C o n genit al M yo p at h i e s

a n d M u s c u l a r D y s t ro p h i e s
a b b,
Heather R. Gilbreath, PA-C , Diana Castro, MD , Susan T. Iannaccone, MD *

KEYWORDS
 Congenital muscular dystrophy  Congenital myopathy
 Ullrich congenital muscular dystrophy  Nemaline myopathy
 Central core myopathy  Centronuclear myopathy
 Merosin deficiency congenital muscular dystrophy

KEY POINTS
 Diagnosis most often depends on muscle biopsy and mutation analysis, but the physician
in charge must be aware of the expertise of both the biopsy laboratory and that of the DNA
diagnostic laboratory.
 There are many pitfalls that can result in misinterpretation of both the biopsy and the DNA;
these are best avoided by working with laboratories that have the highest expertise.
 It is important that patients and families receive complete information regarding the diag-
nostic process and the results, including hard copies for their child’s own records.
 There are now published guidelines for the management of children with congenital
muscular dystrophies (CMD) and congenital myopathies (CM).
 Patient groups are lobbying for support of clinical trials for patients with CMD and CM, and
some studies may well be seen coming online in the next few years.

INTRODUCTION

The congenital muscular dystrophies (CMD) and myopathies (CM) are a diverse group
of diseases that share features such as early onset of symptoms (in the first year of
life), genetic causes, and high risks for restrictive lung disease and orthopedic defor-
mities. The classification of these disorders is historically based and first depended on
muscle biopsy findings. CMDs were identified with dystrophic biopsies and CMs with
peculiar structural changes seen with histochemistry or electron microscopy. Thus,

Funding Sources: NIH (NS077323), ISIS, GSK, PTC Therapeutics, MDA (259206), Santhera, Sar-
epta Therapeutics (S.T. Iannaccone, D. Castro).
Conflict of Interest: S.T. Iannaccone serves as advisor to Sarepta and ISIS; D. Castro: None.
a
Department of Advanced Practice, Children’s Medical Center of Dallas, 2350 Stemmons
Freeway, Dallas, TX 75207, USA; b Departments of Pediatrics and Neurology and Neurothera-
peutics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas,
TX 75390-9063, USA
* Corresponding author.
E-mail address: [email protected]

Neurol Clin 32 (2014) 689–703

http://dx.doi.org/10.1016/j.ncl.2014.04.006 neurologic.theclinics.com
0733-8619/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
690 Gilbreath et al

the CMDs were first described early in the twentieth century,1 whereas CMs were not
recognized until cryostat sections and histochemistry came into use in the late 1960s.2
At that time, it was apparent that most patients with CMs had nonprogressive weak-
ness, whereas the CMDs were thought to be similar to other dystrophies with progres-
sive limb girdle weakness. As each of the entities was associated with unique gene
mutations, some understanding for disease mechanism became available and a fairly
well-structured genotype-phenotype correlation for all the CMDs and CMs is now
available.
Diagnosis should begin with a suspicion, the consideration of whether creatine ki-
nase (CK) is elevated, and a look at involvement outside the skeletal muscles.
Abnormal brain imaging, cognitive involvement, early orthopedic deformities, epi-
lepsy, and structural changes in the eye should suggest a CMD. Nondystrophic bi-
opsy, facial and bulbar weakness, and no eye involvement other than gaze palsy
would suggest a CM. Once brain imaging or muscle histology support a specific dis-
ease, then diagnosis should be confirmed by mutation analysis. This confirmation will
allow for accurate prognostication, educated anticipatory guidance, and informed
family planning.
To illustrate best the clinical spectrum and diagnostic algorithm for these diseases,
this article presents 5 cases with discussion immediately following. The cases repre-
sent the most common forms of CMD and CM and provide an opportunity to review
important clues to diagnosis and guidelines for management.

CASE 1

A 4-year-old boy was referred to the Neuromuscular Disease Clinic for joint laxity. Birth
history was reported to be significant for hypotonia, respiratory difficulties requiring
oxygen via nasal cannula, poor feeding, and congenital hip dislocation. The patient
had motor delay. Specifically, he began sitting for brief periods of time at 7 months
of age, and combat crawling after 1 year of age. He eventually walked without assis-
tance but was noted to suffer from significant weakness. At presentation, he was un-
able to stand independently from a seated position. Social and language function was
normal.
Physical examination demonstrated a well-developed child with long myopathic
facies, a high palate, and mild ptosis bilaterally. Lung and heart examinations were
normal. Musculoskeletal examination was significant for mild flexion contractures of
both elbows and knees with hyperlaxity of both wrists. On neurologic examination,
the patient was found to be hypotonic with decreased muscle bulk, proximal greater
than distal muscle weakness, and decreased reflexes.
CK level was 280 iU/L. Electrodiagnostic studies were normal. Cardiac evaluation
was negative. Muscle biopsy (Fig. 1) revealed dystrophic changes, including marked
variability in fiber size with regenerating fibers and central nuclei. Immunohistochem-
istry demonstrated reduced reaction to 300 kDa merosin and sarcoglycan antibodies.
Magnetic resonance imaging (MRI) of brain was normal. Skin fibroblast testing
confirmed a splicing mutation in exon 16 of the COL6A gene.
The patient lost his ability to ambulate at 5 years of age. By late childhood, he had
severe restrictive lung disease with a forced vital capacity of 0.4 L or 16% predicted
and required noninvasive ventilation intermittently during the day and all night.
This young boy had symptoms from birth with hyptonia, weakness, and joint con-
tractures. The differential diagnosis included CMD and CM, but the progressive nature
of his contractures and restrictive lung disease are much more consistent with CMD.
Furthermore, the distal laxity and normal CK level are typical of collagen mutations or
 Congenital Myopathies and Muscular Dystrophies 691

Fig. 1. (A) Hematoxylin and eosin (H&E) stain for light microscopy of muscle biopsy from
Case 1 obtained when patient was 3 years old. There are many features of a dystrophic pro-
cess including marked variation in fiber diameter, increased fibrosis and fat infiltration, and
ring fibers (original magnification 20). (B) Modified Gomori trichrome (GT) stain of the
same biopsy. There is an increase in internal nuclei with hypertrophied and severely atro-
phied fibers (original magnification 20).

Ullrich congenital muscular dystrophy (UCMD). Other characteristics of UCMD, the

skin manifestations of keloid formation and follicular hyperkeratosis (hyperkeratosis
pilaris), were not seen on presentation. However, skin changes may not be present
in early childhood and often progress dramatically after puberty.3 Biopsy in this
case was dystrophic but the immunohistology was misleading, suggesting a merosin
deficiency, whereas the normal brain imaging was against that diagnosis. Staining for
collagen 6 may be normal or abnormal in UCMD, so diagnosis depends on mutation
analysis that is now available on blood.4
Bethlem myopathy is allelic with UCMD and usually associated with dominant mu-
tations. However, there is a spectrum of disease with many patients showing overlap,
such as severe Bethlem caused by recessive mutations and mild UCMD caused by
heterozygous mutations. Cardiomyopathy has never been reported associated with
either recessive or dominant mutations in these patients, setting them apart from other
CMD as well as the CM (Table 1).
Other forms of CMD are caused by mutations in laminin a2, a7 b1 integrin, and
several genes responsible for glycosylation of dystroglycan (Box 1). The most com-
mon of these are mutations in laminin a2 (LAMA) that cause merosin deficiency
CMD (see Case 3). Among people of Japanese origin, mutations of the fukutin gene
(FKN) are the most common cause of CMD.5 Abnormalities of merosin and glycosyl-
ation are usually associated with structural changes in the brain and brain stem. Pa-
tients may have epilepsy or mental retardation. Exceptions are patients who have a

Table 1
Characteristics of UCMD

Onset of weakness Neonatal or infancy

Congenital hip dislocation Common
Joint contractures Begin in infancy or early childhood
CK Normal or slightly elevated
Restrictive lung disease Severe and progressive
Cardiomyopathy Never seen
Brain MRI Normal
692 Gilbreath et al

Box 1
Classification: CMD and linked genes

Ullrich COL6A
MDC1A (Merosin deficiency) LAMA2
Congenital muscular dystrophy with integrin a7 defect ITGA7
Walker Warburg syndrome POMT1,2; LARGE
Fukuyama CMD FKTM
Muscle eye brain-like CMD FKTM, FKRP
MDC1C (fukutin-related protein deficiency) FKRP
MDC1D (LARGE deficiency) LARGE
Muscle eye brain disease POMGNT1, FKTM, FKRP
SEPN1-related myopathy SEPN1
L-CMD (LMNA-related CMD) LMNA

limb girdle dystrophy phenotype caused by mutations in glycosylation. They lie at the
mild end of the spectrum and generally do not have any involvement of brain or eye.6,7
Management is symptomatic and must include anticipatory guidance.
The patient presented here benefited from noninvasive ventilation and aggressive
pulmonary toilet (airway clearance). Although he suffered from relentless contractures,
reconstructive surgery was of limited help. Dynamic bracing may slow progression of
contractures but there are no controlled studies to determine this. Most patients
cannot maintain daily use of orthotics because of discomfort and many find recur-
rence of contractures after surgery. Unfortunately, for the typical child with UCMD,
life expectancy is shortened and death from respiratory failure or infection is common
in the second and third decades.

CASE 2

A 6-month-old boy presented to the Neuromuscular Disease Clinic with hypotonia and
dysphagia. Pregnancy, labor, and delivery were reported to be uncomplicated. How-
ever, the patient had significant sucking and swallowing difficulties at birth, necessi-
tating gavage feedings and then gastrostomy by age 1 month. Family members
denied respiratory difficulties.
On physical examination, the patient was a well-developed, well-nourished boy in
no acute distress. General examination was significant for a long myopathic face
(Fig. 2) with a high, narrow palate as well as pectus excavatum deformity of the chest
wall. Eye movements were normal as were lung and heart examinations. On neuro-
logic examination, the patient was profoundly hypotonic with decreased muscle
mass throughout and proximal muscle weakness. Deep tendon reflexes were absent.
CK was normal. A muscle biopsy (Fig. 3) demonstrated poor fiber-type differentia-
tion and the presence of nemaline rods. Sequencing of the nebulin (NEB) gene was
significant for heterozygous mutations: one at the junction of intron 11 and exon 12
predicted to disrupt the intron 11 splice acceptor site and another in exon 18 predicted
to result in frame-shift and premature protein termination. These mutations confirmed
a diagnosis of recessive nemaline myopathy.
The patient continued to gain developmental milestones slowly, ultimately walking
independently near 30 months of age. However, he suffered from nonprogressive
proximal muscle weakness and moderate restrictive lung disease. At 10 years of
age, a polysomnogram revealed alveolar hypoventilation with bradypnea and hyper-
capnia. He was treated with noninvasive nocturnal ventilation (BiPAP).
 Congenital Myopathies and Muscular Dystrophies 693

Fig. 2. Case 2, toddler with his older brother. Note the long, myopathic facies and asthenic
body habitus in both, which are typical of patients with CM.

This baby had severe hypotonia with swallowing and breathing problems from birth.
The differential diagnosis was spinal muscular atrophy (SMA) versus CM, although
CMD could not be ruled out on physical examination. He had no tongue fasciculations,
a finding against SMA. Although an electromyogram might have helped differentiate, it
would most likely require anesthesia. More commonly, SMA can be ruled out by mu-
tation analysis and the recommendation made for muscle biopsy.
The CM are best diagnosed by muscle biopsy using sophisticated histochemistry
and electron microscopy (Tables 2 and 3). When the characteristic structural changes
in the muscle fiber are found, mutation analysis is directed for genes at risk. In many
patients, the characteristic rods are not seen, even after as many as 4 muscle bi-
opsies. The absence of rods could be due to a sampling error with variation among
muscles or related to stage of disease. When rods are not seen, there will be fiber
size disproportion or lack of fiber type differentiation, both important clues to the diag-
nosis of CM.8
Nemaline and central core disease are the most common disorders of the CMs (see
Case 5). In this case, there was an affected older brother that informed the workup.
Nemaline myopathy, however, is not always a recessive disorder; there are several
mutations that are heterozygous or dominant in nature. Central core disease is typi-
cally dominant in inheritance but can be seen with de novo or sporadic mutations
and negative family history.
The management for nemaline myopathy is similar to that for the CMDs and SMA;
see published guidelines (Box 2).9,10 It is important to note that, although rare, cardio-
myopathy occurs with some regularity and, thus, monitoring with echocardiography is
694 Gilbreath et al

Fig. 3. (A) Muscle biopsy from Case 2 showing clusters of rods in nearly all fibers. This stain is
GT and rods stain as dark blue. (B) High power view of the same muscle sample with GT stain
shows the elongated shape of the rods. (C) Use of green fluorescent tag for v-actinin labels
the rods in a high power view. Nuclei are labeled red. (D) Electron microscopy of a muscle
biopsy from another nemaline patient shows several small rods disrupting the normal sarco-
meric pattern. (Courtesy of M. Vainzof, University of Sao Paolo, Brazil.)

important.11,12 More common are respiratory complications often with bulbar weak-
ness. Patients are at high risk for sleep hypoventilation as well as airway obstruction
regardless of the severity of their limb girdle weakness. There is a peculiar association
between diaphragm paralysis and nemaline myopathy (with little genotype/phenotype
correlation).13 Thus, annual pulmonary function tests sitting and supine and sleep
studies are crucial for preventing serious complications.

Table 2
Some phenotypic clues for CM

Nemaline myopathy Diaphragm weakness

Distal weakness in lower extremities (LEs)
Severe facial and bulbar weakness
Central core disease (including minicore) Muscle pain/cramps
MH
Dominant inheritance
Fiber type disproportion Low tone without other distinguishing
characteristics
Centronuclear myopathy (including Progressive ophthalmoparesis
myotubular myopathy) Early respiratory failure in boys
Progressive craniofacial deformities
 Congenital Myopathies and Muscular Dystrophies 695

Table 3
Congenital myopathies and their genes

Name Genes Mutated Inheritance

Nemaline myopathy TPM3 (1q21.3) AD or AR
NEB (2q22.3) AR
ACTA 1 (1q42.13) AD or sporadic, AR
TPM2 (9p13.3) AD
TNNT1 (19q13.42) AR (Amish private mutation)
KBTBD 13 (15q22.31) AD
CFL2 (14q13.1) AR
Core myopathy (including RYR1 (19q13.1) AR
minicore) SEPN1 (1p36.11) AR or sporadic
TTN (2q31.2) AR
MYH7 (14q12) AD
Fiber type disproportion ACTA1 (1q42.1) AD
Locus 2 (Xq13.1-q22.1) AR
SEPN1 (1p36.11) AR
TPM3 (1q21.2) AD
TPM2 (9p13) AD
MYL2 (12q24.11) AR
Centronuclear myopathy (including MTM1 (Xq28) X-linked
myotubular myopathy) DNM2 (19q13.1) AD
MYF6 (12q21.31) AD
CCDC78 (16p13.3) AD
BIN1 (2q14.3) AR

Abbreviations: AD, autosomal dominant; AR, autosomal recessive.

Orthopedic complications are common as well but not so predictable. They typically
affect the distal lower extremities and scoliosis is common. Many patients exhibit poor
weight gain and experience significant fatigue. There are no guidelines for exercise
beyond stretching, although some patients seem to benefit from aquatherapy
(Box 3). As a CM, progressive weakness is not expected but occurs often by the fourth
and fifth decades.

CASE 3

A 6-week-old baby boy presented to the Neuromuscular Disease Clinic for severe hy-
potonia. He was reported to have required an extended neonatal intensive care unit
admission following birth due to respiratory and feeding difficulties.
Physical examination demonstrated an alert infant with moderate facial weakness
and pectus excavatum deformity. Lung and heart examinations were normal.

Box 2
Management pearls: annual monitoring for CM

Pulmonary function tests (PFTs), sitting and supine

Electrocardiogram, echocardiogram according to risk
Nutrition and growth parameters
Swallowing and bulbar weakness
Polysomnogram if PFTs less than 65% predicted or symptoms of sleep disturbance
Orthopedic: range of motion, scoliosis screen
696 Gilbreath et al

Box 3
Management pearls: intervention

Avoid use of oxygen without ventilation

Avoid ventilation with high expiratory positive airway pressure (ie, >5 mm Hg)
Procedures requiring sedation/anesthesia should be done in pediatric specialty hospital with
access to pulmonology and cardiology expertise
Encourage use of dynamic bracing for prevention or reversal of contractures, especially in
lower extremities
Encourage aerobic, low-impact exercise but avoid fatigue

Neurologic examination demonstrated markedly decreased tone throughout with se-

vere head lag. Extraocular movements were full except for decreased upgaze bilater-
ally. In the supine position, there was no spontaneous movement of any muscle
groups except fingers and toes. There were no tongue fasciculations. Deep tendon re-
flexes were absent throughout.
CK was elevated at 16,000. Electrodiagnostic studies demonstrated a mild axonal
neuropathy. Brain MRI revealed abnormal white matter and pontine hypoplasia
(Fig. 4).
Muscle biopsy was significant for active myopathic changes, including rare degen-
erating and regenerating myofibers (Fig. 5). Immunohistochemistry revealed absent
a-2 laminin consistent with merosin-deficient congenital muscular dystrophy. DNA
mutation analysis showed him to be compound heterozygous for mutations in
LAMA2. He was heterozygous at the intron-exon 4 junction of the LAMA2 gene for a
mutation defined as c.396+1G>T and he was also heterozygous in exon 4 of
LAMA2 for a mutation defined as c.498G>A. At 8 years of age, the patient had signif-
icant dysphagia as well as restrictive lung disease and sleep-disordered breathing.
Merosin deficiency (MDC1A) represents the most common form of CMD after Ullrich
among people of western European origin.14 Mutations are recessive and affected

Fig. 4. (A, B) MRI images of the brain in Case 3. The white matter of both hemispheres is
abnormal and the brain stem is flattened.
 Congenital Myopathies and Muscular Dystrophies 697

Fig. 5. (A) H&E section from the biopsy of Case 3 shows myopathic features and secondary
inflammation by macrophages. (B) High power view of the same region emphasizes the pre-
dominance of macrophages, a characteristic of this disease early in its course. (C) Alkaline
phosphatase labels regenerating fibers of which there are many, evidence that this is an
active process such as muscular dystrophy. (D) Immunohistology using peroxidase tag shows
that dystrophin labeling is normal. (E) Immunohistology using antibody for v-dystroglycan
demonstrates normal labeling. (F) Immunohistology using 300-kDa antibody for merosin
demonstrates nearly complete absence of that protein, diagnostic for merosin deficiency
or MDC 1A. (Courtesy of D. Burns, UT Southwestern Medical Center, Dallas, TX.)

siblings and cousins are often encountered. Patients clinically look very similar to SMA
type 1 or severe type 2 cases but do not have tongue fasciculations. Brain imaging and
nerve conduction studies are usually abnormal after the age of 6 months and can aid in
early diagnosis.15 However, diagnosis should be confirmed by mutation analysis in all
cases providing for accurate prognosis and family planning.
There is a spectrum of disease from the severe infantile form with symptoms at birth
to mild weakness seen with partial merosin deficiency. Partial merosin deficiency is
defined by immunohistochemistry on muscle biopsy. It requires the use of 2
698 Gilbreath et al

antibodies for this protein against the 80-kDa and 300-kDa moieties. Most patients
with complete deficiency never walk.
One clue in this case was the abnormal vertical gaze that has been described in
many patients. The association with gaze palsies is seen in only a few CM and some-
times raises the possibility of congenital myasthenic syndrome. Cardiomyopathy has
been described but is rare, although all patients, whether they have partial or complete
deficiency, are at risk for epilepsy, of all types and at all ages.16
Management is as described above for other patients with CMs or CMDs. Patients
should be monitored for seizures but their cognitive function remains normal through
life (Fig. 6).

CASE 4

A 3-year-old boy presented to the Neuromuscular Disease Clinic with a history of inter-
mittent toe walking and frequent falls. In addition, the patient had difficulty climbing
stairs. He did not complain of muscle pain or muscle cramping and there were no con-
cerns for bulbar or respiratory weakness.
On physical examination, the patient was a well-developed and well-nourished boy.
General examination was significant for a slightly high and narrow palate. Respiratory
and cardiac examinations were normal. Musculoskeletal examination did not show ev-
idence of scoliosis but was concerning for scapular winging bilaterally. On neurologic
examination, the patient was found to be hypotonic with a slight increase in muscle
bulk in both calves. He was noted to have full antigravity movements of all 4 extrem-
ities. His gait demonstrated hyperextension of both knees, but he could heel and toe

Fig. 6. This young man was diagnosed by muscle biopsy with MDC1A in early childhood (A),
confirmed by mutation analysis later. He had dysphagia, gastrointestinal dysmotility, severe
progressive restrictive lung disease, and relentless orthopedic deformities but no seizures.
He uses BiPAP when asleep and enteral feedings. At the age of 21 years (B), he attended
clinic appointments alone via public transportation.
 Congenital Myopathies and Muscular Dystrophies 699

walk appropriately. The Gowers sign was positive and deep tendon reflexes were ab-
sent except for ankle jerks that were 21.
CK was elevated at 1300 iU/L. Electrodiagnosis did not demonstrate electrophysi-
ologic evidence for a neuropathy or irritative myopathy, although voluntary motor units
could not be assessed. A muscle biopsy was significant for disproportionately small
type 1 myofibers that contained centrally located nuclei (Figs. 7 and 8). DNA testing
for the DMPK (myotonic dystrophy) and MTM1 (myotubular myopathy) genes was
negative as was mutation analysis for ACTA1 and COL6 genes. Ultimately, the patient
was confirmed to be a compound heterozygote for Gln23354Stop and c.100185delA
mutations in the titin (TTN) gene, confirming his diagnosis of centronuclear myopathy.
This case is a good example of the “diagnostic odyssey” that many people with CM
experience. If the biopsy shows only nonspecific changes or the mutation analysis for
the most commonly associated genes (DMPK and MTM1 in this case) are negative, it
can be extremely difficult to counsel the patient and family regarding prognosis and
inheritance. This patient’s mutation was identified through collaboration with Dr Alan
Beggs at Boston Childrens’ Hospital.17 There is high hope that next-generation
sequencing will end such odysseys, but prohibitive costs, denied access, and varia-
tions in technique may prevent such hopes from being attained. The results of all
gene sequencing must be interpreted in the clinical context. When results are unclear,
consultation with a genetic counselor may be indicated. Therefore, for the CM, the
muscle biopsy remains the best means of narrowing the search for gene mutations.
As with many patients with recessive centronuclear myopathy or central core dis-
ease (see discussion below), the limb girdle weakness is mild. Many patients have pro-
gressive ophthalmoparesis, an important clinical finding that can indicate diagnosis.
This boy could still develop ophthalmoparesis in the second decade of life. There is
not much propensity for cardiomyopathy, although the risk remains as does that for
restrictive lung disease and orthopedic complications. Thus, the management is the
same as described above.

CASE 5

A 10-year-old girl presented to the Neuromuscular Disease Clinic for hypotonia. Birth
and developmental history were reported to be normal. However, family members

Fig. 7. (A) GT stain of biopsy from Case 4 shows some chronic but mild myopathic changes.
(B) H&E section shows variation in fiber diameter and internal nuclei in nearly half of all
fibers. (Courtesy of D. Burns, UT Southwestern Medical Center, Dallas, TX.)
700 Gilbreath et al

Fig. 8. Electron microscopy of the muscle from Case 4 shows a very small fiber with single
internal nucleus (arrow) in cross-section, typical of centronuclear myopathy. (Courtesy of
D. Burns, UT Southwestern Medical Center, Dallas, TX.)

recalled that the patient had been previously evaluated by an orthopedist as a toddler
due to an abnormal gait. She was diagnosed as being “pigeon-toed” and no interven-
tions were deemed necessary. At 8 years of age, the patient was noted to have diffi-
culty arising from the floor. She was referred for physical therapy services and
improved. Nevertheless, the patient continued to have difficulty climbing stairs as
well as running and jumping. Family members denied a history of muscle fatigue or
frequent falls.
On physical examination, the patient was a well-developed, well-nourished girl in no
acute distress. Lung and heart examinations were normal. Musculoskeletal examina-
tion was significant for slight scapular winging. On neurologic examination, the patient
was noted to have decreased muscle tone and decreased muscle bulk throughout.
Minimal ptosis was evident in the right eye with facial weakness including difficulty
burying eyelashes. Manual muscle testing demonstrated mild limb girdle weakness.
Shoulder abduction was 4 , elbow flexion 4 , hip flexion 3, and knee extension
31; all were symmetric. Her gait was significant for decreased heel strike bilaterally.
The Gowers sign was positive. Deep tendon reflexes were absent in the upper extrem-
ities and 11 in the lower extremities and symmetric.
Pulmonary function testing showed mild restrictive lung disease with forced vital ca-
pacity of 1.26 L or 63% predicted. CK was normal. The electromyogram was consis-
tent with a myopathic process. A muscle biopsy showed marked type 1 fiber
predominance and type 2 fiber atrophy. DNA testing of the ACTA1 gene was normal.
The patient’s weakness was nonprogressive. She had a repeat muscle biopsy per-
formed approximately 3 years after the first that again demonstrated type 1 myofiber
predominance (Figs. 9 and 10). There were rare fibers with core/targetoid-like change
and a mild loss of randomness of fiber-type distribution. Mutation analysis of the RYR1
gene was positive for a heterozygous mutation in exon 91, an undocumented variant
of uncertain clinical significance defined as c.12727G>A, which was predicted to
result in the amino acid substitution p.Glu4243Lys. Parental testing was negative, sup-
porting the conclusion that the patient carried a de novo, clinically significant mutation.
 Congenital Myopathies and Muscular Dystrophies 701

Fig. 9. (A) H&E stain of muscle biopsy from Case 5 shows minimal myopathic changes. (B) GT
section. (C) ATPase stain at pH 9.4. (D) ATPase stain at pH 4.3. (Courtesy of D. Burns, UT
Southwestern Medical Center, Dallas, TX.)

This patient had no history for malignant hyperthermia (MH) but RYRY1 (as well as
SEPN1) mutations are commonly associated with a significant risk of MH.18,19 There-
fore, identification of the mutation in individual patients as well as their family members
is crucial to avoid life-threatening events (Box 4). Although most pediatric-trained an-
esthesiologists avoid pharmacologic triggers when working with children with any
neuromuscular disorder, it is cost-effective to know the exact risk for a given case.

Fig. 10. Electron microscopy of muscle from Case 5 shows disruption of sarcomeric structure
suggestive of minicore formation. (Courtesy of D. Burns, UT Southwestern Medical Center,
Dallas, TX.)
702 Gilbreath et al

Box 4
Some triggers for MH/rhabdomyolysis

Succinylcholine (depolarizing muscle blockade)

Halothane (inhalational agents)
Excessive exercise, especially in heat with poor hydration

The general recommendation is that children with RYR1 or SEPN1 mutations or histo-
logic evidence of core myopathy wear a medical alert in the form of dog tag or bracelet
stating MH as a risk. Moreover, parents (and those of all children affected by neuro-
muscular disease) should be advised to avoid surgery outside a pediatric subspecialty
hospital, not only because of the risk of MH but also because of many possible post-
operative complications including respiratory failure, cardiac arrhythmias, and bowel
paralysis. Such children at risk are particularly susceptible to narcotic effects. There
are published guidelines for preoperative and postoperative management of children
with Duchenne muscular dystrophy, although 2 consensus statements address CMD
and CM specifically.10,20–24

SUMMARY

The cases presented in this article provide a survey of the CMDs and CMs commonly
seen in the pediatric neuromuscular clinic. Diagnosis most often depends on muscle
biopsy and mutation analysis, but the physician in charge must be aware of the exper-
tise of the biopsy laboratory and that of the DNA diagnostic laboratory. There are many
pitfalls that can result in misinterpretation of both the biopsy and the DNA; these are
best avoided by working with laboratories that have the highest expertise. Further-
more, it is important that patients and families receive complete information regarding
the diagnostic process and the results, including hard copies for their child’s own
records.
There are now published guidelines for the management of children with CMD and
CM. The guidelines have been publicized and distributed by several patient advocacy/
support organizations including the Muscular Dystrophy Association of USA, Cur-
eCMD, and the Joshua Frase Foundation. Such groups are lobbying for support of
clinical trials for patients with CMD and CM and some studies may well be seen online
in the next few years.

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