MUSCLE AND NERVE PATHOLOGY

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CHAPTER 17 MUSCLE AND NERVE PATHOLOGY

Muscle biopsy
Muscular dystrophy

Dystrophinopathies (Duchenne and Becker muscular dystrophy)
Facioscapulohumeral muscular dystrophy
Defects in nuclear membrane proteins (including Emery–Dreifuss dystrophy)
Myotonic dystrophy
Limb girdle muscular dystrophies

Myotilinopathy
Caveolinopathies
Calpainopathy
Dysferlinopathies
Sarcoglycanopathies
Rare limb girdle muscular dystrophies
Congenital muscular dystrophies

Dystroglycanopathies
Merosin deficiency
Collagen VI deficiency
Integrin α7 deficiency
Rigid spine with muscular dystrophy
Plectin deficiency
Congenital myopathies

Central core disease
Multi-mini core disease
Nemaline myopathies
Actinopathies
X-linked myotubular myopathy
Centronuclear myopathies
Congenital fiber type disproportion
Hyaline body myopathy
Cylindrical spirals myopathy
Reducing body myopathy
Tubular aggregate myopathy
Sarcotubular myopathy
Myopathy with fingerprint bodies
Cap body myopathy
Zebra body myopathy
Myofibrillar/desmin myopathies and related disorders

Myofibrillar (desmin) myopathies
Hereditary inclusion body myopathies
Metabolic myopathies and related diseases

Glycogen storage disease Type II
LAMP-2 deficiency / Danon’s disease
X-linked myopathy with excessive autophagy
Vacuolar myopathy
Glycogen storage disease type III
Glycogen storage disease IV
Glycogen storage disease type V
Glycogen storage disease type VII
Disorders associated with excess lipid deposition on muscle biopsy
Mitochondrial disorders (disorders of oxidative phosphorylation)
Myoadenylate deaminase deficiency
Inflammatory myopathies

Juvenile dermatomyositis
Juvenile polymyositis
Infectious myopathies
Miscellaneous myopathies

Toxic and drug associated myopathies
Neurogenic disorders
Type 2 fiber atrophy
Myosin heavy chain deficiency syndrome
Marinesco–Sjögren syndrome
Malignant hyperthermia
Rhabdomyolysis
Ion channel disorders

Myotonia and paramyotonia
Periodic paralysis
Brody’s disease
Neuromuscular junction defects

Myasthenia gravis
Congenital myasthenic syndrome
Nerve biopsy

MUSCLE BIOPSY

Overview

• Neuromuscular disease responsible for huge burden of disability in children
• Muscle biopsy relatively common diagnostic investigation
• Huge increase in number of genes identified for muscle disease, but

image muscle biopsy still plays an important role in diagnosis

– can direct genetic testing
– often quicker than genetic analysis
– can identify broader differential diagnoses
– diagnosis of acquired disorders

• Pediatric muscle pathology rapidly changing
• Due to their specialist nature, should only be reported by pathologists with a specialist interest in muscle disease and in department familiar with handling these samples
• In children, main indications for muscle biopsy are

image primary genetic muscle disorders

– muscular dystrophy
– inherited myopathies

image suspected metabolic disorders

– may include complex undiagnosed neurological presentations
– in particular

· mitochondrial disease
· glycogen storage disease

image primary inflammatory disorders

– juvenile dermatomyositis

image primary neurogenic disorders

– spinal muscular atrophy (SMA)

• Few diagnoses can be safely made on muscle biopsy in absence of good clinical information including

image clinical history
image examination findings
image electromyogram (EMG) / nerve conduction studies (NCS)
image creatinine kinase
image MRI findings (brain and/or muscle)

• Normal findings in muscle vary from site to site and with age

image imperative to know from which muscle and at what age the biopsy was taken
image biopsy a muscle that is affected but not severely by the underlying disease

– to ensure there are pathological features and not fibrotic end-stage changes

• Muscle biopsies should be avoided from site of previous EMG

image focal destructive change with chronic inflammation should raise the possibility that biopsy has been taken from EMG needle site

Specimen handling

• Muscle biopsies must be transported fresh to the laboratory rapidly wrapped in a damp piece of gauze

image drying or excess fluid produces artefact

• Sample should be rapidly frozen

image analysis should be performed on frozen tissue

– gives best preservation of muscle fiber size, enzymes for histochemistry and respiratory chains for biochemical analysis

• A piece should be separated for fixation for EM prior to freezing
• Should be orientated to obtain transverse sections
• If there is a risk of infection (TB, HIV, Prion, Hepatitis B or C), fixed in paraffin and a number of substitute stains can be undertaken

image analysis may be more restricted

Histochemical and immunohistochemical stains

• Muscle biopsies should be subjected standard panel of histochemical and tinctorial stains
• The following list is based on our practice

image H&E
image Gomori trichrome

– particularly useful for

· mitochondria (ragged red fibers)
· inclusions (eg nemaline rods)

image picrosirius

– connective tissue
– can be assessed on Gomori or van-Gieson as an alternative

image Oil Red O or Sudan black

– lipid

image PAS

– glycogen

image acid phosphatase

– lysosomal storage
– macrophages

image oxidative stains

– cytochrome oxidase (COX)

· mitochondria

– succinic dehydrogenase (SDH)

· mitochondria

– reduced nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR)

· mitochondria
· sarcoplasmic reticulum
· gives an indication of myofiber architecture

image ATPase for fiber typing

– pH4.6

· Type 1 fibers dark
· Type 2a fibers pale
· Type 2b fibers intermediate

– pH9.4

· Type 1 fibers pale
· Type 2 fibers dark

– poorly differentiated fibers or double staining may be seen in a number of pathological contexts

• Additional stains can be requested for specific diagnoses (eg glycogen storage disorders)

image myophosphorylase
image phosphofructose kinase
image myoadenylate deaminase

• Similarly a standard panel of immunohistochemistry is recommended as secondary changes are common and interpretation requires a full panel

image dystrophy panel

– dystrophin (Dys 1, 2 and 3)
– merosin
– sarcoglycans
– utrophin
– desmin
– dysferlin
– α and β dystroglycan
– collagen VI
– spectrin

· as positive control to check that the membrane-associated proteins are intact (cf necrotic fiber)
· must always be performed
· if negative on a fiber then other membrane-associated proteins may be non-specifically negative

image inflammatory panel

– CD3, CD4, CD8, CD20, CD68
– major histocompatibility complex type 1 (MHC)
– membrane attack complex (MAC)
– CD31
– dysferlin

image fiber typing

– fast and slow myosin
– developmental or neonatal myosin

Myopathic changes

• For full discussion of interpretation of muscle biopsies reference should be made to specialist texts on muscle pathology
• General morphological changes that should be reported

image fiber size

– compared to normal size range for age and site
– measure the diameter in the shorter axis of a fiber cross section

· avoids artefact due to obliquely cut or kinked fibers

– are small fibers rounded (myopathic) or angular (neurogenic)?
– what is the distribution of atrophic fibers?

· grouped suggests neurogenic atrophy
· perifascicular suggest dermatomyositis

image internal nuclei (Fig 17.1)

– most nuclei are under the fiber membrane
– <3% muscle nuclei should be internal
– may be that in young children even less should be accepted as normal
– often explained as representing a regenerative change
– geographically central nuclei (as opposed to simply internal) in centronuclear/myotubular myopathy
– frequent internal nuclei in myotonic dystrophy
image split fibers (Fig 17.2)

– non-specific myopathic feature
– frequent in dystrophies
– nucleus at the end of split is a useful sign
image necrotic fibers (Figs 17.3, 17.4)

– pale on H&E or Gomori
– infiltrated by macrophages

· acid phosphatase histochemistry

image regenerating fibers (Fig 17.5)

– basophilic on H&E
– internal enlarged, sometimes vesicular, nuclei
image inflammation

– inflammatory myopathies
– dystrophies with inflammation

· facioscapulohumeral dystrophy
· dysferlinopathy
· some cases of dystrophinopathy

– site of previous EMG

image connective tissue

– normal endomysial collagen is limited to the basal membrane
– fatty replacement occurs in end stage muscle disease

image inclusions and vacuoles

– see specific entities

image fiber typing (Fig 17.6)

– is the fiber type distribution normal for the muscle and age?
– are the pathological changes more prominent in one fiber type?
– is there fiber-type grouping or group atrophy?

· see neurogenic atrophy

image glycogen and lipid content

– see metabolic myopathies

image mitochondrial/oxidative staining patterns

– see mitochondrial myopathies

image

Fig 17.1 Photomicrograph showing multiple internal nuclei in a muscle fiber.

image

Fig 17.2 Photomicrograph showing split fibers. The association of a nucleus with the splits is useful confirmation that they are real splits.

image

Fig 17.3 Photomicrograph showing a necrotic fiber (arrow). The fiber is pale and has been infiltrated by macrophages.

image

Fig 17.4 Photomicrograph of a necrotic fiber infiltrated by macrophages. The macrophages are stained red in this acid phosphatase preparation.

image

Fig 17.5 Photomicrograph of a regenerating fiber. The regenerating fiber is more basophilic and has larger nuclei than the surrounding fibers.

image

Fig 17.6 Normal fiber typing by ATPase histochemistry (left hand panel pH4.6; right hand panel pH9.6 – see text) in a quadriceps biopsy. There is an even mixture of the three fiber types.

Common artefacts

• There are numerous artefacts that affect muscle biopsy interpretation, the more common including

image ice crystal

– slow freezing or thawing is associated with spaces in the fiber

image saline artefact

– samples sent in large volumes of saline contain vacuoles

image myotendinous insertion

– biopsies close to the tendinous insertion show ‘myopathic’ changes

· fiber size variation, internal nuclei and excess collagen

image site of previous EMG

– focal inflammation or scarring

MUSCULAR DYSTROPHY

General features

• Genetic degenerative diseases of muscle
• See also

image limb girdle muscular dystrophy
image congenital muscular dystrophy

Histopathological features

• Marked variation of fiber size

image both atrophy and hypertrophy of fibers

• Evidence of active fiber destruction

image necrosis and regeneration

• Other myopathic features

image eg split fibers, central nuclei

• Marked connective tissue accumulation and fatty replacement
• Variable chronic inflammation

DYSTROPHINOPATHIES (DUCHENNE AND BECKER MUSCULAR DYSTROPHY)

• Commonest forms of muscular dystrophy in Western World (Figs 17.7–17.9)
• Mutations in the large dystrophin gene
image

Fig 17.7 Photomicrograph of a muscle biopsy from a patient with Duchenne muscular dystrophy. There is marked variation in fiber size due to a mixture of atrophic and hypertrophic fibers. There are excess internal nuclei, increased endomysial collagen and regenerating fibers (see Fig 17.5 for detail).

image

Fig 17.8 Photomicrograph of a muscle biopsy from a patient with Duchenne muscular dystrophy stained for dystrophin. The majority of fibers are negative but there are a few revertant fibers.

image

Fig 17.9 Photomicrograph of a muscle biopsy from a patient with Duchenne muscular dystrophy (left hand panel) and a control muscle (right hand panel) both stained for utrophin. In the control, utrophin labeling is seen only in the blood vessels. In contrast in the patient’s biopsy, there is positive sarcolemmal staining.

Genetics

• X-linked mutations in the dystrophin gene (Xp21)

image most mutations are exonic (or multi-exonic) deletions

– 60–65% of Duchenne
– <80% of Becker’s

image point mutations
image duplications occur (10–15%)
image severe phenotypes (Duchenne)

– associated with null mutations often due to frame shift

image milder phenotypes (Becker)

– associated with shorter semi-functional proteins often due to in-frame mutations

• High frequency of new mutations

image only one-third of Duchenne boys will have positive family history

Clinical features

Duchenne

• 1/3500 live born males
• Common presentation is delayed walking
• Loss of independent ambulation by age of 12 years
• Progressive severe symmetrical muscle weakness

image particularly proximal limb muscles

– waddling gait
– difficulty rising from sitting

· associated with Gower’s maneuver

• ‘Pseudo-hypertrophy’ of calf muscles
• Late manifestations

image contractures
image respiratory impairment
image thoracic deformity
image cardiomyopathy

– dilated or hypertrophic

• Retinal abnormality associated with night-blindness
• Reduced IQ
• Rhabdomyolysis

Becker

• Similar distribution of muscle weakness to Duchenne

image presenting later
image milder symptoms
image less aggressive course

• Great range of clinical presentation recognized since advent of molecular testing

image eg presentation with calf pain on exercise

• Cardiac disease common in adults

image 70% of patients over 40 years
image frequently severe

– more commonly dilated cardiomyopathy

• Intellectual impairment may occur

image much less severe than Duchenne

X-linked dilated cardiomyopathy

• Young men (late teens or early 20s) or middle aged women
• Rapidly progressive dilated cardiomyopathy

image without prominent skeletal muscle symptoms

• Biochemical (raised creatinine kinase) and histological evidence of skeletal muscle involvement

Manifesting carriers

• Females carrying dystrophin mutations presenting with

image muscle weakness

– typically asymmetric

image mild cardiomyopathy
image more commonly Duchenne than Becker carriers

Atypical presentations

• Other rare presentations include

image floppy infants
image limb girdle dystrophy with distal weakness
image pain/cramps of exercise

– often with myoglobinuria

image weakness limited to quadriceps

Histopathological features

• Features are those of dystrophy (see above)

image hypercontracted, atrophic and hypertrophic fibers
image necrosis and regeneration
image fibrosis and fatty replacement
image internal nuclei
image split fibers
image variable inflammation

• Fiber typing may be indistinct
• Extent and chronicity of changes depends on

image severity of clinical phenotype
image stage of disease

– late stage biopsies show ‘end stage’ muscle changes

· extensive replacement by fat and collagen

Immunohistochemical staining

• Reduced or absent immunostaining with antibodies to dystrophin

image antibodies to multiple regions of the protein are required

– typically three antibodies used

· Dys1 rod domain
· Dys2 C-terminus
· Dys3 N-terminus

• Duchenne dystrophy

image loss of staining on almost every fiber for all three antibodies

– occasional ‘revertant’ fibers may be positive

• Becker’s dystrophy

image range of changes including reduced/absent staining with one or more antibodies
image may be patchy

• X-linked cardiomyopathy

image skeletal muscle staining may be intact

• Carriers

image asymptomatic

– rare negative fibers

image manifesting

– mosaic pattern of loss of dystrophin staining

Secondary changes

• Up-regulation of sarcolemmal utrophin

image not specific

– may be seen in regenerating fibers and in other dystrophies

• Secondary changes in other linked proteins

image decreased labeling for dystroglycans
image decreased labeling for sarcoglycans
image loss of nNOS

Molecular diagnosis

• Constitutional mutational analysis is standard part of diagnosis

Differential diagnoses and pitfalls

• Major differential diagnosis is from other dystrophies
• Inflammation may be present histologically

image distinction must be made from inflammatory myopathy

• Small (needle) biopsies or biopsies of severely affected muscles may show non-specific or end-stage changes only

FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY

• Common muscular dystrophy (Tawil 2008)

image due to a 3.3kb subtelomeric deletion on 4q
• Diagnosis depends on molecular genetics
• Biopsy is rare

Genetics

• Deletion in 3.3kb repeat sequence in the subtelomeric region of 4q (D4Z4)
• Autosomal dominant
• Sporadic mutations common

Clinical features

• Onset typically before age of 20 years

image onset before 10 years in some

• Facial and shoulder girdle weakness
• Variable rate of progression
• Hearing loss
• Retinal vasculopathy
• No cardiac or CNS involvement

Histopathological features

• Myopathic features

image no specific diagnostic features

• Variable histology depending on severity of biopsied muscle
• Inflammation may be prominent
• Lobulated fibers may occur

Immunohistochemical staining

• No specific immunohistochemistry

image performed to exclude other disorders
image MHC expression is variable

Differential diagnoses and pitfalls

• Main morphological pitfall is overlap with inflammatory myopathy and other dystrophies in which inflammation may be prominent

DEFECTS IN NUCLEAR MEMBRANE PROTEINS (INCLUDING EMERY–DREIFUSS DYSTROPHY)

• Spectrum of clinical disorders (Brown et al 2008)
• Mutations in the genes encoding for nuclear membrane proteins, emerin and Lamin A/C

Genetics

• Mutations in emerin gene

image X chromosome

• Mutations in the Lamin A/C gene

image Lamin A and C are generated from the same gene by alternate splicing

Clinical features

Emery–Dreifuss muscular dystrophy

• Muscle weakness

image humero-peroneal distribution (X-linked form)
image scapulo-humero-peroneal distribution (autosomal form)

• Early contractures
• Cardiomyopathy

image presents with conduction defects
image may present as sudden death

• X-linked form

image mutations in the gene encoding emerin

• Autosomal dominant form

image Lamin A/C mutations
image frequent new mutations

• Very rare autosomal recessive

image Lamin A/C mutations

Limb girdle muscular dystrophy Type 1B (limb girdle muscular dystrophy with arterio-ventricular conduction block)

• Autosomal dominant

image Lamin A/C mutations

• Proximal symmetrical muscle weakness
• Conduction block

image dysrhythmias

• Contractures late or absent

Dilated cardiomyopathy with conduction defect

• Dilated cardiomyopathy
• Lamin A/C mutations
• May be in same families as Emery–Dreifuss

Dunnigan-type of familial partial lipodystrophy

• Rare
• Onset during puberty
• Loss of subcutaneous fat

image face
image limbs
image gluteal region

• May develop glucose intolerance

Other syndromes associated with Lamin A/C mutations

• Charcot–Marie–Tooth type 2B1
• Mandibuloacral disease
• Premature ageing
• Restrictive dermopathy

Histopathological features

• Emery–Dreyfus and LGMD1B

image dystrophic/myopathic features (Fig 17.10)

– necrosis and regeneration usually not prominent

image

Fig 17.10 Photomicrograph of a muscle biopsy from a patient with Emery–Dreifuss muscular dystrophy showing fiber size variation and internal nuclei.

Immunohistochemical staining

• Loss of emerin staining from muscle nuclei

image present in most cases of emerin mutations
image can be demonstrated in non-muscle tissue

– occasionally mosaic

image light hematoxylin counter-stain may aid interpretation

• Lamin A/C staining not diagnostically useful

image normal even in cases with proven mutations

Special investigations

• EM may show abnormal nuclei

image abnormalities of chromatin
image defects in nuclear membrane
image chromatin in cytoplasm
image not invariable

• Immunoblotting
• Genetic analysis

Differential diagnosis and pitfalls

• Histochemical features overlap with other myopathies/dystrophies
• Lamin A/C mutations cannot be diagnosed by histology alone

MYOTONIC DYSTROPHY

• Autosomal dominant
• Myotonia, weakness and wasting

Genetics

• Trinucleotide repeat diseases

image anticipation

• DM1 (19q)

image CTG expansion
image relatively common

• DM2 (3q)

image CTG expansion
image rare
image proximal myotonic myopathy (PROMM)

Clinical features

• Myotonia in both disorders
• DM1

image distal muscle involvement
image facial weakness common
image cardiac failure
image CNS involvement
image cataracts
image diaphragmatic weakness
image frontal balding
image gonadal atrophy

• DM2

image proximal muscle involvement
image facial weakness rare
image cardiac failure / CNS involvement

– less common than DM1

image cataracts
image frontal balding
image gonadal atrophy

Histopathological features

• Fiber size

image DM1

– atrophy of type 1 fibers
– hypertrophy of type 2 fibers

image DM2

– atrophy of type 2 fibers

• Nuclei

image DM1

– internal nuclei very common
– chains of nuclei in longitudinal section

image DM2

– pyknotic clumps of nuclei may be prominent

• Destructive changes (degeneration, regeneration, fibrosis) rare
• Architectural changes

image ring fibers
image moth-eaten fibers
image whorled fibers
image dark stained zones

– sarcoplasmic masses
– DM1

Immunohistochemical staining

• Myosin subtypes highlight fiber type changes

Differential diagnoses and pitfalls

• Centronuclear/myotubular myopathy

LIMB GIRDLE MUSCULAR DYSTROPHIES (LGMD)

• Wide range of dystrophies associated with dominant (LGMD type 1) or recessive inheritance (LGMD type 2) (Guglieri et al 2008; Table 17.1)
• Progressive shoulder and pelvic muscular weakness
• Occasional distal weakness
• Facial muscles usually spared

Table 17.1 Limb girdle muscular dystrophies

image

MYOTILINOPATHY

• Limb girdle muscular dystrophy type 1A (LGMD1A)
• Histology shows non-specific dystrophic features

image rimmed vacuoles may be present
image rods may occur
image may show Z-band streaming

CAVEOLINOPATHIES

• Spectrum of autosomal dominant muscle disease

image mutations in the gene encoding for caveolin-3

– caveolin is major protein component of intracellular membrane bound structure, caveolae

Genetics

• Autosomal dominant mutations in caveolin-3 gene

Clinical features

• Limb girdle muscular dystrophy type 1C (LGMD1C)

image age of onset typically around 5 years
image calf hypertrophy
image moderate proximal muscle wasting and weakness
image high CK
image muscle cramps after exercise

• Isolated hyperCKemia

image patients with raised serum CK but no muscle wasting or weakness

• Inherited rippling muscle disease

image disorder associated with electrically silent muscle rippling
image often precipitated by percussion of the muscle
image muscle stiffness, pain or cramps following exercise

Histopathological features

• Non-specific myopathic features
• No specific features distinguish caveolinopathies form other myopathies

Immunohistochemical staining

• Immunohistochemistry for caveolin

image reduced staining
image not widely undertaken

Special diagnostic investigations

• Immunoblotting of muscle protein extracts shows reduced caveolin

Differential diagnoses and pitfalls

• Morphologically cannot be distinguished from other myopathies

CALPAINOPATHY

• One of the commonest forms of limb girdle muscular dystrophy (LGMD)

image mutations in calpain gene

Genetics

• Responsible for autosomal recessive LGMD-2A
• Multiple different mutations in calpain-3 gene

Clinical features

• Age of onset varies from 3 to 30 years

image mean 8–12 years

• Limb girdle muscles preferentially affected
• Distal involvement may occur
• Slowly progressive
• Facial and cardiac muscle is spared

Histopathological features

• Dystrophic features

image necrosis
image regeneration
image fibrosis later in disease

• Lobulated fibers may be prominent in late disease

Immunohistochemical staining

• Calpain-3 immunostaining is not diagnostically helpful

Special diagnostic investigations (including EM)

• Biochemistry important for diagnosis

Differential diagnoses and pitfalls

• Other dystrophies

DYSFERLINOPATHIES

• Spectrum of autosomal recessive muscle disease

image mutations in dysferlin gene

Genetics

• Autosomal recessive mutations in dysferlin (2p11)

Clinical features

• Myopathies with onset typically in teens or early adulthood
• Limb girdle muscular dystrophy 1D (LGMD2B)

image proximal muscle weakness

– particularly in lower limbs

• Miyoshi myopathy

image distal muscle weakness

– particularly in lower limbs (especially gastrocnemius)

· eg difficulty with tiptoeing

image proximal weakness develops with disease progression
image often non-ambulant after 10 years

Histopathological features

• Non-specific myopathic features
• Inflammation may be prominent

Immunohistochemical staining

• Dysferlin absent or severely reduced compared to normal pattern at sarcolemma

image some show cytoplasmic dysferlin staining

• Secondary loss of dysferlin can also be seen in other dystrophies
• MHC may be up-regulated

Special diagnostic investigations

• Immunoblotting of muscle protein extracts is important to investigate secondary changes

Differential diagnoses and pitfalls

• Morphological features not specific
• Secondary loss of dysferlin staining may be seen in other dystrophies

SARCOGLYCANOPATHIES

• Autosomal recessive
• Mutations in one of four membrane proteins associated with the dystroglycan associated complex (Fig 17.11)
image

Fig 17.11 Photomicrograph of a muscle biopsy from a patient with a β-sarcoglycanopathy (left hand panel) and a control muscle (right hand panel) both stained for β-sarcoglycan. In the patient’s biopsy, there is loss of staining from the sarcolemma.

Genetics

• Four sarcoglycan genes responsible for muscular dystrophy (α, β, γ and δ; Table 17.2)
• Gene mutations vary with ethnic background
• Mutations in α-sarcoglycan are commonest

image typically missense
image show wide range of clinical phenotype

• Deletion in other subunits more frequently associated with more severe phenotypes

Table 17.2 Sarcoglycanopathies

  Syndrome Ethnicity
α LGMD2D No association
β LGMD2E  
γ LGMD2C  
  Severe childhood autosomal recessive muscular dystrophy (SCARMD) North Africa
  Recessive muscular dystrophy of European Gypsies European Gypsies
δ LGMD2F Brazil

Clinical features

• Clinically mimics dystrophinopathies from severe Duchenne-like presentation to asymptomatic hyperCKemia
• High CK present in all cases
• Cardiac involvement typically sub-clinical
• Cases are relatively rare outside the context of specific ethnic groups

image North African and European gypsies

Histopathological features

• Morphological features similar to dystrophinopathies

Immunohistochemical staining

• Immunohistochemical staining may be performed for all four subunits

image mutations in one leads to decreased staining of all four

– some advocate use of one or two antibodies only

• Complete loss of sarcoglycan staining with intact dystrophin is usually associated with sarcoglycan mutations

image more subtle changes are not specific

• Dystrophin staining is typically intact

image may be reduced in β-sarcoglycan mutations

Special diagnostic investigations

• Immunoblotting may be required to demonstrate reduced sarcoglycan expression
• Mutational analysis

image complicated but specific mutations are common in different ethnic groups

Differential diagnoses and pitfalls

• Sarcoglycan staining may be reduced in the dystrophinopathies as a secondary change
• Differential diagnosis from other muscular dystrophies

RARE LIMB GIRDLE MUSCULAR DYSTROPHIES

Telethonin deficiency / limb girdle muscular dystrophy 2G (LGMD2G)

• Very rare dystrophy

image mutations in Telethonin gene
image Brazilian population

• Clinical presentation in childhood with difficulty walking
• Muscle biopsy

image dystrophic changes
image rimmed vacuoles

TRIM32 mutations / limb girdle muscular dystrophy 2H (LGMD2H)

• Very rare
• Hutterite Canadians
• European cases reported

Titin mutations / limb girdle muscular dystrophy 2J (LGMD2J)

• Rare
• Finland
• Vacuoles may be present

CONGENITAL MUSCULAR DYSTROPHIES

• Clinical syndrome of infants with severe muscle weakness

image often with contractures and/or developmental delay

DYSTROGLYCANOPATHIES

• Diseases associated with deficiencies of O-linked glycosylation of α-dystroglycan (Muntoni et al 2008)

Clinical features

• An increasing range of phenotypes associated with mutations in a set of proteins known or believed to be involved in O-linked glycosylation
• Range from severe CNS involvement and congenital muscular dystrophy to limb girdle muscular dystrophies

Fukuyama muscular dystrophy

• Mutations in fukutin
• Common in Japan
• Muscle weakness

image respiratory failure by the second decade

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