Review Article - Stony Brook School of Medicine · Recent Findings: Congenital myopathies refer to a heterogeneous group of genetic ... are being updated based on advances in molecular

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An Overview ofCongenital Myopathies

Jean K. Mah, MD, MSc, FRCPC; Jeffrey T. Joseph, MD, PhD

ABSTRACTPurpose of Review: This article uses a case-based approach to highlight the clinicalfeatures as well as recent advances in molecular genetics, muscle imaging, and patho-physiology of the congenital myopathies.Recent Findings: Congenital myopathies refer to a heterogeneous group of geneticneuromuscular disorders characterized by early-onset muscle weakness, hypotonia, anddevelopmental delay. Congenital myopathies are further classified into core myopathies,centronuclear myopathies, nemaline myopathies, and congenital fiber-type dispropor-tion based on the key pathologic features found in muscle biopsies. Genotype andphenotype correlations are hampered by the diverse clinical variability of the genesresponsible for congenital myopathies, ranging from a severe neonatal course with earlydeath to mildly affected adults with late-onset disease. An increasing number of geneshave been identified, which, in turn, are associated with overlapping morphologicchanges in the myofibers. Precise genetic diagnosis has important implications fordisease management, including family counseling; avoidance of anesthetic-relatedmuscle injury for at-risk individuals; monitoring for potential cardiac, respiratory, ororthopedic complications; as well as for participation in clinical trials or potentialgenetic therapies.Summary: Collaboration with neuromuscular experts, geneticists, neuroradiologists, neu-ropathologists, and other specialists is needed to ensure accurate and timely diagnosisbased on clinical and pathologic features. An integrated multidisciplinary model of carebased on expert-guided standards will improve quality of care and optimize outcomes forpatients and families with congenital myopathies.

Continuum (Minneap Minn) 2016;22(6):1932–1953.

INTRODUCTIONCongenital myopathies refer to a geneti-cally and clinically heterogeneous groupof inherited skeletal muscle diseasesassociated with early infantile or child-hood onset of motor weakness, hypoto-nia, and developmental delay, which havea static or slowly progressive course.1

Variants of congenital myopathies withonset or progression of muscle weaknessin adulthood have also been described.Pathologically, congenital myopathieshave characteristic but not pathogno-monic morphologic features such as thepresence of focal myofibrillar disorgani-zation, nuclear centralization, and pro-

tein aggregation.2,3 The three majorgroups of congenital myopathies include:(1) core myopathies, which have focidevoid of oxidative enzymes in myo-fibers4; (2) centronuclear or myo-tubular myopathies, which are definedby the presence of internally locatedmyonuclei5; and (3) nemaline myopa-thies, which are marked by the presenceof electron-dense nemaline bodies orrods within myofibers.6 Variants ofnemaline myopathy include cap myopa-thy, zebra body myopathy, and core-rodmyopathy. Other pathologic features ofcongenital myopathies include hyalinebody or myosin storage myopathy, neck-lace fibers, radial sarcoplasmic strands,

Address correspondence toDr Jean K. Mah, AlbertaChildren’s Hospital, Division ofPediatric Neurology, 2888Shaganappi Trail NW, Calgary,AB T3B 6A8, Canada,[email protected].

Relationship Disclosure:Dr Mah has received personalcompensation as a consultantfor aTyr Pharma and PTCTherapeutics and has receivedresearch/grant support as studyand site investigator for AlbertaChildren’s Hospital, Bristol-MyersSquibb, Children’s Hospital ofEastern Ontario, CooperativeInternational NeuromuscularResearch Group, Eli Lilly andCompany, FSHD GlobalResearch Foundation, FSHSociety, the Hospital for SickChildren, Muscular DystrophyCanada, Novartis AG, PfizerInc, PTC Therapeutics, andSanofi Genzyme. Dr Josephhas received research/grantsupport from the EndowedChair of the University ofCalgary to create the braintissue bank and receivespublishing royalties fromUpToDate, Inc and WoltersKluwer. Dr Joseph also gaveexpert testimony for AlbertaJustice, for which he did notreceive compensation.

Unlabeled Use of

Products/InvestigationalUse Disclosure:Drs Mah and Joseph reportno disclosures.

* 2016 American Academyof Neurology.

1932 www.ContinuumJournal.com December 2016

Review Article

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

mailto:[email protected]

mailto:[email protected]

and congenital fiber-type disproportion.The latter is defined by the presenceof type 1 fiber hypotrophy with meandiameter being uniformly smaller thantype 2 fibers by more than 35% to 40%,in the absence of other structural ab-normalities and accompanied by clinicalfeatures consistent with congenital my-opathies.7 Each of the pathologic fea-tures can be attributed to a number ofgenetic mutations; furthermore, thebiopsy findings can be nonspecific orevolve over time.1

To date, more than 20 genes havebeen associated with the congenitalmyopathies (refer to Table 9-1 as wellas to the useful websites section at theend of this article), and additional genesare being updated based on advancesin molecular diagnostics.8 Emerging evi-dence suggests shared pathophysiolo-gic pathways among the congenitalmyopathies, including defects in musclemembrane remodeling, impairedexcitation-contraction coupling, mito-chondrial dysfunction, abnormal myofi-brillar force generation, and imbalancerelated to protein synthesis or degradation.2

EPIDEMIOLOGYCongenital myopathies are rare disor-ders; the overall prevalence is estimatedat 1 in 25,000 individuals.9 Previous pointprevalence of congenital myopathiesranged from 1.37 per 100,000 of all agegroups in northern England10 to 5 per100,000 of the pediatric population inwestern Sweden.11 The true prevalenceis likely to be higher because ofunderrecognition of mildly affected in-dividuals as well as a substantial propor-tion of cases with nonspecific histologicfindings. Core myopathies includingcentral core and multiminicore myopa-thy are the most common histopatho-logic subtypes of congenital myopathies.12

Mutations of the ryanodine receptor 1(RYR1) gene are most often implicatedas the cause of congenital myopathies,13

with a point prevalence of 1 in 90,000of the pediatric population in the United

States, as reported by Amburgey andcolleagues.14 In another study, the carrierfrequency of RYR1 mutation was esti-mated to be 1 in 2000 individuals in theJapanese population.15

Clinically, the diagnosis of congenitalmyopathies remains challenging be-cause of the variable phenotypes. Sig-nificant heterogeneity exists even withinfamily members affected by the samegenetic mutation. In one large caseseries of congenital myopathies, approx-imately one-third of patients remainedgenetically unresolved.12 The lack ofmolecular confirmation was in partrelated to the nonspecific clinical fea-tures (especially during the neonatalperiod), the genetic heterogeneity ofcongenital myopathies, as well as thelarge size of some involved genes,especially TTN and NEB.14 Recently, atargeted exome sequencing strategy incombination with muscle histologyhas been proposed to identify disease-causing mutations in myopathies ofunknown causes. The sequencing in-cludes coverage of each exon of knowngenes implicated in congenital myopa-thies to enable more precise geneticdiagnosis.9

DIAGNOSTIC APPROACHThe history and neurologic examinationare important first steps in the diagnosticapproach. Careful review of the preg-nancy, birth, growth and development,family history, and direct examination ofthe parents is essential to exclude otherinherited neuromuscular disorders. Inaddition to muscle weakness and hypo-tonia, clues to the diagnosis of congeni-tal myopathies include the early onset ofsymptoms, static or slow rate of diseaseprogression, the presence of myopathicfacies, ophthalmoplegia, or bulbar in-volvement, as well as associated signssuch as muscle atrophy, hyporeflexia,spinal deformity, clubfoot, or otherorthopedic complications. Systemic in-volvement may manifest as cardiomy-opathy, malignant hyperthermia, or

KEY POINTS

h Congenital myopathies

are characterized by

early-onset muscle

weakness, hypotonia, and

developmental delay,

which have a static or

slowly progressive course.

h The three major types of

congenital myopathies

are core myopathies,

centronuclear or

myotubular myopathies,

and nemaline myopathies.

h The pathologic features

in congenital myopathies

can be attributed to a

number of genetic

mutations; furthermore,

the muscle biopsy findings

can be nonspecific or

change over time. A

repeat muscle biopsy with

muscle imaging guidance is

sometimes necessary.

h More than 20 genes have

been associated with

congenital myopathies.

h A targeted exome

sequencing strategy in

combination with the

clinical features and

muscle histology can

help identify

disease-causing mutations

in unspecified cases.

1933Continuum (Minneap Minn) 2016;22(6):1932–1953 www.ContinuumJournal.com


respiratory insufficiency.1 Sensation andintelligence are generally preserved. In-fants with a prenatal onset of muscleweakness due to severe congenital my-opathies often present with a historyof reduced fetal movement and poly-hydramnios. The consequence of fetalakinesia (or lack of movement in utero)includes craniofacial dysmorphism, mul-tiple joint contractures (or arthrogry-posis), pulmonary hypoplasia, hipdysplasia, muscle atrophy, and profoundgeneralized weakness. Severe hypotoniaplus bulbar and respiratory insufficiencymay necessitate invasive mechanical ven-tilation and gastrostomy tube feedingfrom birth.

KEY POINTS

h In addition to muscle

weakness and hypotonia,

clues to the diagnosis of


include the early onset

of symptoms, static or

slow rate of disease

progression, the presence

of myopathic facies,

ophthalmoplegia, or

bulbar involvement, as

well as associated signs

such as muscle atrophy,

hyporeflexia, spinal

deformity, clubfoot,

or other orthopedic

complications.

h Infants with a prenatal

onset of muscle weakness

due to severe congenital

myopathies often present

with a history of reduced

fetal movement and

polyhydramnios.

TABLE 9-1 Genes and Mode ofInheritanceAssociated

With Congenital Myopathies

b Nemaline Myopathy

TPM3 (autosomal dominant,autosomal recessive)

NEB (autosomal recessive)

ACTA1 (autosomal dominant,autosomal recessive)

TPM2 (autosomal dominant)

TNNT1 (autosomal recessive)

KBTBD13 (autosomal recessive)

CFL2 (autosomal recessive)

KLHL40 (autosomal recessive)

KLHL41 (autosomal recessive)

LMOD3 (autosomal recessive)

b Central Core Myopathy

RYR1 (autosomal dominant,autosomal recessive)

SEPN1 (autosomal recessive)

ACTA1 (autosomal dominant)

TTN (autosomal recessive)

b Multiminicore Myopathy



MYH7 (autosomal dominant)


b Core-rod Myopathy



KBTBD13 (autosomal dominant)

CFL2 (autosomal recessive)

b Centronuclear Myopathy

MTM1 (X-linked)

DNM2 (autosomal dominant)

BIN1 (autosomal recessive)

RYR1 (autosomal recessive)

TABLE 9-1 Continued


MTMR14 (autosomal recessive)

CCDC78 (autosomal dominant)

SPEG (autosomal recessive)

b Congenital Fiber-typeDisproportion





RYR1 (autosomal recessive)


b Myosin Storage Myopathy


b Cap Myopathy




b Zebra Body Myopathy


b Distal Myopathy With No Rods



Congenital Myopathies


INVESTIGATIONS ANDDIFFERENTIAL DIAGNOSISThe most helpful tools for the diagnosticworkup of congenital myopathies areserum creatine kinase (CK), nerve con-duction study and EMG, muscle imaging,muscle biopsy, and selective biochemicaland genetic testing. Serum CK is usuallynormal or mildly elevated (less than fivetimes the upper limit of normal) incongenital myopathies; significantlyraised levels (more than 10 times theupper limit of normal) are suggestive ofalternative diagnoses such as musculardystrophies. Nerve conduction studiesoften yield normal motor and sensoryresponses, apart from reduced com-pound motor action potential (CMAP)amplitudes. EMG may reveal a myopathicrecruitment pattern with occasionallynonspecific findings or neurogenicchanges due to severe muscle atrophy.Increased jitter or significant electro-decremental responses can be seen incongenital myopathies associated withsecondary neuromuscular junction de-fects, including cap myopathy due tomutations in the TPM2 gene, centro-nuclear myopathies related to DNM2 orX-linked MTM1 mutations, and congeni-tal fiber-type disproportion caused byTPM3 and RYR1 mutations.16

Muscle imaging using MRI or ultra-sound provides additional noninvasivediagnostic clues as genetic myopathiesare often associated with specific patternsof muscle involvement, particularly earlyin the course of the disease.1 In contrastto CT, MRI provides excellent soft tissuecontrast without the use of ionizingradiation and is frequently the modalityof choice for skeletal muscle imaging,although sedation may be required inyoung children. Based on a relativelysimple algorithm of an anterior versusposterior pattern of muscle involvementof the thighs followed by the sameassessment of the lower legs, Wattjes andcolleagues17 proposed the use of MRI todistinguish among the different subtypesof congenital myopathies (Figure 9-1).The differential diagnosis was further

expanded by Quijano-Roy and col-leagues.18 Similar to MRI, muscle ultra-sound performed by skilled clinicianscan also be used to detect various typesof congenital myopathies.1 This tech-nique is particularly useful as a screeningtool in pediatric patients younger than5 years of age and does not requiresedation. In one study, muscle ultra-sound was abnormal in 23 out of 25patients (92%) with core myopathies,with a specificity of 26.3% and a positivepredictive value of 62.2%.12

The differential diagnoses of hypoto-nia and severe generalized weakness inthe newborn or early infancy periodinclude congenital myopathies, congeni-tal muscular dystrophies, congenital myo-tonic dystrophy, congenital myasthenicsyndromes, myofibrillar myopathies,other myopathies, congenital neuropa-thies, spinal muscular atrophy, as well asgenetic and metabolic conditions suchas Prader-Willi syndrome or glycogen-storage disease.19 The presence ofencephalopathy, microcephaly, or uppermotor neuron signs such as increasedtone, hyperreflexia, sustained clonus, andobligate extensor plantar responses maypoint to an alternative diagnosis suchas hypoxic ischemic encephalopathy orother central nervous system disorders.

CORE MYOPATHIESCore myopathies are characterized path-ologically by the absence of oxidativeenzyme activity in the central area of themyofiber due to mitochondrial deple-tion. Core myopathies are among themost common form of congenital myop-athies12,13 and are further divided intocentral core and multiminicore myopa-thies. Pathologically, central cores arelongitudinally extensive areas within thecenter of the myofiber that are devoid ofmitochondrial enzymatic activity, whereasmultiple smaller areas of reduced activitythat affect shorter segments of the myofi-ber are characteristic of multiminicoremyopathy.4 On electron microscopy, thecores represent areas of abnormalsarcomeric structure, including Z-band

KEY POINTS

h The most helpful tools for

the diagnostic workup of

congenital myopathies are

serum creatine kinase,

nerve conduction study

and EMG,muscle imaging,

muscle biopsy, and

selective biochemical

and genetic testing.

h Muscle imaging using

MRI or ultrasound

provides additional

noninvasive diagnostic

clues as genetic

myopathies are often

associated with specific

patterns of muscle

involvement, particularly

early in the course

of the disease.



FIGURE 9-1 Muscle MRI approach to congenital myopathies (A) and muscle MRI (T1-weighted)of the lower limbs in congenital myopathies (B). Mild fatty infiltration of thegluteus maximus and quadriceps muscles in a teenage boy with RYR1 mutation

(B, left column). Severe involvement in a young girl with an unspecified myopathy showingatrophy and fibroadipose changes of the pelvis, posterior more than anterior thighs, and anteriorcompartment of the lower leg muscles (B, right column).

Panel A reprinted with permission from Wattjes MP, et al, Eur Radiol.17

B 2010, The Authors. link.springer.com/article/10.1007/s00330-010-1799-2.




http://link.springer.com/article/10.1007/s00330-010-1799-2

http://link.springer.com/article/10.1007/s00330-010-1799-2

streaming, complete myofibrillary disor-ganization, and accumulation of Z-bandmaterial. The abnormal regions are de-void of mitochondria, which correlatewith the loss of mitochondrial enzymaticactivity in histochemical (eg, NADH,succinate dehydrogenase [SDH], or cyto-chrome oxidase [COX]) stains.20

Similar to other congenital myopa-thies, the pathologic features may evolveover time with earlier biopsies showingminimal changes or no abnormalities.

Core myopathies are mostly caused byautosomal dominant or recessive muta-tions in the skeletal muscle ryanodinereceptor (RYR1) gene on chromosome19q13.1 or autosomal recessive muta-tions in the selenoprotein N 1 (SEPN1)gene on chromosome 1p36 that encodesan endoplasmic reticulum glycoprotein.4

Mutations in the skeletal muscle "-actin1 (ACTA1) and titin (TTN) can also resultin core myopathies.1 Rarely, mutations ofRYR1 or NEB genes have been associatedwith a combination of rods and coresalso known as core-rod myopathy.21,22

Type 1 fiber predominance, as well as anincrease in internal nuclei, are also com-mon pathologic findings in RYR1-relatedcore myopathies.

Core myopathies can present withvariable phenotypes, ranging from mildto severe. In milder cases, affected in-dividuals usually present with hypotonia,joint laxity, motor developmental delay,and weakness affecting the hip girdle oraxial muscles. Marked clinical variabilitycan occur within the same family withsome individuals remaining asymptomaticaside from occasional muscle stiffness,exertional myalgia, or rhabdomyolysis aspresenting symptoms.4 Orthopedic com-plications, as illustrated in Case 9-1, arecommon and include recurrent shoulderor patella dislocation and congenital hipdysplasia due to marked ligamentouslaxity. Muscle ultrasound or MRI showsa striking pattern of muscle involvementin RYR1-related core myopathies. Unlikeother congenital myopathies that pre-dominantly affect the posterior thighmuscles, selective involvement of the

anterior and medial compartments ofthe thighs, including the quadriceps, isoften seen in RYR1-related myopathies,even in relatively asymptomatic individ-uals. The rectus femoris and gracilismuscles are typically spared.1

Most individuals with central coredisease related to autosomal dominantRYR1 mutations experience mild or mod-erate weakness with a static or slowlyprogressive course. As seen with themother of the patient in Case 9-1, preg-nancy can worsen the underlying muscleweakness.4 Furthermore, patients withcentral core myopathy, especially thosewith confirmed RYR1 mutations, are atrisk for developing malignant hyper-thermia; both conditions are allelic dis-orders related to RYR1 mutations thatlead to impaired excitation-contractioncoupling and abnormal calcium homeo-stasis.2,23 These patients need to becounseled regarding potentially fatal ad-verse reaction to volatile anesthetics ormuscle relaxants, and wearing a medicalalert bracelet is generally advisable in caseof any unexpected emergency.

Prognosis for severe neonatal cen-tral core myopathy remains guarded(Case 9-2). The presence of marked jointlaxity, generalized muscle weakness, andatrophy may preclude the possibility ofindependent ambulation and necessitateongoing mechanical ventilation. Naturalhistory studies suggested that early respi-ratory and nutritional support includ-ing gastrostomy feeding had a significantimpact on overall survival and the clinicaloutcomes of neonatal central core myop-athy.12,13 Depending on their dietaryintake, patients should be encouraged totake vitamin D and calcium supplementsto maximize bone health. Intermittentassessments of bone mineral density areindicated, especially for those with a his-tory of fragility fractures or for those whohave other risk factors for osteoporosis.

Multiminicore myopathy may presentduring infancy (Case 9-3) with feedingdifficulties, axial hypotonia, progressivescoliosis with or without spinal rigidity,

KEY POINTS

h Individuals with core

myopathies related to

RYR1 mutations are at

risk for developing

malignant hyperthermia

and should be counseled

regarding potential

anesthesia-related

muscle injury accordingly.

h Natural history studies

suggest that early

respiratory and nutritional

support can have a

positive impact on the

overall survival and clinical

outcomes of children with

severe neonatal central

core myopathy.



and early respiratory impairment that isoften out of proportion to the degree ofskeletal muscle weakness.4 Classicmultiminicore myopathy is most oftencaused by autosomal recessive SEPN1mutations. To date, no cases of malignanthyperthermia due to SEPN1-related my-opathies have been reported. Autosomalrecessive RYR1 mutations may also resultin a similar clinical phenotype, exceptthat ophthalmoplegia is more prominentin RYR1-related multiminicore myopa-thy.1 Malignant hyperthermia is a poten-tial risk for RYR1-related multiminicoremyopathies. Genetic counseling includinganesthetic precaution should be dis-cussed. Rarely, mutations in the myosinheavy chain 7 (MYH7) or titin (TTN) geneshave been found in multiminicore myop-

athies, especially when associated withcardiomyopathy. Minicores can also beseen in other conditions such as mus-cular dystrophies as well as collagenVIYrelated myopathies.1

Treatment for core myopathies re-mains symptomatic. The frequent associ-ation with orthopedic complications suchas congenital hip dislocation or scoliosisrequires ongoing monitoring in a multi-disciplinary setting with input from pedi-atric orthopedic and rehabilitationspecialists. Judicious aerobic exercisesuch as cycling or swimming may helppromote aerobic fitness. As respiratoryimpairment is another common complica-tion, particularly in multiminicore myopa-thies, regular pulmonary function testingand polysomnography studies are necessary

KEY POINT

h Treatment for


remains symptomatic.

Management of

potential complications

will require ongoing

monitoring in a

multidisciplinary setting

with input from pediatric

orthopedic, pulmonary,

cardiology, and

rehabilitation specialists.

Case 9-1A 12-year-old girl presented with malignant hyperthermia intraoperativelyduring elective knee surgery. Her medical history was remarkable for recurrentshoulder dislocation. She sustained a fracture to the right lateral femoralcondyle during a basketball game and was admitted for surgical repair, duringwhich isoflurane was used as part of general anesthesia. Shortly after, shedeveloped hyperthermia, tachycardia, increased carbon dioxide retention, andmyoglobinuria. She responded to IV dantrolene, supplementary oxygen, andcessation of inhalational anesthetic.

Physical examination was normal apart from joint hypermobility, scapularwinging, and mild symmetric proximal weakness (grade 4 out of 5). She had noknown family history of malignant hyperthermia. However, her older brotherhad recurrent patellae subluxation with wasting of the quadriceps and pescavus feet. The patient’s mother had previously been diagnosed withcongenital hip dysplasia and had walked with a cane since early adulthoodbecause of slowly progressive hip girdle weakness; her muscle weakness hadbeen aggravated by each subsequent pregnancy.

Investigations in the patient showed raised serum creatine kinase (CK) of2232 IU/L approximately 12 hours postsurgery, which returned to normal after2 days. EMG and muscle biopsy were deferred. Molecular genetic testingconfirmed two heterozygous mutations of the RYR1 gene. The first was amissense variant of unknown significance in exon 41. In addition, a secondgene change was found in exon 103. This change had been previously reportedas an autosomal dominant mutation in other patients with central coremyopathy. The same heterozygous mutations were found in the patient’solder brother, andhermother carried the dominantmutation involving exon103.

Comment. This case illustrates the milder spectrum of central core myopathyas well as its important association with malignant hyperthermia; bothconditions are allelic disorders related to RYR1 mutations that lead to impairedexcitation-contraction coupling and abnormal calcium homeostasis.2,23




Case 9-2A 4-year-old boy presented for a follow-up visit in the pediatric neuromuscular clinic with progressive scoliosis.He had a history of arthrogryposis, bilateral hip dislocation, undescended testes, severe generalizedweakness, hypotonia, developmental delay, scoliosis, and respiratory failure since birth. Hismother’s pregnancyhad been remarkable for reduced fetal movements and polyhydramnios, and the patient’s birth weight wasonly 1.9 kg (4.2 lb) at term. The patient had been intubated at birth because of low Apgar scoresand required ongoing mechanical ventilation and gastrostomy tube feeding. The boy had learned to sitwith support after age 1, had scooted on his bottom at 2.5 years of age, and had begun to speak in fullsentences through his tracheostomy after his third birthday. Family history was unremarkable.

Physical examination at 1 year of age had revealed that the boy was small for his age and had generalizedamyotrophy and alert interactive facies. He had no ptosis, and extraocular movements were full. He had verylax fingers and hands, prominent head lag, and severe scoliosis. His movements were limited because ofgeneralized weakness, and he could only move his distal arms and legs with gravity assistance.

Initial investigations shortly after birth had been normal, including serum creatine kinase (CK), brain MRI,karyotype, and metabolic screening and genetic testing for spinal muscular atrophy, myotonic dystrophy type 1,and Prader-Willi syndrome. Nerve conduction study and EMG suggested a myopathic process. A neonatal muscle

FIGURE 9-2 Neonatal muscle biopsy of the patient with central core myopathy in Case 9-2. A, In thishematoxylin and eosin (H&E) section, much of the muscle consists of tiny fibers intermixedwith an occasional larger myofiber. Adipose replacement has formed (black arrow). Because of

the extensive muscle atrophy, the intramuscular nerve twigs appear quite prominent (white arrows). B, Athigher magnification in the Gomori trichrome stain section, a few near-normal myofibers are intermixed withmany small and tiny fibers. Endomysial connective tissue is greatly increased (green staining material) (redarrow). C, In central cores, many of the large fibers contain central areas devoid of mitochondria (succinatedehydrogenase histochemistry). D, The electron micrograph shows one of the large fibers having a centralcore. In this fiber, the center of the core contains only some glycogen, while its rim is composed of disorganizedor aggregated sarcomeric material (black arrows). Around the periphery of the large myofiber are manysmall, poorly formed myofibers (red arrows) that have a few scattered sarcomeric structures or aggregates.

Continued on page 1940



to monitor for decline in respiratory func-tion that might necessitate noninvasivepositive-pressure ventilation.12 Severeearly-onset cases often require invasivemechanical ventilation.4 In addition, in-dividuals with core myopathies unrelatedto RYR1 or SEPN1 mutations will requireperiodic cardiac assessments to monitorfor potential cardiac complications, es-pecially in those with associated respira-tory impairment. Results from a recentpilot study and case report suggested thatalbuterol, a "-2 agonist, may be helpfulfor the treatment of core myopathies24,25;further recommendations must awaitconfirmation from a larger prospectivestudy. Similarly, N-acetylcysteine will beevaluated as part of a clinical trial regardingits role as antioxidant therapy for RYR1-related congenital myopathies.26

CENTRONUCLEAR MYOPATHIESCentronuclear myopathies refer to aheterogeneous group of genetic myopa-thies characterized pathologically by thepresence of abundant, centrally locatednuclei.27 Early case reports were pro-vided by Spiro and colleagues in 1966and Sher and colleagues in 1967.28

To date, 8 genes have been associatedwith centronuclear myopathies, in-cluding X-linked recessive mutations inMTM1 encoding myotubularin 1; auto-somal dominant mutations in DNM2encoding dynamin 2, the BIN1 geneencoding amphiphysin 2, and CCDC78gene encoding coiled-coil domain-containing protein 78; autosomal reces-

sive mutations in BIN1, MTMR14encoding hJumpy, RYR1 encoding theskeletal muscle ryanodine receptor, TTNencoding titin, and SPEG encoding striatedmuscle preferentially expressed proteinkinase.1,29 The majority of mutationsrelated to centronuclear myopathies todate (including MTM1, DNM2, BIN1, andMTMR14) involve proteins being impli-cated in various aspects of membranetrafficking and remodeling relevant toendocytosis, vesicle transport, autophagy,and other essential cellular processes.2,27

DNM2 is the most common cause ofcentronuclear myopathy and usuallypresents as a relatively mild form ofautosomal dominant late-childhood orearly-adult onset distal myopathy, and denovo mutations with a severe early-onsetphenotype have also been described.28

X-linked myotubular myopathy iscaused by mutations of the MTM1 gene,which encodes a 3¶-phosphoinositidesphosphatase called myotubularin 1.Affected neonates have the most severephenotype of all centronuclear myopa-thies, includingmarked extraocular, facial,respiratory, and axial muscle weakness(Case 9-4). Most boys with X-linked myo-tubular myopathy die despite supportivetreatment. Recently, pathologic recessivemutations of the gene encoding striatedmuscle preferentially expressed proteinkinase (SPEG), an MTM1-interacting pro-tein localized to the sarcoplasmic reticu-lum, were found to result in severecentronuclear myopathy with dilatedcardiomyopathy.29

biopsy (Figure 9-2) showed features of severe central core myopathy, including a few larger fibers that hadcentral cores, many tiny myofibers, and extensive fibroadipose replacement. Gene testing at 3 months of agehad confirmed a de novo dominant RYR1 mutation involving exon 91.

He required bilateral orchidopexy and vertical expandable prosthetic titanium rib implantation fortreatment of his scoliosis. He received intermittent IV bisphosphonate infusions due to a fragility fractureof the left humerus and generalized osteopenia seen on bone density x-rays.

Comment. This case illustrates the severe spectrum of central core myopathy with reduced fetal movements,pulmonary hypoplasia, arthrogryposis, congenital hip dislocation, and scoliosis due to profound muscleweakness. Extraocular movements are often spared in severe RYR1-related myopathies, which may serve todistinguish it from other severe forms of congenital myopathies with ophthalmoparesis, such as congenitalnemaline or centronuclear myopathy secondary to ACTA1, NEB, DNM2, MTM1, or KLHL40 mutations.4

Continued from page 1939




Case 9-3A 9-year-old boy presentedwith a history of hypotonia, developmental delay, exercise intolerance, shortness ofbreath, and progressive scoliosis that he had experienced since early childhood. He had been born after anuncomplicated pregnancy and birth. He had required aortopexy surgery during infancy for tracheomalacia,recurrent chest infections, and failure to thrive. His motor developmental milestones had been delayed. He hadwalked after 2 years of age and had continued to struggle with climbing stairs. Family history wasunremarkable; he was an only child.

Physical examination revealed a tall boy with height, weight, and head circumference in approximately the95th percentile. General examination was remarkable for a pear-shaped body habitus, high-arched palate,retrognathia, pectus excavatum, reduced muscle bulk in his anterior chest and upper arms, increased lumbarlordosis, rigid spine, severe scoliosis, and bilateral pes planus feet. He hadmild ptosis and bifacial weakness. Thepatient’s extraocular movements were spared. Motor examination revealed mild (grade 4 out of 5) proximalmore than distalmuscleweakness, with a positiveGowers sign. Reflexeswere 2+ throughoutwith flexor plantarresponses, and sensation and coordinationwere intact. Prior investigations at 7 years of age had included serumcreatine kinase (CK), karyotype, comparative genomic hybridization microarray, metabolic screen, ECG, Holtermonitoring, echocardiogram, nerve conduction study and EMG, and MRI brain and spine, all of which had beenunremarkable. The initial quadriceps muscle biopsy performed at age 7 had shown mild type 2 myofiberatrophy, and a repeat biopsy of the paraspinal muscle (Figure 9-3) at age 9 showed type 2 myofiber atrophy butalso showed frequent myofibers that had one to several sarcoplasmic cores devoid of mitochondrial enzymes,

FIGURE 9-3 Muscle biopsy of the patient with multiminicore myopathy in Case 9-3. A, Hematoxylinand eosin (H&E) stain demonstrates some myofiber size variation. A few myofiberscontain eosinophilic aggregates that have a light basophilic stippling around their

edges (arrows). B, Gomori trichrome stain shows no significant endomysial connective tissue but doesshow various aggregates inside several of the fibers (arrows). C, On NADH histochemistry, manyfibers contain one to several minicores that display reduced enzyme reactivity. D, Electron micrographdemonstrates a larger core on the right that has extensive sarcomeric disruption and Z-band materialaggregation, as well as several much smaller areas of myofibrillary disarray (arrow).




Individuals with late-onset MTM1mutations are clinically distinct fromthe severe neonatal-onset X-linkedmyotubular myopathy (Case 9-5). Gen-erally, symptoms are milder and wellcompensated for during childhood withprogression of motor dysfunction, exer-cise intolerance, and fatigable weaknessdeveloping after the first 2 decades oflife.5 As seen in Case 9-5, hemiatrophyand asymmetric weakness have beendescribed in women with late-onsetMTM1-related myopathy.32

Autosomal recessive centronuclearmyopathies caused by BIN1 mutationsare generally very rare.33 Affected indi-viduals usually present as an intermediateform of disease between the severeneonatal-onset X-linked MTM1 and theautosomal dominant late-childhoodYonsetDNM2 forms of centronuclear myopathy.34

Marked fiber size disproportion betweentype 1 and type 2 fibers are commonlyseen in DNM2-related centronuclear my-opathies, whereas fiber diameters aremore uniform in BIN1-related mutations.Similarly, RYR1-related centronuclear my-opathies have variable degrees of muscleweakness, are associated with prominentmyofibrillar disarray in the muscle biop-sies, and are usually inherited as autoso-mal recessive disorders.1 Muscle biopsiesfrom patients with centronuclear myop-athies and occasionally other severeforms of congenital myopathies can havea variable degree of endomysial fibrosisand adipose tissue replacement.35 Thesefindings sometimes have led to a diag-nosis of muscular dystrophy, despite thelack of frank muscle necrosis. The pres-ence of ptosis and ophthalmoplegia onclinical examination should help to dis-

tinguish centronuclear myopathy fromcongenital muscular dystrophy.1

Individuals with centronuclear myop-athies can present with myasthenicfeatures with positive response to anti-cholinesterase therapy or evidence of im-paired neuromuscular transmission basedon electrophysiologic (repetitive stimula-tion or single-fiber) studies (Case 9-5).Indeed, defects in neuromuscular trans-mission have recently been recognizedas one of the pathogenic mechanismsamong subtypes of congenital myopathies,particularly in cases related toMTM1, BIN1,DNM2, TPM2, TPM3, and RYR1 muta-tions.2,16 The use of pyridostigmine, anacetylcholinesterase inhibitor, can some-times be associated with significant clin-ical improvement.

NEMALINE MYOPATHIESShy and colleagues36 first described aninfant girl with early-onset hypotoniaand muscle weakness, and the termnemaline myopathy was coined be-cause of the presence of threadlike (theprefix nema refers to thread) or rodlikestructures found in her muscle biopsy.The clinical spectrum is wide, rangingfrom a severe congenital form to mildadult-onset nemaline myopathy. Promi-nent axial and limb-girdle weakness oc-curs initially, followed by progression toinvolve the distal muscles.37 A distal or apredominantly lower-extremity patternof weakness has also been described.6

Currently, 10 genes have been asso-ciated with nemaline myopathy, includ-ing dominant mutations of skeletalmuscle "-actin 1 (ACTA1) or recessivemutations of nebulin (NEB) genes.1

Other mutations include muscle-specific

KEY POINT

h Defects in

neuromuscular

transmission

have recently been

recognized as one of the

pathogenic mechanisms

among subtypes of

congenital myopathies.

Anticholinesterase

therapy may be beneficial

in some cases.

indicative of multiminicore myopathy. Genetic testing for RYR1 mutation was negative at age 9. He requirednoninvasive mechanical pressure support ventilation for progressive respiratory muscle weakness during adolescence.

Comment. This case illustrates the challenge of carrying out an initial muscle biopsy in a patient withcongenital myopathy as the muscle biopsy will occasionally only show nonspecific changes. The typicalhistopathologic findings of core myopathies in some cases may evolve over time and can be absent whenthe biopsy is performed at an early age. A repeat muscle biopsy with muscle imaging (MRI or ultrasound)guidance is sometimes necessary. Genetic testing is required for confirmation of diagnosis and counseling.





Case 9-4A term 37-week gestational age infant boy was born to a 28-year-old woman by cesarean delivery because offetal tachycardia. The infant’s birth weight was 2.76 kg (6 lb). Because of significant hypotonia and poorrespiratory effort, the infant was intubated at birth and then switched to continuous positive airway pressureby nasal prong the next day. He was fed by nasogastric tube from birth because of poor feeding. Family historywas unremarkable; his parents had no evidence of muscle wasting, myotonia, or fatigable weakness.

Physical examination revealed a severely hypotonic infant with tachypnea, moderate indrawing, and pectusexcavatum. His head circumference was normal. He had a myopathic face with bilateral ptosis, limitedextraocular movements, inverted V-shaped upper lip, high-arched palate, and reduced facial movements. Nocataracts or tongue fasciculations were noted. His cry and gagwereweak. Motor examination revealed paucityof spontaneous movements due to generalized weakness. Deep tendon reflexes were 1+ in both knees andabsent elsewhere. Primitive reflexes including rooting, suck, Moro, and grasp were absent.

Laboratory investigations including complete blood count, serum electrolytes, lactate, thyroid functions,blood and urine cultures, and a screen for toxoplasmosis, other infections, rubella, cytomegalovirus infection,and herpes simplex (TORCH) were negative. Serum creatine kinase (CK) was 198 IU/L. Karyotypewas 46 XX, andmolecular genetic testing for spinal muscular atrophy, myotonic dystrophy type 1, and facioscapulohumeralmuscular dystrophy were negative. Metabolic screens, including plasma amino acids, urine organic acids, liverfunction tests, acylcarnitine profile, and veryYlong-chain fatty acids, were negative. In addition, his brain MRI,EEG, and echocardiogram were normal. Nerve conduction studies and EMG revealed small-amplitudepolyphasic motor units with occasional fibrillation potentials. Muscle biopsy of the right vastus lateralis at2weeks of age showednormalmuscle fascicular architecturewithout fiber necrosis, regeneration, or proliferationof connective tissue. ATPase showed mild (60%) predominance of type 2 fibers with normal glycogen, lipid,and oxidative enzymatic activities. Trichrome stain revealed no ragged red fibers. A repeat muscle biopsy at3 months of age showed type 1 fiber predominance with preserved fascicular architecture. One-half of themyofibers had a single internal nucleus with surrounding pale-staining core (Figure 9-4). The infant died at6 months of age because of aspiration pneumonia. An autopsy was declined.

FIGURE 9-4 Muscle biopsy of patient with neonatal centronuclear myopathy in Case 9-4. Both the hematoxylinand eosin (H&E) (A, 40X) and Gomori trichrome stains (B, 40X) at high magnification fromthe biopsy at 3 months of age contained many internalized nuclei (several identified with black or

white arrows). Neither showed myofiber necrosis or degeneration. Internalized nuclei were significantly lessfrequent in the biopsy at 2 weeks of age (toluidine blue plastic section, 100X) (C, black arrows).




cofilin 2 (CFL2), troponin T1 slowskeletal type (TNNT1), "-tropomyosin2 (TPM2), "-tropomyosin 3 (TPM3),kelch-like family member 40 (KLHL40),kelch-like family member 41 (KLHL41),and muscle-specific ubiquitin ligase(KBTBD13) genes. KBTBD13 can causeboth core-rod myopathy and nemalinemyopathy.1 Recently, recessive muta-tions of leiomodin 3 (LMOD3) werefound to be associated with a severeand often fatal form of congenitalnemaline myopathy.38 Mutations associ-ated with nemaline myopathies are dis-tributed worldwide, apart from troponinT1 slow skeletal type (TNNT1), which isresponsible for a distinct form ofnemaline myopathy among the OldOrder Amish families.39 Genetic confir-mation of nemaline myopathies is oftencomplicated by the large number ofgenes involved as well as the large sizeof the nebulin (NEB) gene.

Pathologically, nemaline rods appearas dark red staining inclusions with theGomori trichrome stain. The majorconstituents of rods include !-actinin,tropomyosin, and Z-diskYrelated pro-teins such as actin, myotilin, andnebulin, which are all components ofthe sarcomere. The presence ofintranuclear nemaline bodies, as op-posed to the more common sarcoplas-mic location, is exclusive to ACTA1mutations and can be associated with amore severe disease phenotype.6

A mutation involving the NEB gene isgenerally the most common cause ofnemaline myopathies. The disease isclinically variable. Severe cases presentingin the neonatal period (classic form)usually have significant facial, respiratory,

axial, and generalized muscle weakness.40

Most patients with NEB mutations havepredominant proximal weakness; how-ever, distal-predominant involvement alsohas been observed, particularly in late-onset cases.41

In addition to nemaline rods, muta-tions in the skeletal muscle "-actin gene(ACTA1) are associated with other path-ologic features, including cap myopathy,intranuclear rod myopathy, and congen-ital fiber-type disproportion. The clinicalphenotypes are also variable, rangingfrom severe neonatal onset (with hypo-tonia, generalized weakness, and earlydeath), late childhood (Case 9-6), orearly-adult presentation with slowly pro-gressive proximal weakness.40 Rarely,childhood-onset muscle stiffness andhypertonia has been described as theresult of an ACTA1 mutation.42 Similarly,mutations in the TPM2 gene can causecap myopathy and congenital arthro-gryposis in addition to nemaline myopa-thy.1 The clinical phenotypes of TPM2and TPM3 mutations are quite variable,including early-onset hypotonia, motordevelopmental delay, as well as slowly pro-gressive proximal- or distal-predominantmuscle weakness.43

Treatment for nemaline myopathyremains largely symptomatic, includingrange of motion exercise, use of orthot-ics for footdrop, positive-pressure me-chanical ventilation, and nasogastrictube feeding for nutritional support.Regular low-impact aerobic exercisemay help to maintain cardiovascularfitness. Tyrosine has been reported asa potentially beneficial supplement fornemaline myopathy44; however, themechanism of action of tyrosine in

Comment: Severe neonatal centronuclear myopathy in a male infant is often caused by mutations of theMTM1 gene. MTM1 gene testing was not done in this case as it had not been available at that time. Rarely,skewed X inactivation of MTM1 as well as de novo dominant mutations of DNM2 can result in a severeneonatal phenotype in females. As congenital myotonic dystrophy type 1 is also associated with prominentcentral nuclei in muscle biopsies,30 clinical examination of the mother and DMPK genetic testing should beconsidered to exclude this diagnosis.





Case 9-5A 34-year-old woman presentedwith progressive limb-girdle weakness as well as left arm and face hemiatrophy.At birth, she had been floppy with a weak suck reflex and had required brief nasogastric tube feeding. Shehadwalked at 14months but was unable to jump or climb stairs without assistance. Over time, she had repeatedfalls and eventually became partially wheelchair dependent in her early twenties. Review of systems was notablefor increased tendency to choke with liquids, myalgia, shortness of breath on exertion, and fluctuating ptosis.Physical examination revealed mild bilateral ptosis with left more than right facial weakness, high-arched palate,micrognathia, scoliosis, and scapularwinging.Motor examination revealedmoderate asymmetricmuscleweakness.She had atrophy of her thenar and hypothenarmuscles,whichwasworse on the left side. She had prominent calveswith mild contractures in her heel cords, elbows, shoulders, and long finger flexors bilaterally. Gait examinationshowed bilateral footdrop.

The patient’s serum creatine kinase (CK) was 105 IU/L. Genetic testing for myotonic dystrophy types 1 and2 (DMPK and CNBP) were both negative. ECG and echocardiogram were normal. Pulmonary function testingshowed a reduced forced vital capacity of 67% predicted. Her first muscle biopsy at 8 years of age had shownmany central nuclei, frequent rounded fibers, increased connective tissue, type 1 fiber predominance, and some

FIGURE 9-5 Muscle biopsy of the patient with myotubular myopathy in Case 9-5. In this adultversion of myotubular myopathy, the hematoxylin and eosin stain (H&E) (A)shows moderate to marked variation in myofiber size and increased internalized

nuclei. Only a few fibers have central nuclei (A, white arrow) or central nuclear clumps (A,black arrow). The Gomori trichrome stain (B) has similar features, including some fibers withabundant internalized nuclei (B, white arrow) and also emphasizes the increased endomysialconnective tissue (B, black arrow). Different necklace fibers on H&E stain (C, D) and NADHhistochemistry (E, F) are illustrated. H&E stains also demonstrate the increased connectivetissue (D, black arrow). Necklace fibers have internalized nuclei that are often equidistantfrom the sarcolemma and often have a gossamer string that connects them together (CYF,white arrows). The gossamer string is basophilic in H&E stains (D, white arrow) and hasincreased NADH activity in NADH histochemistry (E, F, white arrows). Some fibers have beencut in a plane that misses the nuclei and shows only the string (F, white arrow).




nemaline myopathies remains unclear.Other experimental therapies fornemaline myopathies involving musclestem cells, antisense oligonucleotides,and gene replacement will depend onthe underlying genetic mutations andongoing research.45

CONGENITAL FIBER-TYPEDISPROPORTIONBrooke and Engel46 first coined the termcongenital fiber-type disproportion in1973 to describe the presence of discor-dant fiber size, with type 1 fibers beingsmaller by 12% or more in muscle bi-opsies from 14 patients. However, a milddegree of fiber size disproportion is non-specific and can be observed in a varietyof conditions, including diseases of thecentral nervous system, metabolic disor-ders, spinal muscular atrophy, and mus-cular dystrophies. For example, mutationsin SEPN1, lamin A/C (LMNA), collagentype VI alpha 1 (COL6A1), and DMPK, aswell as other congenital myopathies, canbe associated with a predominance ofsmall type 1 fibers. The diagnosis of con-genital fiber-type disproportion is re-served for cases of congenital myopathywith type 1 fibers being consistentlysmaller in diameter than type 2 fibers bymore than 35% to 40% in the absence ofother histopathologic abnormalities.7

The presence of rods, cores, abundantcentral nuclei, or other structural fea-tures of congenital myopathies indicatesan alternative diagnosis other than con-genital fiber-type disproportion.

Currently, at least five different geneshave been associated with congenital

fiber-type disproportion. Most affectedindividuals have a static or slowly pro-gressive course of generalized muscleweakness (Case 9-7), consistent withthe clinical features of congenital myop-athies as well as variable degrees of hy-potonia, respiratory insufficiency, facialdiplegia, dysphagia, and ophthalmo-paresis. Ophthalmoparesis can also beseen in RYR1-related myopathy withfiber-type disproportion. The most com-mon genetic causes in descending orderof frequency are slow !-tropomyosin3 (TPM3), ryanodine receptor 1 (RYR1),skeletal muscle !-actin 1 (ACTA1), myosinheavy chain 7 (MYH7), "-tropomyosin 2(TPM2), and selenoprotein N 1 (SEPN1)mutations, which are all inherited aseither autosomal dominant or recessivedisorders.1 An unspecified X-linked formof congenital fiber-type disproportion hasbeen described, but the genetic cause re-mains unclear.47 In addition to congeni-tal fiber-type disproportion, mutations inthe MYH7 gene can present with myosinstorage or hyaline body myopathy,multiminicore myopathy, early childhoodYonset Laing distal myopathy, as well ashereditary cardiomyopathies.48,49

Detection of specific genetic muta-tions resulting in congenital fiber-typedisproportion can help with ongoingdisease monitoring and genetic counsel-ing. For example, pulmonary functiontesting is particularly important in pa-tients with TPM3 mutations. Muscleweakness generally follows a relativelystable or slowly progressive course duringchildhood and adolescence. In general,scoliosis and joint contractures (apartfrom mild Achilles tendon contractures)

ring fibers. A repeat biopsy at 24 years of age (Figure 9-5) had shown many internalized nuclei and frequentnecklace fibers without necrosis. Genetic testing confirmed a heterozygous mutation of part of the MTM1gene. Treatment with pyridostigmine led to symptomatic improvement in her motor function and endurance.

Comment. The presence of necklace fibers in the second muscle biopsy plus the abundance of centralmyonuclei in the first muscle biopsy were helpful diagnostic clues in this case. Necklace fibers refer to asubsarcolemmal zone of nuclei linked by obliquely oriented small myofibrils associated with a higherdensity of mitochondria and sarcoplasmic reticulum, which have been described in sporadic late-onset casesof MTM1- or DNM2-related centronuclear myopathies.31


KEY POINT

h Congenital myopathy

with fiber-type

disproportion is defined

by significant type 1

fiber hypotrophy in the

absence of other

structural abnormalities.




Case 9-6An 11-year-old girl presented with gross motor delay, proximal muscle weakness, and recurrent myalgiainvolving her calves, hamstrings, and biceps. Shewas the product of a normal term pregnancy. As an infant, thegirl had rolled at 6 months, sat up at 9 months, pulled up to stand at 15 months, and walked independentlyat 20 months. Her parents described her as a ‘‘clumsy’’ child as she tripped easily. She also struggled withclimbing steps and could do so only with support. Physical examination revealed a slender young girl with ahigh-arched palate, mild bilateral ptosis, and small hands and feet. Her weight was in the 10th percentile,and her height and head circumference were in the 50th percentile for her age. Cranial nerve examinationshowed mild bifacial weakness. She had reduced muscle bulk as well as mild symmetric proximal more thandistal muscle weakness. Truncally, she rolled to one side to get up and used a one-handed Gowers sign to getup from the floor. She had no scoliosis, scapular winging, or spinal rigidity. Apart from mild heel cordtightness, she had no fixed contractures. Deep tendon reflexes were 2+ and symmetric throughout with flexorplantar responses, and sensation and coordination were intact. Investigations including serum creatinekinase (CK), pulmonary function tests, ECG, and echocardiogramwere normal.Muscle biopsy (Figure 9-6) showedsingle and clustered rodlike structures in the Gomori trichrome stain that had ultrastructural parallel andperpendicular striations typical of nemaline rods.

Comment. This case illustrates a patient with a mild form of nemaline myopathy. Muscle imaging (MRIor ultrasound) may also help with the differential diagnosis. In mild cases, relative sparing of the thigh withearly involvement of the tibialis anterior can be seen.18 More severe cases are associated withdiffuse changes in the lower limbs with relative sparing of the gastrocnemius muscles.1

FIGURE 9-6 Muscle biopsy of patient with nemaline myopathy in Case 9-6. A, The muscle inthe hematoxylin and eosin (H&E) stain has mild variation in myofiber size. B,In contrast, the Gomori trichrome stain reveals numerous clumps of darkly staining

nemaline rods both within the sarcoplasm and clumped into aggregates at some myofibercorners or edges. C, D, Ultrastructurally, these nemaline aggregates consists of bands of darkmaterial that are interconnected by thin filaments. D, At higher magnification, the darkmaterial is oriented parallel to the thin filaments but also has a distinct periodicity that isperpendicular to the filaments. This pattern is characteristic of nemaline.



are relatively uncommon, and cardiacabnormalities are rare. Cardiac surveillanceevery 2 to 3 years is indicated for patientswith MYH7- or TPM2-related myopathiesor unconfirmed molecular diagnosis.Physical therapy and regular aerobic exer-cise such as cycling and swimming shouldbe encouraged as much as possible.Nocturnal noninvasive ventilation,gastrostomy tube feeding, and scoliosissurgery may be required for those with amore severe or progressive disease.

GUIDELINESAs congenital myopathies are relativelyuncommon, many clinicians may notbe familiar with the management ofaffected individuals. Fortunately, a panelof experts convened in 2010 and createda guideline in order to optimize care andimprove outcomes for congenital my-opathies.3 A patient and family versionof the guideline is available through theCure CMD (congenital muscular dys-trophy) website (see the useful web-site section at the end of this article). Theguideline focuses on five major manage-ment areas: diagnostics/genetics, neurol-

ogy, pulmonary, orthopedics/rehabilitation,and gastroenterology/nutrition. Neuro-logic care includes the provision of keyinformation related to the diagnosis,prognosis, treatment plan, geneticcounseling, as well as family support andcommunity resources. The risk of malig-nant hyperthermia secondary to RYR1-related myopathies as well as the earlyand disproportionate degree of re-spiratory involvement in SEPN1-relatedmyopathies should be discussed with thepatient and family. Follow-up care andanticipatory guidance are best providedusing an integrated multidisciplinary ap-proach in collaboration with orthopedicsurgeons, physiatrists, pulmonologists,cardiologists, gastroenterologists, psychol-ogists, pediatricians/internists, as well asphysical therapists, occupational thera-pists, respiratory therapists, speech-language pathologists, nurses, and socialworkers. Each visit should include a care-ful review of systems, including growthand development for pediatric patients,as well as a thorough physical examinationwith focus on potential complications suchas respiratory insufficiency, feeding

Case 9-7A 2-month-old boy presented with hypotonia and generalized weakness since birth. He had been born after anormal term pregnancy, apart from reduced fetal movements in utero. He required resuscitation for transienttachypnea, had increaseddifficulty breathing, andhad feedingdifficulty that necessitatednasogastric tube feeding.Family history was negative, and both parents were healthy with no evidence of neuromuscular disease.

Physical examination revealed normal growth parameters for his age. He was mildly tachypneic at rest withalert facies and a paucity of spontaneous movements of all four limbs. Cranial nerves II through XII were intactapart fromweak cry and reduced facial expression. He had no tongue fasciculations. Truncally, he was significantlyhypotonic with head lag on pull to sit, and he slipped through the examiner’s hands when held by the axilla onvertical suspension.Motor examination revealedhyperextensible joints, scapularwinging, and reducedbulk. Hehadnear antigravity strength (grade 2) in his elbows, with no antigravity movements in his proximal upper and lowerlimbs. Primitive reflexes including Moro, Galant, and atonic neck response could not be elicited. Deep tendonreflexes were absent in all four extremities. The rest of his general examination was normal.

Serum creatine kinase (CK) was 80 IU/L, and brain MRI was normal. Metabolic screen and gene mutationanalysis for spinal muscular atrophy, myotonic dystrophy type 1, and Prader-Willi syndrome were negative. Nerveconduction study and EMG suggested a myopathic process. Muscle biopsy of the right vastus lateralis revealed apredominance of moderately small type 1 myofibers intermixed with occasional normally sized type 2 fibers, incontrast to relatively homogenous sizes of type 1 and 2 fibers seen in a normalmuscle biopsy (Figure 9-7). In theabsence of other structural abnormalities, such as rods or cores, the findings were indicative of congenitalmuscle fiber-type disproportion.





Comment. This case illustrates the natural history of congenital myopathy with fiber-type disproportion.Over time, the patient’s gross motor delay slowly improved. He sat at 1 year, walked independently at 2 years,and climbed stairs at 3 years of age. He continued to struggle with jumping, hopping, and running due toproximal muscle weakness. At the last examination at age 8, he had good functional ability despite pes planusgait and hyperextensible joints.

FIGURE 9-7 Muscle biopsy of the patient in Case 9-7 with congenital fiber-type disproportion andnormal control. The only anomaly in the muscle from this infant, performed at 5 monthsof age, on either hematoxylin and eosin (H&E) (A) or Gomori trichrome stains (B) is the

presence of two distinct populations of myofibers based on their size. No other aggregated material,nemaline rods, or cores are present. The larger population of normally sized myofibers are all of type 2(ATPase histochemistry, pH 4.3 in panel C and pH 10.4 in panel D). The type 1 fibers are more than 30%smaller in diameter and much smaller in area than the type 2 myofibers. Compared to panels AYD thatshow congenital fiber-type disproportion, panel E and panel F illustrate a more normal muscle from a7-month-old infant that lacks the two distinct populations of myofiber sizes, although it does havesome fiber size variation (panel E, with the same magnification as in panel A). The pH 4.3 ATPasehistochemistry (panel F, with the same magnification as in panel C) demonstrates that the fiber sizevariation is not selective for either type 1 (darker at this pH) or type 2 (red from the counterstain used at thispH) myofibers.




difficulty, or scoliosis. Optimal weight,diet, physical activity, range-of-motion ex-ercises, calcium and vitamin D supplemen-tation to promote bone health, up-to-dateimmunizations, education, and careerplanning should be addressed. Specificissues related to congenital myopathiesinclude: (1) screening for potential ocu-lar, cardiac, and respiratory involvement;(2) management of respiratory andorthopedic complications; (3) monitor-ing for motor deterioration due to diseaseprogression; and (4) family counselingregarding avoidance of anesthesia-induced muscle injury, and perioperativemanagement, as carefully summarized byWang and colleagues.3 A formal videofluoroscopic swallowing study may beindicated for infants with feeding con-cerns or failure to thrive. Baseline andfollow-up ECG and echocardiographyshould also be considered for all individ-uals with unspecified congenital myopa-thies. The presence of cardiomyopathymay suggest specific genes such asMYH7,TTN, SPEG, or, rarely, ACTA1 mutations.

Respiratory complications beyond theinfancy period are uncommon; they aremore likely to occur in congenitalmyopathyYrelated mutations involvingMTM1, SEPN1, ACTA1, TPM3, NEB, andDNM2. Close monitoring of respiratoryfunction is required to detect early respi-ratory insufficiency. The use of mechani-cal or manual cough-assisted devices,lung volume recruitment exercises, aswell as airway clearance techniquesshould be offered as prophylactic respira-tory care strategies for affected individ-uals in addition to noninvasive positive-pressure ventilation as indicated based onpulmonary function tests, overnight pulseoximetry, and polysomnography. Painand fatigue are common patient-reportedsymptoms but may be underrecognizedby clinicians. Beyond identifying thecause (such as skeletal fracture or sec-ondary neuromuscular junction transmis-sion defects) and excluding treatableconditions (such as sleep-disorderedbreathing or nutritional or hormonal

deficiency), appropriate use of mobilitydevices and physical therapistYguidedexercise programs should improve pa-tients’ overall function and endurance.

Severity of disease in the neonatal orearly infantile period correlates with in-creased mortality during the first year oflife. Clear genotype-phenotype correla-tions among the severe congenital my-opathies (related to ACTA1, KLHL40, orX-linked MTM1) will help provide an-ticipatory guidance for subsequentpregnancies. The exception to this ap-pears to be neonates with severe weak-ness and RYR1 mutations, most of whomsurvived and improved clinically in thestudy by Colombo and colleagues,13 thussuggesting a more benign course forcongenital RYR1-related myopathies.

Maggi and colleagues12 found thatwhile the majority (93.4%) of 66 patientswith congenital myopathies in theirseries remained stable or improved,progression of muscle weakness wasexperienced by a subset (6.6%) ofaffected individuals. Colombo and col-leagues13 further found that eight out of89 patients (9%) who lost ambulationwere often late walkers, thus the loss ofindependent ambulation may reflect theadditional burden of increased growthon already substantially compromisedmuscle function. Furthermore, one-halfof all 17 patients with scoliosis in theirnatural history study were ambulant atthe time of surgery. The development ofscoliosis may be more related to the dis-proportionate axial weakness rather thanchange in the ambulatory function.13

NEW EMERGING THERAPIESBeyond recognizing the association ofmyasthenic syndrome and centronuclearmyopathies, modulation of the neuro-muscular junction represents a potentialdisease-modifying option for the treat-ment of other types of congenital myop-athies. Larger prospective clinical trialsare needed to determine the role ofantioxidants (such as N-acetylcysteine)as adjunctive treatment. Research using




animal or zebra fish models of diseaseprovides insight into pathogenesis aswell as important proof of conceptregarding further therapeutic trials forcongenital myopathies.50 For example, asingle intravascular administration of arecombinant adeno-associated virus(AAV) serotype 8 vector expressing theMTM1 gene rescued the muscle pathol-ogy and dramatically improved thesurvival of MTM1-deficient mice anddogs, thus laying the groundwork forfuture AAV-mediated gene therapy trialsfor X-linked myotubular myopathy.51

Similar to other neuromuscular disor-ders, the treatment of the congenitalmyopathies will likely require multiplestrategies addressing the underlyingdisease processes, including gene ther-apy, enzyme replacement, upregulationof compensatory genes or proteins,antiapoptosis approaches, myostatinmodulators, muscle troponin activa-tors, or other regulators of calciumhomeostasis.2 Advances in basic scienceresearch offer a glimmer of hope thatnew emerging therapies may soon be-come available for many subtypes ofcongenital myopathies.

CONCLUSIONGenetic advances have identified agrowing list of more than 20 genesresponsible for congenital myopathies.Each gene can be associated with mul-tiple histopathologic abnormalities inthe myofibers that may change overtime; at the same time, each distinctpathologic feature can be caused bymultiple different genes. The clinicalphenotypes related to the congenitalmyopathies are highly diverse. Accuratediagnosis requires a systematic approach,incorporating clues from the history,physical examination, nerve conductionstudy and EMG, and ancillary studies suchas muscle imaging to help select theappropriate site for muscle biopsy as wellas targeted next-generation gene se-quencing. Guidelines are available to helpclinicians, patients, and their families

navigate through treatment options forcongenital myopathies. Those with sec-ondary neuromuscular junction defectsmay benefit from anticholinesterase ther-apy or other strategies to enhance synap-tic function. Recent advances in theunderstanding of molecular genetics andshared pathophysiologic mechanismsshould help identify novel therapeuticoptions for congenital myopathies.

USEFUL WEBSITESThe Care of Congenital Myopathies: AGuide for Families

www.curecmd.org/wp-content/uploads/resources/cm-guide-view.pdf

Genetics Home Reference

ghr.nlm.nih.gov

Leiden Open Variation database

www.lovd.nl

Online Mendelian Inheritance of Man

www.omim.org

ACKNOWLEDGMENTS

The authors would like to thank thepatients and families for allowing usto share and learn from their expe-rience. As well, we acknowledge thevaluable contributions of the many in-dividuals in regard to diagnosis, genetictesting, or patient management includingCarsten Bonnemann, MD, PhD, JahannazDastgir, MD, and Sandra Donkorvoort,MS, from the National Institutes of Health;Anne Rutkowski, MD, from Cure CMD;Micheil Innes, MD, and Linda MacLaren,MS, from the from the Alberta Children’sHospital, Department of Medical Genet-ics; Sameer Chhibber, MD, from theAlberta South Health Campus, AdultNeuromuscular Program; and KellieLombardo, RN, and Angela Chiu, RPT,from the Alberta Children’s Hospital,Pediatric Neuromuscular Program.

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KEY POINT

h Recent advances in the

understanding of

molecular genetics and

shared pathophysiologic

mechanisms should help

identify novel therapeutic

options for congenital

myopathies.



http://www.curecmd.org/wp-content/uploads/resources/cm-guide-view.pdf

http://www.curecmd.org/wp-content/uploads/resources/cm-guide-view.pdf

http://ghr.nlm.nih.gov

http://www.lovd.nl

http://www.omim.org

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Review Article - Stony Brook School of Medicine · Recent Findings: Congenital myopathies refer to a heterogeneous group of genetic ... are being updated based on advances in molecular