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The Limb-GirdleMuscularDystrophiesandthe Dystrophinopathies

Stanley Jones P. Iyadurai, MSc, PhD, MD; John T. Kissel, MD, FAAN

ABSTRACTPurpose of Review: The classic approach to identifying and accurately diagnosing limb-girdle muscular dystrophies (LGMDs) relied heavily on phenotypic characterization andancillary studies including muscle biopsy. Because of rapid advances in genetic sequencingmethodologies, several additional LGMDs have been molecularly characterized, and thediagnostic approach to these disorders has been simplified. This article summarizes theepidemiology, clinical features, and genetic defects underlying the LGMDs.Recent Findings: In recent years, the advent of next-generation sequencing has heraldedan era of molecular diagnosis in conjunction with physical characterization. Inadvertently,this process has also led to the ‘‘next-generation aftermath,’’ whereby variants of unknownsignificance are identified in most patients. Similar to the published diagnostic and treat-ment guidelines for Duchenne muscular dystrophy, diagnostic and treatment guidelineshave recently been published for LGMDs. In addition, the first medication (based on theexon-skipping strategy) for treatment of patients with a subset of Duchenne musculardystrophy has been recently approved by the US Food and Drug Administration (FDA).Summary: The LGMDs are a heterogeneous group of hereditary, progressive, anddegenerative neuromuscular disorders that present with primary symptoms of shouldergirdle and pelvic girdle weakness. Although a combination of clinical and molecular geneticevaluations may be sufficient for accurate diagnosis of LGMDs in many cases, thecontribution of imaging and histopathologic correlations still remains a critical, if not anecessary, component of evaluation in some cases.

Continuum (Minneap Minn) 2016;22(6):1954–1977.

INTRODUCTIONThe limb-girdle muscular dystrophies(LGMDs) are a heterogeneous group ofgenetic disorders generally characterizedbyweakness of the shoulder and the pelvicgirdle muscles. Based on the inheritancepatterns, autosomal dominant (LGMDtype 1), autosomal recessive (LGMDtype 2), and X-linked forms of LGMDhave been described. Successive letters ofthe alphabet have been used to name theLGMDs according to the chronology ofidentification of the genetic locus. Whilestraightforward and convenient, this sys-tem has sometimes generated confusionin regard to more traditionally named en-

tities (eg, Emery-Dreifuss muscular dys-trophy) and with entities not necessarilypresenting in a limb-girdle pattern ofweakness (eg, dysferlinopathies).

The dawn of molecular genetics in the1990s and, more recently, the increasingapplication of next-generation massiveparallel-sequencing technologies haveresulted in a fundamental change in howthese disorders are defined, identified,diagnosed, and managed. For example,in the traditional approach, muscle bi-opsies were performed routinely on es-sentially all patients with LGMD as partof the characterization and diagnosticprocess. However, the lack of specificity

Address correspondence toDr Stanley Jones P. Iyadurai,Ohio State University, WexnerMedical Center, Departmentof Neurology, 395 W 12thAve, Columbus, OH 43210,[email protected].

Relationship Disclosure:

Dr Iyadurai has receivedpersonal compensation forserving on the advisoryboards of Allergan; AlnylamPharmaceuticals, Inc; CSLBehring; and Pfizer, Inc. DrKissel has received personalcompensation for serving ona consulting board of AveXis,Inc; as journal editor of Muscle& Nerve; and as a consultantfor Novartis AG. Dr Kissel hasreceived research/grantfunding as principal investigatorof a study from the NationalInstitutes of Health and hasreceived funding for clinicaltrials from AveXis, Inc;AxelaCare Health Solutions,LLC; BioMarin; CSL Behring;Cytokinetics, Inc; IonisPharmaceuticals; and Quintiles,Inc; and receives publishingroyalties from OxfordUniversity Press.

Unlabeled Use ofProducts/InvestigationalUse Disclosure:Drs Iyadurai and Kisseldiscuss the unlabeled/investigational use ofcorticosteroids to treatDuchennemuscular dystrophy.

* 2016 American Academyof Neurology.

Supplemental digital content:Videos accompanying thisarticle are cited in the text asSupplemental Digital Content.Videos may be accessed byclicking on links provided in theHTML, PDF, and app versionsof this article; the URLs are pro-vided in the print version. Videolegends begin on page 1976.

1954 www.ContinuumJournal.com December 2016

Review Article

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

mailto:[email protected]

and significant overlap in biopsy find-ings among the various LGMDs (eg, thepresence of inflammatory cells) haverendered this invasive technique lessuseful and necessary in this day of readilyavailable genetic testing. However, somemuscle biopsy findings are fairly charac-teristic of certain LGMDs (eg, the pres-ence of eosinophils in calpainopathy) andare useful diagnostic tools in some caseswhen next-generation sequencing analysisof a patient with LGMD fails to establisha genetic diagnosis. Similarly, ultrasoundor MRI of the muscle may be helpful inproviding data about the pattern of in-volved muscles and serve as a useful guidefor the appropriate muscle for biopsy orto help guide focused genetic testing.

EPIDEMIOLOGYThe LGMDs have a general estimated in-cidence of 1 to 6 out of 100,000. How-ever, this is likely an underestimategiven that significant genetic, phenotypic,and regional variability confound thesefigures, as do variable and incompletepenetrance, and care access. Whilepopulation-basedwhole-genome sequenc-ing strategies may be helpful in estimatingthe prevalence more accurately, thisapproach is currently not practical be-cause of the cost and labor intensivenessof the current whole-genome sequenc-ing technologies. In the United States,calpainopathy, dysferlinopathy, anddystrophinopathies are the most com-mon forms of LGMD.

CLINICAL FEATURES ANDDIAGNOSISAlthough the LGMDs are, by definition,congenital disorders, clinical manifesta-tions can begin at almost any time fromearly childhood to late adulthood.Most ofthe disorders, in fact, manifest in adult-hood with a range of presentation aslate as the seventies and eighties. LGMDsoften manifest with the simultaneousonset of weakness in both the pelvic and

shoulder girdle muscles, although specificdisorders may initially manifest moreprominently in one region (eg, hips) com-pared to the shoulders. With progression,weakness may spread outside of thepelvic and the shoulder girdle to moredistal groups, the neck and axial muscles,or both. Depending on the type of LGMD,the pulmonary musculature and heartmay also be involved. Creatine kinase(CK) levels may be normal, mildly elevated(usually in LGMD1s), or highly elevated(usually in LGMD2s or X-linked LGMD)depending on the disorder. Extraocularmuscles are usually spared, as are cranialmuscles, except in certain disorders wherethe facial muscles may be involved.

The current diagnostic approach stillrelies on careful phenotypic delineationof the pattern of weakness, a search forother associated features (eg, contractures,heart involvement), distinctive EMG find-ings (including abnormal spontaneousactivity, complex repetitive discharges,myotonic discharges), and focused genetictesting for suspected causative gene de-fects. Currently,multigene next-generationpanels are commercially available andpermit testing of a large number of genesin one step. For example, specific LGMDpanels may evaluate 25 to 35 genes, ora general myopathy panel may evaluate180 genes in a single pass. Although pow-erful, the process of screening multiplegenes at the same time (multigene paneltesting) for LGMDs typically results inidentification of multiple so-called vari-ants of unknown significance. These mayinclude novel variants not reported indisease or population databases, whichin many cases are not causative. When var-iants of unknown significance (eithersingle or multiple) are identified, familytesting to establish segregation as well asadditional muscle biopsy studies (such asimmunostaining) may help establish thediagnosis, at least in some cases. Whileintuitively and intellectually appealing,such large panel testing increases cost

KEY POINTS

h Limb-girdle musculardystrophies have anestimated incidence of1 to 6 out of 100,000.

h Limb-girdle musculardystrophies are ofdominant, recessive, orX-linked forms.

h The typical pattern ofweakness in limb-girdlemuscular dystrophiesinvolves the shouldergirdle and the pelvicgirdle muscles, withvariable involvement ofthe cardiac andpulmonary musculature.

h The combination ofphenotypic evaluation,electrodiagnostic andmuscle biopsy features,and gene panel testingare helpful in diagnosisof the limb-girdlemuscular dystrophies.

h Contractures andscoliosis are common inlimb-girdle musculardystrophies.

1955Continuum (Minneap Minn) 2016;22(6):1954–1977 www.ContinuumJournal.com


and invariably leads to testing of genesirrelevant to the presenting phenotypeand,worse yet, identification of unexpected/irrelevant variants of unknown significancein other unwanted genes in the panel.Therefore, the selection of the mostappropriate gene panel from the manyavailable must be based on precise phe-notypic and laboratory characterizationand the best guess as to the most likelydiagnosis.

Even with multigene panel testing,a significant proportion of LGMD cases(up to 25% in some instances) may re-main undiagnosed.1 In such cases, whole-exome sequencing may be performed, aprocess that typically involves sequencingof all known exons in a given individual,with variants called based on comparisonsmade to standard sequences. Althoughevidence suggests that whole-exome se-quencing of the trio (the patient and thebiological mother and father) increasesthe diagnostic hit rate,2 it is importantto bear in mind that exome sequencingdoes not provide complete coverage ofall coding exons and typically does notdetect deletions and duplications. In ad-dition, genetic diagnosis via multigenepanel testing and whole-exome sequenc-ing may be limited by insurance cover-age, requires technical expertise, and isusually restricted to specialized neuro-muscular centers around the country. Thegenetic evaluation of patients with nega-tive results in whole-exome sequencing istherefore best pursued only at specializedresearch centers.

Genetic and molecular characteriza-tions have revealed that the LGMD geneproducts are localized to various parts ofthe muscle fiber (nucleus, cytosol, Golgiapparatus, sarcolemma, sarcoplasmic re-ticulum, extracellularmatrix, cytoskeleton[cytoplasmic structural framework], andcontractile cytoskeleton [motor andmotor-associated proteins]) and perform a vari-ety of related functions, resulting in aplethora of clinical phenotypes. In certain

disorders, different allelic alterations re-sult in different phenotypic expressionsfrom defects in the same gene. For exam-ple, LGMD2B (dysferlinopathy) can pres-ent as a classic LGMD phenotype or adistal-predominant myopathy (ie, Miyoshimyopathy). The following discussion high-lights the characteristics of the variousLGMDs based on the standard alphanu-meric nomenclature followed in paren-theses by the involved protein.

Limb-Girdle MuscularDystrophy Type 1 (DominantForms of Limb-GirdleMuscular Dystrophy)To date, eight LGMD1 loci with domi-nant inheritance have been describedbased on clinical and genetic criteria;other dominant LGMDs will certainly beidentified in the future. Sporadic formsof LGMD1 are often encountered sincede novo dominant mutations can presentwith the disease phenotype (with anobvious lack of family history). At times,the lack of penetrance and expressivityand broad range of clinical variabilityprecludes the identification of the phe-notype in the carrier parent. The LGMD1disorders are usually adult onset and ingeneral have a milder phenotype thanthe LGMD2 disorders so that affectedpatients are usually in good health atreproductive age. To date, mutations inseven genes have been identified ascausative for LGMD1 disorders, withcommercial testing available for mostof the disorders. The LGMD1 subtypes,characteristic features, clinical features,and limited gene information are sum-marized in Table 10-13 and describedbriefly in the following sections.

Limb-girdle muscular dystrophytype 1A (myotilinopathy). The onsetof this late-onset disease is variable fromthe midtwenties to midseventies. Weak-ness is symmetric and starts in the legsand then progresses to the arms. Distalweakness is observed with further


Limb-Girdle Muscular Dystrophies


progression, although some patients maypresent with footdrop. In the upperextremities, weakness is noticed in thewrist extensors, fingers extensors, anddeltoid muscles. Facial and neck extensormuscle weakness may occur. Some pa-tients develop dysarthria (due to palatalweakness),4 myalgia, and joint contrac-tures mainly of the ankles. Tendon re-flexes are absent at the knees and theankles but loss of tendon reflexes may bediffuse. Cardiomyopathy is present inone-half of patients, with onset betweenages 60 and 70. Progression of weaknessis slow, with loss of ambulation usuallywithin 10 years of onset. Serum CK can benormal to 15-fold elevated. Needle EMGrevealsmyopathic changes and fibrillationpotentials, and myotonic discharges are

seen in some patients. Muscle biopsyreveals a myopathic pattern with signifi-cant size variability, rounded fibers,rimmed or autophagic vacuoles, hyalineinclusions, and spheroid bodies onATPase staining. Mutations in myotilingene cause LGMD1A.

Limb-girdle muscular dystrophy type1B (laminopathy). LGMD1B usually man-ifests before the age of 20 with symmet-rical weakness affecting the proximallower extremities (Case 10-1). However,a variant of this syndrome (Arg377His mu-tation of the lamin A/C gene, infra vida)may result in early and predominantquadriceps involvement. Progression isgenerally slow, with the upper extremitiesusually involved in the third or fourth de-cade. Cardiac abnormalities are noted in

TABLE 10-1 Limb-Girdle Muscular Dystrophy Type 1 Characteristicsa

Clinical Information Gene Information

TypeTypicalOnset Progressionb

CreatineKinase Level

HeartInvolvement

Gene/Locus Protein

LGMD1A Adulthood Slow 1Y15X Yes MYOT Myotilin

LGMD1B Variable;childhood toadulthood

Slow 1Y6X Yes LMNA Lamin A/C

LGMD1C Childhood Slow tomoderate

10Y15X Yes CAV3 Caveolin 3

LGMD1D Adulthood Slow 1Y6X Not usual DNAJB6 HSP40

LGMD1E Adulthood Slow 2Y4X Yes DES Desmin

LGMD1F Variable;infancy toadulthood

Rapid Variable;normal to 15X

No TNPO3 Transportin 3

LGMD1G Adulthood Slow Variable;normal to 10X

No HNRPDL HeterogeneousnuclearribonucleoproteinDYlike protein

LGMD1H Variable;childhood toadulthood

Slow Variable;normal to 10X

No 3p23 To be identified

LGMD = limb-girdle muscular dystrophy.a Modified with permission from Iyadurai SJ, Kassar D, Springer.3 B 2013 Springer Science+Business Media.b Progression of the disease as noted by time frame (arbitrarily assigned) of loss of ambulation: rapid is 2 years from diagnosis; moderate is 5 yearsfrom diagnosis; slow is more than 5 years from diagnosis.



about 60% of patients and are typified bycardiomyopathy, atrioventricular conduc-tion block, bradycardia, and sudden car-diac death.5 Specific mutations such asthe Arg377His have been associated withdilated cardiomyopathy. Serum CK maybe either normal or mildly elevated.Muscle biopsy shows rounded fibers,variability in fiber size, increased

endomysial thickness, and mislocalizedand aggregated lamin. Mutations in thelamin A/C gene underlie the LGMD1Bphenotype and also many other pheno-types. For example, patients with certainmutations in the lamin A/C gene mani-fest as Emery-Dreifuss muscular dys-trophy phenotype characterized bycontractures of the posterior cervical

Case 10-1This 28-year-old woman with diffuse weakness and atrophy was seen initially as a 16-month-old girl whenher mother noted that she had difficulty running and arising from the floor. Muscle biopsy revealed adystrophic process. On follow-up examination at age 4, the patient used a wheelchair for all mobility.Laboratory evaluation showed a mildly elevated creatine kinase level at that time. On follow-upexamination at age 21, generalized atrophy of the appendicular muscles was noted. The cranial, facial,and truncal muscles were spared. Contractures were noted in the hips, ankles, and elbows. Pulmonaryfunction tests showed a vital capacity of 75% predicted. Gene sequencing identified a mutation in thelamin A/C gene compatible with limb-girdle muscular dystrophy type 1B (Figure 10-1).

Comment. This case demonstrates a classic onset and progression as would be expected in patients withlamin A/C mutations, an autosomal dominant limb-girdle muscular dystrophy. These patients have delayedmotor milestones, contractures, scoliosis, elevated creatine kinase levels, and develop pulmonarydysfunction and cardiac abnormalities. Cranial nerves are not usually affected.

FIGURE 10-1 Patient in Case 10-1 with limb-girdle muscular dystrophy type 1B. Notice thesparing of cranial musculature and severe atrophy of arm muscles (A). Elbowand knee contractures, scoliosis, and scapular winging are common (B).




muscles, elbows, and ankles; cardiac in-volvement; slowly progressive weaknessinvolving the humeral and peroneal mus-cles with some pelvic girdle involvement;tendon areflexia; and slight elevation inCK levels. Recently, recessive mutationsin lamin A/C resulting in the LGMD1Bphenotype have been described.

Limb-girdle muscular dystrophy type1C (caveolinopathy and ripplingmuscledisease). LGMD1C is an early-onset dis-order with manifestation between 5 yearsof age and adulthood. Proximal weaknessin the lower extremities, difficulty walk-ing, and a positive Gowers sign are usuallynoted. Patients with LGMD1C may alsoexperience cramps after exercise. Vari-able clinical manifestations may occur ina single family, and the disorder often hasa benign clinical course. No evidence ofrespiratory impairment occurs, and lifeexpectancy is not reduced. Hypertrophiccardiomyopathy has been noted inpatients, although rarely. EMG may benormal or reveal myopathic changes.Usually, muscle biopsy demonstratesvariability in muscle fiber size, fiberswith internal nuclei, degenerating andregenerating fibers, and increased con-nective tissue. Caveolin 3 mutations un-derlie LGMD1C. In muscle biopsiesobtained from patients with LGMD1C,caveolin 3 is invariably reduced bothby immunohistochemistry and immuno-blot analysis.

Another manifestation of patients withcaveolin 3 mutations results in ripplingmuscle disease phenotype. Rippling mus-cle disease is characterized by severalspecific behaviors of the muscle: worm-like movements on the surface of themuscle, percussion-related contraction,and muscle mounding. Muscle hyper-trophy is common in caveolinopathy. Attimes, a parent may be a benign carrierwith muscle hypertrophy but have noother signs or symptoms. The presentingmanifestations are usually fatigue, tiptoewalking difficulty, and myalgia. The pa-

tients usually experience muscle cramps,pain, and stiffness (particularly with exer-cise), and serum CK is elevated up to 10times the normal value.

Limb-girdle muscular dystrophy type1D (HSP40 proteinopathy). LGMD1Dusually presents with onset of weaknessat 20 to 60 years of age, although mostpatients have weakness, slowness, andclumsiness of movements as children. Hipgirdle weakness and waddling gait arenoted first, followed variably by progres-sion to the shoulder girdle. Progression isgradual, with need for a wheelchair usuallyoccurring 20 to 30 years after diagnosis.Dysphagia occurs in about 20% of the pa-tients, and dysarthria may occur. Cardiacor respiratory involvement has not beenobserved with LGMD1D. Most patientshave elevated serum CK (up to five timesnormal). Mild calf hypertrophy may bepresent. Myopathic changes are noted onEMG. Muscle biopsy usually shows variedfiber size, rounded fibers, endomysialthickening, rimmed vacuoles, eosinophiliccytoplasmic bodies, and dystrophic fibers.Mutations in DNAJB6 underlie LGMD1Dphenotype.6

Limb-girdle muscular dystrophy type1E (desminopathy). LGMD1E is charac-terized by dilated cardiomyopathy, cardiacconduction system disease, and adult-onset myopathy.7 Cardiac manifestationsinclude arrhythmia, which manifests at20 to 25 years of age, and congestiveheart failure with four-chamber enlarge-ment during the third to fifth decade.Cardiac sudden death has been noted asa major familial symptomatology.8 Mus-cle biopsy shows significant variability isfiber size, increased endomysial thicken-ing, cytoplasmic bodies, and eosinophilicinclusions. Mutations in desmin genewere found to be causative of LGMD1Ephenotype.

Limb-girdle muscular dystrophytype 1F (transportinopathy). Onset ofLGMD1F is typically in the third or fourthdecade but can manifest in infancy. All

KEY POINT

h Patients with certainmutations in the lamin A/Cgene manifest asEmery-Dreifuss musculardystrophy phenotypecharacterized bycontractures of theposterior cervical muscles,elbows, and ankles; cardiacinvolvement; slowlyprogressive weaknessinvolving the humeral andperoneal muscles withsome pelvic girdleinvolvement; tendonareflexia; and slightelevation in creatinekinase levels.



affected patients show characteristic pel-vic and shoulder girdle proximal weak-ness. Pelvic girdle impairment precedesthe shoulder girdle weakness, and distalweakness often occurs later. Respiratorymuscles are clinically affected in somepatients with juvenile-onset LGMD1F.Serum CK is normal in 40% of patientsand varies between normal to as high as15 times the normal levels. EMG ofproximal muscles shows myopathicchanges including short-duration, low-amplitude potentials and polyphasia. Noabnormalities in sensory and motor nerveconduction velocities are noted. Musclebiopsy shows fiber size variability, in-creased connective tissue (both endo-mysial and perimysial), rimmed vacuoles,central nuclei, and scattered dystrophicfibers. Gene defects in transportin 3 areassociated with LGMD1F.

Limb-girdle muscular dystrophytype 1G (HNRPDL proteinopathy). Theage of onset in LGMD1G is in the thirdor fourth decade. The initial symptomsare seen in the proximal lower limbs as-sociated with muscle cramps followedby weakness of the upper limbs. Pro-gressive finger and toe flexion limitationwith decreased range of motion in inter-phalangeal joints also occurs. However,intrinsic hand muscles are not usuallyaffected. CK may be normal or elevatedup to 10 times the upper level ofnormal. Muscle biopsy shows fiber sizevariability, perimysial thickening, rimmedvacuoles, and necrotic fibers. Interest-ingly, scattered areas of angulatedfibers may also be noted. Mutations inthe heterogeneous nuclear ribonucleo-protein DYLike protein underlie theLGMD1G phenotype.

Limb-girdle muscular dystrophytype 1H. LGMD1H is extremely rare andhas been described in only 11 membersof a single large family. The disease onsetis usually in the fifth decade andmanifestswith proximal weakness in upper andlower extremities and follows a relatively

slow course. However, atrophy of shoul-der and pelvic girdle muscles is noted.Generalized hyporeflexia and calf hyper-trophy are also characteristically noted.Serum CK levels are usually elevated butcan be normal (normal to 10 times thenormal level). EMG reveals nonirritablemyopathic changes. Muscle histologyshows abnormal fiber size and shapevariation and increased presence of en-domysial and perimysial connective tissue.Central nuclei are occasionally present.Although the LGMD1H mutation hasbeen linked to 3p23Yp25.1,9 the genedefect is unknown.

Limb-Girdle MuscularDystrophy Type 2 (RecessiveForms of Limb-GirdleMuscular Dystrophy)Twenty-three distinct LGMD2 loci withrecessive inheritance have been de-scribed. In most of these disorders, theCK is quite elevated. Although LGMD2sare usually of early childhood onset andquite debilitating, adult-onset formshave also been described. A variable,progressive course is typical. AlthoughLGMD2I (FKRP deficiency) is the mostcommon form of all LGMDs in northernEurope, LGMD2A (calpainopathy) is themost prevalent in many other Europeancountries, as well as in Turkey, Brazil,Japan, Russia, and Australia. LGMD2I,LGMD2B, and LGMD2A remain themost common autosomal recessiveLGMDs in North America. The LGMD2subtypes, characteristic features, clinicalfeatures, and genetic information arelisted in Table 10-2. Individual LGMD2subtypes are described in the follow-ing sections.

Limb-girdle muscular dystrophy type2A (calpainopathy). LGMD2A is charac-terized by a wide variability in clinicalfeatures and rates of progression. Althoughthe mean age at onset is approximately14 years, a considerable variation in pre-sentation from ages 2 to 40 years has

KEY POINT

h In most of the limb-girdlemuscular dystrophytype 2 disorders, thecreatine kinase is quiteelevated. Althoughlimb-girdle musculardystrophy type 2disorders are usuallyof early childhood onsetand quite debilitating,adult-onset forms havealso been described.




TABLE 10-2 The Subtypes of Limb-Girdle Muscular Dystrophy Type 2a


Type Typical Onset Progression

CreatineKinaseLevel

HeartInvolvement Gene Protein

LGMD2A 12Y30 years Slow Markedlyelevated

No CAPN3 Calpain 3

LGMD2B Adolescence Slow 10X Possible; notcommon

DYSF Dysferlin

LGMD2C Early childhood Moderate torapid

20Y30X Yes SGCG +-Sarcoglycan

LGMD2D Variable Rapid 20X Yes SGCA !-Sarcoglycan

LGMD2E Early childhood Moderate torapid

20X Yes SGCB "-Sarcoglycan

LGMD2F Early childhood Rapid 10Y50X Yes SGCD G-Sarcoglycan

LGMD2G Childhood,adolescence

Moderate 3Y30X Yes,approximately50%

TCAP Telethonin

LGMD2H Adolescence,adulthood

Slow 1Y20X No TRIM32 E3 ubiquitin ligase

LGMD2I Early childhoodand lateadulthood

Rapid to slow 5Y40X Yes FKRP Fukutin-relatedprotein

LGMD2J Childhood,adulthood

Slow 10Y15X No TTN Titin

LGMD2K Childhood Slow 10Y40X No POMT1 ProteinO-mannosyltransferase 1

LGMD2L Adulthood Slow 1Y100X No ANO5 Anoctamin 5

LGMD2M Early infancy Slow 50Y100X Possible FKTN Fukutin

LGMD2N Prenatal to infancy Rapid 6Y12X No POMT2 ProteinO-mannosyltransferase 2

LGMD2O Late childhood Moderate 2Y10X No POMGNT1 Protein O-linkedmannose "1,2-N-acetylglucosaminyltransferase

LGMD2P Early childhood Moderate 20X No DAG1 Dystroglycan

LGMD2Q Early childhood Slow 10Y50X No PLEC1 Plectin 1

LGMD2R Childhood toyoung adulthood

Slow Normal Yes DES Desmin

LGMD2S Early childhood Slow 10Y15X No TRAPPC11 Trafficking protein particlecomplex 11

Continued on page 1962



been described. Ambulation is affectedduring adolescence but is affected earlierin infantile-onset disease. The disorderis characterized by a symmetric, selectiveatrophic involvement of limb-girdle andtrunk muscles.10 Muscle weakness usuallybegins in the pelvic girdle, with difficultyrunning, climbing stairs, or rising from achair. The pelvic girdle muscles are themost severely affected, even when thedisease starts in the shoulder girdle. Hipadductors and gluteus maximus are theearliest clinically affected muscles and,to a lesser degree, the hip flexors andposterior thigh muscles are also affected.The distal leg muscles and proximal hipabductors are relatively spared. The weak-ness in the upper extremity muscles andthe shoulder girdle occurs later in thedisease course. Scapular winging is evi-dent. Abdominal muscles may also beinvolved. Early in the disease course,contractures are seen in the calves, wrists,elbows, and fingers. As a result, toewalking may be noted in early stages. Inlater disease, contractures in the proximalparts of the body (including the spine)are noted.

Although no significant cardiac involve-ment occurs, worsening of respiratoryfunction may lead to cardiac complica-tions. Strangely, CK levels may be normalor elevated, even up to 500 times thenormal values. With progression of thedisease, the CK values may begin to drop,consistent with worsening atrophy of theaffected muscles. EMG shows an irritablemyopathy characterized by increasedinsertional activity, fibrillation potentials,and positive sharp waves. Muscle biopsyshows variability of muscle fiber size, en-domysial thickening, necrotic fibers andrare regenerating fibers, type 1 predom-inance, lobulation of type 1 fibers, andinflammation in perivascular or endomysialareas.11 Eosinophilic infiltrates are char-acteristic. Imaging of the thigh musclesmay show marked atrophy of the ham-strings and hip adductors and moderateatrophy in quadriceps with sparing of thesartorius. With progression of the disease,other thigh muscles are also affecteddepending on clinical severity; the adduc-tors and semimembranosus muscles areinvolved in young patients with minimalfunctional motor impairment. In patients

TABLE 10-2 The Subtypes of Limb-Girdle Muscular Dystrophy Type 2aContinued from page 1961


Type Typical Onset Progression

CreatineKinaseLevel

HeartInvolvement Gene Protein

LGMD2T Variable Slow Variable Possible GMPPB GDP-mannosepyrophosphorylase B

LGMD2U Early childhood Rapid tomoderate

6Y50X Possible ISPD Isoprenoid synthasedomain containing

LGMD2V Variable Usually slow 1Y20X Yes,predominantly ininfantile-onsetcases

GAA Acid !-1,4-glucosidase

LGMD2W Childhood Variable, butusually slow

Up to 25X Possible LIMS2 LIM zinc fingerdomain containing 2

LGMD = limb-girdle muscular dystrophy.a Modified with permission from Iyadurai SJ, Kassar D, Springer.3 B 2013 Springer Science+Business Media.




with restricted ambulation, a diffuse in-volvement of the posterolateral musclesof the thigh and of the vastus intermediusis found with relative sparing of the vastuslateralis, sartorius, and gracilis. Imaging ofthe calf muscles reveals involvement ofthe soleus muscle and the medial headof the gastrocnemius with relative sparingof the lateral head. LGMD2A is caused bymutations in the CAPN3 gene, whichencodes for a muscle-specific proteolyticenzyme called calpain 3 (Case 10-2).

Limb-girdle muscular dystrophytype 2B (dysferlinopathy). LGMD2B has awide range of clinical presentations, froma classic limb-girdle presentation to spe-

cific distal myopathies such as Miyoshimyopathy (also known as Miyoshi mus-cular dystrophy type 1) and distal myop-athy with anterior tibial onset. Symptomonset of LGMD2B ranges from adoles-cence to late adulthood (10 to 40 years ofage), with significant variability in pre-sentation between family members anddifferent families. Usually, the muscleweakness starts in the pelvic girdle, man-ifesting as difficulty running and walkingup the stairs. Early difficulty with walkingis usually associated with involvement ofthe gastrocnemius (specifically the me-dial head). In later stages of the disease,upper extremity muscles are involved.

Case 10-2A 50-year-old woman presented with arm and leg weakness and a history of motor difficulties that shehad experienced since childhood. (She stated, ‘‘I was a klutzy kid.’’) However, she had experiencednoticeable weakness only at age 30 when she had difficulty going up stairs. Laboratoryevaluations showed an elevated creatine kinase level of 1300 IU/L (six times the upper limit of normal).Muscle biopsy demonstrated significant size variability, many small rounded fibers, central nuclei,increased endomysial connective tissue, and necrotic fibers, but no inflammation. Physical examinationshowed normal cognition, normal cranial nerves, scapular winging, proximal and distal weakness,hyperlordotic posture, generalized atrophy, and normal sensation (Figure 10-2). Gene testing revealedcompound heterozygous mutations in the calpain 3 gene, diagnostic of limb-girdle musculardystrophy (LGMD) type 2A.

Comment. This case demonstrates common features associated with autosomal recessive LGMDs.Creatine kinase is usually elevated to a higher level (compared to autosomal dominant LGMDs in general).Early-onset motor delay and normal cognition are usually noted. While scapular winging can be variablyseen, cranial musculature is usually preserved.

FIGURE 10-2 Patient in Case 10-2 with limb-girdle muscular dystrophy type 2A. The patienthas notable shoulder abduction weakness (A) and scapular winging (B).



Specifically, biceps are affected approx-imately 10 years after the onset of lowerextremity weakness. The disease followsa fairly slow course of progression, andloss of ambulation is noted at 30 years ofage. However, some patients do not loseambulation until age 60. Hypertrophy ofseveral muscles (deltoid, biceps, and thecalves) is noted early in the course of thedisease. Classic diamond on quadricepssign is seen in most patients. This signrepresents the characteristic shape ac-quired by the anterior compartmentmuscles of the thigh when the patientattempts to sit down (lower his or hertorso or back as if sitting in a chair) withfeet firmly and flatly planted on theground. In some patients, cramps andmuscle discomfort may be the only earlypresenting symptoms. The allelic formof Miyoshi distal myopathy may presentin early adulthood with the inability towalk on or get up on toes. However, theanterior tibialYonset variant may presentwith footdrop and steppage gait. In thesedistal-predominant allelic forms, the prox-imal muscles and the upper limbs be-come affected later in the disease course.

Serum CK levels are considerablyincreased. Muscle imaging confirms aselective involvement of the soleus andgastrocnemius (medial head) and earlymuscle edema. Miyoshi and LGMD phe-notypes can be present in the same family.The exact reason behind the differencesin presentation within a given family isunclear. EMG shows typical myopathicchanges. Muscle pathology shows inflam-mation, necrosis, and degeneration ofmus-cle fibers, fiber size variability, and rarely,fiber splitting. Endomysial thickening isalso commonly noted. Amyloid depositionat the muscle membrane, endomysium,or perivascular spaces are noted in somepatients. Given the predominant inflam-mation seen in the muscle biopsies inthese patients, a misdiagnosis of polymyo-sitis is not uncommon. However, in thesepatients, dysferlin immunostaining re-

veals either a reduction or lack of staining.Mutations in the skeletal muscle proteindysferlin underlie LGMD2B.

Limb-girdle muscular dystrophytypes 2C TO 2F (!, ", +, and G sarco-glycanopathies). The age of onset andclinical presentation has a wide inter- andintrafamilial variability. The clinical pre-sentation can vary from a Duchennemuscular dystrophy (DMD)Ylike courseto intermediate to a mild Becker mus-cular dystrophy (BMD)Ylike phenotypein a given family. The onset of the diseaseis approximately 5 or 6 years of age withinvolvement mainly of proximal muscles,although distal involvement may occur.The inability to walk may occur anywherebetween the second and the fourthdecade. The glutei, adductors, paraspinal,abdominal, subscapular, and soleus mus-cles are affected whereas quadriceps isspared in some patients.12 Patients maydevelop calf and tongue hypertrophy anddeafness. Respiratory failure occurs inthe third decade of life. Cardiac functionsare fairly spared. Serum CK is noted to beextremely high. EMG shows small-amplitude, short-duration, polyphasicmotor unit action potentials. Musclebiopsy shows fiber size variability,rounded fibers, increased endomysialthickness, and necrotic fibers. Rarely,inflammatory infiltrates are also found.The immunoreactivity of the affectedsarcoglycan may be reduced or absent.Secondary reductions in other sarco-glycans may also be noted. Occasionally,reductions in dystrophin staining mayalso be noted. However, how the second-ary reduction in other sarcoglycan or de-creased dystrophin staining relate to thephenotype is unclear. The individual sar-coglycans and their deficiencies relate tothe specific LGMD type (2C, 2D, 2E, and2F). Sarcoglycans appear to play a role inmaintaining muscle membrane integrity.

Limb-girdle muscular dystrophy type2G (telethoninopathy). Patients withLGMD2G usually present at a mean age

KEY POINT

h Miyoshi and limb-girdlemuscular dystrophyphenotypes can bepresent in the samefamily. The exact reasonbehind the differences inpresentation within agiven family is unclear.




of onset of 12 years with difficulty walking,running, and climbing stairs. Althoughthis condition spares the gastrocne-mius (which is affected in LGMD2B/dysferlinopathy), these patients have dif-ficulty walking on their heels. The tibialisanterior is severely affected, and difficul-ties with foot dorsiflexion and footdropensue. Atrophy of the shoulder girdlemuscles is prominent. In the lower ex-tremities, the pelvic girdle muscles anddistal muscles are affected. About 40% ofpatients with LGMD2G become nonam-bulatory by the third or fourth decade.Interestingly, calf atrophy or hypertrophymay be noted as the first sign of disease inone-half of patients. Serum CK may bemildly elevated (three times the normallevel) or quite highly elevated (30 timesthe normal level). Muscle biopsy showssignificant variability in fiber size, in-creased number of fibers with centralnuclei, necrotic and regenerating fibers,and rimmed vacuoles. In Western blotanalysis, telethonin is absent. LGMD2G ismost commonly seen in patients withBrazilian ancestry and is caused by muta-tions in the gene encoding telethonin.13,14

Other variant telethonin syndromes in-clude dilated cardiomyopathy 1N andcongenital muscular dystrophy.

Limb-girdle muscular dystrophytype 2H (TRIM32 proteinopathy/sarcotubular myopathy). To date,LGMD2H has been described only in theHutterite population of North America15

and is amild formof recessive LGMDwitha variable clinical presentation. Diseaseonset is usually within the second or thirddecade of life and progression is slow;most patients continue walking into theirsixth decade. Quadriceps and pelvic gir-dle muscles are primarily involved, andpatients show a waddling gait and diffi-culty rising from the squatting position.Cardiac and facial involvement does notoccur. The serum CK is high (up to 20times the normal level), and EMG showsmyopathic changes. Muscle histology re-

veals mild dystrophic changes includingfiber size variability, endomysial fibrosis,and muscle fiber degeneration and regen-eration. Fiber splitting and internal nucleiare observed.

Another allelic variant of LGMD2His sarcotubular myopathy. As the nameimplies, distinctive features in musclebiopsy led to the name. Patients with thesarcotubular myopathy allelic variant pres-ent with exercise-induced fatigue andmuscle pain. In addition to the weaknessof pelvic and shoulder girdle muscles,neck flexion weakness is also noted. Otheraccompanying features include mild facialweakness, scapular winging, calf hyper-trophy, and Gowers sign. In general, themuscle atrophy noted in successive ex-aminations is a fair indication of progres-sive weakness. Contractures in the Achillestendons are noted frequently, and deeptendon reflexes are either normal ordepressed. Serum CK levels may be ele-vated up to 20 times the normal values.Muscle biopsy shows fiber size variability,rounded fibers, and in addition, smallrounded vacuoles in type 2 fibers. Smallabnormal spaces are noted in segmentsof many muscle fibers. The gene muta-tions underlying LGMD2H involve thegene encoding tripartite motif-containingprotein32 (TRIM32).

Limb-girdle muscular dystrophy type2I (fukutin-related proteinopathy).LGMD2I is one of the most commonLGMDs with a carrier frequency of 1 in400 in the white population. The combi-nation of limb-girdle weakness, respiratoryinsufficiency, and dilated cardiomyopathyis noted in patients with LGMD2I.16 Thedisease onset may be as early as infancy(5 months) or as late as midadulthood(40 years). Patients with early-onset diseasesymptomsmay present with hypotonia anddisplay delayed motor milestones. Tonguehypertrophy is often noted, althoughother muscles may also display hypertro-phy. These patients usually lose ambula-tion by their early teens (much like

KEY POINT

h Limb-girdle musculardystrophy type 2I is oneof the most commonlimb-girdle musculardystrophies with a carrierfrequency of 1 in 400 inthe white population.



patients with DMD). The loss of am-bulation is usually followed by cardiomy-opathy.17 The patients with adult-onsetsymptoms usually have a milder form ofthe disease and a slow course of pro-gression. However, hypertrophy of mus-cles may be noted; the calf, anterior thighmuscles, brachioradialis, and tongue maybe prominently involved. These patientsmay also report nonspecific symptomssuch as cramps and myalgia, especiallyafter exercise. In selected cases, myoglo-binuria may occur. Brain MRI and cogni-tion are normal.18 Serum CK is elevatedbetween 10 to 30 times the normal level.Muscle biopsy shows fiber size variation,necrosis, and regeneration of musclefibers, increased endomysial connectivetissue, and type 1 predominance. LGMD2Iis caused by mutation in Fukutin-relatedprotein gene (FKRP), which also affectsglycosylation of dystroglycans, which isdiscussed in the following section onLGMD types 2K, 2M, 2N, 2O, and 2P.

Limb-girdle muscular dystrophytype 2J (titinopathy/Finnish distal my-opathy). LGMD2J is most prevalent inpatients from Finland or of Finnish origin.The onset of symptoms may be variableand can occur anywhere from childhoodto adulthood (third decade). LGMD2Jclassically presents as a myopathy involv-ing distal muscles, specifically of the leg.The initial manifestation is noted in thetibialis anterior muscle, and hence is alsoknown as tibial muscular dystrophy. MRIof the muscles show prominent involve-ment of the tibialis anterior and theextensor digitorum longus. In general,LGMD2J follows a slow course of pro-gression. Usually patients becomenonambulatory about 20 years aftersymptom onset. In these patients, car-diomyopathy is not usually noted. SerumCK can be elevated up to 20 times thenormal level. Muscle biopsy shows myo-pathic features. Immunohistochemistryreveals secondary reduction in calpain3.19 Mutations in the titin gene are

responsible for LGMD2J. However,it should be emphasized that titin is alarge protein, and mutations/truncationsaffecting several distinct domains withinthe protein may lead to specific pheno-types including selective involvementof the cardiac, skeletal, or respiratorymuscles. The details of the genotype-phenotype correlation are still beingworked out.

Limb-girdle muscular dystrophytype 2L (anoctaminopathy). LGMD2Lusually presents as an asymmetric dis-order and that involves the muscles ofthe scapula. The onset is usually in adult-hood, anywhere from 20 years to 55 years.Asymmetric atrophy of muscles is com-monly noted in quadriceps femoris,biceps brachii, and gastrocnemius. Insome patients, calf hypertrophy is noted;however, calf atrophy ensues with pro-gression of the disease, usually in anasymmetric fashion. While proximalweakness is prominent in both the shoul-der and the pelvic girdle, distal weaknessis not usually noted. Selected patientsmay develop subtle facial weakness.Myalgia, either due to exertional or non-exertional causes, is a common present-ing symptom in these patients. Serum CKcan have a very wide range, from normallevels to 80 times the normal level. EMGshows an irritable myopathy. Musclebiopsy shows rounded fibers, fiber sizevariability, increased endomysial connec-tive tissue, degenerating fibers, and occa-sionally inflammatory infiltrates and fibersplitting. Mutations in the anoctamin 5(ANO5) gene underlie LGMD2L. Recently,dominant mutations in ANO5 havebeen noted to be associated with theLGMD2L phenotype.

Limb-girdle muscular dystrophytypes 2K, 2M, 2N, 2O, 2P. This groupof LGMD disorders shares a commonfeature in that they all result from hypo-glycosylation of !-dystroglycan. Theproteins involved are as follows: type2K: POMT1 proteinopathy; type 2M:




fukutinopathy; type 2N: POMT2 pro-teinopathy; type 2O: POMGNT1 pro-teinopathy; and type 2P: dystroglycan 1proteinopathy. These disorders all usuallypresent in early childhood as congenitalmuscular dystrophies withmultiple organsinvolved (muscle, eye, brain). Variablerates of progression, proximal muscleweakness, mild pseudohypertrophy, mi-crocephaly, and mild mental retardationwith an IQ ranging from 50 to 76 is usuallynoted. Joint contractures occur in aboutone-half of patients.20 The serum CK is 40times the normal level. Muscle histologyshows fiber size variability and reduced !-dystroglycan. In LGMD2M, muscle hyper-trophy is seen in the posterior leg and, insome patients, the tongue. Spinal rigidity,joint contractures, and cardiomyopathymay occur.21,22 Although brain MRI maybe normal, vermis hypoplasia andpolymicrogyria may be seen.

Limb-girdle muscular dystrophy type2Q (plectinopathy). Plectinopathy hasbeen reported in Turkish, Indian, English,and Egyptian families/backgrounds.The disease onset occurs in early child-hood and is usually accompanied bymicrocephaly and mental/intellectualdisabilities. The CK is elevated up to 20times the normal level. EMG showsmyopathic changes, and muscle biopsyreveals a dystrophic picture, variedfiber size, internal nuclei, necrosis/regeneration, and reduced plectin stain-ing. Mutations in the plectin gene under-lie LGMD2Q.

Limb-girdle muscular dystrophytype 2R (desminopathy). Patients withthis desmin variant syndrome (as op-posed to LGMD1E) have a recessivemode of inheritance. The disease onsetis usually early (childhood to the seconddecade of life) and involves facial weak-ness and respiratory muscle weaknessin addition to the proximal weakness.High-arched palate and scoliosis arealso noted. All patients have severeatrioventricular conduction defects and

require cardiac pacemaker placement.Muscle pathology is significant for hya-line accumulations and amorphoussubsarcolemmal inclusions. Recessivemutations in desmin underlie LGMD2R.As noted in the previous section, dom-inant mutations in desmin underlieLGMD1E.

Limb-girdle muscular dystrophytype 2S (TRAPPC11 proteinopathy).Patients with LGMD2S have an earlychildhood onset of proximal weakness,scapular winging, and mild myopathicfacies. CK is elevated up to 10 times thenormal values. In addition, global devel-opmental delay, infantile-onset hyperki-netic movements (dystonia/chorea), andtruncal ataxia are noted. EMG reveals amyopathic picture, and MRI of the brainmay reveal cerebral volume loss. Thegene defect underlying this LGMD is inthe trafficking protein particle complex11 gene.

Limb-girdle muscular dystrophytype 2T (GDP-mannose pyrophos-phorylase B proteinopathy). The dis-ease onset is quite variable with onsetfrom birth to age 40 and has a fairly slowprogression of proximal weakness. In-fants with early-onset LGMD2T have hy-potonia at birth and intellectual disabilities,sometimes with concurrent onset ofseizures. In older patients, enlargedcalves, rhabdomyolysis, and cramps arenoted. Some patients may have cardiacinvolvement. EMG is myopathic andmuscle biopsy reveals a dystrophic pic-ture, internal nuclei, muscle fiber necro-sis, and endomysial thickening. The genedefect underlying this LGMD has beenlocalized to the GDP-mannose pyrophos-phorylase B gene.

Limb-girdle muscular dystrophy type2U (ISPD proteinopathy). The diseaseonset is in early childhood with a pro-gressive course of proximal-predominantweakness. Hypotonia, gait disorder, andGowers sign may be noted. Loss of am-bulation occurs early, around 10 to 12 years

KEY POINT

h Limb-girdle musculardystrophy types 2K, 2M,2N, 2O, and 2P usuallypresent in early childhoodas congenital musculardystrophies with multipleorgans involved (muscle,eye, brain).



of age. Hypertrophy of muscles may benoted. Cardiac involvement with leftventricular dysfunction may be notedas well. MRI of the brain is usuallynormal. CK is usually elevated three to50 times the normal level. Muscle biopsyshows a dystrophic picture. The genedefect associated with this disease is inthe isoprenoid synthase domain-containing gene.

Limb-girdle muscular dystrophytype 2V (Pompe disease). Preisler andcolleagues23 have suggested that Pompedisease (acid maltase deficiency or !-1,4-glucosidase deficiency) should beincluded as an LGMD because it wasidentified in 8% of patients in a group ofunclassified LGMDs. Pompe disease canhave infantile-onset, adolescent-onset,and adult-onset forms. Respiratory insuf-ficiency and thigh adductor weakness iscommonly seen in conjunction with prox-imal weakness. EMG reveals complexrepetitive discharges and myotonic dis-charges, specifically in thoracic paraspinalmuscles. Muscle biopsy shows character-istic subsarcolemmal periodic acid-SchiffYpositive inclusions. The genedefect lies in the deficiency of the acid!-glucosidase enzyme (GAA). Identifica-tion of this disorder is crucial since IVenzyme replacement therapy is life-savingfor infants with the disorder and improvesambulation and respiratory status inadults with the disease.

Limb-girdle muscular dystrophy type2W (LIMS2 proteinopathy). LGMD2Whas onset in childhood with severe weak-ness noted proximally and with fairly slowprogression. Cardiac involvement mayhappen in the third decade. Macroglossia,calf hypertrophy, and triangular tongueare unique features of this condition. CKis elevated up to 25 times the normallevel. Muscle biopsy shows variability infiber size, internal nuclei, and increasedendomysial thickness. Defects in theLIMS2 gene underlie LGMD2W.

General Treatment Approachfor the Dominant andRecessive Forms of Limb-GirdleMuscular DystrophiesAll of the LGMD syndromes cause pro-gressive weakness, although the ratesof progression vary considerably. CertainLGMD syndromes have cardiac involve-ment, and affected patients are prone tocardiac conduction system defects, whichmay lead to sudden death. Rarely, respi-ratory insufficiencymay occur, but usuallyin late stages of the disease and in pa-tients severely affected. In general, later-onset disease predicts a better prognosis.Except for LGMD2V (acid maltase defi-ciency), where enzyme replacement ther-apy is an available treatment option, nospecific disease-altering treatments cur-rently exist for any of the LGMD1 orLGMD2 disorders, although corticoste-roids have been reported helpful inmaintaining muscle function in LGMD2I.However, novel therapies and treatmentapproaches are being explored in disor-ders where inflammatory pathways mayplay a role (eg, dysferlinopathies). Exon-skipping strategies are also being ex-plored in several disorders.

For most patients, physical therapyand occupational therapy should be en-couraged to prevent the formation ofcontractures and to maximize limb use.Some patients with LGMD report crampsin the muscles, and symptomatic treat-ment may be provided with either baclo-fen, tizanidine, or gabapentin. Geneticcounselingmay be helpful for the affectedfamilies and the patients.

In the subset of patients with heartinvolvement (ie, LGMD types 1A, 1B, 1C,2C, 2D, 2E), serial ECG and echocardio-grams are mandatory for monitoringcardiac status. In these patients, cardiacMRI is increasingly being used to identifyearlymyocardial fibrotic changes. In thesepatients, cardiologic follow-up is crucialfor management of cardiomyopathy and

KEY POINTS

h Identification of limb-girdlemuscular dystrophy type2V (Pompe disease, alsoknown as acid maltasedeficiency) is crucial sinceIV enzyme replacementtherapy is life-saving forinfants with the disorderand improves ambulationand respiratory status inadults with the disease.

h Pompe disease canhave infantile-onset,adolescent-onset, andadult-onset forms.Respiratory insufficiencyand thigh adductorweakness is commonlyseen in conjunction withproximal weakness.

h For most patients with alimb-girdle musculardystrophy, physical therapyand occupational therapyshould be encouraged toprevent the formationof contractures and tomaximize limb use.

h In the subset of patientswith a limb-girdlemuscular dystrophy withheart involvement, serialECG and echocardiogramsare mandatory formonitoring cardiac status,and cardiac MRI isincreasingly being used toidentify early myocardialfibrotic changes.




placement of intracardiac pacemaker ordefibrillators when indicated. Respiratoryinvolvement is common in most LGMDtypes, especially in those with severe pe-ripheral weakness (including Pompe dis-ease), and pulmonary function tests areuseful in identification of respiratory weak-ness. Noninvasive or invasive methodsof ventilation are helpful in this clinicalsetting, although which is preferable issomewhat controversial.

X-Linked Limb-Girdle MuscularDystrophyThe X-linked LGMDs are summarizedin Table 10-3. Only the dystrophino-pathies will be discussed in this article.

Dystrophinopathies. Dystrophinopa-thies, as the name implies, result from

gene alterations in the X-linked dystro-phin gene (and resultant abnormaldystrophin protein), leading to a phe-notypic spectrum that includes a milderBMD to severe DMD. However, dys-trophinopathies can also manifest asisolated quadriceps myopathy, asymptom-atic or symptomatic hyperCKemia, “aches,cramps, and pains” syndrome, rhabdo-myolysis, manifesting female carriers,X-linked dilated cardiomyopathy, anddisorders of cognition such as develop-mental delay, attention deficit hyperactiv-ity disorder, and impaired intelligence.

Dystrophin gene structure, clinicaland molecular genetic diagnosis. Muta-tions in the dystrophin gene, located onthe X chromosome, cause DMD/BMD.The dystrophin gene is one of the largest

KEY POINTS

h Duchenne musculardystrophy is caused byalterations in thedystrophin gene, and theincidence has beenreported to be 1 per3500 male live births.

h Boys with Duchennemuscular dystrophyusually present betweenages 2 and 5 years.

TABLE 10-3 Selected List of X-linked Limb-Girdle Muscular Dystrophiesa

Clinical Phenotype Gene Information

ConditionTypicalOnset Progression

CreatineKinaseLevel Allelism Gene Protein

Duchennemusculardystrophy

Earlychildhood

Slow tomoderate

100Y200X Becker musculardystrophy

DMD Dystrophin

Becker musculardystrophy

Latechildhood

Slow 10Y15X Duchennemusculardystrophy

DMD Dystrophin

Barth syndrome Infancy Moderate Normal X-linked dilatedcardiomyopathy

TAZ Tafazzin

Emery-Dreifussmusculardystrophy type 1

Variable;teenageyears

Slow 2Y10X X-linked sinusnode dysfunction

EMD Emerin

Emery-Dreifussmusculardystrophy type 6

Adulthood Slow 2Y10X Hyaline bodymyopathy;X-linked myopa-thy with posturalmuscles atrophy

FHL1 Four-and-one-half-LIM domains1

Danon disease Earlychildhood

Moderate 4Y35X X-linked vacuolarcardiomyopathyand myopathy

LAMP2 Lysosomal-associatedmembraneprotein 2

a Modified with permission from Iyadurai SJ, Kassar D, Springer.3 B 2013 Springer Science+Business Media.



genes in the human genome (by genomicsize, including large introns), spanningabout 2.3 megabases. The extent ofintronic sequences is such that out ofthe whole transcript (preYmessenger RNA),the 79 exons only make 0.6% of the gene.The dystrophin gene encodes a major3685 amino acid, 427 kD skeletal muscleprotein. Eight other promoters directtranscription of seven other transcripts,with expression in skeletal, cardiac, andsmoothmuscle cells and inmultiple othertissue cell types including the brain. Thedystrophin protein connects the contrac-tile apparatus to the extracellular matrixvia the muscle membrane.

The dystrophinopathies are inheritedin an X-linked recessive fashion; ie, amale child receives (inherits) the muta-tion from the mother. However, in asizeable minority of cases (20% to 30%),the mutation identified in the affectedson is not identified in the mother bygene testing. In such cases, the mutationis thought to arise de novo or reflectgermline mosaicism. In a mother whotests negative for the mutation becauseof germline mosaicism, the possibility ofdelivering another affected boy in asubsequent pregnancy is not excluded,and caution should be used in geneticcounseling in such cases. Prenatal diag-nosis or preimplantation genetic testingis available for mothers who test nega-tive for their son’s mutation or in whomgermline mosaicism is suspected. Femalecarriers may exhibit a DMD/BMD-likephenotype (including dilated cardiomy-opathy) due to random lyonization of theX chromosome (heterochromatinizationor inactivation of the X chromosome). Iflyonization occurs to the chromosomecontaining the wild-type dystrophin, andthe chromosome containing the mutantdystrophin is expressed, a DMD/BMD-like phenotype may be observed in thefemale patient.

A positive family history, in conjunc-tion with an elevated CK level, cardiomy-

opathy, or limb-girdleYtype weaknessshould raise suspicion of the condition.Boys with delayed motor milestones,enlarged calves, proximal weakness (in-cluding Gowers sign), and elevated CKlevels (100 to 200 times the normal level)should be suspected having of DMD.Diagnosis relies on DNA analysis of thedystrophin gene. Deleterious DNA alter-ations include deletions (50% to 60%; inframeor out of frame), sequence alterations(20% to 35%), duplications (5% to 10%), orleading missense and nonsense mutations,splice siteYaltering mutations, and crypticintronic mutations. Deletions and duplica-tions may be detected by multiplex poly-merase chain reaction (PCR), multiplexligation-dependent probe amplification,and chromosome microarray techniques;sequence alterations may be detected bySanger or next-generation sequencing.

Epidemiology. The incidence of DMDin live male births is estimated between 1in 3500 and 1 in 5000. BMD is much lesscommon with a prevalence of 1 in 17,500to 1 in 50,000. As expected, the preva-lence of BMD is higher in comparison tothat of DMD mainly because of theshortened survival in the latter group.

Clinical features. Boys with DMDpresent at a young age, usually between2 and 5 years of age with delayed motormilestones, falls, and difficulties runningand jumping. Prominent head lag, calfenlargement (often termed pseudo-hypertrophy, a partial misnomer as theenlargement results from a combinationof fibrotic replacement and true fiberhypertrophy), and Gowers sign are almostalways seen. Progression is steady, anduntreated patients typically are in wheel-chairs by age 12. Clinically, respiratory andcardiac issues ensue. By classic conven-tion, boys still walking after their 16thbirthday are considered to have BMD,and boys who stop walking by age 12 areconsidered to have DMD. This distinctionis in some ways artificial since corticoste-roid therapy may prolong ambulation by

KEY POINT

h Boys with delayed motormilestones, enlargedcalves, proximal weakness(including Gowers sign),and elevated creatinekinase levels (100 to200 times the normal level)should be suspected ofhaving Duchennemuscular dystrophy.




1 to 3 years, thus blurring the clinicaldistinction between BMD and DMD.

Patients with dystrophinopathy havehighly elevated CKs, usually 100 to200 times the normal level. EMG usuallyshows an irritable, proximal-predominantmyopathy. Currently, muscle biopsy isvery seldom indicated but will showrounded fibers, significant size variability,increased endomysial thickness, hyper-contracted fibers, inflammatory cells, andoccasional ring fibers. Immunohisto-chemical stains with antibodies generatedagainst the various epitopes (DYS3, DYS1,and DYS2) may show absent staining incertain fibers.

Dystrophinopathies are multisystemdisorders with multidisciplinary teamsnecessary for optimal management. Pa-tients with dystrophinopathies eventuallyhave involvement of the cardiac, pulmo-nary, musculoskeletal, and cognitive sys-tems. Cardiac involvement progresseswith progression of the muscle disease.Sinus tachycardia, arrhythmia, dilated or

hypertrophic cardiomyopathy, and con-gestive heart failure are common. RegularsurveillancewithECG, long-termheartmon-itoring, and echocardiogram in conjunc-tion with a cardiologist is recommended.Angiotensin-converting enzyme inhibitorsand beta-blockers have been proven tobe beneficial. Lung functions decline withdisease progression as well. Pulmonaryfunctions can be followed with time, andnecessary noninvasive/invasive strategiesmay be employed (in conjunction witha pulmonologist) to improve the qualityof life. In consultation with orthopedicsurgeons, scoliosis may be surgicallyfixed if indicated and necessary. Patientswith DMD demonstrate calf hypertro-phy (Figure 10-3) in earlier stages andcontractures in later stages (Figure 10-4)and may experience severe nighttimecramps. Cramps may be readily treatedwith nighttime stretches and gabapentin.Several types of cognitive issues, includingattention deficit disorder, autism spectrumdisorders, obsessive-compulsive disorder,

KEY POINTS

h Steroids help patientswith Duchennemuscular dystrophyprolong ambulation andincrease longevity.

h Cardiomyopathy iscommon in patientswith Duchennemuscular dystrophy.

FIGURE 10-3 Images of a 6-year-old boy with Duchennemuscular dystrophy showing calf hypertrophyevaluated from posterior view (A) and fromlateral view, further accentuated by standingon toes (B).



and depression are commonly seen.Referral to a psychiatrist and treatment ofthese disorders are helpful in improving

the quality of life of the patient and thefamily members (Case 10-3).

Becker muscular dystrophy. In gen-eral, patients with BMD display a milderphenotype in comparison to patients withDMD, and the weakness onset is also later.Late onset of weakness is associated witha milder phenotype. Despite the milderweakness noted in the skeletal muscles,the cardiac muscles are affected just thesame as in patients with DMD. Therefore,treatments for cardiac managementshould not be delayed. Breathing func-tions are affected as in patients with DMD,but at a later time course. Some patientswith BMD may require noninvasive venti-lation. Although the benefit of corticoste-roids in patients with BMD is unclear,some clinicians employ prednisone at0.75mg/kg/d in patients with BMD as well.

Female carriers of dystrophin muta-tions. Female carriers of the X-linkeddystrophin mutations may present witha DMD-like phenotype. However, it is

KEY POINT

h Female carriers ofdystrophin mutations maypresent with a Duchennemuscular dystrophyYlikephenotype and may havecardiomyopathy as well.

FIGURE 10-4 Contractures in a patient with Duchennemuscular dystrophy. Ankle and footcontractures are common in the later courseof Duchenne muscular dystrophy.

Case 10-3A 5-year-old boy was brought by his mother to his pediatrician because of‘‘running difficulties.’’ The mother noted that the boy was the product of anormal pregnancy, but was not able to walk until 16 months of age. She alsohad noticed prominent calves in the boy. She volunteered the history of herbrother who had had similar calves and had died at the age of 12 with heartcomplications. The patient’s vital signs were significant for mild hypertension.Examination revealed normal cranial nerves, proximal weakness of the upperand lower extremities, calf hypertrophy, diminished reflexes (except at theankles), normal sensation, and normal plantar responses bilaterally. Laboratoryevaluation revealed an elevated creatine kinase level at 200 times the upperlimit of normal. Based on the clinical presentation and family history,Duchenne muscular dystrophy (DMD) was suspected, and the patient wasreferred to a local neuromuscular expert for further evaluation. Gowers sign(Supplemental Digital Content 10-1, links.lww.com/CONT/A210) was notedon that examination. DNA analysis of the dystrophin gene revealed adeletion of exons 21 to 24, leading to premature termination of thedystrophin protein, and a diagnosis of DMD was confirmed. The patientwas started on prednisone 1 mg/kg/d, and a cardiology referral was made.

Comment. This case demonstrates a classic presentation of DMD in ayoung boy with early-onset motor delay and calf hypertrophy. Wheneverhigh creatine kinase, motor delay, and calf hypertrophy are encountered,dystrophinopathy should be considered.




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more common in affected women at ages30 or older. In subtle cases, the manifes-tation may be related to asymptomatic orsymptomatic hyperCKemia or nocturnalcramps. Although these symptoms maybe benign, dilated cardiomyopathy andleft ventricular dilatation are noted in 20%of the carriers.24 These patients should bereferred to cardiologists as well for opti-mal management and treatment. For thisreason, from a genetic standpoint, femalefirst-degree relatives of male patients withDMD/BMD and sisters of mothers of malepatients with DMD/BMD should be of-fered testing for the dystrophin mutationidentified in the affected male relative.

Treatment of dystrophinopathies.As with the other LGMDs, no definitivetreatment for dystrophinopathies cur-rently exists. In addition to the generaloutline for treatments described previouslyfor all of the LGMDs, patients with DMD(and probably BMD) respond to treatmentwith various regimens of corticosteroids(prednisone, deflazacort, or prednisolone)with unequivocal benefit in prolongingambulation, delaying the decline of musclefunction, reducing falls, and delayingpulmonary and (probably) cardiac com-plications.25 Corticosteroids (mainlyprednisone in the United States) areusually started in patients of ages 5 andup, but some clinicians choose to startcorticosteroid treatment at diagnosis,even at younger ages. Prednisone treat-ment of 0.75 mg/kg/d has been usedquite widely. Other regimens involve com-bining this weekly dose to be distributedon Saturdays and Sundays. Prophylaxiswith calcium, vitamin D, proton pumpinhibitors, and antidepressants may benecessary, concomitant with steroid treat-ment. A large international FOR-DMD(Finding the Optimal Steroid Regimenfor Duchenne Muscular Dystrophy) studyis currently comparing deflazacort andprednisone regimens for managing DMD.

In addition, novel treatment method-ologies have relied on correcting the DMD

mutation either by supplying additionalwild-type dystrophin or minidystrophinunder high-expression promoters (genetherapy strategies), or “reading” throughpremature stop codons introduced bymissense mutations (premature termina-tion elimination), or skipping the exonscontaining out-of-frame mutations (exonskipping technology). Clinical trials areunderway to assess the efficacy of thesespecific therapeutic agents in patientswith DMD/BMD, with several companiesseeking approval by the US Food andDrug Administration (FDA) for specificexon skipping agents. At the time of thiswriting, the FDA has approved the firstexon-skipping medication, eteplirsen, foruse in a select subset of patients withDMD. This medication enables preYmessenger RNA to skip exon 51 in thedystrophin reading frame, producingtruncated dystrophin. Approximately20% of boys with DMD have mutationsin exon 51 of the dystrophin gene andmaybenefit from this treatment. However,although the medication has been ap-proved by the FDA, there remains somecontroversy within the academic commu-nity over whether the studies to datedemonstrate enough clinical benefit tojustify the approval. The study that wasdone contained only 12 patients and usedhistorical controls to assess changes in a6-minute walk test, which was the func-tional end point. Follow-up biopsies didshow a significant increase in dystrophin,but this was not clearly shown to correlatewith functional improvement.26,27

CONCLUSIONThe LGMDs are a heterogeneous groupof disorders that, as the name suggests,manifest as weakness in the shouldergirdle and the pelvic girdle muscles.Dominant, recessive, and X-linkedforms of LGMDs have been described.The current classification system ofLGMDs uses the notation type 1 fordominant forms and type 2 for recessive

KEY POINT

h Gene therapy,exon-skipping strategies,and suppression ofpremature terminationapproaches are beingdeveloped for treatmentof Duchennemuscular dystrophy.



forms. Physical characterization and di-agnostic imaging may be helpful inidentifying the specific form. Specificdistinguishing characteristics (Table 10-4),involvement of muscle pattern onMRI (Table 10-5) and muscle biopsyfeatures (Table 10-6) may be helpful indelineating between the subtypes. How-ever, definite diagnosis is achieved bygenetic testing. Several commercial next

generationYbased multigene LGMDpanel gene-testing options are availableto help with diagnosis. Multigene paneltesting combined with traditionalphenotype-based approaches havebeen instrumental in identifying newerLGMDs. With the advancement ofsequencing technologies, the list ofLGMDs has grown and is expected togrow. Understanding of gene functions

TABLE 10-4 Distinguishing Features of Limb-Girdle MuscularDystrophies

Type Feature

LGMD1A (myotilinopathy) Upper extremities distal weakness andcontractures, dysarthria, palatal hypophonia,footdrop, and areflexia

LGMD1B (laminopathy) Contractures and cardiac conduction defects

LGMD1C (caveolinopathy) Rippling muscles and muscle hypertrophy

LGMD1E (desminopathy) Facial weakness and cardiac conduction defect

LGMD1F (transportinopathy) Early respiratory muscle involvement

LGMD1G (HNRPDLproteinopathy)

Finger and toe flexion limitation

LGMD2A (calpainopathy) Contractures and atrophy of shoulder and pelvicgirdle muscles

LGMD2B (dysferlinopathy) Medial gastrocnemius atrophy

LGMD2C, LGMD2D, LGMD2F(sarcoglycanopathies)

Tongue hypertrophy

LGMD2H (sarcotubular myopathy,TRIM32 proteinopathy)

Scapular winging and calf hypertrophy

LGMD2I (fukutinopathy) Tongue and calf hypertrophy, cardiac andrespiratory muscle involvement

LGMD2L (anoctaminopathy) Asymmetric atrophy of muscles, mandibular dysplasia

LGMD2R (desminopathy) Facial weakness, respiratory muscle involvement,high-arched palate

LGMD2S (TRAPPC11proteinopathy)

Scapular winging, hyperkinetic movements

LGMD2V (acid maltase deficiency) Proximal weakness and respiratory insufficiency

LGMD2W (LIMS2 proteinopathy) Calf and tongue hypertrophy and triangular tongue

Dystrophinopathy Calf hypertrophy, distal contractures, preservedankle reflex despite the weakness

LGMD = limb-girdle muscular dystrophy.




TABLE 10-5 Pattern of Affected Thigh Muscles in MagneticResonance Imaging Evaluation of Patients WithLimb-Girdle Muscular Dystrophy

Type Affected Thigh Muscle(s)

LGMD1A (myotilinopathy) Adductor magnus, biceps femoris, semimembranosus,vastus medialis, vastus intermedius

LGMD1B (laminopathy) Adductor magnus, biceps femoris, vastus medialis andvastus lateralis

LGMD1C (caveolinopathy) Normal at the level of the thigh

LGMD1D (HSP40proteinopathy)

Adductor magnus, biceps femoris, semimembranosus,adductor longus

LGMD1E (desminopathy) Semitendinosus, sartorius, gracilis

LGMD1F(transportinopathy)

Vastus lateralis

LGMD2A (calpainopathy) Adductor magnus, semimembranosus

LGMD2B (dysferlinopathy) Adductor magnus, vastus lateralis, semimembranosus

LGMD2I (fukutinopathy) Adductor magnus, biceps femoris, semimembranosus

LGMD2L(anoctaminopathy)

Adductor magnus, biceps femoris, semimembranosus,semitendinosus, rectus femoris, vastus medialis andvastus lateralis

LGMD2V (acid maltasedeficiency)

Adductor magnus, vastus medialis, vastus intermedius,biceps femoris

Dystrophinopathy (Duchennemuscular dystrophy)

Adductor magnus, vastus medialis and vastus lateralis,rectus femoris

Dystrophinopathy (Beckermuscular dystrophy)

All anterior and posterior compartment muscles,sparing sartorius, gracilis


TABLE 10-6 Muscle Biopsy Features of Limb-Girdle MuscularDystrophies

Type Feature(s)

LGMD1A, LGMD1E, LGMD1F, LGMD1G Rimmed or autophagic vacuoles

LGMD1A, LGMD2R Hyaline inclusions, spheroid bodies

LGMD1B Mislocalization of lamin

LGMD1C, LGMD2A, LGMD2B,sarcoglycanopathies, LGMD2L,dystrophinopathies

Inflammation

LGMD1E Eosinophilic inclusions, cytoplasmic bodies

LGMD1F, LGMD1H Central nuclei

Continued on page 1976



and mutation pathology will give insightinto the disease process and possibletherapy in the future. Given the lack ofdefinitive treatment, as of now, only strat-egies for management and supportivetreatment have been suggested as guide-lines.25,28 However, several clinical trialsutilizing various therapeutic approachesare currently underway. The day ofdefinitive treatments for these inheriteddisorders is not far away.

VIDEO LEGENDSupplemental Digital Content 10-1Gowers sign. A 5-year-old boy withDuchenne muscular dystrophy demon-strating the Gowers sign. Notice how he“climbs on himself” to stand up.

links.lww.com/CONT/A210B 2016 American Academy of Neurology.

REFERENCES1. Ankala A, da Silva C, Gualandi F, et al.

A comprehensive genomic approach forneuromuscular diseases gives a highdiagnostic yield. Ann Neurol 2015;77(2):206Y214. doi:10.1002/ana.24303.

2. Ghaoui R, Cooper ST, Lek M, et al. Use ofwhole-exome sequencing for diagnosisof limb-girdle muscular dystrophy:outcomes and lessons learned. JAMA Neurol2015;72(12):1424Y1432. doi:10.1001/jamaneurol.2015.2274.

3. Iyadurai SJ, Kassar D. Limb-girdle musculardystrophies. In: Katirji B, Kaminski HJ,Ruff RJ, editors. Neuromuscular disorders inclinical practice. 2nd ed. New York, NY:Springer, 2013:1193Y1212.

4. Hauser MA, Conde CB, Kowaljow V, et al.Myotilin mutation found in second pedigreewith LGMD1A. Am J Hum Genet 2002;71(6):1428Y1432. doi:10.1086/344532.

5. Verhaert D, Richards K, Rafael-Fortney JA,Raman SV. Cardiac involvement in patientswith muscular dystrophies: magneticresonance imaging phenotype and genotypicconsiderations. Circ Cardiovasc Imaging2011;4(1):67Y76. doi:10.1161/CIRCIMAGING.110.960740.

6. Harms MB, Sommerville RB, Allred P, et al.Exome sequencing reveals DNAJB6mutations in dominantly-inherited myopathy.Ann Neurol 2012;71(3):407Y16. doi:10.1002/ana.22683.

7. Messina DN, Speer MC, Pericak-Vance MA,McNally EM. Linkage of familial dilatedcardiomyopathy with conduction defect andmuscular dystrophy to chromosome 6q23.Am J Hum Genet 1997;61(4):909Y917.doi:10.1086/514896.

TABLE 10-6 Muscle Biopsy Features of Limb-Girdle MuscularDystrophies Continued from page 1975

Type Feature(s)

LGMD1G Atrophic angular fibers

LGMD2A Lobulated fibers

LGMD2A Eosinophilic infiltrates

LGMD2A Amyloid deposition (Congo red positivity)

LGMD2H Small rounded vacuoles in type 2 fibers

LGMD2I Type 1 predominance

LGMD2Q, LGMD2T, LGMD2W Increased internal nuclei

LGMD2R, LGMD2V Periodic acid-SchiffYpositive or Ynegative,amorphous subsarcolemmal inclusions

Dystrophinopathies Hypercontracted fibers

Dystrophinopathies Ring fibers





http://links.lww.com/CONT/A210

8. Weihl CC, Iyadurai S, Baloh RH, et al. Autophagicvacuolar pathology in desminopathies.Neuromuscul Disord. 2015;25(3):199Y206.doi:10.1016/j.nmd.2014.12.002.

9. Bisceglia L, Zoccolella S, Torraco A, et al. A newlocus on 3p23-p25 for an autosomal-dominantlimb-girdle muscular dystrophy, LGMD1H.Eur J Hum Genet 2010;18(6):636Y641.doi:10.1038/ejhg.2009.235.

10. Gallardo E, Saenz A, Illa I. Limb-girdlemuscular dystrophy 2A. Handb ClinNeurol 2011;101:97Y110. doi:10.1016/B978-0-08-045031-5.00006-2.

11. Pathak P, Sharma MC, Sarkar C, et al. Limbgirdle muscular dystrophy type 2A in India: astudy based on semi-quantitative proteinanalysis, with clinical and histopathologicalcorrelation. Neurol India 2010;58(4):549Y554.doi:10.4103/0028-3886.68675.

12. Merlini L, Kaplan JC, Navarro C, et al.Homogeneous phenotype of the gypsylimb-girdle MD with the gamma-sarcoglycanC283Y mutation. Neurology 2000;54(5):1075Y1079. doi:10.1212/WNL.54.5.1075.

13. Moreira ES, Vainzof M, Marie SK, et al. Theseventh form of autosomal recessive limb-girdlemuscular dystrophy is mapped to 17q11-12. AmJ Hum Genet 1997;61(1):151Y159.

14. Moreira ES, Wiltshire TJ, Faulkner G, et al.Limb-girdle muscular dystrophy type 2Gis caused by mutations in the gene encodingthe sarcomeric protein telethonin. NatGenet 2000;24(2):163Y166. doi:10.1086/513889.

15. Frosk P, Del Bigio MR, Wrogemann K,Greenberg CR. Hutterite brothers both affectedwith two forms of limb girdle musculardystrophy: LGMD2H and LGMD2I. Eur J HumGenet 2005;13(8):978Y982. doi:10.1038/sj.ejhg.5201436.

16. Yilmaz A, Gdynia HJ, Ponfick M, et al. Theproteoglycan-dystrophin complex in geneticcardiomyopathiesVlessons from three siblingswith limb-girdle muscular dystrophy-2I (LGMD-2I).Clin Res Cardiol 2011;100(7):611Y615. doi:10.1007/s00392-011-0291-6.

17. Bushby K, Anderson LV, Pollitt C, et al.Abnormal merosin in adults. A new formof late onset muscular dystrophy not linkedto chromosome 6q2. Brain 1998;121(pt 4):581Y588. doi:10.1093/brain/121.4.581.

18. Palmieri A, Manara R, Bello L, et al. Cognitiveprofile and MRI findings in limb-girdlemuscular dystrophy 2I. J Neurol 2011;258(7):1312Y1320. doi:10.1007/s00415-011-5930-3.

19. Haravuori H, Vihola A, Straub V, et al. Secondarycalpain3 deficiency in 2q-linked muscular

dystrophy: titin is the candidate gene.Neurology 2001;56(7):869Y877. doi:10.1212/WNL.56.7.869.

20. Dinçer P, Balci B, Yuva Y, et al. A novel formof recessive limb girdle muscular dystrophywith mental retardation and abnormalexpression of alpha-dystroglycan. NeuromusculDisord 2003;13(10):771Y778. doi:10.1016/S0960-8966(03)00161-5.

21. Godfrey C, Clement E, Mein R, et al. Refininggenotype phenotype correlations in musculardystrophies with defective glycosylation ofdystroglycan. Brain 2007;130(pt 10):2725Y2735.doi:10.1093/brain/awm212.

22. Godfrey C, Escolar D, Brockington M,et al. Fukutin gene mutations insteroid-responsive limb girdle musculardystrophy. Ann Neurol 2006;60(5):603Y610.doi:10.1002/ana.21006.

23. Preisler N, Lukacs Z, Vinge L, et al. Late-onsetPompe disease is prevalent in unclassifiedlimb-girdle muscular dystrophies. Mol GenetMetab 2013;110(3):287Y289. doi:10.1016/j.ymgme.2013.08.005.

24. Hoogerwaard EM, van der Wouw PA,Wilde AA, et al. Cardiac involvement incarriers of Duchenne and Beckermuscular dystrophy. Neuromuscul Disord1999;9(5):347Y351. doi:10.1016/S0960-8966(99)00018-8.

25. Abbs S, Tuffery-Giraud S, Bakker E, et al.Best practice guidelines on moleculardiagnostics in Duchenne/Becker musculardystrophies. Neuromuscul Disord 2010;20(6):422Y427. doi:10.1016/j.nmd.2010.04.005.

26. Mendell JR, Goemans N, Lowes LP, et al;Eteplirsen Study Group and Telethon FoundationDMD Italian Network. Longitudinal effect ofeteplirsen versus historical control on ambulationin Duchenne muscular dystrophy. Ann Neurol79(2):257Y271. doi:10.1002/ana.24555.

27. Mendell JR, Rodino-Klapac LR, Sahenk Z, et al;Eteplirsen Study Group. Eteplirsen for thetreatment of Duchenne muscular dystrophy.Ann Neurol 74(5):637Y647. doi:10.1002/ana.23982.

28. Narayanaswami P, Weiss M, Selcen D, et al.Evidence-based guideline summary: diagnosis andtreatment of limb-girdle and distal dystrophies:report of the guideline developmentsubcommittee of the American Academy ofNeurology and the practice issues reviewpanel ofthe American Association of Neuromuscular &Electrodiagnostic Medicine. Neurology2014;83(16):1453Y1463. doi:10.1212/WNL.0000000000000892.



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