The Limb Girdle Muscular Dystrophies and The 15

Review Article
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The Limb-Girdle
Address correspondence to
Dr Stanley Jones P. Iyadurai,
Ohio State University, Wexner
Medical Center, Department
of Neurology, 395 W 12th
Ave, Columbus, OH 43210,
stanley.iyadurai@gmail.com.
Muscular Dystrophies and
Relationship Disclosure:
Dr Iyadurai has received
personal compensation for
the Dystrophinopathies
serving on the advisory
boards of Allergan; Alnylam
Stanley Jones P. Iyadurai, MSc, PhD, MD; John T. Kissel, MD, FAAN
Pharmaceuticals, Inc; CSL
Behring; and Pfizer, Inc. Dr
Kissel has received personal ABSTRACT
compensation for serving on
a consulting board of AveXis, Purpose of Review: The classic approach to identifying and accurately diagnosing limb-
Inc; as journal editor of Muscle girdle muscular dystrophies (LGMDs) relied heavily on phenotypic characterization and
& Nerve; and as a consultant
for Novartis AG. Dr Kissel has
ancillary studies including muscle biopsy. Because of rapid advances in genetic sequencing
received research/grant methodologies, several additional LGMDs have been molecularly characterized, and the
funding as principal investigator diagnostic approach to these disorders has been simplified. This article summarizes the
of a study from the National
Institutes of Health and has
epidemiology, clinical features, and genetic defects underlying the LGMDs.
received funding for clinical Recent Findings: In recent years, the advent of next-generation sequencing has heralded
trials from AveXis, Inc; an era of molecular diagnosis in conjunction with physical characterization. Inadvertently,
AxelaCare Health Solutions,
LLC; BioMarin; CSL Behring;
this process has also led to the ‘‘next-generation aftermath,’’ whereby variants of unknown
Cytokinetics, Inc; Ionis significance are identified in most patients. Similar to the published diagnostic and treat-
Pharmaceuticals; and Quintiles, ment guidelines for Duchenne muscular dystrophy, diagnostic and treatment guidelines
Inc; and receives publishing
royalties from Oxford
have recently been published for LGMDs. In addition, the first medication (based on the
University Press. exon-skipping strategy) for treatment of patients with a subset of Duchenne muscular
Unlabeled Use of dystrophy has been recently approved by the US Food and Drug Administration (FDA).
Products/Investigational Summary: The LGMDs are a heterogeneous group of hereditary, progressive, and
Use Disclosure:
Drs Iyadurai and Kissel degenerative neuromuscular disorders that present with primary symptoms of shoulder
discuss the unlabeled/ girdle and pelvic girdle weakness. Although a combination of clinical and molecular genetic
investigational use of evaluations may be sufficient for accurate diagnosis of LGMDs in many cases, the
corticosteroids to treat
Duchenne muscular dystrophy. contribution of imaging and histopathologic correlations still remains a critical, if not a
* 2016 American Academy necessary, component of evaluation in some cases.
of Neurology.
Continuum (Minneap Minn) 2016;22(6):1954–1977.
INTRODUCTION tities (eg, Emery-Dreifuss muscular dys-

The limb-girdle muscular dystrophies trophy) and with entities not necessarily
(LGMDs) are a heterogeneous group of presenting in a limb-girdle pattern of
genetic disorders generally characterized weakness (eg, dysferlinopathies).
by weakness of the shoulder and the pelvic The dawn of molecular genetics in the
girdle muscles. Based on the inheritance 1990s and, more recently, the increasing
patterns, autosomal dominant (LGMD application of next-generation massive
type 1), autosomal recessive (LGMD parallel-sequencing technologies have
type 2), and X-linked forms of LGMD resulted in a fundamental change in how
Supplemental digital content: have been described. Successive letters of these disorders are defined, identified,
Videos accompanying this
article are cited in the text as the alphabet have been used to name the diagnosed, and managed. For example,
Supplemental Digital Content. LGMDs according to the chronology of in the traditional approach, muscle bi-
Videos may be accessed by
clicking on links provided in the identification of the genetic locus. While opsies were performed routinely on es-
HTML, PDF, and app versions straightforward and convenient, this sys- sentially all patients with LGMD as part
of this article; the URLs are pro-
vided in the print version. Video
tem has sometimes generated confusion of the characterization and diagnostic
legends begin on page 1976. in regard to more traditionally named en- process. However, the lack of specificity
1954 www.ContinuumJournal.com December 2016
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

KEY POINTS
and significant overlap in biopsy find- shoulder girdle muscles, although specific h Limb-girdle muscular
ings among the various LGMDs (eg, the disorders may initially manifest more dystrophies have an
presence of inflammatory cells) have prominently in one region (eg, hips) com- estimated incidence of
rendered this invasive technique less pared to the shoulders. With progression, 1 to 6 out of 100,000.
useful and necessary in this day of readily weakness may spread outside of the h Limb-girdle muscular
available genetic testing. However, some pelvic and the shoulder girdle to more dystrophies are of
muscle biopsy findings are fairly charac- distal groups, the neck and axial muscles, dominant, recessive, or
teristic of certain LGMDs (eg, the pres- or both. Depending on the type of LGMD, X-linked forms.
ence of eosinophils in calpainopathy) and the pulmonary musculature and heart h The typical pattern of
are useful diagnostic tools in some cases may also be involved. Creatine kinase weakness in limb-girdle
when next-generation sequencing analysis (CK) levels may be normal, mildly elevated muscular dystrophies
involves the shoulder
of a patient with LGMD fails to establish (usually in LGMD1s), or highly elevated
girdle and the pelvic
a genetic diagnosis. Similarly, ultrasound (usually in LGMD2s or X-linked LGMD)
girdle muscles, with
or MRI of the muscle may be helpful in depending on the disorder. Extraocular variable involvement of
providing data about the pattern of in- muscles are usually spared, as are cranial the cardiac and
volved muscles and serve as a useful guide muscles, except in certain disorders where pulmonary musculature.
for the appropriate muscle for biopsy or the facial muscles may be involved. h The combination of
to help guide focused genetic testing. The current diagnostic approach still phenotypic evaluation,
relies on careful phenotypic delineation electrodiagnostic and
EPIDEMIOLOGY of the pattern of weakness, a search for muscle biopsy features,
The LGMDs have a general estimated in- other associated features (eg, contractures, and gene panel testing
cidence of 1 to 6 out of 100,000. How- heart involvement), distinctive EMG find- are helpful in diagnosis
of the limb-girdle
ever, this is likely an underestimate ings (including abnormal spontaneous
muscular dystrophies.
given that significant genetic, phenotypic, activity, complex repetitive discharges,
and regional variability confound these myotonic discharges), and focused genetic h Contractures and
scoliosis are common in
figures, as do variable and incomplete testing for suspected causative gene de-
limb-girdle muscular
penetrance, and care access. While fects. Currently, multigene next-generation dystrophies.
population-based whole-genome sequenc- panels are commercially available and
ing strategies may be helpful in estimating permit testing of a large number of genes
the prevalence more accurately, this in one step. For example, specific LGMD
approach is currently not practical be- panels may evaluate 25 to 35 genes, or
cause of the cost and labor intensiveness a general myopathy panel may evaluate
of the current whole-genome sequenc- 180 genes in a single pass. Although pow-
ing technologies. In the United States, erful, the process of screening multiple
calpainopathy, dysferlinopathy, and genes at the same time (multigene panel
dystrophinopathies are the most com- testing) for LGMDs typically results in
mon forms of LGMD. identification of multiple so-called vari-
ants of unknown significance. These may
CLINICAL FEATURES AND include novel variants not reported in
DIAGNOSIS disease or population databases, which
Although the LGMDs are, by definition, in many cases are not causative. When var-
congenital disorders, clinical manifesta- iants of unknown significance (either
tions can begin at almost any time from single or multiple) are identified, family
early childhood to late adulthood. Most of testing to establish segregation as well as
the disorders, in fact, manifest in adult- additional muscle biopsy studies (such as
hood with a range of presentation as immunostaining) may help establish the
late as the seventies and eighties. LGMDs diagnosis, at least in some cases. While
often manifest with the simultaneous intuitively and intellectually appealing,
onset of weakness in both the pelvic and such large panel testing increases cost
Continuum (Minneap Minn) 2016;22(6):1954–1977 www.ContinuumJournal.com 1955

Limb-Girdle Muscular Dystrophies
and invariably leads to testing of genes disorders, different allelic alterations re-
irrelevant to the presenting phenotype sult in different phenotypic expressions
and, worse yet, identification of unexpected/ from defects in the same gene. For exam-
irrelevant variants of unknown significance ple, LGMD2B (dysferlinopathy) can pres-
in other unwanted genes in the panel. ent as a classic LGMD phenotype or a
Therefore, the selection of the most distal-predominant myopathy (ie, Miyoshi
appropriate gene panel from the many myopathy). The following discussion high-
available must be based on precise phe- lights the characteristics of the various
notypic and laboratory characterization LGMDs based on the standard alphanu-
and the best guess as to the most likely meric nomenclature followed in paren-
diagnosis. theses by the involved protein.
Even with multigene panel testing,
a significant proportion of LGMD cases Limb-Girdle Muscular
(up to 25% in some instances) may re- Dystrophy Type 1 (Dominant
main undiagnosed.1 In such cases, whole- Forms of Limb-Girdle
exome sequencing may be performed, a Muscular Dystrophy)
process that typically involves sequencing To date, eight LGMD1 loci with domi-
of all known exons in a given individual, nant inheritance have been described
with variants called based on comparisons based on clinical and genetic criteria;
made to standard sequences. Although other dominant LGMDs will certainly be
evidence suggests that whole-exome se- identified in the future. Sporadic forms
quencing of the trio (the patient and the of LGMD1 are often encountered since
biological mother and father) increases de novo dominant mutations can present
the diagnostic hit rate,2 it is important with the disease phenotype (with an
to bear in mind that exome sequencing obvious lack of family history). At times,
does not provide complete coverage of the lack of penetrance and expressivity
all coding exons and typically does not and broad range of clinical variability
detect deletions and duplications. In ad- precludes the identification of the phe-
dition, genetic diagnosis via multigene notype in the carrier parent. The LGMD1
panel testing and whole-exome sequenc- disorders are usually adult onset and in
ing may be limited by insurance cover- general have a milder phenotype than
age, requires technical expertise, and is the LGMD2 disorders so that affected
usually restricted to specialized neuro- patients are usually in good health at
muscular centers around the country. The reproductive age. To date, mutations in
genetic evaluation of patients with nega- seven genes have been identified as
tive results in whole-exome sequencing is causative for LGMD1 disorders, with
therefore best pursued only at specialized commercial testing available for most
research centers. of the disorders. The LGMD1 subtypes,
Genetic and molecular characteriza- characteristic features, clinical features,
tions have revealed that the LGMD gene and limited gene information are sum-
products are localized to various parts of marized in Table 10-13 and described
the muscle fiber (nucleus, cytosol, Golgi briefly in the following sections.
apparatus, sarcolemma, sarcoplasmic re- Limb-girdle muscular dystrophy
ticulum, extracellular matrix, cytoskeleton type 1A (myotilinopathy). The onset
[cytoplasmic structural framework], and of this late-onset disease is variable from
contractile cytoskeleton [motor and motor- the midtwenties to midseventies. Weak-
associated proteins]) and perform a vari- ness is symmetric and starts in the legs
ety of related functions, resulting in a and then progresses to the arms. Distal
plethora of clinical phenotypes. In certain weakness is observed with further

TABLE 10-1 Limb-Girdle Muscular Dystrophy Type 1 Characteristicsa
Clinical Information Gene Information

Typical Creatine Heart Gene/
Type Onset Progressionb Kinase Level Involvement Locus Protein
LGMD1A Adulthood Slow 1Y15X Yes MYOT Myotilin
LGMD1B Variable; Slow 1Y6X Yes LMNA Lamin A/C
childhood to
adulthood
LGMD1C Childhood Slow to 10Y15X Yes CAV3 Caveolin 3

moderate
LGMD1D Adulthood Slow 1Y6X Not usual DNAJB6 HSP40
LGMD1E Adulthood Slow 2Y4X Yes DES Desmin

LGMD1F Variable; Rapid Variable; No TNPO3 Transportin 3
infancy to normal to 15X
adulthood
LGMD1G Adulthood Slow Variable; No HNRPDL Heterogeneous

normal to 10X nuclear
ribonucleoprotein
DYlike protein
LGMD1H Variable; Slow Variable; No 3p23 To be identified
childhood to normal to 10X
adulthood
LGMD = limb-girdle muscular dystrophy.
a
Modified with permission from Iyadurai SJ, Kassar D, Springer.3 B 2013 Springer Science+Business Media.
b
Progression of the disease as noted by time frame (arbitrarily assigned) of loss of ambulation: rapid is 2 years from diagnosis; moderate is 5 years
from diagnosis; slow is more than 5 years from diagnosis.
progression, although some patients may seen in some patients. Muscle biopsy
present with footdrop. In the upper reveals a myopathic pattern with signifi-
extremities, weakness is noticed in the cant size variability, rounded fibers,
wrist extensors, fingers extensors, and rimmed or autophagic vacuoles, hyaline
deltoid muscles. Facial and neck extensor inclusions, and spheroid bodies on
muscle weakness may occur. Some pa- ATPase staining. Mutations in myotilin
tients develop dysarthria (due to palatal gene cause LGMD1A.
weakness),4 myalgia, and joint contrac- Limb-girdle muscular dystrophy type
tures mainly of the ankles. Tendon re- 1B (laminopathy). LGMD1B usually man-
flexes are absent at the knees and the ifests before the age of 20 with symmet-
ankles but loss of tendon reflexes may be rical weakness affecting the proximal
diffuse. Cardiomyopathy is present in lower extremities (Case 10-1). However,
one-half of patients, with onset between a variant of this syndrome (Arg377His mu-
ages 60 and 70. Progression of weakness tation of the lamin A/C gene, infra vida)
is slow, with loss of ambulation usually may result in early and predominant
within 10 years of onset. Serum CK can be quadriceps involvement. Progression is
normal to 15-fold elevated. Needle EMG generally slow, with the upper extremities
reveals myopathic changes and fibrillation usually involved in the third or fourth de-
potentials, and myotonic discharges are cade. Cardiac abnormalities are noted in

about 60% of patients and are typified by endomysial thickness, and mislocalized
cardiomyopathy, atrioventricular conduc- and aggregated lamin. Mutations in the
tion block, bradycardia, and sudden car- lamin A/C gene underlie the LGMD1B
diac death.5 Specific mutations such as phenotype and also many other pheno-
the Arg377His have been associated with types. For example, patients with certain
dilated cardiomyopathy. Serum CK may mutations in the lamin A/C gene mani-
be either normal or mildly elevated. fest as Emery-Dreifuss muscular dys-
Muscle biopsy shows rounded fibers, trophy phenotype characterized by
variability in fiber size, increased contractures of the posterior cervical
Case 10-1
This 28-year-old woman with diffuse weakness and atrophy was seen initially as a 16-month-old girl when
her mother noted that she had difficulty running and arising from the floor. Muscle biopsy revealed a
dystrophic process. On follow-up examination at age 4, the patient used a wheelchair for all mobility.
Laboratory evaluation showed a mildly elevated creatine kinase level at that time. On follow-up
examination at age 21, generalized atrophy of the appendicular muscles was noted. The cranial, facial,
and truncal muscles were spared. Contractures were noted in the hips, ankles, and elbows. Pulmonary
function tests showed a vital capacity of 75% predicted. Gene sequencing identified a mutation in the
lamin A/C gene compatible with limb-girdle muscular dystrophy type 1B (Figure 10-1).
FIGURE 10-1 Patient in Case 10-1 with limb-girdle muscular dystrophy type 1B. Notice the
sparing of cranial musculature and severe atrophy of arm muscles (A). Elbow
and knee contractures, scoliosis, and scapular winging are common (B).
Comment. This case demonstrates a classic onset and progression as would be expected in patients with
lamin A/C mutations, an autosomal dominant limb-girdle muscular dystrophy. These patients have delayed
motor milestones, contractures, scoliosis, elevated creatine kinase levels, and develop pulmonary
dysfunction and cardiac abnormalities. Cranial nerves are not usually affected.

KEY POINT
muscles, elbows, and ankles; cardiac in- tients usually experience muscle cramps, h Patients with certain
volvement; slowly progressive weakness pain, and stiffness (particularly with exer- mutations in the lamin A/C
involving the humeral and peroneal mus- cise), and serum CK is elevated up to 10 gene manifest as
cles with some pelvic girdle involvement; times the normal value. Emery-Dreifuss muscular
tendon areflexia; and slight elevation in Limb-girdle muscular dystrophy type dystrophy phenotype
CK levels. Recently, recessive mutations 1D (HSP40 proteinopathy). LGMD1D characterized by
contractures of the
in lamin A/C resulting in the LGMD1B usually presents with onset of weakness
posterior cervical muscles,
phenotype have been described. at 20 to 60 years of age, although most elbows, and ankles; cardiac
Limb-girdle muscular dystrophy type patients have weakness, slowness, and involvement; slowly
1C (caveolinopathy and rippling muscle clumsiness of movements as children. Hip progressive weakness
disease). LGMD1C is an early-onset dis- girdle weakness and waddling gait are involving the humeral and
order with manifestation between 5 years noted first, followed variably by progres- peroneal muscles with
of age and adulthood. Proximal weakness sion to the shoulder girdle. Progression is some pelvic girdle
in the lower extremities, difficulty walk- gradual, with need for a wheelchair usually involvement; tendon
areflexia; and slight
ing, and a positive Gowers sign are usually occurring 20 to 30 years after diagnosis.
elevation in creatine
noted. Patients with LGMD1C may also Dysphagia occurs in about 20% of the pa- kinase levels.
experience cramps after exercise. Vari- tients, and dysarthria may occur. Cardiac
able clinical manifestations may occur in or respiratory involvement has not been
a single family, and the disorder often has observed with LGMD1D. Most patients
a benign clinical course. No evidence of have elevated serum CK (up to five times
respiratory impairment occurs, and life normal). Mild calf hypertrophy may be
expectancy is not reduced. Hypertrophic present. Myopathic changes are noted on
cardiomyopathy has been noted in EMG. Muscle biopsy usually shows varied
patients, although rarely. EMG may be fiber size, rounded fibers, endomysial
normal or reveal myopathic changes. thickening, rimmed vacuoles, eosinophilic
Usually, muscle biopsy demonstrates cytoplasmic bodies, and dystrophic fibers.
variability in muscle fiber size, fibers Mutations in DNAJB6 underlie LGMD1D
with internal nuclei, degenerating and phenotype.6
regenerating fibers, and increased con- Limb-girdle muscular dystrophy type
nective tissue. Caveolin 3 mutations un- 1E (desminopathy). LGMD1E is charac-
derlie LGMD1C. In muscle biopsies terized by dilated cardiomyopathy, cardiac
obtained from patients with LGMD1C, conduction system disease, and adult-
caveolin 3 is invariably reduced both onset myopathy.7 Cardiac manifestations
by immunohistochemistry and immuno- include arrhythmia, which manifests at
blot analysis. 20 to 25 years of age, and congestive
Another manifestation of patients with heart failure with four-chamber enlarge-
caveolin 3 mutations results in rippling ment during the third to fifth decade.
muscle disease phenotype. Rippling mus- Cardiac sudden death has been noted as
cle disease is characterized by several a major familial symptomatology.8 Mus-
specific behaviors of the muscle: worm- cle biopsy shows significant variability is
like movements on the surface of the fiber size, increased endomysial thicken-
muscle, percussion-related contraction, ing, cytoplasmic bodies, and eosinophilic
and muscle mounding. Muscle hyper- inclusions. Mutations in desmin gene
trophy is common in caveolinopathy. At were found to be causative of LGMD1E
times, a parent may be a benign carrier phenotype.
with muscle hypertrophy but have no Limb-girdle muscular dystrophy
other signs or symptoms. The presenting type 1F (transportinopathy). Onset of
manifestations are usually fatigue, tiptoe LGMD1F is typically in the third or fourth
walking difficulty, and myalgia. The pa- decade but can manifest in infancy. All

KEY POINT
h In most of the limb-girdle affected patients show characteristic pel- slow course. However, atrophy of shoul-
muscular dystrophy vic and shoulder girdle proximal weak- der and pelvic girdle muscles is noted.
type 2 disorders, the ness. Pelvic girdle impairment precedes Generalized hyporeflexia and calf hyper-
creatine kinase is quite the shoulder girdle weakness, and distal trophy are also characteristically noted.
elevated. Although weakness often occurs later. Respiratory Serum CK levels are usually elevated but
limb-girdle muscular muscles are clinically affected in some can be normal (normal to 10 times the
dystrophy type 2
patients with juvenile-onset LGMD1F. normal level). EMG reveals nonirritable
disorders are usually
of early childhood onset
Serum CK is normal in 40% of patients myopathic changes. Muscle histology
and quite debilitating, and varies between normal to as high as shows abnormal fiber size and shape
adult-onset forms have 15 times the normal levels. EMG of variation and increased presence of en-
also been described. proximal muscles shows myopathic domysial and perimysial connective tissue.
changes including short-duration, low- Central nuclei are occasionally present.
amplitude potentials and polyphasia. No Although the LGMD1H mutation has
abnormalities in sensory and motor nerve been linked to 3p23Yp25.1,9 the gene
conduction velocities are noted. Muscle defect is unknown.
biopsy shows fiber size variability, in-
creased connective tissue (both endo- Limb-Girdle Muscular
mysial and perimysial), rimmed vacuoles, Dystrophy Type 2 (Recessive
central nuclei, and scattered dystrophic Forms of Limb-Girdle
fibers. Gene defects in transportin 3 are Muscular Dystrophy)
associated with LGMD1F. Twenty-three distinct LGMD2 loci with
Limb-girdle muscular dystrophy recessive inheritance have been de-
type 1G (HNRPDL proteinopathy). The scribed. In most of these disorders, the
age of onset in LGMD1G is in the third CK is quite elevated. Although LGMD2s
or fourth decade. The initial symptoms are usually of early childhood onset and
are seen in the proximal lower limbs as- quite debilitating, adult-onset forms
sociated with muscle cramps followed have also been described. A variable,
by weakness of the upper limbs. Pro- progressive course is typical. Although
gressive finger and toe flexion limitation LGMD2I (FKRP deficiency) is the most
with decreased range of motion in inter- common form of all LGMDs in northern
phalangeal joints also occurs. However, Europe, LGMD2A (calpainopathy) is the
intrinsic hand muscles are not usually most prevalent in many other European
affected. CK may be normal or elevated countries, as well as in Turkey, Brazil,
up to 10 times the upper level of Japan, Russia, and Australia. LGMD2I,
normal. Muscle biopsy shows fiber size LGMD2B, and LGMD2A remain the
variability, perimysial thickening, rimmed most common autosomal recessive
vacuoles, and necrotic fibers. Interest- LGMDs in North America. The LGMD2
ingly, scattered areas of angulated subtypes, characteristic features, clinical
fibers may also be noted. Mutations in features, and genetic information are
the heterogeneous nuclear ribonucleo- listed in Table 10-2. Individual LGMD2
protein DYLike protein underlie the subtypes are described in the follow-
LGMD1G phenotype. ing sections.
Limb-girdle muscular dystrophy Limb-girdle muscular dystrophy type
type 1H. LGMD1H is extremely rare and 2A (calpainopathy). LGMD2A is charac-
has been described in only 11 members terized by a wide variability in clinical
of a single large family. The disease onset features and rates of progression. Although
is usually in the fifth decade and manifests the mean age at onset is approximately
with proximal weakness in upper and 14 years, a considerable variation in pre-
lower extremities and follows a relatively sentation from ages 2 to 40 years has

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

Creatine
Kinase Heart
Type Typical Onset Progression Level Involvement Gene Protein
LGMD2A 12Y30 years Slow Markedly No CAPN3 Calpain 3
elevated
LGMD2B Adolescence Slow 10X Possible; not DYSF Dysferlin

common
LGMD2C Early childhood Moderate to 20Y30X Yes SGCG +-Sarcoglycan

rapid
LGMD2D Variable Rapid 20X Yes SGCA !-Sarcoglycan
LGMD2E Early childhood Moderate to 20X Yes SGCB "-Sarcoglycan

rapid
LGMD2F Early childhood Rapid 10Y50X Yes SGCD G-Sarcoglycan
LGMD2G Childhood, Moderate 3Y30X Yes, TCAP Telethonin

adolescence approximately
50%
LGMD2H Adolescence, Slow 1Y20X No TRIM32 E3 ubiquitin ligase

adulthood
LGMD2I Early childhood Rapid to slow 5Y40X Yes FKRP Fukutin-related

and late protein
adulthood
LGMD2J Childhood, Slow 10Y15X No TTN Titin
adulthood
LGMD2K Childhood Slow 10Y40X No POMT1 Protein
O-mannosyltransferase 1
LGMD2L Adulthood Slow 1Y100X No ANO5 Anoctamin 5
LGMD2M Early infancy Slow 50Y100X Possible FKTN Fukutin
LGMD2N Prenatal to infancy Rapid 6Y12X No POMT2 Protein

O-mannosyltransferase 2
LGMD2O Late childhood Moderate 2Y10X No POMGNT1 Protein O-linked

mannose "1,2-N-
acetylglucosaminyltransferase
LGMD2P Early childhood Moderate 20X No DAG1 Dystroglycan
LGMD2Q Early childhood Slow 10Y50X No PLEC1 Plectin 1
LGMD2R Childhood to Slow Normal Yes DES Desmin

young adulthood
LGMD2S Early childhood Slow 10Y15X No TRAPPC11 Trafficking protein particle

complex 11
Continued on page 1962

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

Creatine
Kinase Heart
Type Typical Onset Progression Level Involvement Gene Protein
LGMD2T Variable Slow Variable Possible GMPPB GDP-mannose
pyrophosphorylase B
LGMD2U Early childhood Rapid to 6Y50X Possible ISPD Isoprenoid synthase

moderate domain containing
LGMD2V Variable Usually slow 1Y20X Yes, GAA Acid !-1,4-glucosidase

predominantly in
infantile-onset
cases
LGMD2W Childhood Variable, but Up to 25X Possible LIMS2 LIM zinc finger
usually slow domain containing 2
a
been described. Ambulation is affected Although no significant cardiac involve-

during adolescence but is affected earlier ment occurs, worsening of respiratory
in infantile-onset disease. The disorder function may lead to cardiac complica-
is characterized by a symmetric, selective tions. Strangely, CK levels may be normal
atrophic involvement of limb-girdle and or elevated, even up to 500 times the
trunk muscles.10 Muscle weakness usually normal values. With progression of the
begins in the pelvic girdle, with difficulty disease, the CK values may begin to drop,
running, climbing stairs, or rising from a consistent with worsening atrophy of the
chair. The pelvic girdle muscles are the affected muscles. EMG shows an irritable
most severely affected, even when the myopathy characterized by increased
disease starts in the shoulder girdle. Hip insertional activity, fibrillation potentials,
adductors and gluteus maximus are the and positive sharp waves. Muscle biopsy
earliest clinically affected muscles and, shows variability of muscle fiber size, en-
to a lesser degree, the hip flexors and domysial thickening, necrotic fibers and
posterior thigh muscles are also affected. rare regenerating fibers, type 1 predom-
The distal leg muscles and proximal hip inance, lobulation of type 1 fibers, and
abductors are relatively spared. The weak- inflammation in perivascular or endomysial
ness in the upper extremity muscles and areas.11 Eosinophilic infiltrates are char-
the shoulder girdle occurs later in the acteristic. Imaging of the thigh muscles
disease course. Scapular winging is evi- may show marked atrophy of the ham-
dent. Abdominal muscles may also be strings and hip adductors and moderate
involved. Early in the disease course, atrophy in quadriceps with sparing of the
contractures are seen in the calves, wrists, sartorius. With progression of the disease,
elbows, and fingers. As a result, toe other thigh muscles are also affected
walking may be noted in early stages. In depending on clinical severity; the adduc-
later disease, contractures in the proximal tors and semimembranosus muscles are
parts of the body (including the spine) involved in young patients with minimal
are noted. functional motor impairment. In patients

with restricted ambulation, a diffuse in- cific distal myopathies such as Miyoshi
volvement of the posterolateral muscles myopathy (also known as Miyoshi mus-
of the thigh and of the vastus intermedius cular dystrophy type 1) and distal myop-
is found with relative sparing of the vastus athy with anterior tibial onset. Symptom
lateralis, sartorius, and gracilis. Imaging of onset of LGMD2B ranges from adoles-
the calf muscles reveals involvement of cence to late adulthood (10 to 40 years of
the soleus muscle and the medial head age), with significant variability in pre-
of the gastrocnemius with relative sparing sentation between family members and
of the lateral head. LGMD2A is caused by different families. Usually, the muscle
mutations in the CAPN3 gene, which weakness starts in the pelvic girdle, man-
encodes for a muscle-specific proteolytic ifesting as difficulty running and walking
enzyme called calpain 3 (Case 10-2). up the stairs. Early difficulty with walking
Limb-girdle muscular dystrophy is usually associated with involvement of
type 2B (dysferlinopathy). LGMD2B has a the gastrocnemius (specifically the me-
wide range of clinical presentations, from dial head). In later stages of the disease,
a classic limb-girdle presentation to spe- upper extremity muscles are involved.
Case 10-2
A 50-year-old woman presented with arm and leg weakness and a history of motor difficulties that she
had experienced since childhood. (She stated, ‘‘I was a klutzy kid.’’) However, she had experienced
noticeable weakness only at age 30 when she had difficulty going up stairs. Laboratory
evaluations showed an elevated creatine kinase level of 1300 IU/L (six times the upper limit of normal).
Muscle biopsy demonstrated significant size variability, many small rounded fibers, central nuclei,
increased endomysial connective tissue, and necrotic fibers, but no inflammation. Physical examination
showed normal cognition, normal cranial nerves, scapular winging, proximal and distal weakness,
hyperlordotic posture, generalized atrophy, and normal sensation (Figure 10-2). Gene testing revealed
compound heterozygous mutations in the calpain 3 gene, diagnostic of limb-girdle muscular
dystrophy (LGMD) type 2A.
FIGURE 10-2 Patient in Case 10-2 with limb-girdle muscular dystrophy type 2A. The patient
has notable shoulder abduction weakness (A) and scapular winging (B).
Comment. This case demonstrates common features associated with autosomal recessive LGMDs.
Creatine kinase is usually elevated to a higher level (compared to autosomal dominant LGMDs in general).
Early-onset motor delay and normal cognition are usually noted. While scapular winging can be variably
seen, cranial musculature is usually preserved.

KEY POINT
h Miyoshi and limb-girdle Specifically, biceps are affected approx- veals either a reduction or lack of staining.
muscular dystrophy imately 10 years after the onset of lower Mutations in the skeletal muscle protein
phenotypes can be extremity weakness. The disease follows dysferlin underlie LGMD2B.
present in the same a fairly slow course of progression, and Limb-girdle muscular dystrophy
family. The exact reason loss of ambulation is noted at 30 years of types 2C TO 2F (!, ", +, and G sarco-
behind the differences in age. However, some patients do not lose glycanopathies). The age of onset and
presentation within a
ambulation until age 60. Hypertrophy of clinical presentation has a wide inter- and
given family is unclear.
several muscles (deltoid, biceps, and the intrafamilial variability. The clinical pre-
calves) is noted early in the course of the sentation can vary from a Duchenne
disease. Classic diamond on quadriceps muscular dystrophy (DMD)Ylike course
sign is seen in most patients. This sign to intermediate to a mild Becker mus-
represents the characteristic shape ac- cular dystrophy (BMD)Ylike phenotype
quired by the anterior compartment in a given family. The onset of the disease
muscles of the thigh when the patient is approximately 5 or 6 years of age with
attempts to sit down (lower his or her involvement mainly of proximal muscles,
torso or back as if sitting in a chair) with although distal involvement may occur.
feet firmly and flatly planted on the The inability to walk may occur anywhere
ground. In some patients, cramps and between the second and the fourth
muscle discomfort may be the only early decade. The glutei, adductors, paraspinal,
presenting symptoms. The allelic form abdominal, subscapular, and soleus mus-
of Miyoshi distal myopathy may present cles are affected whereas quadriceps is
in early adulthood with the inability to spared in some patients.12 Patients may
walk on or get up on toes. However, the develop calf and tongue hypertrophy and
anterior tibialYonset variant may present deafness. Respiratory failure occurs in
with footdrop and steppage gait. In these the third decade of life. Cardiac functions
distal-predominant allelic forms, the prox- are fairly spared. Serum CK is noted to be
imal muscles and the upper limbs be- extremely high. EMG shows small-
come affected later in the disease course. amplitude, short-duration, polyphasic
Serum CK levels are considerably motor unit action potentials. Muscle
increased. Muscle imaging confirms a biopsy shows fiber size variability,
selective involvement of the soleus and rounded fibers, increased endomysial
gastrocnemius (medial head) and early thickness, and necrotic fibers. Rarely,
muscle edema. Miyoshi and LGMD phe- inflammatory infiltrates are also found.
notypes can be present in the same family. The immunoreactivity of the affected
The exact reason behind the differences sarcoglycan may be reduced or absent.
in presentation within a given family is Secondary reductions in other sarco-
unclear. EMG shows typical myopathic glycans may also be noted. Occasionally,
changes. Muscle pathology shows inflam- reductions in dystrophin staining may
mation, necrosis, and degeneration of mus- also be noted. However, how the second-
cle fibers, fiber size variability, and rarely, ary reduction in other sarcoglycan or de-
fiber splitting. Endomysial thickening is creased dystrophin staining relate to the
also commonly noted. Amyloid deposition phenotype is unclear. The individual sar-
at the muscle membrane, endomysium, coglycans and their deficiencies relate to
or perivascular spaces are noted in some the specific LGMD type (2C, 2D, 2E, and
patients. Given the predominant inflam- 2F). Sarcoglycans appear to play a role in
mation seen in the muscle biopsies in maintaining muscle membrane integrity.
these patients, a misdiagnosis of polymyo- Limb-girdle muscular dystrophy type
sitis is not uncommon. However, in these 2G (telethoninopathy). Patients with
patients, dysferlin immunostaining re- LGMD2G usually present at a mean age

KEY POINT
of onset of 12 years with difficulty walking, veals mild dystrophic changes including h Limb-girdle muscular
running, and climbing stairs. Although fiber size variability, endomysial fibrosis, dystrophy type 2I is one
this condition spares the gastrocne- and muscle fiber degeneration and regen- of the most common
mius (which is affected in LGMD2B/ eration. Fiber splitting and internal nuclei limb-girdle muscular
dysferlinopathy), these patients have dif- are observed. dystrophies with a carrier
ficulty walking on their heels. The tibialis Another allelic variant of LGMD2H frequency of 1 in 400 in
the white population.
anterior is severely affected, and difficul- is sarcotubular myopathy. As the name
ties with foot dorsiflexion and footdrop implies, distinctive features in muscle
ensue. Atrophy of the shoulder girdle biopsy led to the name. Patients with the
muscles is prominent. In the lower ex- sarcotubular myopathy allelic variant pres-
tremities, the pelvic girdle muscles and ent with exercise-induced fatigue and
distal muscles are affected. About 40% of muscle pain. In addition to the weakness
patients with LGMD2G become nonam- of pelvic and shoulder girdle muscles,
bulatory by the third or fourth decade. neck flexion weakness is also noted. Other
Interestingly, calf atrophy or hypertrophy accompanying features include mild facial
may be noted as the first sign of disease in weakness, scapular winging, calf hyper-
one-half of patients. Serum CK may be trophy, and Gowers sign. In general, the
mildly elevated (three times the normal muscle atrophy noted in successive ex-
level) or quite highly elevated (30 times aminations is a fair indication of progres-
the normal level). Muscle biopsy shows sive weakness. Contractures in the Achilles
significant variability in fiber size, in- tendons are noted frequently, and deep
creased number of fibers with central tendon reflexes are either normal or
nuclei, necrotic and regenerating fibers, depressed. Serum CK levels may be ele-
and rimmed vacuoles. In Western blot vated up to 20 times the normal values.
analysis, telethonin is absent. LGMD2G is Muscle biopsy shows fiber size variability,
most commonly seen in patients with rounded fibers, and in addition, small
Brazilian ancestry and is caused by muta- rounded vacuoles in type 2 fibers. Small
tions in the gene encoding telethonin.13,14 abnormal spaces are noted in segments
Other variant telethonin syndromes in- of many muscle fibers. The gene muta-
clude dilated cardiomyopathy 1N and tions underlying LGMD2H involve the
congenital muscular dystrophy. gene encoding tripartite motif-containing
Limb-girdle muscular dystrophy protein32 (TRIM32).
type 2H (TRIM32 proteinopathy/ Limb-girdle muscular dystrophy type
sarcotubular myopathy). To date, 2I (fukutin-related proteinopathy).
LGMD2H has been described only in the LGMD2I is one of the most common
Hutterite population of North America15 LGMDs with a carrier frequency of 1 in
and is a mild form of recessive LGMD with 400 in the white population. The combi-
a variable clinical presentation. Disease nation of limb-girdle weakness, respiratory
onset is usually within the second or third insufficiency, and dilated cardiomyopathy
decade of life and progression is slow; is noted in patients with LGMD2I.16 The
most patients continue walking into their disease onset may be as early as infancy
sixth decade. Quadriceps and pelvic gir- (5 months) or as late as midadulthood
dle muscles are primarily involved, and (40 years). Patients with early-onset disease
patients show a waddling gait and diffi- symptoms may present with hypotonia and
culty rising from the squatting position. display delayed motor milestones. Tongue
Cardiac and facial involvement does not hypertrophy is often noted, although
occur. The serum CK is high (up to 20 other muscles may also display hypertro-
times the normal level), and EMG shows phy. These patients usually lose ambula-
myopathic changes. Muscle histology re- tion by their early teens (much like

patients with DMD). The loss of am- responsible for LGMD2J. However,
bulation is usually followed by cardiomy- it should be emphasized that titin is a
opathy.17 The patients with adult-onset large protein, and mutations/truncations
symptoms usually have a milder form of affecting several distinct domains within
the disease and a slow course of pro- the protein may lead to specific pheno-
gression. However, hypertrophy of mus- types including selective involvement
cles may be noted; the calf, anterior thigh of the cardiac, skeletal, or respiratory
muscles, brachioradialis, and tongue may muscles. The details of the genotype-
be prominently involved. These patients phenotype correlation are still being
may also report nonspecific symptoms worked out.
such as cramps and myalgia, especially Limb-girdle muscular dystrophy
after exercise. In selected cases, myoglo- type 2L (anoctaminopathy). LGMD2L
binuria may occur. Brain MRI and cogni- usually presents as an asymmetric dis-
tion are normal.18 Serum CK is elevated order and that involves the muscles of
between 10 to 30 times the normal level. the scapula. The onset is usually in adult-
Muscle biopsy shows fiber size variation, hood, anywhere from 20 years to 55 years.
necrosis, and regeneration of muscle Asymmetric atrophy of muscles is com-
fibers, increased endomysial connective monly noted in quadriceps femoris,
tissue, and type 1 predominance. LGMD2I biceps brachii, and gastrocnemius. In
is caused by mutation in Fukutin-related some patients, calf hypertrophy is noted;
protein gene (FKRP), which also affects however, calf atrophy ensues with pro-
glycosylation of dystroglycans, which is gression of the disease, usually in an
discussed in the following section on asymmetric fashion. While proximal
LGMD types 2K, 2M, 2N, 2O, and 2P. weakness is prominent in both the shoul-
Limb-girdle muscular dystrophy der and the pelvic girdle, distal weakness
type 2J (titinopathy/Finnish distal my- is not usually noted. Selected patients
opathy). LGMD2J is most prevalent in may develop subtle facial weakness.
patients from Finland or of Finnish origin. Myalgia, either due to exertional or non-
The onset of symptoms may be variable exertional causes, is a common present-
and can occur anywhere from childhood ing symptom in these patients. Serum CK
to adulthood (third decade). LGMD2J can have a very wide range, from normal
classically presents as a myopathy involv- levels to 80 times the normal level. EMG
ing distal muscles, specifically of the leg. shows an irritable myopathy. Muscle
The initial manifestation is noted in the biopsy shows rounded fibers, fiber size
tibialis anterior muscle, and hence is also variability, increased endomysial connec-
known as tibial muscular dystrophy. MRI tive tissue, degenerating fibers, and occa-
of the muscles show prominent involve- sionally inflammatory infiltrates and fiber
ment of the tibialis anterior and the splitting. Mutations in the anoctamin 5
extensor digitorum longus. In general, (ANO5) gene underlie LGMD2L. Recently,
LGMD2J follows a slow course of pro- dominant mutations in ANO5 have
gression. Usually patients become been noted to be associated with the
nonambulatory about 20 years after LGMD2L phenotype.
symptom onset. In these patients, car- Limb-girdle muscular dystrophy
diomyopathy is not usually noted. Serum types 2K, 2M, 2N, 2O, 2P. This group
CK can be elevated up to 20 times the of LGMD disorders shares a common
normal level. Muscle biopsy shows myo- feature in that they all result from hypo-
pathic features. Immunohistochemistry glycosylation of !-dystroglycan. The
reveals secondary reduction in calpain proteins involved are as follows: type
3.19 Mutations in the titin gene are 2K: POMT1 proteinopathy; type 2M:

KEY POINT
fukutinopathy; type 2N: POMT2 pro- require cardiac pacemaker placement. h Limb-girdle muscular
teinopathy; type 2O: POMGNT1 pro- Muscle pathology is significant for hya- dystrophy types 2K, 2M,
teinopathy; and type 2P: dystroglycan 1 line accumulations and amorphous 2N, 2O, and 2P usually
proteinopathy. These disorders all usually subsarcolemmal inclusions. Recessive present in early childhood
present in early childhood as congenital mutations in desmin underlie LGMD2R. as congenital muscular
muscular dystrophies with multiple organs As noted in the previous section, dom- dystrophies with multiple
organs involved (muscle,
involved (muscle, eye, brain). Variable inant mutations in desmin underlie
eye, brain).
rates of progression, proximal muscle LGMD1E.
weakness, mild pseudohypertrophy, mi- Limb-girdle muscular dystrophy
crocephaly, and mild mental retardation type 2S (TRAPPC11 proteinopathy).
with an IQ ranging from 50 to 76 is usually Patients with LGMD2S have an early
noted. Joint contractures occur in about childhood onset of proximal weakness,
one-half of patients.20 The serum CK is 40 scapular winging, and mild myopathic
times the normal level. Muscle histology facies. CK is elevated up to 10 times the
shows fiber size variability and reduced !- normal values. In addition, global devel-
dystroglycan. In LGMD2M, muscle hyper- opmental delay, infantile-onset hyperki-
trophy is seen in the posterior leg and, in netic movements (dystonia/chorea), and
some patients, the tongue. Spinal rigidity, truncal ataxia are noted. EMG reveals a
joint contractures, and cardiomyopathy myopathic picture, and MRI of the brain
may occur.21,22 Although brain MRI may may reveal cerebral volume loss. The
be normal, vermis hypoplasia and gene defect underlying this LGMD is in
polymicrogyria may be seen. the trafficking protein particle complex
Limb-girdle muscular dystrophy type 11 gene.
2Q (plectinopathy). Plectinopathy has Limb-girdle muscular dystrophy
been reported in Turkish, Indian, English, type 2T (GDP-mannose pyrophos-
and Egyptian families/backgrounds. phorylase B proteinopathy). The dis-
The disease onset occurs in early child- ease onset is quite variable with onset
hood and is usually accompanied by from birth to age 40 and has a fairly slow
microcephaly and mental/intellectual progression of proximal weakness. In-
disabilities. The CK is elevated up to 20 fants with early-onset LGMD2T have hy-
times the normal level. EMG shows potonia at birth and intellectual disabilities,
myopathic changes, and muscle biopsy sometimes with concurrent onset of
reveals a dystrophic picture, varied seizures. In older patients, enlarged
fiber size, internal nuclei, necrosis/ calves, rhabdomyolysis, and cramps are
regeneration, and reduced plectin stain- noted. Some patients may have cardiac
ing. Mutations in the plectin gene under- involvement. EMG is myopathic and
lie LGMD2Q. muscle biopsy reveals a dystrophic pic-
Limb-girdle muscular dystrophy ture, internal nuclei, muscle fiber necro-
type 2R (desminopathy). Patients with sis, and endomysial thickening. The gene
this desmin variant syndrome (as op- defect underlying this LGMD has been
posed to LGMD1E) have a recessive localized to the GDP-mannose pyrophos-
mode of inheritance. The disease onset phorylase B gene.
is usually early (childhood to the second Limb-girdle muscular dystrophy type
decade of life) and involves facial weak- 2U (ISPD proteinopathy). The disease
ness and respiratory muscle weakness onset is in early childhood with a pro-
in addition to the proximal weakness. gressive course of proximal-predominant
High-arched palate and scoliosis are weakness. Hypotonia, gait disorder, and
also noted. All patients have severe Gowers sign may be noted. Loss of am-
atrioventricular conduction defects and bulation occurs early, around 10 to 12 years

KEY POINTS
h Identification of limb-girdle of age. Hypertrophy of muscles may be General Treatment Approach
muscular dystrophy type noted. Cardiac involvement with left for the Dominant and
2V (Pompe disease, also ventricular dysfunction may be noted Recessive Forms of Limb-Girdle
known as acid maltase as well. MRI of the brain is usually Muscular Dystrophies
deficiency) is crucial since normal. CK is usually elevated three to All of the LGMD syndromes cause pro-
IV enzyme replacement 50 times the normal level. Muscle biopsy gressive weakness, although the rates
therapy is life-saving for
shows a dystrophic picture. The gene of progression vary considerably. Certain
infants with the disorder
and improves ambulation
defect associated with this disease is in LGMD syndromes have cardiac involve-
and respiratory status in the isoprenoid synthase domain- ment, and affected patients are prone to
adults with the disease. containing gene. cardiac conduction system defects, which
h Pompe disease can Limb-girdle muscular dystrophy may lead to sudden death. Rarely, respi-
have infantile-onset, type 2V (Pompe disease). Preisler and ratory insufficiency may occur, but usually
adolescent-onset, and colleagues23 have suggested that Pompe in late stages of the disease and in pa-
adult-onset forms. disease (acid maltase deficiency or !- tients severely affected. In general, later-
Respiratory insufficiency 1,4-glucosidase deficiency) should be onset disease predicts a better prognosis.
and thigh adductor included as an LGMD because it was Except for LGMD2V (acid maltase defi-
weakness is commonly identified in 8% of patients in a group of ciency), where enzyme replacement ther-
seen in conjunction with
unclassified LGMDs. Pompe disease can apy is an available treatment option, no
proximal weakness.
have infantile-onset, adolescent-onset, specific disease-altering treatments cur-
h For most patients with a and adult-onset forms. Respiratory insuf-
limb-girdle muscular
rently exist for any of the LGMD1 or
dystrophy, physical therapy
ficiency and thigh adductor weakness is LGMD2 disorders, although corticoste-
and occupational therapy commonly seen in conjunction with prox- roids have been reported helpful in
should be encouraged to imal weakness. EMG reveals complex maintaining muscle function in LGMD2I.
prevent the formation repetitive discharges and myotonic dis- However, novel therapies and treatment
of contractures and to charges, specifically in thoracic paraspinal approaches are being explored in disor-
maximize limb use. muscles. Muscle biopsy shows character- ders where inflammatory pathways may
h In the subset of patients istic subsarcolemmal periodic acid- play a role (eg, dysferlinopathies). Exon-
with a limb-girdle SchiffYpositive inclusions. The gene skipping strategies are also being ex-
muscular dystrophy with defect lies in the deficiency of the acid plored in several disorders.
heart involvement, serial
!-glucosidase enzyme (GAA). Identifica- For most patients, physical therapy
ECG and echocardiograms
tion of this disorder is crucial since IV and occupational therapy should be en-
are mandatory for
monitoring cardiac status,
enzyme replacement therapy is life-saving couraged to prevent the formation of
and cardiac MRI is for infants with the disorder and improves contractures and to maximize limb use.
increasingly being used to ambulation and respiratory status in Some patients with LGMD report cramps
identify early myocardial adults with the disease. in the muscles, and symptomatic treat-
fibrotic changes. Limb-girdle muscular dystrophy type ment may be provided with either baclo-
2W (LIMS2 proteinopathy). LGMD2W fen, tizanidine, or gabapentin. Genetic
has onset in childhood with severe weak- counseling may be helpful for the affected
ness noted proximally and with fairly slow families and the patients.
progression. Cardiac involvement may In the subset of patients with heart
happen in the third decade. Macroglossia, involvement (ie, LGMD types 1A, 1B, 1C,
calf hypertrophy, and triangular tongue 2C, 2D, 2E), serial ECG and echocardio-
are unique features of this condition. CK grams are mandatory for monitoring
is elevated up to 25 times the normal cardiac status. In these patients, cardiac
level. Muscle biopsy shows variability in MRI is increasingly being used to identify
fiber size, internal nuclei, and increased early myocardial fibrotic changes. In these
endomysial thickness. Defects in the patients, cardiologic follow-up is crucial
LIMS2 gene underlie LGMD2W. for management of cardiomyopathy and

KEY POINTS
placement of intracardiac pacemaker or gene alterations in the X-linked dystro- h Duchenne muscular
defibrillators when indicated. Respiratory phin gene (and resultant abnormal dystrophy is caused by
involvement is common in most LGMD dystrophin protein), leading to a phe- alterations in the
types, especially in those with severe pe- notypic spectrum that includes a milder dystrophin gene, and the
ripheral weakness (including Pompe dis- BMD to severe DMD. However, dys- incidence has been
ease), and pulmonary function tests are trophinopathies can also manifest as reported to be 1 per
3500 male live births.
useful in identification of respiratory weak- isolated quadriceps myopathy, asymptom-
ness. Noninvasive or invasive methods atic or symptomatic hyperCKemia, “aches, h Boys with Duchenne
of ventilation are helpful in this clinical cramps, and pains” syndrome, rhabdo- muscular dystrophy
usually present between
setting, although which is preferable is myolysis, manifesting female carriers,
ages 2 and 5 years.
somewhat controversial. X-linked dilated cardiomyopathy, and
disorders of cognition such as develop-
X-Linked Limb-Girdle Muscular mental delay, attention deficit hyperactiv-
Dystrophy ity disorder, and impaired intelligence.
The X-linked LGMDs are summarized Dystrophin gene structure, clinical
in Table 10-3. Only the dystrophino- and molecular genetic diagnosis. Muta-
pathies will be discussed in this article. tions in the dystrophin gene, located on
Dystrophinopathies. Dystrophinopa- the X chromosome, cause DMD/BMD.
thies, as the name implies, result from The dystrophin gene is one of the largest
a
TABLE 10-3 Selected List of X-linked Limb-Girdle Muscular Dystrophies
Clinical Phenotype Gene Information

Creatine
Typical Kinase
Condition Onset Progression Level Allelism Gene Protein
Duchenne Early Slow to 100Y200X Becker muscular DMD Dystrophin
muscular childhood moderate dystrophy
dystrophy
Becker muscular Late Slow 10Y15X Duchenne muscular DMD Dystrophin
dystrophy childhood dystrophy
Barth syndrome Infancy Moderate Normal X-linked dilated TAZ Tafazzin
cardiomyopathy
Emery-Dreifuss Variable; Slow 2Y10X X-linked sinus EMD Emerin
muscular teenage node dysfunction
dystrophy type 1 years
Emery-Dreifuss Adulthood Slow 2Y10X Hyaline body FHL1 Four-and-

muscular myopathy; one-half-
dystrophy type 6 X-linked myopa- LIM domains
thy with postural 1
muscles atrophy
Danon disease Early Moderate 4Y35X X-linked vacuolar LAMP2 Lysosomal-

childhood cardiomyopathy associated
and myopathy membrane
protein 2
a

KEY POINT
h Boys with delayed motor genes in the human genome (by genomic opathy, or limb-girdleYtype weakness
milestones, enlarged size, including large introns), spanning should raise suspicion of the condition.
calves, proximal weakness about 2.3 megabases. The extent of Boys with delayed motor milestones,
(including Gowers sign), intronic sequences is such that out of enlarged calves, proximal weakness (in-
and elevated creatine the whole transcript (preYmessenger RNA), cluding Gowers sign), and elevated CK
kinase levels (100 to the 79 exons only make 0.6% of the gene. levels (100 to 200 times the normal level)
200 times the normal level)
The dystrophin gene encodes a major should be suspected having of DMD.
should be suspected of
having Duchenne
3685 amino acid, 427 kD skeletal muscle Diagnosis relies on DNA analysis of the
muscular dystrophy. protein. Eight other promoters direct dystrophin gene. Deleterious DNA alter-
transcription of seven other transcripts, ations include deletions (50% to 60%; in
with expression in skeletal, cardiac, and frame or out of frame), sequence alterations
smooth muscle cells and in multiple other (20% to 35%), duplications (5% to 10%), or
tissue cell types including the brain. The leading missense and nonsense mutations,
dystrophin protein connects the contrac- splice siteYaltering mutations, and cryptic
tile apparatus to the extracellular matrix intronic mutations. Deletions and duplica-
via the muscle membrane. tions may be detected by multiplex poly-
The dystrophinopathies are inherited merase chain reaction (PCR), multiplex
in an X-linked recessive fashion; ie, a ligation-dependent probe amplification,
male child receives (inherits) the muta- and chromosome microarray techniques;
tion from the mother. However, in a sequence alterations may be detected by
sizeable minority of cases (20% to 30%), Sanger or next-generation sequencing.
the mutation identified in the affected Epidemiology. The incidence of DMD
son is not identified in the mother by in live male births is estimated between 1
gene testing. In such cases, the mutation in 3500 and 1 in 5000. BMD is much less
is thought to arise de novo or reflect common with a prevalence of 1 in 17,500
germline mosaicism. In a mother who to 1 in 50,000. As expected, the preva-
tests negative for the mutation because lence of BMD is higher in comparison to
of germline mosaicism, the possibility of that of DMD mainly because of the
delivering another affected boy in a shortened survival in the latter group.
subsequent pregnancy is not excluded, Clinical features. Boys with DMD
and caution should be used in genetic present at a young age, usually between
counseling in such cases. Prenatal diag- 2 and 5 years of age with delayed motor
nosis or preimplantation genetic testing milestones, falls, and difficulties running
is available for mothers who test nega- and jumping. Prominent head lag, calf
tive for their son’s mutation or in whom enlargement (often termed pseudo-
germline mosaicism is suspected. Female hypertrophy, a partial misnomer as the
carriers may exhibit a DMD/BMD-like enlargement results from a combination
phenotype (including dilated cardiomy- of fibrotic replacement and true fiber
opathy) due to random lyonization of the hypertrophy), and Gowers sign are almost
X chromosome (heterochromatinization always seen. Progression is steady, and
or inactivation of the X chromosome). If untreated patients typically are in wheel-
lyonization occurs to the chromosome chairs by age 12. Clinically, respiratory and
containing the wild-type dystrophin, and cardiac issues ensue. By classic conven-
the chromosome containing the mutant tion, boys still walking after their 16th
dystrophin is expressed, a DMD/BMD- birthday are considered to have BMD,
like phenotype may be observed in the and boys who stop walking by age 12 are
female patient. considered to have DMD. This distinction
A positive family history, in conjunc- is in some ways artificial since corticoste-
tion with an elevated CK level, cardiomy- roid therapy may prolong ambulation by

KEY POINTS
1 to 3 years, thus blurring the clinical hypertrophic cardiomyopathy, and con- h Steroids help patients
distinction between BMD and DMD. gestive heart failure are common. Regular with Duchenne
Patients with dystrophinopathy have surveillance with ECG, long-term heart mon- muscular dystrophy
highly elevated CKs, usually 100 to itoring, and echocardiogram in conjunc- prolong ambulation and
200 times the normal level. EMG usually tion with a cardiologist is recommended. increase longevity.
shows an irritable, proximal-predominant Angiotensin-converting enzyme inhibitors h Cardiomyopathy is
myopathy. Currently, muscle biopsy is and beta-blockers have been proven to common in patients
very seldom indicated but will show be beneficial. Lung functions decline with with Duchenne
rounded fibers, significant size variability, disease progression as well. Pulmonary muscular dystrophy.
increased endomysial thickness, hyper- functions can be followed with time, and
contracted fibers, inflammatory cells, and necessary noninvasive/invasive strategies
occasional ring fibers. Immunohisto- may be employed (in conjunction with
chemical stains with antibodies generated a pulmonologist) to improve the quality
against the various epitopes (DYS3, DYS1, of life. In consultation with orthopedic
and DYS2) may show absent staining in surgeons, scoliosis may be surgically
certain fibers. fixed if indicated and necessary. Patients
Dystrophinopathies are multisystem with DMD demonstrate calf hypertro-
disorders with multidisciplinary teams phy (Figure 10-3) in earlier stages and
necessary for optimal management. Pa- contractures in later stages (Figure 10-4)
tients with dystrophinopathies eventually and may experience severe nighttime
have involvement of the cardiac, pulmo- cramps. Cramps may be readily treated
nary, musculoskeletal, and cognitive sys- with nighttime stretches and gabapentin.
tems. Cardiac involvement progresses Several types of cognitive issues, including
with progression of the muscle disease. attention deficit disorder, autism spectrum
Sinus tachycardia, arrhythmia, dilated or disorders, obsessive-compulsive disorder,
FIGURE 10-3 Images of a 6-year-old boy with Duchenne

muscular dystrophy showing calf hypertrophy
evaluated from posterior view (A) and from
lateral view, further accentuated by standing
on toes (B).

the quality of life of the patient and the

family members (Case 10-3).
Becker muscular dystrophy. In gen-
eral, patients with BMD display a milder
phenotype in comparison to patients with
DMD, and the weakness onset is also later.
Late onset of weakness is associated with
a milder phenotype. Despite the milder
weakness noted in the skeletal muscles,
the cardiac muscles are affected just the
same as in patients with DMD. Therefore,
treatments for cardiac management
should not be delayed. Breathing func-
tions are affected as in patients with DMD,
but at a later time course. Some patients
with BMD may require noninvasive venti-
Contractures in a patient with Duchenne lation. Although the benefit of corticoste-
FIGURE 10-4
muscular dystrophy. Ankle and foot roids in patients with BMD is unclear,
contractures are common in the later course
of Duchenne muscular dystrophy. some clinicians employ prednisone at
0.75 mg/kg/d in patients with BMD as well.
Female carriers of dystrophin muta-
KEY POINT and depression are commonly seen. tions. Female carriers of the X-linked
h Female carriers of Referral to a psychiatrist and treatment of dystrophin mutations may present with
dystrophin mutations may a DMD-like phenotype. However, it is
these disorders are helpful in improving
present with a Duchenne
muscular dystrophyYlike
phenotype and may have
cardiomyopathy as well. Case 10-3
A 5-year-old boy was brought by his mother to his pediatrician because of
‘‘running difficulties.’’ The mother noted that the boy was the product of a
normal pregnancy, but was not able to walk until 16 months of age. She also
had noticed prominent calves in the boy. She volunteered the history of her
brother who had had similar calves and had died at the age of 12 with heart
complications. The patient’s vital signs were significant for mild hypertension.
Examination revealed normal cranial nerves, proximal weakness of the upper
and lower extremities, calf hypertrophy, diminished reflexes (except at the
ankles), normal sensation, and normal plantar responses bilaterally. Laboratory
evaluation revealed an elevated creatine kinase level at 200 times the upper
limit of normal. Based on the clinical presentation and family history,
Duchenne muscular dystrophy (DMD) was suspected, and the patient was
referred to a local neuromuscular expert for further evaluation. Gowers sign
(Supplemental Digital Content 10-1, links.lww.com/CONT/A210) was noted
on that examination. DNA analysis of the dystrophin gene revealed a
deletion of exons 21 to 24, leading to premature termination of the
dystrophin protein, and a diagnosis of DMD was confirmed. The patient
was started on prednisone 1 mg/kg/d, and a cardiology referral was made.
Comment. This case demonstrates a classic presentation of DMD in a
young boy with early-onset motor delay and calf hypertrophy. Whenever
high creatine kinase, motor delay, and calf hypertrophy are encountered,
dystrophinopathy should be considered.

KEY POINT
more common in affected women at ages mutation either by supplying additional h Gene therapy,
30 or older. In subtle cases, the manifes- wild-type dystrophin or minidystrophin exon-skipping strategies,
tation may be related to asymptomatic or under high-expression promoters (gene and suppression of
symptomatic hyperCKemia or nocturnal therapy strategies), or “reading” through premature termination
cramps. Although these symptoms may premature stop codons introduced by approaches are being
be benign, dilated cardiomyopathy and missense mutations (premature termina- developed for treatment
of Duchenne
left ventricular dilatation are noted in 20% tion elimination), or skipping the exons
muscular dystrophy.
of the carriers.24 These patients should be containing out-of-frame mutations (exon
referred to cardiologists as well for opti- skipping technology). Clinical trials are
mal management and treatment. For this underway to assess the efficacy of these
reason, from a genetic standpoint, female specific therapeutic agents in patients
first-degree relatives of male patients with with DMD/BMD, with several companies
DMD/BMD and sisters of mothers of male seeking approval by the US Food and
patients with DMD/BMD should be of- Drug Administration (FDA) for specific
fered testing for the dystrophin mutation exon skipping agents. At the time of this
identified in the affected male relative. writing, the FDA has approved the first
Treatment of dystrophinopathies. exon-skipping medication, eteplirsen, for
As with the other LGMDs, no definitive use in a select subset of patients with
treatment for dystrophinopathies cur- DMD. This medication enables preY
rently exists. In addition to the general messenger RNA to skip exon 51 in the
outline for treatments described previously dystrophin reading frame, producing
for all of the LGMDs, patients with DMD truncated dystrophin. Approximately
(and probably BMD) respond to treatment 20% of boys with DMD have mutations
with various regimens of corticosteroids in exon 51 of the dystrophin gene and may
(prednisone, deflazacort, or prednisolone) benefit from this treatment. However,
with unequivocal benefit in prolonging although the medication has been ap-
ambulation, delaying the decline of muscle proved by the FDA, there remains some
function, reducing falls, and delaying controversy within the academic commu-
pulmonary and (probably) cardiac com- nity over whether the studies to date
plications.25 Corticosteroids (mainly demonstrate enough clinical benefit to
prednisone in the United States) are justify the approval. The study that was
usually started in patients of ages 5 and done contained only 12 patients and used
up, but some clinicians choose to start historical controls to assess changes in a
corticosteroid treatment at diagnosis, 6-minute walk test, which was the func-
even at younger ages. Prednisone treat- tional end point. Follow-up biopsies did
ment of 0.75 mg/kg/d has been used show a significant increase in dystrophin,
quite widely. Other regimens involve com- but this was not clearly shown to correlate
bining this weekly dose to be distributed with functional improvement.26,27
on Saturdays and Sundays. Prophylaxis
with calcium, vitamin D, proton pump CONCLUSION
inhibitors, and antidepressants may be The LGMDs are a heterogeneous group
necessary, concomitant with steroid treat- of disorders that, as the name suggests,
ment. A large international FOR-DMD manifest as weakness in the shoulder
(Finding the Optimal Steroid Regimen girdle and the pelvic girdle muscles.
for Duchenne Muscular Dystrophy) study Dominant, recessive, and X-linked
is currently comparing deflazacort and forms of LGMDs have been described.
prednisone regimens for managing DMD. The current classification system of
In addition, novel treatment method- LGMDs uses the notation type 1 for
ologies have relied on correcting the DMD dominant forms and type 2 for recessive

forms. Physical characterization and di- generationYbased multigene LGMD

agnostic imaging may be helpful in panel gene-testing options are available
identifying the specific form. Specific to help with diagnosis. Multigene panel
distinguishing characteristics (Table 10-4), testing combined with traditional
involvement of muscle pattern on phenotype-based approaches have
MRI (Table 10-5) and muscle biopsy been instrumental in identifying newer
features (Table 10-6) may be helpful in LGMDs. With the advancement of
delineating between the subtypes. How- sequencing technologies, the list of
ever, definite diagnosis is achieved by LGMDs has grown and is expected to
genetic testing. Several commercial next grow. Understanding of gene functions
TABLE 10-4 Distinguishing Features of Limb-Girdle Muscular

Dystrophies
Type Feature
LGMD1A (myotilinopathy) Upper extremities distal weakness and
contractures, dysarthria, palatal hypophonia,
footdrop, and areflexia
LGMD1B (laminopathy) Contractures and cardiac conduction defects
LGMD1C (caveolinopathy) Rippling muscles and muscle hypertrophy
LGMD1E (desminopathy) Facial weakness and cardiac conduction defect

LGMD1F (transportinopathy) Early respiratory muscle involvement
LGMD1G (HNRPDL Finger and toe flexion limitation

proteinopathy)
LGMD2A (calpainopathy) Contractures and atrophy of shoulder and pelvic

girdle muscles
LGMD2B (dysferlinopathy) Medial gastrocnemius atrophy
LGMD2C, LGMD2D, LGMD2F Tongue hypertrophy

(sarcoglycanopathies)
LGMD2H (sarcotubular myopathy, Scapular winging and calf hypertrophy

TRIM32 proteinopathy)
LGMD2I (fukutinopathy) Tongue and calf hypertrophy, cardiac and

respiratory muscle involvement
LGMD2L (anoctaminopathy) Asymmetric atrophy of muscles, mandibular dysplasia
LGMD2R (desminopathy) Facial weakness, respiratory muscle involvement,

high-arched palate
LGMD2S (TRAPPC11 Scapular winging, hyperkinetic movements

proteinopathy)
LGMD2V (acid maltase deficiency) Proximal weakness and respiratory insufficiency
LGMD2W (LIMS2 proteinopathy) Calf and tongue hypertrophy and triangular tongue
Dystrophinopathy Calf hypertrophy, distal contractures, preserved

ankle reflex despite the weakness

TABLE 10-5 Pattern of Affected Thigh Muscles in Magnetic
Resonance Imaging Evaluation of Patients With
Limb-Girdle Muscular Dystrophy
Type Affected Thigh Muscle(s)

LGMD1A (myotilinopathy) Adductor magnus, biceps femoris, semimembranosus,
vastus medialis, vastus intermedius
LGMD1B (laminopathy) Adductor magnus, biceps femoris, vastus medialis and

vastus lateralis
LGMD1C (caveolinopathy) Normal at the level of the thigh
LGMD1D (HSP40 Adductor magnus, biceps femoris, semimembranosus,

proteinopathy) adductor longus
LGMD1E (desminopathy) Semitendinosus, sartorius, gracilis

LGMD1F Vastus lateralis
(transportinopathy)
LGMD2A (calpainopathy) Adductor magnus, semimembranosus

LGMD2B (dysferlinopathy) Adductor magnus, vastus lateralis, semimembranosus
LGMD2I (fukutinopathy) Adductor magnus, biceps femoris, semimembranosus
LGMD2L Adductor magnus, biceps femoris, semimembranosus,

(anoctaminopathy) semitendinosus, rectus femoris, vastus medialis and
vastus lateralis
LGMD2V (acid maltase Adductor magnus, vastus medialis, vastus intermedius,

deficiency) biceps femoris
Dystrophinopathy (Duchenne Adductor magnus, vastus medialis and vastus lateralis,

muscular dystrophy) rectus femoris
Dystrophinopathy (Becker All anterior and posterior compartment muscles,

muscular dystrophy) sparing sartorius, gracilis
TABLE 10-6 Muscle Biopsy Features of Limb-Girdle Muscular

Dystrophies
Type Feature(s)
LGMD1A, LGMD1E, LGMD1F, LGMD1G Rimmed or autophagic vacuoles
LGMD1A, LGMD2R Hyaline inclusions, spheroid bodies

LGMD1B Mislocalization of lamin
LGMD1C, LGMD2A, LGMD2B, Inflammation

sarcoglycanopathies, LGMD2L,
dystrophinopathies
LGMD1E Eosinophilic inclusions, cytoplasmic bodies

LGMD1F, LGMD1H Central nuclei
Continued on page 1976

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

Dystrophies Continued from page 1975
Type Feature(s)
LGMD1G Atrophic angular fibers
LGMD2A Lobulated fibers
LGMD2A Eosinophilic infiltrates
LGMD2A Amyloid deposition (Congo red positivity)
LGMD2H Small rounded vacuoles in type 2 fibers

LGMD2I Type 1 predominance
LGMD2Q, LGMD2T, LGMD2W Increased internal nuclei
LGMD2R, LGMD2V Periodic acid-SchiffYpositive or Ynegative,

amorphous subsarcolemmal inclusions
Dystrophinopathies Hypercontracted fibers
Dystrophinopathies Ring fibers

and mutation pathology will give insight 2. Ghaoui R, Cooper ST, Lek M, et al. Use of
whole-exome sequencing for diagnosis
into the disease process and possible
of limb-girdle muscular dystrophy:
therapy in the future. Given the lack of outcomes and lessons learned. JAMA Neurol
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egies for management and supportive
treatment have been suggested as guide- 3. Iyadurai SJ, Kassar D. Limb-girdle muscular
dystrophies. In: Katirji B, Kaminski HJ,
lines.25,28 However, several clinical trials Ruff RJ, editors. Neuromuscular disorders in
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VIDEO LEGEND 5. Verhaert D, Richards K, Rafael-Fortney JA,
Supplemental Digital Content 10-1 Raman SV. Cardiac involvement in patients
with muscular dystrophies: magnetic
Gowers sign. A 5-year-old boy with
resonance imaging phenotype and genotypic
Duchenne muscular dystrophy demon- considerations. Circ Cardiovasc Imaging
strating the Gowers sign. Notice how he 2011;4(1):67Y76. doi:10.1161/CIRCIMAGING.
“climbs on himself” to stand up. 110.960740.
6. Harms MB, Sommerville RB, Allred P, et al.

links.lww.com/CONT/A210 Exome sequencing reveals DNAJB6
B 2016 American Academy of Neurology. mutations in dominantly-inherited myopathy.
Ann Neurol 2012;71(3):407Y16. doi:10.1002/
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INTRODUCTION tities (eg, Emery-Dreifuss muscular dys-

1954 www.ContinuumJournal.com December 2016

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Clinical Information Gene Information

LGMD1C Childhood Slow to 10Y15X Yes CAV3 Caveolin 3

LGMD1D Adulthood Slow 1Y6X Not usual DNAJB6 HSP40

LGMD1E Adulthood Slow 2Y4X Yes DES Desmin

LGMD1G Adulthood Slow Variable; No HNRPDL Heterogeneous

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Clinical Information Gene Information

LGMD2B Adolescence Slow 10X Possible; not DYSF Dysferlin

LGMD2C Early childhood Moderate to 20Y30X Yes SGCG +-Sarcoglycan

LGMD2D Variable Rapid 20X Yes SGCA !-Sarcoglycan

LGMD2E Early childhood Moderate to 20X Yes SGCB "-Sarcoglycan

LGMD2F Early childhood Rapid 10Y50X Yes SGCD G-Sarcoglycan

LGMD2G Childhood, Moderate 3Y30X Yes, TCAP Telethonin

LGMD2H Adolescence, Slow 1Y20X No TRIM32 E3 ubiquitin ligase

LGMD2I Early childhood Rapid to slow 5Y40X Yes FKRP Fukutin-related

LGMD2M Early infancy Slow 50Y100X Possible FKTN Fukutin

LGMD2N Prenatal to infancy Rapid 6Y12X No POMT2 Protein

LGMD2O Late childhood Moderate 2Y10X No POMGNT1 Protein O-linked

LGMD2Q Early childhood Slow 10Y50X No PLEC1 Plectin 1

LGMD2R Childhood to Slow Normal Yes DES Desmin

LGMD2S Early childhood Slow 10Y15X No TRAPPC11 Trafficking protein particle

Continued on page 1962

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Clinical Information Gene Information

LGMD2U Early childhood Rapid to 6Y50X Possible ISPD Isoprenoid synthase

LGMD2V Variable Usually slow 1Y20X Yes, GAA Acid !-1,4-glucosidase

been described. Ambulation is affected Although no significant cardiac involve-

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1964 www.ContinuumJournal.com December 2016

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1966 www.ContinuumJournal.com December 2016

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Clinical Phenotype Gene Information

Emery-Dreifuss Adulthood Slow 2Y10X Hyaline body FHL1 Four-and-

Danon disease Early Moderate 4Y35X X-linked vacuolar LAMP2 Lysosomal-

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