

CAV3 CHKB CCDC78 DES DES CLCN1 KCNJ2 CHRNA1 LMNA CAV3DAG1 COL6A1 CFL2 CRYAB FHL1 HSPG2 CHRNB1 SYNE1 DYSF

CCDC78 COL6A2 CNTN1 DNM2 FLNC SCN4A CHRND SYNE2 FKRPDES COL6A3 DNM2 DYSF LDB3 DMPK †(DM1) CHRNE TMEM43 FKTN

DMD†† DNM2 KBTBD13 FLNC MYOT CNBP†(DM2) COLQ LMNADNAJB6 DPM2 KLHL40 GNE TTN DOK7 MYOT

DYSF FHL1 MEGF10 KLHL9 SEPN1 DPAGT1 SGCA††

EMD FKRP MTM1 LDB3 GFPT1 SGCBFHL1 FKTN MYBPC3 MATR3 MUSK SGCDFKRP POMGNT2 MYH2 MYH7 RAPSN SGCG††

FKTN ISPD MYH7 MYOT SCN4A DNAJB6ISPD ITGA7 NEB NEB DES

LMNA LAMA2 RYR1 TTN TCAPMYOT LMNA SEPN1 VCP TRIM32PLEC LARGE TNNT1 TIA1 TTN

POMGNT1 POMGNT1 TPM2 POMT1POMT1 POMT1 TPM3 POMT2POMT2 POMT2 TRIM32 POMGNT1

PTRF SEPN1 TTN PLECSGCA†† TCAP DAG1SGCB TMEM5 TRAPPC11SGCD

SGCG††

SMCHD1SYNE1SYNE2TCAP

TMEM43TRAPPC11TRIM32

TTN

NOTE: *Test available in mid-2015 † Repeat Expansion Analysis †† Sequencing and Duplication/Deletion

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Athena Diagnostics Phenotype-Based Testing for the Causes of Neuromuscular DiseaseTest selection is intuitive - conveniently arranged by clinically relevant groups of neuromuscular phenotypes. This approach is especially useful in diagnosing cases with broad phenotypes and non-specific clinical findings.

MUSCULARDYSTROPHIES

(MD)

• Characterized by wasting of skeletalmuscle and progressive muscleweakness; can leadto premature death

• Severity, age ofonset, rate of progression, predominant distribution pattern of muscle weakness,mode of inheritance,complications andprognosis varygreatly among thedifferent forms1

5501, Muscular Dystrophy Advanced Evaluation 33 genes tested

Some forms of MD include: • Duchenne muscular

dystrophy (DMD)• Becker muscular

dystrophy (BMD)• Emery-Dreifuss

muscular dystrophy(EDMD)

• Limb-girdle musculardystrophy (LGMD)

• Facioscapulohumeralmuscular dystrophy(FSHD)

• Congenital musculardystrophy (CMD)

• Distal muscular dystrophy (DM)

TES

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E/N

MD

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LUATIO

N

LIMB GIRDLE MUSCULARDYSTROPHY

• Weakness and wastingrestricted to the limbmusculature, proximalgreater than distal

• Most individuals showrelative sparing ofheart and bulbar mus-cles, although excep-tions occur dependingon genetic subtype

• Onset, progression, anddistribution of weak-ness and wasting varyconsiderably among in-dividuals and geneticsubtypes

• AD or AR inheritance 27

5519, Limb Girdle Muscular Dystrophy Advanced Evaluation 23 genes tested

LGMD consists of many genetically distinct subtypes, including:•LGMD2L•LGMD2A (Calpainopathy) •LGMD2R •LGMD2B (Dysferlinopathy) •LGMD2I (MDDGC5) •LGMD2G •LGMD2H •LGMD2D (alphasarcogly-canopathy) •LGMD2E (betasarcogly-canopathy) •LGMD2F (deltasarcogly-canopathy) •LGMD2C (gammasarcogly-canopathy) •LGMD2J •LGMD2K (MDDGC1) •LGMD2N (MDDGC2) •LGMD2O (MDDGC3) •LGMD2Q •LGMD2P (MDDGC9) •LGMD2S •LGMD2M (MDDGC4)

CONGENITALMUSCULAR

DYSTROPHIES (CMD)

• Visible at birth orearly infancy

• Congenital hypotonia• Delayed motor

development and contractures

• Progressive muscleweakness

• Dystrophic featureson muscle biopsy

• Possible CK elevation• Respiratory and car-

diac complicationsare common

• Abnormalities of eye,skin and brain

• Seizures are fre-quently associated,especially in thosewith brain malformations3,4

5502, Congenital Muscular Dystrophy Advanced SequencingEvaluation 23 genes tested

The most common CMDsubtypes, grouped by protein function inwhich causative muta-tions occur, include:• LAMA2-related • Collagen VI-deficient• Dystroglycanopathy-

related • SEPN1-related • LMNA-related.6,7

Subtypes within thesegroups include: LAMA2-related muscular dys-trophy, Ullrichcongenital musculardystrophy (UCMD),Bethlem CMD, muscle-eye-brain(MEB) disease,Fukuyama CMD(FCMD), and rigid spine CMD.2,5,8

CONGENITALMYOPATHIES

• Skeletal muscle weak-ness of variable severity

• AR, AD or X-linked in-heritance

• Relatively stable mus-cle weakness from birthor soon after is common

• Delayed motor mile-stones

• Hypotonia• Hypoactive tendon

deep reflexes • Reduced muscle bulk• Commonly-long narrow

face and high archedpalate

• Presentations varyfrom severe neonatalforms with fetal akinesia to mild adult-onset forms9,10

5503, Congenital Myopathy Advanced Sequencing Evaluation 21 genes tested

Many forms of congeni-tal myopathy have beenidentified. The generalcategories include:• Congenital myopathies

with cores• Congenital myopathies

with protein aggregates

• Myosin storage myopathy

• Congenital myopathieswith central nuclei

• Congenital myopathieswith abnormal fiber ratios or sizes9,10

DISTALMYOPATHIES

• Distal muscles of upperor lower limbs are selectively or disproportionately affected

• AR or AD inheritance• Different forms vary in

phenotype regardingage of onset and pattern of muscle in-volvement11,12,13

5504, Distal MyopathyAdvanced SequencingEvaluation 17 genes tested

Major forms of DistalMyopathy include:• Welander distal

myopathy • Tibial muscular

dystrophy• Distal myotilinopathy• ZASPopathy • Vocal cord and pharyn-

geal distal myopathy• Alpha-B crystallin mu-

tated distal myopathy • Desminopathy • Distal ABD-

filaminopathy• Laing distal myopathy• KLHL9 mutated distal

myopathy • Distal nebulin

myopathy• Miyoshi myopathy • Distal Anoctaminopa-

thy• Distal myopathy with

rimmed vacuoles11,14

EMERY-DREIFUSSMUSCULARDYSTROPHY

• Age of onset, severity,and progression ofmuscle and cardiac involvement vary inter- and intrafamilialy

• Clinically variable fromearly onset; severepresentation in child-hood to late onset withslow progression inadulthood.

• AD, AR, X-linked inheritance

• Symptoms generallyappear as clinical triad:1. Joint contractures

during the first twodecades

2. Followed by muscleweakness and wast-ing

3. Cardiac involvementusually occurs afterthe second decade26

5518, Emery-DreifussMuscular Dystrophy Advanced SequencingEvaluation 6 genes tested

The organization of Athena Diagnostics Evaluations is based on evidence from publications using NGS as a diagnostic tool forneuromuscular disorders and relevant variant databases.*

* Data on file. ** Testing available in mid-2015.

DYSTROPHIN-OPATHIES

Spectrum of muscle disease with X-linked inheritance can presentas: • Mild-muscle cramps

with myoglobinuriaand quadriceps myopathy

• Severe-progressivemuscle diseases classified as Duchenne(DMD)/Becker (BMD)when skeletal muscleis primarily affectedand as DMD-associ-ated dilated cardiomy-opathy (DCM) whenheart is primarily affected

• DMD usually presentsin early childhood withdelayed milestones,including delays in sitting and standingindependently; rapidlyprogressive

• BMD is characterizedby later-onset skeletalmuscle weakness28

5530, DMD Evaluation5531, DMD Duplication/Deletion

Forms include: • Duchenne muscular

dystrophy (DMD)• Becker muscular

dystrophy (BMD)• DMD-associated

dilated cardiomyopa-thy (DCM)28

MYO-FIBRILLAR

MYOPATHIES

• Slowly progres-sive weakness indistal and/or proximal muscles of individuals

• Distal muscleweakness is morepronounced andcommon (80%)than proximal(25%)

• Sensory symp-toms, musclestiffness, aching,or cramps may occur

• Peripheral neu-ropathy present in20% of cases

• Overt cardiomy-opathy present in15-30%15

5505, Myofibrillar Myopathy Ad-vanced SequencingEvaluation 9 genes tested

MFM consists ofseveral geneticallydistinct subtypes: • Myofibrillar My-

opathy 1 (MFM1)Desmin-related

• Myofibrillar My-opathy 2 (MFM2)

• Myofibrillar My-opathy 3 (MFM3)Myotilinopathy

• Myofibrillar My-opathy 4 (MFM4)ZASP-related

• Myofibrillar My-opathy 5 (MFM5)

• Myofibrillar My-opathy 6 (MFM6)

• Congenital Myopa-thy with Fiber-TypeDisproportion

• Early-onset myopa-thy with fatal car-diomyopathy

• FHL1-related my-ofibrillar myopa-thy15

MYOTONICSYNDROMES

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are progressive disorders, associated with cardiac defects, endocrine abnormalities, neurological dysfunctions and cataracts • DM1, the most common form of adult

onset MD, characterized by markedvariability between and within familymembers. The most severe form iscongenital, showing developmentaldelay, severe muscle weakness, hypotonia.

• DM2 patients may have milder clinical presentation than DM1, and in mildest form, DM2 can be difficultto recognize.16,17

Non-dystrophic myotonic disorders area heterogeneous group of skeletal muscle disorders. • Myotonia Congenita (MC) is the

most common skeletal muscle channelopathy. There are two forms:autosomal dominant (Thomsen), andautosomal recessive (Becker). Bothshow a remarkable degree of pheno-typic and genotypic variability, and are more severe in men than inwomen. Variable age of onset.18

5506, Myotonic Syndromes Advanced Sequencing Evaluation 7 genes tested

Myotonia comprises a small group of muscle diseases: • Myotonic dystrophies

Myotonic dystrophy type 1 (DM1),Myotonic dystrophy type 2 (DM2)

• Non-dystrophic myotonic disorders, includingMyotonia Congenita (MC), Thomsen's Disease and Becker's Disease

PERIODICPARALYSIS

• Episodes of muscle weakness associ-ated with changes in serum potassium concentration

• Hyperkalemic PP (hyperPP) is charac-terized by attacks of flaccid limb paraly-sis with weakness associated withabnormally elevated levels in bloodpotassium concentrations. Three clini-cally distinct manifestations: (1) withoutmyotonia, (2) with clinical or elec-tromyographic (EMG) myotonia, or (3)with paramyotonia congenital (PMC).Attacks typically begin in the firstdecade of life, increase in frequency and severity over time.19

• Hypokalemic PP (hypoPP) is generallycharacterized by reversible attacks ofmuscle weakness associated with an abnormal decrease in blood potassiumconcentrations. Recovery occurs whenserum potassium normalizes.20

• Andersen-Tawil syndrome (ATS) is characterized by a unique phenotypeconsisting of periodic paralysis, cardiacarrhythmias, and skeletal dysmorphic abnormalities. Paralysis may occur witheither hyperkalemia or hypokalemia thatexacerbate the cardiac arrhythmia withsudden cardiac arrest in 10% of patients.29

5507, Periodic Paralysis Advanced Sequencing Evaluation 3 genes tested

Periodic paralyses are classified into groups: • Hyperkalemic PP (hyperPP)• Hypokalemic PP (hypoPP)• Andersen-Tawil syndrome• Thyrotoxic PP

MALIGNANTHYPERTHERMIA

• In most cases, first signs(tachycardia and tachyp-nea) may appear when patient is given anesthesia,during anesthetization or early post-op

• Affected patient can pres-ent with metabolic acidosis,hypercapnia, tachycardia,hyperthermia, muscle rigid-ity, hyperkalemia with riskfor cardiac arrhythmia orcardiac arrest, muscle break-down with CK increase, andmyoglobinuria with risk forrenal failure

• AD inheritance21,22

• Clinical manifestation maydepend on genetic predis-position, dose of triggeragents, or duration of expo-sure. Almost all individualswith MH appear normalwithout any pathologicsigns; it is impossible to diagnose susceptibilitywithout either the exposureto triggering agents or byspecific diagnostic testing.30

5508, Malignant Hyperthermia Advanced Sequencing Evaluation 2 genes tested

CONGENITALMYASTHENICSYNDROMES*

• Muscle weakness (i.e. ocular, bulbar, limb muscles, but nocardiac orsmooth musclemovement)

• Motor develop-mental delay

• Exercise intolerance

• Apneas• Risk to infection • Earlier onset

cases typicallydisplay:– Difficulty

feeding – Weak cry and

suckling– Choking spells

• Specific clinicalcourse and severity are oftenhighly variable

• Subsets can beAD or AR23,24,25

5511**, Congenital Myasthenic Syn-drome AdvancedSequencing Evaluation** 13 genes tested

13 subsets are identified by gene:• ARGN• CHAT• COLQ• CHRNE• CHRNA1 • CHRNB1• CHRND• RAPSN • DOK7• DPAGT1• MUSK• GFPT1• SCN4A

Whole Blood, Test Test Lavender Top Tube/ TurnaroundCode Name Minimum Volume* (mL) Time

5501 Muscular Dystrophy Advanced Evaluation 6-8 Adult, 1-2 Pediatric 6 weeks CPT Codes**: 81404 x4, 81405 x9, 81406 x8, 81408 x2, 81161, 81479

5502 Congenital Muscular Dystrophy Advanced Sequencing Evaluation 6-8 Adult, 1-2 Pediatric 6 weeks CPT Codes: 81404 x2, 81405 x2, 81406 x3, 81407 x3, 81408, 81479

5503 Congenital Myopathy Advanced Sequencing Evaluation 6-8 Adult, 1-2 Pediatric 6 weeks CPT Codes: 81406 x2, 81407 x2, 81408 x2, 81479

5504 Distal Myopathy Advanced Sequencing Evaluation 6-8 Adult, 1-2 Pediatric 6 weeks CPT Codes: 81404, 81405 x2, 81406 x3, 81407, 81408 x2, 81479

5505 Myofibrillar Myopathy Advanced Sequencing Evaluation 6-8 Adult, 1-2 Pediatric 6 weeks CPT Codes: 81404, 81405 X2, 81406, 81479

5506 Myotonic Syndromes Advanced Sequencing Evaluation 6-8 Adult, 1-2 Pediatric 6 weeks CPT Codes: 81401, 81404, 81406, 81479

5507 Periodic Paralysis Advanced Sequencing Evaluation 6-8 Adult, 1-2 Pediatric 6 weeks CPT Codes: 81403, 81406, 81479

5508 Malignant Hyperthermia Advanced Sequencing Evaluation 6-8 Adult, 1-2 Pediatric 6 weeks CPT Codes: 81408, 81479

5518 Emery-Dreifuss Muscular Dystrophy Advanced Sequencing Evaluation 6-8 Adult, 1-2 Pediatric 6 weeks CPT Codes: 81404, 81405, 81406 X2, 81479

5519 Limb Girdle Muscular Dystrophy Advanced Evaluation 6-8 Adult, 1-2 Pediatric 6 weeks CPT Codes: 81404 x3, 81405 x7, 81406 x6, 81408, 81479

5511 Congenital Myasthenic Syndrome Advanced Sequencing Evaluation*** 6-8 Adult, 1-2 Pediatric 6 weeks

5530 DMD Evaluation (new code, existing test) 6-8 Adult, 1-2 Pediatric 6 weeks CPT Codes: 81161, 81408

5531 DMD Duplication/Deletion (new code, existing test) 6-8 Adult, 1-2 Pediatric 6 weeks CPT Code: 81161

*We require whole blood in EDTA tubes (lavender top tubes). Adults: 10 mL; Children: 4 mL; Infants: 2 mL. Outside DNA is discouraged; however, highquality extracted DNA that meet our standards can be accepted. The test requires a minimum of 20 ug of DNA at a concentration of 50 ng/ul with aminimum volume of 400 ul. **The CPT codes provided are based on AMA guidelines and are for informational purposes only. CPT coding is the soleresponsibility of the billing party. ***Available in mid-2015. Please contact one of our genetic counselors regarding specific acceptance policies andspecimen requirements for prenatal testing at 800-394-4493.

References: 1. Mercuri E, Muntoni F. Muscular dystrophies. Lancet 2013;381:845-60. 2. Sparks S, Quijano-Roy S, Harper A, et al. Congenital Muscular Dystrophy Overview. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, eds. GeneReviews. Seattle (WA); 1993. 3. Wang CH, Bonnemann CG, Rutkowski A, et al. Consensus statement on standard of care forcongenital muscular dystrophies. J Child Neurol 2010;25:1559-81, PMID:21078917. 4. Brockington M, Blake DJ, Prandini P, et al. Mutations in the fukutin-related protein gene (FKRP) cause a form ofcongenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Human Genetics 2001;69:1198-209, PMID:11592034. 5. Kirschner J.Congenital muscular dystrophies. Handbook Clinical Neurol 2013;113:1377-85, PMID:23622361. 6. Prigogine C, Richard P, Van den Bergh P, Groswasser J, Deconinck N. Novel LMNA mutation presentingas severe congenital muscular dystrophy. Pediatric Neurol 2010;43:283-6, PMID:20837309. 7. Quijano-Roy S, Mbieleu B, Bonnemann CG, et al. De novo LMNA mutations cause a new form ofcongenital muscular dystrophy. Annals of Neurol 2008;64:177-86, PMID:18551513. 8. Lampe AK, Flanigan KM, Bushby KM, Hicks D. Collagen Type VI-Related Disorders. In: Pagon RA, Adam MP, BirdTD, Dolan CR, Fong CT, Stephens K, eds. GeneReviews. Seattle (WA); 1993. 9. Wang CH, Dowling JJ, North K, et al. Consensus statement on standard of care for congenital myopathies. Journal ChildNeurol 2012;27:363-82. 10. Romero NB, Clarke NF. Congenital myopathies. Handbook Clinical Neurol 2013;113:132136. 11. Udd B. Distal myopathies--new genetic entities expand diagnostic challenge.Neuromuscular Disorders : NMD 2012;22:5-12. 12. Penisson-Besnier I. Distal myopathies. Revue Neurologique 2013;169:534-45. 13. Senderek J, Garvey SM, Krieger M, et al. Autosomal-dominant distalmyopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3. Am Journal Human Genetics 2009;84:511-8. 14. Kraya T, Zierz S. Distal myopathies:from clinical classification to molecular understanding. J Neural Transm 2013;120 Suppl 1:3-7. 15. Selcen D, Engel AG. Myofibrillar Myopathy. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP,eds. GeneReviews. Seattle (WA); 1993. 16. Turner C, Hilton-Jones D. The myotonic dystrophies: diagnosis and management. J Neurol, Neurosurg, Psych 2010;81:358-67. 17. Timchenko L. Molecularmechanisms of muscle atrophy in myotonic dystrophies. Int’l J Biochem & Cell Bio 2013;45:2280-7. 18. Duno M, Colding-Jorgensen E. Myotonia Congenita. In: Pagon RA, Adam MP, Bird TD, Dolan CR,Fong CT, Stephens K, eds. GeneReviews. Seattle (WA); 1993. 19. Charles G, Zheng C, Lehmann-Horn F, Jurkat-Rott K, Levitt J. Characterization of hyperkalemic periodic paralysis: a survey of geneticallydiagnosed individuals. J Neurol 2013, PMID 23884711. 20. Levitt JO. Practical aspects in the management of hypokalemic periodic paralysis. J Translational Med 2008;6:18, PMID 18426576. 21. Twine N.Delayed onset of malignant hyperthermia in the intensive care unit: a rare but life-threatening disorder. Critical Care Nursing Quarterly 2013;36:213-7, PMID 23470706. 22. Larach MG, Gronert GA,Allen GC, Brandom BW, Lehman EB. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesthesia and Analgesia 2010;110:498-507,PMID 20081135. 23. Finlayson S, Beeson D, Palace J. Congenital myasthenic syndromes: an update. Practical Neurol 2013;13:8091. 24. Schara U, Della Marina A, Abicht A. Congenital myasthenicsyndromes: current diagnostic and therapeutic approaches. Neuropediatrics 2012;43:184-193. 25. Abicht A, Muller J, Lochmuller H. Congenital Myasthenic Syndromes. In: Pagon RA, Adam MP, BirdTD, Dolan CR, Fong CT, Stephens K, eds. GeneReviews. Seattle (WA), 1993. 26. Bonne G, Leturcq F, Ben Yaou R. Emery-Dreifuss Muscular Dystrophy. In: Pagon RA, Adam MP, Bird TD, Dolan CR, FongCT, Stephens K, eds. GeneReviews. Seattle (WA); 1993. 27. Gordon E, Pegoraro E, Hoffman EP. Limb-Girdle Muscular Dystrophy Overview. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, eds.GeneReviews. Seattle (WA); 1993. 28. Darras BT, Miller DT, Urion DK. Dystrophinopathies. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews. Seattle (WA); 1993-2014. Last Update:November 23, 2011. 29. Tengan CH, Antunes AC, Bauab JR, Prado GF, Manzano GM, Gabbai AA. Andersen syndrome: an association of periodic paralysis, cardiac arrhythmia and dysmorphicabnormalities. Arquivos de neuropsiquiatria 2006;64:582-4, PMID 17119796. 30. Kim DC. Malignant hyperthermia. Korean J Anesthesiol 2012;63:391-401, PMID 23198031.

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