Title: What are Neuromuscular Disorders
1????? ???-???? ?????? ????????????
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2What are Neuromuscular Disorders?
- Neuromuscular disorders affect some aspect of the
lower motor neuron pathway - This is distinct from disorders such as cerebral
palsy, traumatic brain injury which affect the
brain /spinal cord i.e. the upper motor neuron
3Upper and Lower Motor neurons
- Upper motor
- Brain and spinal cord
- Lower motor
- Anterior horn cell downwards
4Lower Motor neuron
- Anterior Horn Cell
- Nerves
- Neuromuscular Junction
- Muscle
-
-
5Anterior Horn Cell
- Poliomyelitis
- Spinal Muscular Atrophy
-
-
6Nerves
- Peripheral nerve lesions
- Neuropathies
- e.g. Hereditary motor and sensory neuropathy
-
-
7Neuromuscular Junction
- Myasthenia Gravis
- Congenital Myasthenia
-
-
-
-
8Muscle
- Muscular dystrophies
- Myotonic disorders
- Metabolic myopathies
- Congenital myopathies
- Inflammatory myopathies
9Features of Lower Motor Neuron Lesions
- Muscle wasting
- Fasciculation
- Decreased tone
- Weakness
- Decreased or absent reflexes
10Anterior Horn Cell
- Spinal Muscular Atrophy
- Severe (Type 1)
- (Werdnig-Hoffman disease)
- Intermediate (Type 2)
- Mild (Type 3)
- (Kugelberg-Welander disease)
11Spinal Muscular Atrophy
- Usually autosomal recessive
- Progressive weakness and wasting
- Second most common neuromuscular
- disease in children
-
12Muscular Dystrophies
- About 20 types of muscular dystrophy
- All are caused by faulty genes
- Inheritance may be x-linked, autosomal dominant
or autosomal recessive - All result in progressive muscle weakness due to
a breakdown in muscle
13Examples of Muscular Dystrophies
- X-Linked
- Duchenne Muscular Dystrophy
- Beckers Muscular Dystrophy
- Recessive
- Autosomal Recessive Limb Girdle Muscular
Dystrophy - Dominant
- Fascio-Scapulo-Humeral Dystrophy
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16Myotonic Disorders
- Muscles are slow to relax after contracting
- Slow relaxation often occurs after long periods
of rest - Examples
- Myotonic Dystrophy
- Myotonia Congenita
17Metabolic Myopathies
- Most present in childhood
- Caused by disorders of
- Glycogen storage
- Muscle lipids
- Mitochondria
18Congenital Myopathies
- Present at birth with generalised weakness and
hypotonia - Examples include
- Central core disease
- Multicore disease
- Nemaline Myopathy
19Inflammatory Myopathies
- Prolonged inflammation of many muscles
- Caused by auto-immune response ? Initiated by
viral infection - Can be successfully treated with drugs e.g.
steroids - Examples
- Polymyositis
- Dermatomyositis
20Patterns of Weakness in Neuromuscular Disease
- Muscle weakness presents in different ways in
different neuromuscular diseases - Proximal / Distal
- Selective / Non-selective
- Symmetrical / Asymmetrical
21Muscular Dystrophies
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22Duchenne Muscular Dystrophy
23Duchenne Muscular Dystrophy (DMD)
- Onset
- Early childhood - about 2 to 6 years.
- Symptoms
- Generalized weakness and muscle wasting affecting
limb and trunk muscles first. Calves often
enlarged. - Progression
- Disease progresses slowly but will affect all
voluntary muscles. Survival rare beyond late
twenties. - Inheritance
- X-linked recessive
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- Cardiomyopathy Dilated especially gt 15 years
- Mental retardation mean IQ 88
- Night blindness
- Progression Death 15 - 25 years due to
respiratory or cardiac failure
27Laboratory
- Serum
- CPK Very high
- Troponin I elevated above normal but not to
levels like in cardiac ischemia - Liver enzymes high AST ALT
28??????? ????
- Endomysial fibrosis
- Variable fiber size small fibers rounded
hypercontracted muscle fibers - Myopathic grouping
- Muscle fiber degeneration regeneration
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31?????? ? ???????? X
32???? ??????
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- X-linked recessive inheritance
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33Genetic testing
- ?? 65 ??????? ?? ????? ?? ?????????? ???????
????? Southern blot analysis - Most of the PCR-based tests detect 95-98 of the
deletions/duplications that are found by Southern
blot analysis. - Complex rearrangements are not always detected by
PCR.
34Western blot of dystrophin from dystrophinopathies
- ????? 1,2 BMD
- ???? 3 NORMAL
- ???? 4 DMD
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- ????? ? 3685 ?????? ?????
- 7 ???????????
36????? ??????????
- ????? ??????? ???? ??? ?? ???????. ??????????
???? ????. - ????? ????? ?? ????? ???? muscular dystrophy
??????? ???? ?? ??? ????????? ???? - ?????????? ???? ????? ?????? ????? ??????? ????
???????? ?????
37DMD
- Duchenne muscular dystrophy
- Genotype Dystrophin deficiency
- 96 with frameshift mutation
- 30 with new mutation
- 10 to 20 of new mutations are gonadal mosaic
38Becker Muscular Dystrophy
- Onset
- Adolescence or adulthood.
- Symptoms
- Almost identical to Duchenne but often much less
severe. Can be significant heart involvement. - Progression
- Slower and more variable than Duchenne with
survival well into mid to late adulthood. - Inheritance
- X-linked recessive
39BMD
- Genotype Dystrophin mutations
- Deletion
- 70 of patients Usually In-frame
- Point mutations
- gt 70 identified
40- Clinical features of myopathy
- Onset gt 7 yrs
- Weakness
- Proximal gt Distal symmetric legs arms
- Slowly progressive
- Severity onset age correlate with muscle
dystrophin levels
41May be especially prominent in quadriceps or
hamstrings
- Calf pain on exercise
- Muscle hypertrophy especially calves
- Failure to walk 16 - 80 years
42?????? ?????
43Systemic
- Joint contractures ankles other joints
- Cardiomyopathy may occur before severe weakness
- Mental retardation
44Myotonic Dystrophy
45Myotonic Dystrophy
- Myotonic muscular dystrophy (MMD) is a form of
muscular dystrophy that affects muscles and many
other organs in the body. - Unlike some forms of muscular dystrophy, MMD
often does not become a problem until adulthood
and usually allows people to walk and be
independent throughout their lives.
46Myotonic Dystrophy
- Weakness and wasting of voluntary muscles in the
face, neck, and lower arms and legs are common in
myotonic muscular dystrophy. - Muscles between the ribs and those of the
diaphragm, which moves up and down to allow
inhalation and exhalation of air, can also be
weakened.
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Muscular Dystrophy
48Myotonic Dystrophy
- Myotonic muscular dystrophy is often known simply
as myotonic dystrophy and is occasionally called
Steinert's disease, after a doctor who originally
described the disorder in 1909. - It's also called dystrophia myotonica, a Latin
name, and therefore often abbreviated "DM."
49MD
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???? ?????
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- A long, thin face with hollow temples, drooping
eyelids and in men, balding in the front, is
typical in myotonic dystrophy
51MD
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- ?????? ?????? ??????????? (????? ???????? ??
?????? ?? ???????) - ?????? ????? ????? ??? ??????
- ???? ??"? ???
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52CMD
- ????????? ??? Floppy baby
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53- A child born with congenital myotonic dystrophy
is likely to have facial weakness and an upper
lip that looks "tented." - The eye muscles may also be affected.
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56???
57CTG repeats expansion
58DM1 Myotonin protein kinase (DMPK) protein
- The expanded area of DNA is in a gene that
carries instructions for a protein known as
myotonin protein kinase. - The expanded DNA is not in the "working" part of
the gene - Instead, in MD, the genetic flaw is in a part of
a gene called the untranslated DNA
59Anticipation
- Increased severity with progressive generations
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- It may be that the expanded DNA section affects
the functioning of more than one gene, or it may
cause clumps of genetic material to build up in
the nuclei (control centers) of cells, affecting
many cellular functions.
60Myotubular Myopathy
- Centronuclear myopathy
- X-linked (MTM 1) l Myotubularin
- Chromosome Xq27.3-q28 Recessive
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- Pes equinovarus
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- Severe 2 to skewed X-inactivation
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66Prenatal Diagnosis
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????? ????? - ???? ????? ?? ??????? ?????? ?????? ???? ??????
?? ??? ????
67Congenital Muscular Dystrophies
- ????????? ??? ????????
- "floppy" infants
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68Congenital Muscular Dystrophies
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- It is important to note that just because the
muscle weakness in CMD starts earlier, CMD is not
automatically more severe than other forms of
muscular dystrophy. - The degree and rate of progression of muscle
weakness varies with different forms of CMD and
from one child to the next.
70CMD
- 3 major groups
- merosin-negative
- merosin-positive with out CNS involvement
- merosin-positive with neuronal migration disorders
71Merosin
- ????? ????? ????? ????? ?????? ?? ??? ?????
- ???? ?? laminin alpha 2
- Chromosome 6q22
- Recessive
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72Merosin (laminin a2-chain)
- Location
- Basement membrane
- Muscle, Skin, CNS Peripheral nerve (Schwann
cells) - Binds to a-Dystroglycan in basal lamina
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74Merosin deficient MD
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- ?????? ??? ???? ????? ?? ????? ??? ?????? ?????
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- Laboratory
- CK Moderately high
- MRI of CNS White matter changes (Increased
signal on T2) Cortex usually normal
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- Merosin (Laminin a2) staining
- Usually absent 95 with absent merosin have gene
mutation - Partial merosin loss milder disability or later
onset
78Prenatal Diagnosis
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????? ?????
79Spinal Muscular Atrophy
- In 1850, the first form of the disorder was
identified in adults by two French physicians,
François-Amilcar Aran and Guillaume Duchenne. - Toward the end of the 19th century, two German
doctors, Guido Werdnig and Johann Hoffmann,
described the disease in children. - In the early 1950s, Eric Klas Henrik Kugelberg
and Lisa Welander, identified still another form
of the disease.
80SMA
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81SMA
- Progressive degeneration and loss of the anterior
horn cells (i.e., lower motor neurons) in the
spinal cord and sometimes in the brainstem
nuclei, - Causes lower motor neurons in the base of the
brain and the spinal cord to disintegrate,
preventing them from delivering electrical and
chemical signals that muscles depend on for
normal function.
82SMA
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83SMA
- SMA type 1 Werding Hoffman
- SMA type 2
- SMA type 3 Kugelberg Welander
- Autosomal recessive
- Types 1, 2 and 3 appear to be variants of the
same condition, because they all appear to arise
from a defect in the same gene on chromosome 5. - It is possible that different defects in the same
gene may give rise to the different types of
SMA.
84SMA type 1 Werding Hoffman Infantile Muscular
Atrophy
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86Type II (Chronic)
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??????? - ????? ?????
- ??? ??????
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89Type III Mild Kugelberg-Welander or Juvenile
Spinal Muscular Atrophy
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90The diagnosis of SMA after the neonatal period
- Poor muscle tone and symmetric muscle weakness
that spares the ocular muscles and only involves
the facial muscles and diaphragm late in the
course - Delayed acquisition of motor skills
- Anterior horn involvement evident as tongue
fasciculations (seen in only 65 of patients) and
absence of deep tendon reflexes - Normal reaction to sensory stimuli
- Normal intellect
91??????? ????
- Grouped atrophy
- Small muscle fibers are often rounded
- Pyknotic nuclear clumps are not present.
- Large muscle fibers are hypertrophied
92SMN-survival motor neuron
- ????? ?"? ??????? ? SMN gene (chromosomal
locus 5q11-q13) - The SMN region is unusually complex, with
repetitive sequences, pseudogenes,
retrotransposable elements, deletions, and
inverted duplications
93- ??????? ?? ??? ?????? ?? SMN ?? ?? ???
???????????? SMN1 tel ? SMN2 cent - ???? ?? ??????? ????????????
94Molecular genetic tests of SMNT
- Direct DNA analysis to detect a homozygous
deletion of exon 7 of SMNT (designated D7 SMNT),
which is used for confirmation of the clinical
diagnosis of SMA in about 95 of patients with
SMA and for prenatal testing.
95- Dosage test that determines the number of exon 7
SMNT -containing gene copies present in an
individual, which is used for carrier detection. - Such testing is clinically available in a limited
number of laboratories
96Genotype-Phenotype Correlations
- Several studies have shown that the neuronal
apoptosis inhibitory protein gene (NAIP) gene,
which is in close proximity to the SMN gene, is
more frequently deleted in severe SMA.
Approximately 45 of patients with SMA1 were
shown to have NAIP deletions, whereas only 12-18
of patients with type II and III SMA were deleted
for NAIP
97- SMN1 (SMNT telomeric SMN gene) mutations
- Present in 95 of SMA patients
- Carrier frequency in population 1.8
- Incidence of disease 1 in 6,000 to 8,000 births
98SMN1 SMN2 genes Correlation with disease
severity
- Milder disease (SMA II or III) with Increased
SMN2 gene copy number - Absence of both SMN1 SMN2 genes Lethal
- No SMN1 gene 1 copy of SMN2 Death lt 1 month of
age
995q CHROMOSOMESTypical SMN mutations in SMA
- SMN1 Normal gene
- SMN1 Mutation types
- Deletion More severe SMA
- Conversion to SMN2 gene Milder SMA
- SMN2 gene Variations
- More copies Correlate with milder SMA
- SMN2 mutations alone Do not produce SMA
100Correlation with disease severity
- SMA type I Mostly deletions Few missense point
mutations - SMA type II
- Mutations convert SMN1 gene to SMN2
- SMN2 gene copy number gt 3
- Missense point mutations more common
- SMA type III
- SMN2 gene copy number gt 3
- Missense point mutations more common
- Total full length SMN protein ? Best correlation
with SMA severity
101LIMB-GIRDLE MUSCULAR DYSTROPHIES
- Pediatric Neuromuscular Clinic
- Metabolic-Neurogenetic Service
- Wolfson Medical Center
102Introduction
- The limb-girdle muscular dystrophies (LGMD) are a
group of genetically heterogeneous MD presenting
with weakness of hip and shoulder girdle. - Coined by Stevenson 1953, Walton and Natrass 1954
to account for occurrence of cases not clearly
X-linked or FSH MD. - Continuing problem in classification.
103Introduction
- Clinical overlap with genetically distinct
disorders e.g SMA and mitochondrial and
metabolic myopathies may present with limb-girdle
weakness. - Molecular pathogenesis known in 14 (3AD, 11AR)
types (lt50). - Each type may be clinically heterogeneous.
- Some are allelic with other forms of muscular
dystrophy. - Some have unique pathogenic mechanisms.
104Clinical Criteria
- Onset
- Pelvic or shoulder girdle muscles or both
simultaneously involved. - Onset of weakness in distal, facial or
extra-articular muscles should suggest
alternative diagnoses, though these muscles may
be involved later in the course of the disease. - Most individuals with LGMD begin to exhibit
symptoms between adolescence and adulthood.
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106Clinical
- In more severe cases, symptoms manifest during
childhood. - Progression
- Progression of the weakness is inevitable but
variable. - Involvement of other systems is rare. Proximal
areas are more severely affected than those
muscle groups distal to the body. - The heart and bulbar muscles are generally
spared.
107Clinical
- Proximal weakness.
- Scapular winging.
- Gowers sign.
- Quadriceps myopathy -atrophy of the lower portion
of the quadriceps is most conspicuous.
108Labs
- CK is always elevated in recessive cases and may
be used as a presymptomatic test in families
where elevation of CK has been documented. - In dominant families CK is normally no greater
than 6 times normal, while in recessive families
in may be as high as 200 times normal. - Muscle CT scanning may also provide evidence of
hypodensity of the involved muscles
109Labs
- Electromyography and muscle biopsy usually
provide evidence of non-specific myopathic or
dystrophic changes. - Recruitment of an excessively large number of
motor unit action potential (MUAP) - Alteration in the morphology of MUAP small
shorter and polyphasic. - Increase in insertional activity, fibrillation
potentials and positive sharp waves.
110Genetics
- Mode of inheritance
- The majority of LGMD cases are inherited in an
autosomal recessive manner however several rare
dominantly inherited subtypes have recently been
classified at the molecular level. - Current estimates suggest that approximately 10
of all patients with LGMD may have a dominant
mutation.
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113Biopsy
- Non-specific changes including
- Variation of myofiber size with increased
endomysial connective tissue - Increased central nuclei
114Biopsy
- Degenerating and regenerating fibers are seen but
they are rarely prominent and usually scattered
throughout the muscle with no tendency to group
as in DMD. Necrotic fibers contain Trichrome ()
material that may resemble IBM.
115Biopsy
- Ring fibers are frequent and can be observed in
50 of cases. - In ring fibers, the normal longitudinal
orientation of the myofibrils is lost.
116Biopsy
- Many fibers show a moth eaten appearance with
stains for oxidative enzymes. - Focal decrease in the intermyofibrillar
mitochondrial population, most evident in type 1
fibers
117- Immunohistochemistry may be very useful
- Differentiating from dystrophinopathy
- 17 of suspected LGMD had a dystrophinopathy
(Arikawa, 1991)
118Autosomal Recessive LGMD
119Sarcoglycanopathies
120Sarcoglycanopathies
- Heterotetrameric transmembrane complex .
- Interacts with dystroglycan complex but does not
bind dystrophin directly. - Plasma membrane stabilization.
- Most frequent is a SG (17q)
- b SG (4q) is second most common
- g SG (13q) severe childhood autosomal recessive
muscular dystrophy - d SG (5q) least common (Brazil)
121Sarcoglycanopathies
- Generally manifest earlier in life (3-5 years of
age) than other LGMD. - Clinical presentation
- Limb-girdle muscle weakness with atrophy,
scapular winging. Severe cases resemble DMD. - Pain and cramping typical.
- Calf hypertrophy early.
- Ankle contractures.
- Cardiac involvement not common.
- Extremely elevated CK (10-100 x higher than other
LGMD).
122Sarcoglycanopathies
- Primary mutations in b- or d-sarcoglycan leads to
secondary loss of all elements in the complex. - Mutation in a-sarcoglycan (adhalin) leads to
milder loss. - Mutation in g-sarcoglycan is least disruptive.
- These generalizations not reliable, DNA
confirmation recommended.
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124Calpainopathy (LGMD2A)
125Calpainopathy (LGMD2A)
- The most common single genetic cause of LGMD
- CAPN3 gene (15q).
- Calpain (nonlysosomal Ca dependent protease)
associated with sarcomere. Maintains sarcomere
size and elasticity. - Function in the myofiber is not known probable
role in membrane signaling and repair. - Calpain is unstable, so immunostain is not
reliable. - Direct sequencing of the gene.
126Calpainopathy (LGMD2A)
- Usually presents in the second decade of life.
- Gluteus maximus and thigh adductors predominately
involved. Spares quadriceps. - Consistently develop heel cord contractures toe
walking, later hips knees and elbows. - Abdominal laxity and hyperlordosis.
- CK elevated but lower than seen in sarcoglycan
disease.
127Dysferlinopathy
128Dysferlinopathy
- LGMD2B caused by mutations in the DYSF gene (2p).
- Dysferlin is normally present at the plasma
membrane probable role in membrane signaling and
repair. - Mutations may lead to either LGMD2B or Miyoshi
myopathy (can have both in same pedigree). These
tend to resemble each other as disease advances. - Diagnosis relies on Western Blot analysis and
immunostaining
129Dysferlinopathy
- Manifests in 2nd decade of life.
- Involves most of leg muscles but tends to spare
shoulder girdle musculature (upper extremity
involvement of biceps). - Usually do not see scapular winging or calf
hypertrophy. - Diagnosis relies on Western Blot analysis and
immunostaining (Note may frequently see
inflammation and rimmed vacuoles on biopsy).
130(No Transcript)
131Telethoninopathy (LGMD 2G )
132Telethoninopathy
- Newly recognized form of AR LGMD
- Described in 4 Brazilian families
- LGMD 2G (17q)
- Telethonin is a sarcomeric protein preferentially
expressed in striated muscle, and accumulates in
the Z line with alpha-actinin - Onset in childhood small or large calves
- Affects upper and lower proximal muscles but also
involves distal leg muscles early ankle
dorsiflexion weakness. - Diagnosis is by immunohistochemistry (may also
see rimmed vacuoles on biopsy)
133Other Autosomal Recessive LGMD
- LGMD 2H seen only in Manitoba Hutterites. TRIM32
mapped to 9q (4.4 kb from fukutin). - LGMD2J Titin deficient late onset distal tibial
myopathy. Double mutants have severe limb-girdle
pattern.
134LGMD 2I (19q)
- Fukutin-related protein (FKRP)
- Involved in glycosylation of a-dystroglycan.
- Mutations cause abnormal glycosylation and
disrupt link between dystroglycan and laminin. - Most are CMDs or simulate dystrophinopathy.
- Milder LGMD with infant to adult onset.
- Severe CMD picture with cerebellar cysts.
- Reduced laminin alpha-2 immunostain.
135Autosomal Dominant LGMD
136Myotilinopathy (LGMD 1A)
137Myotilinopathy
- Myotilin gene (5q).
- Myotilin is a sarcomeric protein that binds to
alpha-actinin and is localized to the Z-line. - Anticipation suggesting unstable trinucleotide
repeat. - LE weakness precedes UE weakness, reduced DTRs.
- Facial weakness in some patients.
- Frequent heel cord contractures.
138Myotilinopathy
- 50 of patients have a distinctive nasal,
dysarthric speech. - CK elevated (2-9 fold).
- Histology rimmed vacuoles.
- EM rod like bodies.
139Laminopathy (LGMD 1B)
140Laminopathy
- Mutation on chromosome 1q resulting in altered
lamin A/C protein product. - Allelic with autosomal dominant Emery-Dreifuss
muscular dystrophy - Onset in childhood in one half.
- LE extremity weakness precedes UE weakness.
- Slowly progressive.
- Cardiac irregularities, AV conduction
disturbances, bradycardia, syncope, sudden
cardiac death.
141Caveolinopathy (LGMD 1C)
142Caveolinopathy
- CAV3 3p25.
- Caveolin is involved in membrane traffic and
signal transduction in smooth and skeletal
muscle. - Manifests in early childhood with mild to
moderate proximal muscle weakness, calf
hypertrophy, elevated CK. - May have muscle rippling or mounding with
percussion. - May be asymmetric.
143LGMD 1D
- Chromosome 6q gene not known
- Significant cardiac pathology familial dilated
cardiomyopathy with conduction disease and
myopathy. - No testing is available
144LGMD 1E
- Two large pedigrees map to 7q
- Adult onset, proximal weakness, dysphagia,
Pelger-Huet anomaly (granulocytes with abnormal
nuclei)