Limb-Girdle Muscular Dystrophy

By: Karen Dabi

 Limb-girdle muscular dystrophies are defined by their clinical and genetic

heterogeneities, with common features of progressive weakness and wasting of
proximal limb-girdle muscles. Limb-girdle muscular dystrophy represents a variety
of autosomal recessive and dominant disorders.
 The clinical characteristics : (pelvic/scapular) and/or distal muscle involvement
with typical sparing of facial muscles, and high serum creatine kinase levels. ( upper
arm of the muscles biceps and deltoid and pelvic girdle).
 Etiology: The various forms of limb-girdle muscular dystrophy are caused by
mutations in many different genes. These genes provide instructions for making
proteins that are involved in muscle maintenance and repair.
- Some of the proteins produced from these genes assemble with other proteins
into larger protein complexes. These complexes maintain the physical integrity
of muscle tissue and allow the muscles to contract. Other proteins participate in
cell signaling, cell membrane repair, or the removal of potentially toxic wastes
from muscle cell
 Epidemiology: 1 in more than 100,000 livebirths
 Onset: Late adolescence: early childhood
 Inheritance: Autosomal recessive or dominant
 Course: Slowly progressive; mild impairment
 LGMD represents a collection of genetically heterogeneous disorders that can be broadly
divided on a genetic basis into two groups.
o LGMD type 1 (LGMD1A through 1H) are all inherited dominantly
- has a typical age of onset in adulthood as late as the seventh decade of life
- Is the result of the absence of myotilin and is very rare. Myotilin is a thin
filament protein associated with the Z disk and involved in assembly of the
contractile mechanism of the cell
- prominent distal weakness > proximal
o LGMD1A
- AKA “myofibrillar myopathy”
- has a typical age of onset in adulthood as late as the seventh decade of life
- prominent distal weakness > proximal
o LGMD1B
- has a wide variability in phenotype depending on mutation type
- This ranges from severe Emery-Dreifuss muscular dystrophy to a somewhat less-
aggressive LGMD-type phenotype
- Cardiac conduction defects are common and need to be aggressively managed.
- In addition, the development of dilated cardiomyopathy is also seen in this
population.
- The contracture pattern: elbow flexion and ankle plantar flexion contractures,
along with trunk and cervical extension contractures, with relative sparing of the
quadriceps muscle strength in most cases.
o LGMD1C (caveolin 3) is one of a number of ways that abnormalities in Caveolin 3 can
present.
 - In this form, first symptoms are typically seen in the first decade with proximal
weakness and the Gowers sign.
- In addition, calf hypertrophy similar to DMD and postexercise soreness is common.
- Caveolin 3 can also present with isolated elevated creatine kinase without
weakness, rippling muscle disease (percussion-induced muscle contraction), or as
an isolated hypertrophic cardiomyopathy.
o LGMD 1D
- onset is typically between the third and sixth decade of life
- ambulation is typically preserved with functional deficits characterized by problems
climbing steps and running.
- Contracture is not a prominent feature in LGMD1D.
- The distribution of weakness of the legs is characterized by proximal weakness in
addition to posterior compartment (hamstring more than quadriceps) weakness
with inconsistent involvement of the arms.

o LGMD1E (Desmin)
- presentation is typically between the second and sixth decade of life, with the
distribution of weakness in a typical LGMD distribution or more distally in a
scapuloperoneal pattern.
- Affected Individuals Duchenne muscular dystrophy with pseudohypertrophy of
calves and lordotic posture that places the weight of the trunk behind the hip joint.
Even though weakness occurs symmetrically, habitual standing postures may create
asymmetries in flexibility in some cases.

LGMD type 2 (LGMD2A through 2Q) are inherited recessively and the most common.
- is the result of a genetic defect on the seventeenth chromosome
- can be that of classic LGMD or, alternatively, either a Miyoshi myopathy
phenotype, which presents with gastrocsoleus involvement as the defining
factor, or as a more rapidly progressive wasting of the anterior tibialis.
-affects proximal more than distal muscles and follows a steady progressive course,
although the course can vary widely even in a given family in some forms.
o LGMD2A (CAPN3)
- include phenotypic variability from first decade of life onset and rapid progression to onset later onset and
slower progression.
- Approximately 70% of affected individuals present between ages 6 and 18 years.
- The typical pattern of involvement is that of a classic limbgirdle pattern, with the gluteal and adductor
muscles most affected.
- The average age of ambulation loss varies considerably (5-39 years) and is related to age of onset.
- The underlying genetics seems to be related to the phenotypic severity.
- Individuals with two null mutations are much more homogeneous, with an average age of presentation of
15 years.
o LGMD2B (Dysferlin)
- The phenotypic presentation of LGMD2B can be that of classic LGMD or, alternatively, either a Miyoshi
myopathy phenotype
- which presents with gastrocsoleus involvement as the defining factor, or as a more rapidly progressive
wasting of the anterior tibialis.
o LGMD2C-F Sarcoglycan
- The typical presentation of LGMD2C-F Sarcoglycan is in the later first decade of life with proximal weakness
similar to that of DMD.
 - However, there is significantly more variability and some individuals present later in the second decade of
life or even in adulthood.
- Cardiomyopathy is most common. Respiratory failure plantarflexion contractures.
o LGMD2G
- (Telethonin) presents primarily as an LGMD pattern of skeletal muscle weakness; however, there are some
reports of congenital presentation or hypertrophic cardiomyopathic presentation.
o LGMD2H
- presents with significant variability between groups of individuals and with typically proximal weakness that
ranges from nonprogressive to slowly progressive.

o LGMD2I
-is one of the dystroglycanopathies.
- Its clinical presentation is widely distributed, ranging from mild, late-onset disease as is found in the
LGMD2I phenotype to a severe form of CMD with brain and eye abnormalities in addition to severe
weakness at birth.
- The severity of the phenotype is dependent on the efficacy of the underlying protein that is produced in the
glycosylation of dystroglycan.
- Many of the genes implicated have both more-severe and less-severe forms, depending on the specific
mutation characteristics and how severely the final protein is effected in terms of its function in the
glycosylation process.
o LGMD2J (Titin)
- can present in two phenotypic varieties.
- In the case where there is a mutation on one allele, the phenotype is one of a tibial muscular dystrophy,
with anterior tibialis and long toe extensor weakness as the first symptoms which may progress to proximal
weakness in old age.
- When there is a mutation to the gene on both alleles, the phenotypic picture is one of LGMD2J and dilated
cardiac myopathy, sometimes without skeletal muscle involvement owing to different splicing in the two
different tissues.
o LGMD2K
- has been designated to identify the milder phenotypic variants of the POMT1 mutation. This is the same
mutation that is found in some of the more severe CMD cases with WWS.
- This form of LGMD is one of the only forms that has intellectual developmental disorder as a component.
- There are some intermediate forms that fall between LGMD and WWS. Like the other glycosylation defects
found in FKRP, there is a spectrum of severity found in people with POMT1 mutations. This is likely the
result of still unknown modifying factors.
o LGMD2L
- Proximal weakness is the most common presentation of LGMD2L, occurring between the ages of 20 and 50
years, with a less-common form that is phenotypically similar to Miyoshi myopathy where the calf is first
involved. In both cases, males are more severely affected.
o LGMD2M
- is the phenotype that is seen in people with the LGMD form of Fukuyama congenital muscular dystrophy,
which has a very broad spectrum of phenotype ranging from the severe CMD presentation to that of
isolated hypercalcemia all resulting from the same FKTN gene.
o LGMD2N
o -is a rare LGMD presentation of Walker-Warberg CMD.
o LGMD2O
- is the LGMD milder presentation of MEB.
o LGMD2Q
- presents with early onset of weakness and delayed motor skills in the first years of life followed by a plateau
with a continuation of ambulation until the third decade (ages 20-30 years).
- Early Symptoms:
 muscle weakness in the pelvic and shoulder girdle muscles, usually the first symptoms
are noticed in adolescence or early adulthood.
 Winging of the scapulae
 lumbar lordosis
 abdominal protrusion
 waddling gait
 poor balance
 inability to raise the arms may also develop.

Diagnosis:

 LGMD presents with markedly increased levels of CK, however, often not to the same
magnitude seen in DMD.
 EMG and muscle biopsy results demonstrate myopathic changes.
 EMG findings reveal positive sharp waves, and fibrillation potentials are absent in some
individuals and increased in others.
 Shortduration, small-amplitude MUAPs and an increased number of MUAPs are
characteristic of LGMD.
 Muscle biopsy specimens present with variable fiber size and atrophy alternating with
hypertrophy; in the later stages connective tissue is increased.
 Muscle in LGMD can be stained for a variety of components of the sarcoglycan complex
as well as many other known protein defects.
 In the context of a suspected sarcoglycanopathy, this often does not provide a specific
diagnosis, because defects in one sarcoglycan can affect incorporation of the others;
however, the clues provided can lead to appropriate genetic testing to confirm the
diagnosis