Congenital myopathies: disorders of excitation

The congenital myopathies are a genetically hetero-

geneous group of early-onset neuromuscular disorders

characterized by variable degrees of muscle weakness

and distinctive structural abnormalities in muscle biopsy

samples. The conditions that have been identified to date

are mostly disorders of muscle excitation–contraction

coupling (ECC) or of proteins primarily involved in

sarcomeric filament assembly and interaction. However,

recent findings suggest other less common pathogenic

mechanisms. The concept of congenital myopathies was

established in the 1950s and 1960s, when the application

of histochemical and ultrastructural techniques to dis-

eased muscle identified histopathological features that

were considered to be pathognomonic. Recognition of

these features — namely, central cores, multi-minicores,

central nuclei and nemaline rods — resulted in the desig-

nation of four novel disease entities, central core disease

(CCD)

, multi-minicore disease (MmD)

, centronuclear

myopathy (CNM)

and nemaline myopathy

, which still

represent the main diagnostic categories.

Considerable progress has been made in under-

standing the phenotypic spectrum, diagnosis and

management of the congenital myopathies. In addition

to primary myopathic features, non-neuromuscular

mani festations are observed in several forms, point-

ing to a role for the defective proteins in non-skeletal

muscle tissues

. Muscle imaging, in particular, muscle

MRI, has emerged as a powerful tool for deep pheno-

typing

. Presentations late in adulthood have now been

recognized

7,8

, and owing to improved standards of care,

even patients with severe early-onset forms increasingly

transition from paediatric to adult neurology services.

Since the identification of dominant mutations in

the skeletal muscle ryanodine receptor 1 (RYR1) gene

as the cause of malignant hyperthermia in 1991 and

CCD in 1993

9,10

, mutations in more than 20 genes have

been identified in patients with congenital myopathies.

Introduction of next-generation sequencing (NGS)

techniques into routine clinical diagnosis

has resulted

in an improved detection rate for mutations in genes

such as RYR1, nebulin (NEB) and titin (TTN). Owing to

their large size, these genes were previously only stud-

ied by Sanger sequencing in a few patients. Novel NGS

techniques have led to the recognition that different

mutations in the same gene can give rise to various histo-

pathological phenotypes, and that mutations in different

*e-mail: f.munt[email protected]

doi:10.1038/nrneurol.2017.191

Published online 2 Feb 2018

Congenital myopathies: disorders

ofexcitation–contraction coupling

andmuscle contraction

Heinz Jungbluth

1,2,3

, Susan Treves

4,5

, Francesco Zorzato

4,5

, Anna Sarkozy

, JulienOchala

Caroline Sewry

, Rahul Phadke

, Mathias Gautel

and FrancescoMuntoni

6,8

Abstract

The congenital myopathies are a group of early-onset, non-dystrophic neuromuscular

conditions with characteristic muscle biopsy findings, variable severity and a stable or slowly

progressive course. Pronounced weakness in axial and proximal muscle groups is a common

feature, and involvement of extraocular, cardiorespiratory and/or distal muscles can implicate

specific genetic defects. Central core disease (CCD), multi-minicore disease (MmD),

centronuclear myopathy (CNM) and nemaline myopathy were among the first congenital

myopathies to be reported, and they still represent the main diagnostic categories. However,

these entities seem to belong to a much wider phenotypic spectrum. To date, congenital

myopathies have been attributed to mutations in over 20 genes, which encode proteins

implicated in skeletal muscle Ca

homeostasis, excitation–contraction coupling, thin–thick

filament assembly and interactions, and other mechanisms. RYR1 mutations are the most

frequent genetic cause, and CCD and MmD are the most common subgroups. Next-generation

sequencing has vastly improved mutation detection and has enabled the identification of novel

genetic backgrounds. At present, management of congenital myopathies is largely supportive,

although new therapeutic approaches are reaching the clinical trial stage.

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genes can cause the same histopathological feature, often

owing to functional associations between the defective

proteins. Moreover, it has become increasingly clear that

many congenital myopathies are characterized by non-

specific or complex pathological abnormalities rather

than a ‘pure’ muscle pathology picture. A classification

based on predominant histopathological and associated

clinical features is still useful; however, it is also help-

ful to consider these conditions according to the main

underlying disease mechanisms.

In this Review, we summarize genetic, clinical and

pathological features of the main congenital myopathies.

Common pathogenic mechanisms, diagnostic and cur-

rent management approaches, and principles of therapy

development will be outlined.

Classification and epidemiology

Data concerning the precise epidemiology of the con-

genital myopathies are limited and are mostly focused on

the four main pathological variants: CCD, MmD, CNM

and nemaline myopathy. The key characteristics of these

entities are detailed below and illustrated in FIG.1.

CCD — initially described in the 1950s

— and

MmD

are often referred to as the ‘core myopathies’

and their names are derived from the histochemical

appearance of focally reduced oxidative enzyme activ-

ity, which corresponds to myofibrillar changes on

ultrastructural examination. CCD is characterized by

centrally located, well-demarcated cores that run along

the fibre axis for a substantial distance on longitudinal

sections, whereas MmD is defined by multiple cores of

less well-defined appearance and more-limitedlength.

The hallmark of CNM is the presence of fibres with

centralized nuclei, which show variations in terms of

numbers and associated features between muscles and

genetic backgrounds. Nemaline myopathy is character-

ized by the presence of numerous nemaline rods that

stain red with Gomori trichrome and can be confirmed

by electron microscopy

The overall prevalence of these congenital myopathy

variants has been estimated at 1 in 26,000

. Nemaline

myopathy was originally considered to be the most fre-

quent form, but emerging data suggest that congenital

myopathies with cores (CCD and MmD) represent the

most common subgroup. Marked genetic heterogeneity

is now acknowledged, as detailed below. RYR1 seems to

be the gene most frequently involved in congenital myo-

pathies, in particular, CCD and MmD. Recessive NEB

mutations and denovo dominant mutations in ACTA1,

which encodes skeletal muscle α-actin, are the most

common known causes of nemaline myopathy, whereas

X-linked recessive mutations in the myotubularin gene

(MTM1) are believed to be the most common cause of

CNM. Mutations in TTN are increasingly recognized and

may be involved in a substantial proportion of currently

unresolved congenital myopathies as well as other neuro-

muscular disorders, including muscular dystrophies

The genes implicated in the congenital myo pathies are

listed in TABLE1, and the key clinicopathological fea-

tures associated with the most common genetic back-

grounds are summarized in TABLE2. Characteristic

histopathological features are illustrated in FIG.1.

Clinicopathology and genetics

Congenital myopathies with cores

In view of their pathological and genetic overlap, CCD,

MmD and malignant hyperthermia are discussed

together in this section.

CCD is closely associated with dominant RYR1

mutations, whereas MmD is genetically more hetero-

geneous. Most cases of MmD have been attributed to

recessive mutations in RYR1

16–18

, SEPN1 (also known

as SELENON)

or — less frequently — MYH7

Histopathological features consistent with MmD have

also been described in some patients with recessive

mutations in MEGF10, which encodes multiple epider-

mal growth factor-like domains protein 10

21–24

. Cores or

minicores in muscle biopsy samples can also be promi-

nent in TTN-related myopathies

, often in conjunction

with other myopathic and dystrophic features, and might

occur in other neuromuscular disorders.

Clinically, CCD due to dominant RYR1 mutations

is usually a mild condition, although early severe pres-

entations, often associated with denovo inheritance, have

been recorded

. Extraocular muscles are usually spared,

and facial, bulbar and respiratory involvement is typically

mild. Congenital dislocation of the hips and scoliosis are

common. Most patients achieve independent ambulation

and have a static or only slowly progressivecourse.

Author addresses

Department of Paediatric Neurology, Neuromuscular Service, Evelina’s Children

Hospital, Guy’s and St Thomas’ Hospital NHS Foundation Trust, London, UK.

Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, King’s

College, London, UK.

Department of Clinical and Basic Neuroscience, Institute of Psychiatry, Psychology

andNeuroscience (IoPPN), King’s College, London, UK.

Departments of Anesthesia and Biomedicine, Basel University and Basel University

Hospital, Basel, Switzerland.

Department of Life Sciences, Microbiology and Applied Pathology Section, University

ofFerrara, Ferrara, Italy.

The Dubowitz Neuromuscular Centre, Developmental Neurosciences Programme,

UCLGreat Ormond Street Institute of Child Health and Great Ormond Street Hospital

for Children, London, UK.

Centre of Human and Aerospace Physiological Sciences, Faculty of Life Science and

Medicine, King’s College, London, UK.

NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK.

Key points

• Congenital myopathies are clinically and genetically heterogeneous conditions

characterized by muscle weakness and distinctive structural abnormalities in muscle

biopsy samples

• Clinically, congenital myopathies have a stable or slowly progressive course, and the

severity varies depending on the causative mutation

• More than 20 genes have been implicated in congenital myopathies

• The most commonly affected genes encode proteins involved in skeletal muscle Ca

homeostasis, excitation–contraction coupling and thin–thick filament assembly and

interactions

• Management of congenital myopathies is largely supportive, although experimental

therapeutic approaches are reaching the clinical trial stage

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The clinical features of MmD are more variable

SEPN1-related myopathies

19,27

are characterized by

marked weakness, early spinal rigidity, scoliosis and res-

piratory impairment. Patients with recessively inherited

RYR1-related core myopathies exhibit a distribution of

weakness and wasting that resembles the SEPN1-related

form but have additional extraocular muscle involve-

ment and, with few exceptions, lack severe respiratory

impairment

17,18

. Various combinations of scoliosis, spinal

rigidity, multiple (mainly distal) contractures and associ-

ated cardiomyopathy can occur in TTN-related and

MYH7‑related forms

20,25

. MEGF10-related myopathies

have a wide clinical spectrum, ranging from a severe

early-onset myopathy with areflexia, respiratory dis-

tress and dysphagia (termed EMARDD)

21,23,24

toadult-

onset cases with minicores in muscle biopsy samples

Muscle MRI can help to differentiate genetically distinct

coremyopathies

28,29

Dominant RYR1-related CCD is allelic to the malig-

nant hyperthermia susceptibility (MHS) trait — a

pharmaco genetic predisposition to malignant hyperther-

mia and severe adverse reactions to volatile anaesthetics

and muscle relaxants

— and some CCD-associated

RYR1 mutations also carry an increased risk of MHS. The

association between MHS and recessive RYR1-related

MmD is less well established; however, some cases

of MmD have been attributed to compound hetero-

zygosity for dominant MHS-associated RYR1 muta-

tions and missense, nonsense or other loss-of-function

mutations

18,31,32

RYR1-related King–Denborough syndrome (KDS)

is an MHS-associated myopathy characterized by dys-

morphic facial features, short stature, spinal rigid-

ity, scoli osis and various histopathological features

Another recently recognized myopathy with similar

clinico pathological features is Native American myo-

pathy (NAM), originally described in the Lumbee popu-

lation of North Dakota and caused by homozygosity for a

founder mutation (Trp284Ser) in STAC3, which encodes

SH3 and cysteine-rich domain-containing protein3

MHS-associated RYR1 mutations have also been

identified as a common cause of exertional myalgia and

rhabdomyolysis (ERM) in otherwise healthy individu-

als with various muscle biopsy findings

. Of note, exer-

tional myalgia can be prominent in CCD

, and mild to

moderate creatine kinase elevations (up to 1,000 inter-

national units (IU)/l), which are unusual in the context

of other congenital myopathies, are not uncommon.

MHS-associated RYR1 mutations can also give rise to

late-onset axial myopathy in previously healthy (or even

athletic) individuals

37,38

Centronuclear myopathy

CNM

is associated with X-linked recessive mutations

in the myotubularin gene MTM1 (a condition termed

X-linked myotubular myopathy or XLMTM)

, auto-

somal dominant mutations in dynamin 2 (DNM2)

and amphiphysin II (BIN1)

, and autosomal recessive

mutations in RYR1

, BIN1

and TTN

. Recessive muta-

tions in SPEG have been identified in a small number of

families

, and dominant mutations in CCDC78

were

found in one isolated pedigree. Heterozygous missense

variants in MTMR14, which have been identified in two

patients with CNM, might represent a genetic modifier

of other genetic backgrounds

In MTM1-related CNM, the central nuclei are usu-

ally spaced out along the long fibre axis, whereas in

DNM2-related cases, these nuclei can form chains.

Inthe rare BIN1-related cases, the central nuclei can

form clusters. In patients with MTM1-related CNM,

typical features of the muscle fibres include central

areas of increased oxidative enzyme activity and a pale

peripheral halo. These features, along with the presence

of central nuclei, are also seen in congenital myotonic

dystrophy. Strictly centralized nuclei are more common

than multiple internalized nuclei in the MTM1‑related,

DNM2-related and BIN1-related forms of CNM

40,41,44

whereas multiple internalized nuclei are more common

in RYR1-related and TTN-related cases

. A radial distri-

bution of sarcoplasmic strands that stain positively with

NADH tetrazolium reductase and periodic acid–Schiff

is often seen in DNM2-related CNM

. ‘Necklace’ fibres

are often seen in patients carrying milder MTM1 muta-

tions or in female carriers of MTM1 mutations

,and

occasionally in patients carrying DNM2 mutations

Ultrastructural triad abnormalities are observed in most

forms ofCNM

From a clinical perspective, extraocular muscle

involvement is a consistent feature of most forms of

CNM

, the exceptions being the TTN-related, SPEG-

related and CCDC78-related forms. The most severe

form, XLMTM, typically manifests in affected males

with profound hypotonia, weakness and contractures

at birth, as well as bulbar and respiratory involvement

that almost always necessitates ventilation for survival.

Although the provision of constant respiratory support

improves life expectancy in patients with XLMTM,

some long-term survivors experience complica-

tions

, probably related to the ubiquitous role of the

defectiveprotein.

Dominantly inherited CNM associated with muta-

tions in DNM2 is frequently a relatively mild condi-

tion

41,54

, although more-severe denovo cases have been

recorded

55,56

. Additional characteristic features of this

condition include distal weakness, calf muscle hyper-

trophy, exertional myalgia and/or fatigue, PNS or CNS

involvement, and multisystem features such as neutro-

penia or cataracts. The peripheral axonal neuropathy

Charcot–Marie–Tooth disease, dominant intermediateB

(CMTDIB) is allelic to DNM2-relatedCNM

Recessively inherited and — less frequently —

dominantly inherited as well as milder forms of

BIN1-related CNM have been reported in a few fam-

ilies

42,44,58

. Recessively inherited CNM due to RYR1

mutations

shows considerable clinical overlap with

other forms of recessively inherited RYR1-related myo-

pathy (see above). Mutations in TTN are often associ-

ated with dysmorphic facial features, scoliosis, spinal

rigidity and contractures

, showing some overlap with

Emery–Dreifuss muscular dystrophy and the KDS spec-

trum. Cardiac involvement has been reported only in the

TTN-related and SPEG-related forms ofCNM.

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Nemaline myopathy

Nemaline myopathy has been associated with muta-

tions in more than ten genes to date, most commonly,

recessive mutations in NEB

59,60

and — usually denovo

— dominant mutations in ACTA1

. Rarer causes of

nemaline myopathy, some of which are limited to single

families, include dominant mutations in tropomyosin3

(TPM3)

, tropomyosin 2 (TPM2)

and KBTBD13

and recessive mutations in ACTA1

, TPM3

, TPM2

TNNT1

, CFL2

, KBTBD13

, KLHL40

, KLHL41

LMOD3

, MYPN

73,74

and MYO18B

The number and distribution of nemaline rods

vary among muscles and patients. Rods are believed

to be derived from Z-lines and may show continuity

with these structures. The rods are mainly cytoplasmic

but can also be nuclear, particularly in ACTA1-related

Nature Reviews | Neurology

a b

100 µm

10 µm

100 µm

10 µm

100 µm

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nemaline myopathy

, where additional actin accumu-

lation and compensatory expression of cardiac actin

can be observed. Nemaline rods are usually seen in

both typeI and typeII muscle fibres, except in patients

with TPM3 mutations, where they are limited to typeI

fibres. Numerous small rectangular rods in fibres with

sparse myofibrils are a feature of KLHL40-related

nemalinemyopathy

Clinically, nemaline myopathy is highly variable and

is conventionally classified by age of onset and sever-

ity. Severe, often lethal cases within the fetal akinesia

spectrum have been reported in association with reces-

sive mutations in KLHL40

, KLHL41

, LMOD3

and

MYO18B

, whereas the typical congenital form charac-

terized by infantile onset, hypotonia and often dispro-

portionate bulbar involvement is most commonly due

to recessive NEB mutations

. Dominant — frequently

denovo — ACTA1 mutations are often associated with

severe congenital presentations, but milder cases have

been reported

65,78–80

. KBTBD13-related nemaline myo-

pathy is an unusual form characterized by progressive

proximal and neck weakness, gait abnormalities, poor

exercise tolerance and peculiar slowness of movement

Extraocular muscle involvement is seen in only a frac-

tion of patients with KLHL40, KLHL41 and LMOD3

mutations. Cardiomyopathy is sometimes seen in

MYPN-associated and MYO18B-associated nemaline

myopathy

74,75

. Marked distal involvement is observed

in numerous forms of nemaline myopathy, and many

of the causative genes have also been implicated in dis-

tinct distal arthrogryposis syndromes

. Muscle MRI

might help to distinguish different genetic forms of

nemalinemyopathy

Other congenital myopathies

In recent years, we have witnessed an expansion of

the phenotypic spectrum associated with the known

congenital myopathy-associated genes, as well as the

description of novel conditions that share some of

the clinical and muscle biopsy findings of the better-

characterized entities without reaching a comparable

level of histopathological ‘purity’. These congenital

myopathies with nonspecific, multiple (structural) and

unusual or other features are summarized in the

sections thatfollow.

Congenital myopathies with nonspecific features.

Marked typeI fibre predominance or uniformity is com-

mon in all congenital myopathies and can be the sole

presenting feature

. TypeI predominance and atrophy

were also reported in one consanguineous family with

clinical features of a congenital myopathy and reces-

sive mutations in 3-hydroxyacyl-CoA dehydratase1

(HACD1)

. Recessive mutations in the corresponding

canine gene cause a form of CNM in dogs

86,87

, although

increased numbers of central nuclei are not a feature in

humans with HACD1 mutations. Congenital fibre type

disproportion, in which typeI fibres are substantially

smaller than typeII fibres, is another common feature

that has been reported in association with mutations in

TPM3

88,89

, RYR1

, ACTA1

, SEPN1

and MYH7

, with

or without additional structural abnormalities.

Congenital myopathies with multiple structural abnor-

malities. Congenital myopathies with multiple structural

abnormalities, which were already recognized in the

pre-molecular era

, have now been largely genetically

resolved and are often attributed to previously identi fied

genetic backgrounds. The common occurrence of cores

and rods (core–rod myopathy) has been ascribed to

mutations in RYR1, ACTA1 and NEB, whereas the com-

bination of cores and central nuclei is seen with RYR1,

TTN, CCDC78, DNM2 and SPEG mutations.

Novel entities that lack a single predominant histo-

pathological abnormality and, therefore, do not readily

fit into the conventional classification are increasingly

recognized. CACNA1S-related myopathy

is character-

ized by marked neonatal hypotonia, generalized weak-

ness with pronounced axial involvement, and variable

extraocular, bulbar and respiratory features. This con-

dition is caused by recessive and dominant mutations

in CACNA1S, which encodes voltage-dependent L-type

channel subunit-α1S (Cav1.1), the pore-form-

ing subunit of the voltage sensing L-type Ca

channel

dihydro pyridine receptor (DHPR) in skeletal muscle.

Allelic DHPR mutations were previously associated

with dominantly inherited forms of periodic paralysis

(and, in rare cases, MHS phenotypes)

96,97

. Characteristic

histopathological features of CACNA1S-related myo-

pathy include sarcoplasmic reticulum (SR) dilatation,

increased numbers of internal nuclei, and myofibrillar

disorganization resembling minicores.

Recessively inherited PYROXD1-related congenital

myopathy

is an early-onset myopathy of moderate

severity characterized by slowly progressive generalized

Fig. 1

Muscle pathology in congenital myopathies. Tissue samples from a child with

dominant RYR1-related central core disease (parts a–c). Muscle shows myopathic fibre

size variation and marked perimysial fatty infiltration (part a). Most fibres contain a single

central or eccentric core with a well-delineated zone of diminished or absent oxidative

staining; some fibres also show a rim of increased oxidative staining surrounding the core

lesion (part b). Fibres are uniformly typeI (part c). Tissue samples from an adolescent with

recessive SEPN1-related multi-minicore disease (parts d–f). Muscle shows myopathic fibre

size variation and perimysial fatty infiltration (part d). Fibre typing is preserved, with a

predominance of typeI fibres (darker staining), and both typeI and typeII fibres display

foci of diminished or absent oxidative staining (multi-minicores) and, occasionally, larger

lesions (parts e,f). Tissues samples from a patient with MTM1‑related centronuclear

myopathy (CNM) (parts g–i). Samples from a male neonate with severe X-linked recessive

myotubular myopathy show many fibres with centrally placed nuclei (part g). Most fibres

display pale peripheral haloes (part h), and typeI fibres predominate (part i). Tissues

samples from an adult with DNM2-related CNM (parts j–l). Muscle shows a marked

increase in central nucleation and perimysial fatty infiltration (part j). Many fibres display

‘radial strands’ emanating from a centrally placed nucleus (part k). TypeI fibre

predominance and hypotrophy create fibre size disproportion; central nuclei are present

in both fibre types (part l). Tissue samples from a severely affected neonate with denovo

dominant ACTA1-related nemaline myopathy (parts m–o). Muscle shows myopathic fibre

size variation with the appearance of two fibre populations: smaller typeI and larger

typeII fibres (part m). Numerous thread-like inclusions are seen in both fibre sizes and

appear red with the modified Gomori trichrome stain (part n) and eosinophilic with

haematoxylin and eosin (part m). Pale-stained typeI fibres are often more severely

affected than typeII fibres, showing atrophy or hypotrophy (part o). Muscle biopsy

samples were stained with haematoxylin and eosin (parts a,d,g,j,m), NADH tetrazolium

reductase (parts b,e,h,k) and modified Gomori trichrome (part n), as well as stains for slow

myosin heavy chain (parts c,f,i,l) and myosin ATPase at pH 4.6 (part o).



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Table 1

Genes implicated in congenital myopathies and related conditions

Gene

symbol

Chromosomal

location

Protein Condition Inheritance

Sarcoplasmic reticulum Ca

release, excitation–contraction coupling and/or triadic assembly

RYR1

19q13.1 Ryanodine receptor 1 (skeletal) CCD

AD, AR

MmD

AD, AR

CNM AR

CFTD AR

KDS AR, AD

STAC3 12q13.3 SH3 and cysteine-rich

domain-containing protein 3

NAM AR

ORAI1 12q24.31 Ca

-release-activated Ca

channel protein 1

TAM AD

STIM1 11p15.4 Stromal interaction molecule 1 TAM AD

Stormorken syndrome AD

MTM1

Xq28 Myotubularin XLMTM X-linked

BIN1

2q14 Amphiphysin II CNM

AR, AD

DNM2

19p13.2 Dynamin 2 CNM AD

SPEG 2q35 Striated muscle preferentially

expressed protein kinase

Congenital myopathy with central

nuclei and cardiomyopathy

CCDC78 16p13.3 Coiled-coil domain-containing

protein 78

Congenital myopathy with cores and

central nuclei

CACNA1S 1q32 Voltage-dependent L-type Ca

channel subunit-α1S

Congenital myopathy with EOM AD, AR

SEPN1

1p36.13 Selenoprotein N MmD

CFTD AR

Thin–thick filament assembly and/or interaction, myofibrillar force generation and protein turnover

NEB

2q22 Nebulin Nemaline myopathy

ACTA1

1q42.1

Actin, α-skeletal muscle

Nemaline myopathy

AD, AR

CFTD AD, AR

Cap myopathy AD, AR

TNNT1 19q13.4 Troponin T, slow skeletal muscle Nemaline myopathy AR

TPM2

9p13

Tropomyosin β-chain

Nemaline myopathy

Cap myopathy AD

DA1A AD

DA2B AD

Escobar syndrome AR

TPM3

1q21.2

Tropomyosin α3-chain

Nemaline myopathy

CFTD AD

Cap myopathy AD

MYH2 17p13.1 Myosin 2 Congenital myopathy with EOM AD, AR

MYH3 17p13.1 Myosin 3 DA2A, DA2B and DA8 AD

MYH7 14q12 Myosin 7 CFTD AD

MmD AR

MSM AR

MYH8 17p13.1 Myosin 8 Trismus–pseudocamptodactyly

syndrome

Carney complex AD

KBTBD13 15q22.31 Kelch repeat and BTB

domain-containing protein 13

Nemaline myopathy with cores AD

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weakness, facial and bulbar involvement, and increased

internalized nuclei and myofibrillar disorganization in

muscle biopsy samples.

Hereditary myosin myopathies (myosinopathies

)

comprise distinct distal arthrogryposis syndromes

caused by dominant mutations in MYH3 and MYH8

(which encode two developmental myosin heavy chain

isoforms), as well as congenital myopathies of variable

onset and severity caused by dominant and recessive

mutations in MYH2 and MYH7. MYH7 mutations are

also implicated in Laing distal myopathy and myosin

storage myopathy. In addition to the variable presence of

cores in muscle biopsy samples, recessive MYH2-related

myopathies

100–102

are characterized by marked reduction

or absence of typeIIA fibres

99,103

, whereas accumulation

of slow myosin (so-called ‘hyaline bodies’) can be seen

in some MYH7-related cases. Other features that may be

seen in MYH7-related and MYH2-related myopathies

include increased connective tissue, internal nuclei,

rimmed vacuoles, and ring and lobulated fibres

20,93,99,103

In the context of overlapping histopathological fea-

tures, the presence of extraocular muscle involve-

ment might cause diagnostic confusion with recessive

RYR1-relatedMmD.

Two other conditions combining ocular involve-

ment, contractures within the distal arthrogryposis

spectrum and features of a congenital myopathy are

recessively inherited ECEL1-related congenital myo-

pathy

104–108

and dominantly inherited PIEZO2-related

congenital myopathy

109

(also classified as distal

Table 1 (cont.)

Genes implicated in congenital myopathies and related conditions

Gene

symbol

Chromosomal

location

Protein Condition Inheritance

Thin–thick filament assembly and/or interaction, myofibrillar force generation and protein turnover (cont.)

KLHL40

2p22.1 Kelch-like protein 40 Nemaline myopathy

KLHL41 2q31.1 Kelch-like protein 41 Nemaline myopathy AR

LMOD3 3p14.1 Leiomodin 3 Nemaline myopathy AR

MYBPC3 11p11.2 Myosin binding protein C,

cardiac-type

Congenital myopathy with

cardiomyopathy

MYPN 10q21.3 Myopalladin Nemaline myopathy with

cardiomyopathy

TTN

2q31 Titin CNM

MmD AR

Other cellular processes or unknown protein functions

CFL2 14q12 Cofilin 2 Nemaline myopathy with cores AR

CNTN1 12q11–q12 Contactin 1 Congenital myopathy lethal AR

ECEL1 2q37.1 Endothelin-converting

enzyme-like 1

DA5 AR

PIEZO2 18p11.21–p22 Piezo-type mechanosensitive

ion channel component 2

Marden–Walker syndrome AD

DA3 AD

DA5 AD

DA with impaired proprioception AR

MEGF10 5q23.2 Multiple epidermal growth

factor-like domains protein 10

Congenital myopathy with minicores AR

Congenital myopathy with areflexia,

respiratory distress and dysphagia

HACD1 10p12.33 Very-long-chain

(3R)-3-hydroxyacyl-CoA

dehydratase 1

Congenital myopathy (nonspecific) AR

SCN4A 17q23.3 Sodium channel, protein type 4

subunit-α

Congenital myopathy (nonspecific) AR

TRIM32 9q33.2 E3 ubiquitin–protein ligase

TRIM32

Sarcotubular myopathy AR

PYROXD1 12p12.1 Pyridine nucleotide-

disulfide oxidoreductase

domain-containing protein 1

Congenital myopathy (nonspecific) AR

AD, autosomal dominant; AR, autosomal recessive; CCD, central core disease; CFTD, congenital fibre type disproportion; CNM,

centronuclear myopathy; DA, distal arthrogryposis; EOM, extraocular muscle involvement; KDS, King–Denborough syndrome;

MmD, multi-minicore disease; MSM, myosin storage myopathy; NAM, North American myopathy; TAM, tubular aggregate

myopathy; XLMTM, X-linked myotubular myopathy.

Genes most commonly implicated in the classic structural congenital

myopathies, and the corresponding conditions.

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arthrogryposis type 5), both of which are associated

with cores and increased internal nuclei in muscle

biopsy samples.

A recessive congenital myopathy due to homozygous

or compound heterozygous mutations in SCN4A, a gene

previously associated with dominantly inherited myo-

tonia and periodic paralysis, was recently described

110

This condition has a wide clinical spectrum, from

severe inutero (often early lethal) presentations to

neonatal- onset conditions of variable severity. The

pheno type is mainly characterized by hypotonia, facial

and neck weakness, respiratory and swallowing difficul-

ties and early-onset spinal deformities, but interestingly,

it is not associated with clinical or electrophysiological

evidence of myotonia. Mutations in the same gene are

associated with a presentation featuring severe neo natal

laryngospasm

111

. Histopathologically, SCN4A-related

congenital myopathy is characterized by a combina-

tion of increased fibre size heterogeneity and variable

increases in fatty tissue and tends to lack more-distinct

structural abnormalities

110

. In fact, many of the genetic

backgrounds implicated in congenital myopathies — in

particular, mutations in RYR1, TTN and DNM2 — are

associated with marked increases in fat and connective

tissue, mimicking a congenital muscular dystrophy

112,113

Congenital myopathies with unusual or other features.

Some of the genes that are associated with nemaline

myopathy — namely, TPM2, TPM3, ACTA1, NEB and

MYPN — have also been implicated in rare myopathies

with unusual histopathological features, such as cap

myopathy and zebra body myopathy

73,114–116

STIM1-related and ORAI1-related congenital myo-

pathies

117

caused by dominant gain-of-function mutations

result in either tubular aggregate myopathy — a slowly

progressive myopathy with varying degrees of extra-

ocular muscle involvement, exertional myalgia and vari-

able calf hypertrophy — or York platelet and Stormorken

syndromes, related disorders that form a clinical con-

tinuum and are characterized by congenital myopathy,

pupillaryand platelet abnormalities and vari able multi-

system involvement. Recessive inheritance of loss-of-

function mutations in ORAI1 and STIM1 leads to various

combinations of severe combined immunodeficiency,

Table 2

Features associated with different genetic backgrounds in congenital myopathies

Feature RYR1

autosomal

dominant

RYR1

autosomal

recessive

SEPN1 TTN MTM1 DNM2 NEB ACTA1 KLHL40

Epidemiology

Frequency of mutations +++ +++ ++ ++ ++ + ++ ++ +

Onset

Infancy ++ +++ + +++ +++ + +++ ++ +++

Childhood +++ ++ +++ + + + + ++ +

Adulthood ++ + – – – +++ – – –

Clinical features

Extraocular muscle

involvement

+ +++ – – +++ +++ – – ++

Bulbar involvement + +++ ++ ++ +++ ++ ++ ++ +++

Distal involvement – + – ++ + +++ ++ + +

Respiratory involvement + ++ +++ ++ +++ + ++ ++ +++

Cardiac involvement – + +

+++

– – – + –

Contractures + + + +++ +++ ++ ++ ++ +++

Histopathology

Cores +++ +++ +++ ++ – + + + –

Central nuclei ++ ++ – +++ +++ +++ – – –

Nemaline rods + + – + – – +++ +++ +++

Fibre type disproportion + +++ + + + – – + –

Connective tissue and/

or fat infiltration

++ ++ ++ +++ – + – – –

Imaging

Muscle MRI (specificity

for genetic defect)

+++ ++ ++ – + +++ +++ + –

Key: –, not reported; +, infrequent; ++, common; +++, very common.

Right ventricular impairment secondary to respiratory

involvement.

Includes both congenital cardiac defects and acquired cardiomyopathies.

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ectodermal dysplasia and congenital myopathy, a com-

bination that was reported in the pre-molecular era in

association with minicores in muscle biopsy samples

118

‘Triadin knockout syndrome’, which is caused by

compound heterozygosity for TRDN null mutations, is

a recessive cardiac arrhythmia syndrome with various

clinical and histopathological features of a congenital

myopathy, the latter features being characterized by

focal dilatation and degeneration of the lateral SR cis-

ternae

119,120

. The reason for the highly variable pene-

trance of the myopathy associated with TRDN mutations

remains unknown.

Mutations in TRIM32 are associated with limb-girdle

muscular dystrophy type2H and sarcotubular myopathy,

and mutations in TRIM54 and TRIM63 are associated

with microtubular abnormalities and myosin-containing

inclusions

121

. These observations illustrate the increas-

ingly fluid boundaries between congenital myopathies

and other neuromuscular disorders, in particular,

myofibrillar, protein aggregate and vacuolar myopathies.

Pathogenesis

The vast majority of the proteins implicated in congenital

myopathies have been associated with primary or sec-

ondary defects of muscle ECC, intracellular Ca

homeo-

stasis and disturbed sarcomeric assembly and function

(FIG.2), although other mechanisms are emerging.

ECC, muscle contraction and relaxation

ECC is the process whereby an electrical signal gener-

ated by a neuronal action potential is converted into a

chemical gradient — that is, an increase in myoplasmic

— leading to muscle contraction. The two main

players in skeletal muscle ECC are RYR1 and DHPR

(FIG.2). RYR1 is located on the SR junctional face mem-

brane, and DHPR is located on the plasmalemma and

transverse tubules (T-tubules) — plasmalemmal invagi-

nations that run deep into the muscle fibre. ECC is

extremely rapid, occurring within a few milliseconds,

and relies on a highly defined subcellular architecture,

with each DHPR positioned opposite an RYR1, and

every other RYR1 tetramer facing four DHPRs arranged

in a characteristic checkerboard shape called atetrad.

In addition to its principal regulation through direct

interaction with DHPR, RYR1 is regulated by Ca

and

and is subjected to post-translational modifications

such as phosphorylation, sumoylation and nitrosylation,

which affect the channel open probability. The junc-

tional SR membrane contains RYR1 as well as many

other smaller proteins, including the structural proteins

triadin and junctin (also known as aspartyl/ asparaginyl

β-hydroxylase), junctional SR protein 1 (JP45), the

high-capacity, low-affinity Ca

binding protein calse-

questrin

122,123

(in an area adjacent to RYR1), and other

proteins with roles in the fine regulation of SR Ca

release or in maintaining the structural integrity of the

release machinery

122,124–131

Following its release from the SR, Ca

binds to

troponin C and interacts directly with thin filaments.

As a consequence, muscle contraction occurs in the

sarcomere, a structure that is principally composed of

parallel thick and thin filaments. Sarcomeric regulation

of contraction involves structural changes in the thin

filament complex (composed of actin, tropomyosin and

troponin), triggered by Ca

binding to troponin. The

simplest model for the regulation of the sarcomere by

is based on steric blocking, whereby tropomyosin

prevents myosin from binding to the actin filament to

generate force. Binding of Ca

to troponin triggers a

chain reaction that results in azimuthal movements of

tropomyosin around the filament to unmask binding

sites on actin for myosin — the molecular motor and

also the main component of thick filaments — allowing

force production and motion

132

. These contractile pro-

teins and related isoforms are differently expressed in

slow-twitch and fast-twitch muscles to fulfil different

functional demands

132

Termination of the contraction cycle and muscle

relaxation is achieved by RYR1 closure and activation

of sarcoplasmic/endoplasmic reticulum Ca

ATPase

(SERCA), the protein component that is responsible for

pumping the Ca

back into the SR

133

. SERCA activity is

modulated by two small regulatory proteins, sarcolipin

and phospholamaban

134–136

Although skeletal muscle ECC can occur in the pres-

ence of extracellular Ca

in the nanomolar range, a wide

consensus exists that Ca

entry from the extracellular

space is essential to ensure prolonged muscle activity.

Two main mechanisms of Ca

entry have been identi-

fied in skeletal muscle: excitation-coupled Ca

entry via

DHPR, which is activated by a train of action potentials or

prolonged membrane depolarization; and store-operated

entry via stromal interaction molecule 1 (encoded

by STIM1) and Ca

-release-activated Ca

channel

protein 1 (ORAI1), which is triggered by depletion of

endoplasmic reticulum and SR Ca

stores

137–141

ECC and Ca

homeostasis abnormalities

Mutations in RYR1 are the most common cause of pri-

mary defects of ECC and Ca

homeostasis

7,18,142,143

Functional studies utilizing cellular and animal

models

144,145

indicate that excessive Ca

release and

lower RYR1 activation thresholds are consequences

of dominantly inherited MHS-associated RYR1 muta-

tions, whereas both SR Ca

store depletion with a

resulting increase in cytosolic Ca

levels (the ‘leaky

channel’ hypothesis) and disturbed ECC (the ‘excitation–

contraction uncoupling’ hypothesis) have been proposed

as mechanisms underlying dominantly inherited CCD

142

On the basis of the limited studies performed so far,

quantitative reduction of RYR1 channels is a more likely

mechanism than qualitative RYR1 dysfunction in reces-

sive RYR1-related myopathies

146–148

. Primary or secondary

reductions in Cav1.1 protein levels are seen in recessive

RYR1-related and CACNA1S-related congenital myo-

pathies

95,146

; the latter conditions also feature disturbed

ECC and, consequently, reduced depolarization- induced

SR Ca

release in myotubes and mature muscle fibres.

STAC3, the gene that is homozygously mutated in NAM,

encodes a protein that targets Cav1.1 to the T-tubules and,

thus, participates in voltage-induced Ca

release

149,150

Disturbances in voltage-induced Ca

release are likely

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to be involved in the recently described triadin knockout

syndrome

119

, although the basis for the highly variable

penetrance of skeletal muscle features in this condition

is currentlyuncertain.

Dominant mutations in STIM1 and ORAI1 are

associated with distinct alterations in store-operated

influx, resulting in increased resting Ca

levels

due to mediation of Ca

influx by constitutively active

molecules independently of SR Ca

levels

140,151

. By con-

trast, recessive ORAI1 mutations, which lead to reduced

ORAI1 expression, result in impaired Ca

influx

152

Secondary defects of ECC and Ca

homeostasis,

probably due to RYR1 redox modifications, have been

demonstrated in SEPN1-mutated myotubes and in the

Sepn1-knockout mouse model

153,154

. Many of the genes

implicated in CNM, including MTM1

, DNM2

and

Dihydropyridine

receptor

RYR1

SERCA

Phospholamban

Myoregulin

Calsequestrin

Sarcalumenin

JP45

α-Actinin

Myomesin

Actin

Actin ﬁlament

Myosin

Titin

Transverse tubule

SR terminal cisternae Longitudinal SRJFM

Nebulin

Myosin

Triadin

Z I A M

Junctin

STAC3

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BIN1

, encode proteins that have an important role in

intricately linked intracellular membrane trafficking

pathways. Mutations in these genes might indirectly

affect muscle Ca

handling and ECC, probably sec-

ondary to abnormalities of triad assembly and the ECC

machinery

155

. Although such abnormalities have been

demonstrated in mouse models of both DNM2-related

and MTM1-related myopathies

156

, a recent study on

MTM1-mutated human myoblasts failed to demonstrate

any alterations in ECC and Ca

release, indicating that

these alterations may reflect long-term effects invivo

157

The pathogenicity of TTN mutations is probably

multifactorial and is likely to involve several mechan-

isms implicated in ECC, including calpain3- mediated

RYR1 recruitment to the triad and obscurin-

mediated interactions between the T-tubules, the SR

and the sarcomere.

Sarcomeric abnormalities

The majority of the genes implicated in nemaline myo-

pathy to date, including NEB

, ACTA1

, TPM2

TPM3

and TNNT1

, are involved in thin filament

assembly and interactions. Pathogenic mutations

in the two most commonly mutated genes, NEB

andACTA1, have been extensively studied

158

. Dominant

ACTA1mutations exert a dominant-negative effect on

muscle function that is mediated through lowered Ca

sensitivity, whereas recessive ACTA1 mutations abol-

ish functional protein expression, with the phenotype

severity probably depending on the expression of com-

pensatory proteins such as actin, α-cardiac muscle1

(ACTC1)

159,160

. In rare cases, ACTA1 mutations result in

increased muscle contractility

161,162

NEB mutations affect the specific function of nebu-

lin in thin filament regulation and force generation

163

The effects of various nemaline myopathy-associated

mutations on the interactions of nebulin with actin

and tropomyosin, thin filament length and force gen-

eration were demonstrated in two invitro studies

164,165

MYO18B, which was found to be mutated in one family

with a severe form of nemaline myopathy

, encodes an

unconventional myosin protein with a more general role

in sarcomeric assembly and maintenance

166,167

KBTBD13, KLHL40, KLHL41 and LMOD3, which

have recently been implicated in nemaline myopathy,

encode a group of Kelch and Kelch-like proteins that are

not primary thin filament components but are involved

in muscle quality control processes

168

and may, thus,

affect myofibrillar assembly and function indirectly.

Evidence for a direct interaction between Kelch-like

protein 40 (KLHL40), nebulin and leiomodin 3 has

beenprovided

169

The myosinopathies

— disorders of the thick fila-

ments — are likely to cause muscle disease through two

principal mechanisms: disturbed thick filament inter-

action and function and, particularly in MYH7-related

congenital myopathies

, aggregation of abnormal

protein.

Other pathogenic mechanisms

Some of the proteins implicated in congenital myo-

pathies are specifically involved in ECC and Ca

homeo stasis, whereas others are thought to have addi-

tional roles in and beyond muscle. Selenoprotein N

(encoded by SEPN1) belongs to a family of proteins

that contain selenium in the form of the 21st amino

acid, selenocysteine. In muscle, this protein has been

specifically implicated in myogenesis — a role that it

shares with the protein encoded by MEGF10, which is

mutated in a rare form of MmD

— and redox regula-

tion

170,171

. The important role of normally functioning

redox regulation for muscle health is also illustrated

by the identification of recessive mutations in the

oxidoreductase- encoding gene PYROXD1 as a cause of

early-onset congenital myopathies

Reflecting their essential roles in intricately linked

intracellular membrane trafficking pathways, mutations

in the CNM-associated genes MTM1, DNM2 and BIN1

have been associated with a wide range of downstream

effects, including defects in mitochondria, the inter-

mediate filament protein desmin, satellite cell activation

and the neuromuscular junction

155

. Abnormalities of

muscle membrane systems have also been described in

association with canine HACD1-related CNM

86,87

, a natu-

rally occurring animal model of a nonspecific congenital

myopathy that has also been described in humans

172

The CNM-associated genes MTM1 and DNM2 have

also been implicated in pathways that affect muscle

protein turnover and/or muscle growth and atrophy

pathways. In zebrafish and mouse models of myotubu-

larin deficiency, disturbances of the autophagy pathway,

associated with F-box only protein 32 upregulation and

atrophy, have been reported

173–175

. Abnormalities of

autophagosome maturation and autophagic flux have

also been described in a mouse model of DNM2‑related

CNM in association with marked muscle atrophy

and weakness

176

. Several mechanisms might affect

Fig. 2

Proteins involved in congenital myopathies. The figure shows the subcellular

localization of the main proteins implicated in skeletal muscle excitation–contraction

coupling (ECC) and thin–thick filament interaction and assembly. Genes encoding

components of the ECC machinery and the thin and thick filaments of skeletal muscle

are commonly mutated in congenital myopathies. The transverse tubules are

invaginations of the plasma membrane where the dihydropyridine receptor complex

(containing SH3 and cysteine-rich domain-containing protein 3 (STAC3)) is located.

Thismembrane compartment faces the sarcoplasmic reticulum (SR) junctional face

membrane (JFM), which contains ryanodine receptor 1 (RYR1) as well as junctional SR

protein 1 (JP45) and the structural proteins triadin and aspartyl/asparaginyl

β-hydroxylase (junctin). Calsequestrin bound to Ca

forms a mesh-like structure within

the lumen of the SR terminal cisternae. JP45 also interacts with calsequestrin via its

lumenal carboxy-terminal domain. Ca

release into the cytosol results in sarcomeric

shortening through specific interactions between thin and thick filaments, in particular,

the sliding of actin past myosin filaments. ECC is terminated through SR Ca

reuptake

through sarcoplasmic/endoplasmic reticulum Ca

ATPase (SERCA) Ca

pumps. SERCAs

are present in the terminal cisternae as well as the longitudinal SR and are regulated by

phospholamban, myoregulin and sarcolipin. The Ca

-buffering protein sarcalumenin is

also located in the longitudinal SR and terminal cisternae and is involved in regulating

SERCA activity. A, A-band; I, I-band; M, M-band; Z, Z-line. Image courtesy of Christoph

Bachmann, Departments of Anesthesia and Biomedicine, Basel University Hospital,

Basel, Switzerland. 3D representations from RSCB PDB: calsequestrin, PDB ID 2VAF

(REF.227); dihydropyridine receptor, PDB ID 4MS2 (REF. 228); phospholamban, PDB ID

1N7L (REF. 229); RYR1, PDB ID 4UWA (REF. 230); SERCA, PDB ID 1SU4 (REF. 231); STAC3,

PDB ID 2DB6 (http://www.rcsb.org/pdb/explore.do?structureId=2db6).



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autophagy and other degradation pathways in TTN-

related CNM. These mechanisms include abrogation

of calpain 3-mediated protein turnover (inthe caseof

C-terminal-truncating TTN mutations), perturba-

tion of the link between titin and the ubiquitin ligase

myospryn

177

, and perturbation of the link between the

titin kinase domain and the autophagy cargo adap-

tors NBR1 (next to BRCA1 gene 1 protein NBR1) and

sequestosome 1 (SQSTM1) by M-band-disrupting TTN

mutations

. Intriguingly, the typical histopathological

features of CNM have also been reported in primary

disorders of autophagy

178,179

, further supporting a

close link between defective autophagy and abnormal

nuclearpositioning.

A novel epigenetic mechanism involving altera-

tions of muscle-specific microRNAs, increased DNA

methy lation and increased expression of classII histone

deacetylases has been reported in RYR1-related myo-

pathies

180

and might also be relevant for other congenital

myopathies

157

The mechanisms through which mutations in

ECEL1, PIEZO2 and SCN4A cause specific early-onset

congenital myopathies are currently uncertain.

Diagnostic approach

The International Standard of Care Committee for

Congenital Myopathies has provided a structured diag-

nostic approach to the congenital myopathies

181

. Many

features, including axially pronounced weakness and

hypotonia, are consistent but nonspecific on clinical

assessment, whereas others — in particular, the degree

of distal, extraocular muscle, cardiac and respiratory

involvement — can indicate specific genetic backgrounds.

Useful laboratory investigations include measure-

ment of serum creatine kinase levels, which are typically

normal or slightly elevated, and assays for acetylcholine

receptor antibodies to exclude autoimmune myasthenic

conditions

182

. Neurophysiological studies, such as elec-

tromyography and nerve conduction studies, are useful

mainly for excluding congenital neuropathies, myotonic

disorders

111

and congenital myasthenic syndromes

183

Muscle imaging

, in particular, muscle ultrasonog-

raphy as a screening test and muscle MRI for a more

detailed assessment, can reveal diagnostic patterns of

selective muscle involvement. Assessment of muscle

biopsy samples with a standard panel of histological,

histochemical and immunohistochemical stains

will

confirm the specific congenital myopathy and exclude

distinct conditions with overlapping pathological fea-

tures, such as the congenital muscular dystrophies

184

myofibrillar myopathies

185

and autophagic vacuolar

myopathies

186

. Electron microscopy helps to clarify the

pathognomonic structural abnormalities that are seen

with light microscopy.

Concomitant analysis of multiple congenital myo-

pathy-associated genes through NGS is rapidly becom-

ing the preferred diagnostic approach. Functional studies

will be increasingly relevant for pathogenicity assessment

ofvariants in large genes such as TTN, NEB and RYR1, as

variants of uncertain significance are not uncommon in

these genes, even in healthy control populations.

Management and therapy development

Supportive management

Supportive management (outlined in detail elsewhere

187

)

is based on a multidisciplinary approach. Regular physio-

therapy and provision of orthotic support is beneficial

to prevent contracture development and to maintain

mobility. Patients with dysarthria and/or feeding dif-

ficulties will benefit from regular speech and language

therapy. In some cases, bulbar involvement and poor

weight gain may necessitate gastrostomy. Regular mon-

itoring of respiratory function (including sleep studies)

and proactive respiratory management (including timely

noninvasive ventilation and cough assistance techniques)

are essential, particularly in conditions where substan-

tial respiratory involvement — often disproportionate

to the degree of limb-girdle weakness — is recognized.

Regular cardiac monitoring is crucial for patients with

congenital myopathies that are consistently associated

with cardiomyopathy (in particular, the TTN-related and

MYH7-related forms) and also for individuals in whom

the genetic defect is uncertain. Given the often-complex

comorbidities associated with congenital myopathies,

orthopaedic surgery, most notably to treat scoliosis,

should be undertaken at a tertiary neuro muscular centre.

MHS must be anticipated in the anaesthetic management

of patients with RYR1 or STAC3 mutations and in those

with unresolved genetic backgrounds.

Mechanism-based therapies

Mechanism-based therapies for the congenital myo-

pathies that are already available or currently in

development have been reviewed in detail elsewhere

188

Genetic therapies. Owing to their enormous size, most of

the genes commonly implicated in congenital myopathies

are not amenable to virus-based gene transfer approaches.

However, delivery of MTM1 via an adeno-associated

virus 8-based vector has been demonstrated to improve

the clinicopathological phenotype in Mtm1-deficient

mice and a canine model of XLMTM

172,189

Restoration of the mRNA reading frame is theoret-

ically applicable to various congenital myopathies in

which nonsense mutations are implicated. Exon skip-

ping has been successfully applied invitro to remove a

pseudo-exon from the mRNA of a child with a recessive

RYR1-related myopathy

190

. Considering that carriers

of truncating RYR1 mutations are asymptomatic

190,191

selective silencing of the mutant gene could be a fea-

sible therapeutic strategy for dominant RYR1-related

myopathies in the future. Pharmacological suppres-

sion of stop codons

192

by compounds such as ataluren

is a potential approach in congenital myopathies that

involve nonsense mutations, although it is currently

uncertain whether such an approach will increase

normal protein levels sufficiently to restore structural

integrity and function, and the effects on the many

loss-of-function variants in the human genome have

yet to be determined

193

Downregulation or upregulation of genes that act

in convergent pathways could be a relevant approach

for various forms of CNM. Studies have demonstrated

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that downregulation of dynamin 2

194

or targeting of

classII and III phosphoinositide 3-kinases in muscle

195

can rescue the phenotype in XLMTM animal models,

suggesting that pharmacological modification of

intricately linked pathways is a potential treatment

modality for XLMTM and, possibly, other forms of

CNM. Upregulation of cardiac actin might be a fea-

sible therapeutic approach for patients with ACTA1

nullmutations

196,197

Enzyme replacement therapy. Enzyme replacement

therapy is currently relevant only to XLMTM caused by

loss of myotubularin function. In Mtm1-knockout mice,

improvements in contractile function and histopatho-

logical features were observed following short-term

myotubularin enzyme replacement

198

Pharmacological therapies. Pharmacological therapies

that are potentially applicable to congenital myopathies

can be grossly divided into three principal approaches:

direct modification of altered protein function (for

example, modification of RYR1 release in RYR1-related

myopathies); enhancement of thin–thick filament inter-

actions (for example, in some nemaline myopathies);

and therapies aimed at nonspecifically ameliorating

downstream effects of the specific gene mutation.

Modification of RYR1 Ca

release by use of the spe-

cific RYR1 antagonist dantrolene

199

is the established

emergency treatment for malignant hyper thermia

and has also been used effectively in a few patients

with RYR1-related ERM

35,200

and CCD

201,202

. Other

compounds with the potential to treat excessive SR

release and/or increased SR Ca

leakage are the

calstabin-stabilizing 1,4-benzothiazepine derivatives

JTV519 and S107

203,204

and the AMP-activated protein

kinase activator 5-aminoimidazole-4- carboxamide

ribonucleotide (AICAR)

205,206

. However, the safety pro-

files of these compounds in humans and their roles

in RYR1-related myopathies associated with reduced

rather than increased Ca

conductance are currently

uncertain.

Enhancement of filament interactions and promo-

tion of force production

207,208

, either by slowing the rate

of Ca

release from troponin C or by directly targeting

myosin molecules, are potentially valuable approaches

for some nemaline myopathies. However, concerns

remain regarding fibre type specificity and potential

cardiac adverse effects of the molecules that are being

utilized.

Modification of the downstream effects of spe-

cific gene mutations encompasses various approaches.

Inhibition of myostatin, an important negative regula-

tor of muscle fibre size

209

, might be applicable to con-

genital myopathies in which fibre atrophy is prominent.

Following observations of increased oxidative stress and

a favourable response to these compounds in animal

models

154,210,211

, antioxidants such as N-acetylcysteine

are currently being investigated in clinical trials con-

cerning RYR1-related and SEPN1-related myopathies.

In light of the neuromuscular junction and transmis-

sion abnormalities in CNM, RYR1-related MmD and

KLHL40-related nemaline myopathy

212–215

, acetylcho-

linesterase inhibitors have been used with some benefit

in a small number of patients. Two other compounds,

salbutamol for core myopathies

216–218

and — supported

by preclinical data from a relevant animal model

219

— -tyrosine in nemaline myopathy

220

, have shown

apparent benefits in open-label pilot studies.

For those disease entities where misfolded proteins

or domains have unequivocal primary roles in the

disease process (for example, titin in autosomal reces-

sive MmD with heart disease), compounds that act

as chemical chaperones show promise. A pharmaco-

chaperone approach, using the small amphipathic com-

pound 4-phenylbutyrate, was shown to alleviate some

of the pathological features in a mouse model of PLEC-

associated epidermolysis bullosa simplex with muscu-

lar dystrophy

221

, although it is uncertain whether the

observed effect was attributable to stabilization of mis-

folded mutant protein or its clearance through induc-

tion of autophagy by the drug

222,223

. A beneficial effect

of 4-phenylbutyrate has also been suggested in a mouse

model of RYR1-related myopathy

224

. The range of chem-

ical chaperones is increasing rapidly

225

, but the half-

maximal inhibitory concentration — a measure of the

ability of a compound to inhibit a specific function — is

often low

226

, and the development of more target-specific

compounds might make this approach more effective

and applicable.

Conclusions and outlook

Widespread clinical implementation of NGS has rapidly

expanded the genetic and clinicopathological spectrum

of the congenital myopathies. In addition to the classic

entities CCD, MmD, CNM and nemaline myopathy,

the congenital myopathies now encompass a wide range

of early-onset, non-dystrophic neuromuscular dis-

orders with various combinations of structural defects.

Congenital myopathies due to mutations in RYR1, the

most common genetic cause, form a continuum with

intermittent induced myopathies, such as malignant

hyperthermia and exertional rhabdomyolysis, in other-

wise healthy individuals. Other forms of congenital myo-

pathy overlap substantially with the distal arthrogryposis

and protein aggregation myopathy spectrum, particularly

in cases where sarcomeric proteins are implicated.

The unravelling of the underlying molecular mech-

anisms has advanced not only our understanding ofthe

congenital myopathies but also our knowledge of nor-

mal muscle physiology and homeostasis. Although

the primary genetic defects and principal pathogenic

mechanisms have largely been elucidated, downstream

effects on muscle growth and atrophy pathways, the

role of genetic and other modifiers, and the molecular

basis of the common histopathological features remain

uncertain.

Specific therapies for congenital myopathies, utiliz-

ing genetic, enzyme replacement and pharmacological

approaches, are currently being developed or are already

reaching the clinical trial stage, emphasizing the need for

comprehensive natural history studies concerning these

clinically variable conditions.

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Author contributions

H.J., S.T., F.Z., J.O., C.S., M.G. and F.M. researched data for

the article. All authors made substantial contributions to dis-

cussion of the content, wrote the article and reviewed and/or

edited the manuscript before submission.

Competing interests statement

The authors declare no competing interests.

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