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

• Mental retardation and seizures

image Type 2 lissencephaly

• Ocular involvement
• Cardiomyopathy
• Arthrogryposis and scoliosis

Muscle eye brain disease (MEB)

• Described in Finland

image but not restricted to Finland

• Mutations of glycosyltransferase, POMGnT1
• Congenital muscular dystrophy
• Ocular involvement

image congenital myopia
image congenital glaucoma
image retinal dysplasia

• CNS involvement

image epilepsy

Walker–Warburg syndrome (WWS)

• Most severe phenotype
• Mutations in POMT-1 or POMT-2
• Cases with LARGE, FKRP and Fukutin mutations described
• Type 2 lissencephaly
• Ocular anomalies
• Death in the first few years of life

Congenital muscular dystrophy 1B (MDC1B)

• Rare

Congenital muscular dystrophy 1C (MDC1C)

• Mutations in FKRP (Fukutin-related protein)

Congenital muscular dystrophy 1D (MDC1D)

• Mutations in LARGE
• Very rare
• Proximal limb weakness
• Muscle hypertrophy
• Spinal rigidity
• Contracture

Limb girdle muscular dystrophy (recessive)

• LGMD2I

image FKRP
image common cause of LGMD

• LGMD2K

image POMT-1

• LGMD2L

image Fukutin

• LGMD2M

image POMGnT1

• LGMD2N

image POMT-2

Histopathological features

• Myopathic and dystrophic features

Immunohistochemical staining

• Antibodies against glycosylation dependent-epitopes on α-dystroglycan

image show reduced glycosylation
image can be technically challenging

– changes can be subtle

image β-dystroglycan can be used as a control

• Secondary loss of merosin has been described in a number of dystroglycanopathies

image Fukuyama
image MEB
image MDC1C

MEROSIN DEFICIENCY

• Deficiency of α2 chain of laminin that forms merosin (Fig 17.12)
• Congenital muscular dystrophy type 1A (MDC1A)
image

Fig 17.12 Photomicrograph of a muscle biopsy from a patient with a merosin-deficient congenital muscular dystrophy (MDC1A) (left hand panel) and a control muscle (right hand panel) both stained for merosin. In the patient’s biopsy, there is a loss of staining from the sarcolemma.

Genetics

• Mutations of the α2 laminin gene on 6q2
• No common mutations or ethnic predisposition

Clinical features

• Floppy from birth
• Do not achieve motor milestones
• High serum CK
• White matter changes on MRI

Histopathological features

• Great variation in histopathological features depending on age

image neonatal biopsies

– often show marked chronic inflammation

image later biopsies

– severe dystrophic pattern
– ultimately leads to end stage muscle

Immunohistochemical staining

• Immunostaining for laminin α2 normally localizes to the muscle fiber basement membrane

image absent, reduced or patchy in laminin α2 deficiency
image may be reduced as a secondary event in other disorders

– presence of white matter change adds specificity to the diagnosis
– see dystroglycanopathies

image usually lost from nerve fiber basement membrane

– rarely lost selectively here

image immunostaining for laminin α2 can also be performed on skin and chorionic villi for early diagnosis

• May see reduction in α-dystroglycan and integrin α7 deficiency

Differential diagnoses and pitfalls

• Main differential diagnosis are the other congenital muscular dystrophies

image distinguished immunohistochemically but note comment on secondary changes
image abnormal myelination on MRI is helpful in differential diagnosis

• Biopsies that show severe inflammation may be mistaken for a primary myositis

image may have in the past been called infantile polymyositis

COLLAGEN VI DEFICIENCY

• Mutations in one of the three genes encoding subunits of collagen VI

image congenital muscular dystrophy (Ullrich)
image later onset limb girdle muscular dystrophy (Bethlem)

Genetics

• Three genes encode for different subunits (α1, 2 and 3) of collagen VI

image mutations can affect any of these

• Autosomal dominant and recessive inheritance

image recessive associated with more severe Ulrich’s
image dominant associated with Bethlem

Clinical features

• Ullrich

image hypotonia and weakness as neonates
image rounded face and prominent ears
image may have kyphosis, torticollis, hip dislocation, proximal contractures
image distal joint laxity
image protuberant calcanei
image follicular hyperkeratosis and keloid
image respiratory failure in first or second decade

• Bethlem

image onset is typically in adulthood

– childhood and congenital cases described

image mild predominantly proximal muscle weakness
image hyperlaxity may occur
image contractures of the finger flexors are a common features
image slowly progressive
image normal or mildly raised CK

Histopathological features

• Myopathic/dystrophic changes

Immunohistochemical staining

• Staining for collagen VI shows marked variation

image may be completely normal
image may be absent
image may be absent only in the basement membrane

• Control stain (eg collagen IV, often as double immunofluorescence) is sometimes advocated to show loss in basement membrane

Differential diagnoses and pitfalls

• Main difficulty in reaching this diagnosis is unreliable nature of immunohistochemistry and biochemistry for collagen VI

INTEGRIN α7 DEFICIENCY

• Mutations in integrin α7
• Extremely rare cause of congenital muscular dystrophy
• Isolated cases reported
• Morphological features show non-specific myopathic/dystrophic process
• Reduced α7 integrin expression can be seen at the sarcolemma

RIGID SPINE WITH MUSCULAR DYSTROPHY

• Clinical syndrome of rigid spine and muscular dystrophy
• Clinical differential diagnosis

image Lamin A/C mutation
image Emerin mutations
image collagen VI mutations
image multi-mini core disease (SEPN1)
image congenital muscular dystrophy, RSMD1

– SEPN1 mutations
– fiber size variation
– increase endomysial connective tissue
– may resemble minicores

PLECTIN DEFICIENCY

• Combination of epidermolysis bullosa simplex and muscular dystrophy

image due to mutations in plectin

• Rare
• Generalized widespread weakness
• Other reported clinical features

image myasthenia
image laryngeal webs
image respiratory complications in infancy
image urethral strictures
image brain atrophy

Histopathological features

• Muscle shows severe dystrophy

image may show rimmed vacuoles
image may show mitochondrial features

– fibers with loss of cytochrome oxidase staining

• Biopsy of skin shows sub-epidermal bulla
• Immunohistochemistry may show cytoplasmic or sarcolemmal accumulation of desmin
• Plectin loss or reduction shown by immunostaining of skin
• Electron microscopy

image wide range of abnormalities

– cytoplasmic or nuclear rods
– myofibrillar disarray
– loss of thick filaments
– large lobulated, hyperchromatic nuclei

CONGENITAL MYOPATHIES

• See Laing 2007, Sewry et al 2008

CENTRAL CORE DISEASE

• Characterized by typical amorphous intracytoplasmic structures (‘cores’) (Treves et al 2008, Fig 17.13)
image

Fig 17.13 Photomicrograph showing multiple central cores, characterized by their pale staining in oxidative stains (NADH-TR preparation).

Genetics

• Most autosomal dominant

image several sporadic cases described with new mutations

• Occasional cases autosomal recessive
• Mutations in ryanodine receptor (RyR1) (19q)
• Mutations in RyR1 cause a range of phenotypes

image central core disease

– often associated with C-terminal mutations

image malignant hyperthermia

– often associated with N-terminal mutations

image multi-minicores or other less specific features
image cases of centronuclear myopathy

• Most mutations are missense but deletions are recognized

Clinical features

• Non-progressive
• Muscle weakness
• Hypotonia
• Delayed motor milestones
• Skeletal problems

image scoliosis
image flat feet
image hip dislocation

• More severe cases have been reported

image fetal akinesia

Histopathological features

• Cores

image definition: area within muscle fiber devoid of oxidative enzyme staining
image often central

– may occasionally be peripheral

image often single large core

– occasional small or multiple
– extend considerable distance in longitudinal section

image rim may show enhanced staining for oxidative enzymes
image more subtle abnormalities of oxidative staining may be seen

– not all cases will have classic ‘cores’

• Internal nuclei may be present
• Nemaline rods may be present
• Type 1 fiber predominance is common

Special stains

• Oxidative stains eg NADH-TR
• ATPase for fiber typing

Immunohistochemical staining

• Not necessary for diagnosis
• Desmin and vimentin may be accentuated in the cores or their rims

Electron microscopy

• Mitochondria are absent in all cores
• By electron microscopy there are two types of core

image structured cores

– sarcomeres are shifted relative to the surrounding sarcomeres

· continues over reasonable length (eg 300µm)

image unstructured cores

– sacromeric structure within the core is not preserved
– may show Z-band streaming

Differential diagnoses and pitfalls

• Cases may show only subtle abnormalities of oxidative stains
• Multi-mini core disease
• Neurogenic disease

image targetoid fibers

MULTI-MINI CORE DISEASE

• Myopathy characterized by multiple small cores

image small areas devoid of mitochondria or mitochondrial staining

• Includes the previous terms mini-core and multi-core

Genetics

• Genetically heterogeneous

image ryanodine receptor mutations (RyR1)
image selenoprotein N1 (SEPN1)

• Minicores also described in

image Marfan’s syndrome
image cerebo-retino-muscular syndrome
image type III glycogenosis
image short chain acyl CoA dehydrogenase deficiency
image anhidrotic ectodermal dysplasia

Clinical features

• Multiple phenotypes

image axial weakness

– spinal rigidity
– scoliosis
– torticollis
– respiratory muscle weakness
– mutations in SEPN1

image proximal and axial weakness

– partial or complete ophthalmoplegia
– RyR1 mutations

image phenotype similar to central core disease

– RyR1 mutations

image arthrogryposis

– dysmorphic
– respiratory impairment
– rare

image myopathy with cardiomyopathy

Histopathological features

• Multiple small areas devoid of staining on oxidative stains
• Central nuclei may be present
• SEPN1 mutations

image both fiber types containing mini-cores
image variation in fiber size

– occasional extensive central nuclei
– endomysial fibrous tissue and fat

• RyR1 mutations

image central nuclei
image type 1 fiber predominance

• Additional occasional features

image whorled fibers
image rods
image RyR1 mutations
image ACTA1 mutations

Special stains

• Oxidative stains are necessary to show the patches of absence staining

image NADH
image succinic dehydrogenase
image cytochrome oxidase

Immunohistochemical staining

• Several proteins may accumulate in the mini-cores

image desmin

– but not around the mini-cores

· cf central cores

image dystrophin

• Neonatal myosin positive fibers often absent in SEPN1 mutations

Special investigations

• Electron microscopy

image important in diagnosis
image small areas devoid of mitochondria
image varying disruption of myofibrillar architecture
image Z-band streaming

Differential diagnosis and pitfalls

• Important to distinguish from focal areas of fiber damage on the NADH in a destructive process

image EM to demonstrate absence of mitochondria

NEMALINE MYOPATHIES

• Diverse group of myopathies (Figs 17.14–17.19)

image characterized by accumulation of ‘rods’ in muscle fibers

– representing excess Z-band material

• See also actinopathies below
image

Fig 17.14 Photomicrograph of a muscle biopsy from a patient with a nemaline myopathy. The nemaline rods can just be seen on H&E as eosinophilic inclusions (arrows). This case also shows bimodal size distribution due fiber-type disproportion.

image

Fig 17.15 Photomicrograph of a muscle biopsy from a patient with a nemaline myopathy. The red inclusions are nemaline rods (see also Fig 17.16) (Gomori trichrome stain).

image

Fig 17.16 Photomicrograph of a muscle biopsy from a patient with a nemaline myopathy. The red inclusions are nemaline rods (arrow) (Gomori trichrome stain).

image

Fig 17.17 Electronmicrograph of a muscle biopsy from a patient with a nemaline myopathy due to an ACTA1 mutation. There are cytoplasmic and nuclear rods. The latter are a specific feature of ACTA1 mutations.

image

Fig 17.18 Electronmicrograph of a muscle biopsy from a patient with a nemaline myopathy. There are multiple cytoplasmic rods.

image

Fig 17.19 Electronmicrograph of a muscle biopsy from a patient with a nemaline myopathy. There are multiple cytoplasmic rods composed of dense cores and thin radiating filaments.

Genetics

• Most forms autosomal recessive

image childhood form may be autosomal dominant

• Genes

image thin filament proteins

– slow tropomyosin (TPM3)
– tropomyosin (TPM2)

· may be associated with caps

– nebulin
– α-actin (ACTA1)

· also see actinopathies

– slow troponin T (TNNT1)
– cofilin

Clinical features

• Age of onset

image severe neonatal form

– autosomal recessive

image congenital (‘classic’) form

– autosomal recessive

image late-onset/adult form

– autosomal recessive

image childhood form

– autosomal dominant

• General features

image proximal or generalized weakness
image facial muscles involved

– long face
– high arched palate
– tent shaped mouth

image other cranial and bulbar muscles spared
image often prominent respiratory involvement
image occasional cardiac involvement
image rare presentation as arthrogryposis

Histopathological features

• Rods

image most apparent on Gomori Trichrome

– dense red/purple
– small multiple
– may be very small and difficult to see

• Fiber type disproportion

image type 1 small

• Core-like structures may be present

Immunohistochemical staining

• Rods stained with antibodies against Z-band proteins

image α-actin
image sarcomeric actin

Special techniques

• Electron microscopy shows rods as

image large electron dense cores

– resembles Z-band material

image fine filaments emanate from the Z-band material
image clustered under sarcolemma
image may be aligned to sarcomeres
image α-actin 1 (ACTA1) mutations

– intranuclear rods
– aggregation of actin filaments in cytoplasm

image RyR1 mutations

– occasional nemaline rods within cores

Differential diagnosis and pitfalls

• In some cases rods may be very subtle on light microscopy and overlooked

image eg severe prenatal forms

• Other dense red structures on Gomori include

image mitochondria
image tubular aggregates
image cytoplasmic bodies

• Nemaline rods are not entirely specific and can occur in other disorders

ACTINOPATHIES

• Myopathies associated with mutations in sarcomeric actin (ACTA1)
• Clinically resemble nemaline myopathies

Histopathological features

• Three groups

image aggregates of thin filaments only
image aggregates of thin filaments and nemaline rods
image nemaline rods only

• Rods may be intranuclear (see nemaline myopathy)

X-LINKED MYOTUBULAR MYOPATHY

• Severe X-linked congenital myopathy

image associated with centrally placed nuclei (Figs 17.20–17.23)

• See also centronuclear myopathy (below)
image

Fig 17.20 Photomicrograph of a muscle biopsy from a patient with a myotubular myopathy showing multiple nuclei within the geographical center of the fibers.

image

Fig 17.21 Photomicrograph of an NADH-TR preparation of a muscle biopsy from a patient with a myotubular myopathy showing dense perinuclear staining. In addition, there is fiber-type disproportion.

image

Fig 17.22 Electronmicrograph of a muscle biopsy showing the centrally placed nucleus and a small amount of perinuclear glycogen as seen in myotubular and centronuclear myopathies.

image

Fig 17.23 Electronmicrograph of a muscle biopsy showing the geographically central nucleus as seen in myotubular and centronuclear myopathies.

Genetics

• X-linked mutations in myotubularin gene (MTM1)

image encodes for putative dual specificity phosphatase

• Many different mutations

Clinical features

• Typically severe congenital myopathy

image polyhydramnios
image reduced movements in utero
image miscarriage
image pre-term labour
image floppy infants
image respiratory failure

• A few milder affected cases occur with long-term survival
• Manifesting female carriers are described

Histopathological features

• Main feature is small fibers containing geographically central nuclei

image resemble fetal myotubes
image both type 1 and 2 fibers
image perinuclear zone

– glycogen rich (PAS)
– mitochondrial rich

· positive with oxidative stains (COX, SDH, NADH)

image periphery of fibers may be pale for oxidative stains

• Type 1 fiber predominance is frequent
• Fiber size variation common
• Necrosis/fibrosis absent

Immunohistochemical staining

• Not necessary for diagnosis
• May express high levels of vimentin, desmin, fetal myosin and utrophin

image not a diagnostic feature

Electron microscopy

• Not necessary for diagnosis
• Central nuclei

image may show peripheral chromatin condensation

• Perinuclear glycogen and mitochondria
• Miscellaneous features

image misalignment of triads
image disorganization of the sarcoplasmic reticulum
image dense tubular material
image focal myofibrillar disorganization

Differential diagnoses and pitfalls

• Myotonic dystrophy
• Other centronuclear myopathies (see below)

CENTRONUCLEAR MYOPATHIES

• Group of myopathies characterized by presence of large numbers of nuclei in geographical center of muscle fiber (Jungbluth et al 2008)
• See also severe X-linked myotubular myopathy (above)

Genetics

• Autosomal dominant and recessive patterns

image dynamin 2 mutations associated with an autosomal dominant form
image amphyphysin-2 mutations associated with autosomal recessive form
image mutations in ryanodine receptor (RyR1) and hJUMPY have been associated with cases

• Sporadic cases reported
• For X-linked myotubular myopathy see above

Clinical features

• Neonatal

image hypotonia
image weak suckling/crying
image not as severe as X-linked myotubular myopathy

• Childhood/adolescence

image insidious onset
image proximal limb weakness
image ophthalmoplegia and ptosis
image facial and masticatory weakness
image reduced or absent reflexes

• Adult-onset

image 2nd to 6th decade
image usually limb girdle pattern of weakness

Histopathological features

• Central nuclei

image geographic center of the fiber
image usually single nuclei

– occasionally multiple

image associated perinuclear halo common on H&E
image proportion of affected fibers varies

– diagnosis is uncertain if less than 1 in 5 fibers

image fibers typically small

• Necrosis/regeneration absent

Special stains

• Fiber typing with ATPase

image area of negative staining around nucleus
image usually small type 1 fibers

– may be type 1 predominance
– may be type 2 hypertrophy

• Oxidative stains (eg cytochrome oxidase)

image perinuclear accentuation
image may show abnormal radial architecture

• PAS

image perinuclear accentuation

• Acid phosphatase

image perinuclear accentuation
image lipofuscin

Immunohistochemical staining

• Desmin

image perinuclear accentuation
image may show radial fibrillar architecture

Electron microscopy

• Central but normally formed nuclei
• Occasional features

image dense bodies
image Z-band streaming
image radial myofibrillar architecture

Differential diagnoses and pitfalls

• X-linked myotubular myopathy

image see above

• Infantile myotonic dystrophy

image rarely truly central nuclei
image mother often myotonic

• Neurogenic disease

image infants with CNS disease

– type 2 small
– occasional centronuclear fibers

CONGENITAL FIBER TYPE DISPROPORTION

• Structural abnormality characterized by predominance and smallness of type 1 fibers (Figs 17.24, 17.25)
• May be feature of a wide range of other abnormalities

image many view as structural phenotype rather than a specific entity
image some cases associated with ACTA1, SEPN1 and α-tropomyosin (TPM3) mutations

• Non progressive congenital myopathy
image

Fig 17.24 Photomicrograph showing fiber type disproportion characterized by two populations of fibers of small and large fibers (see also Fig 17.24).

image

Fig 17.25 Photomicrograph showing fiber type disproportion characterized by two populations of fibers; small fibers staining for slow myosin (left hand panel) and large fibers mostly staining for fast myosin (right hand panel).

Histopathological features

• Uniformly small type 1 fibers
• Type 1 fiber predominant
• Must exclude

image specific congenital myopathies
image congenital myotonic dystrophy

HYALINE BODY MYOPATHY

• Rare myopathy characterized by presence of hyaline bodies
• Onset can be childhood or adult life
• β-cardiac myosin heavy chain (MYH7) mutations (Oldfors 2007)

image some authors include as a myofibrillar myopathy (below)
image also associated with

– distal myopathy with rimmed vacuoles

· Laing myopathy

– familial hypertrophic cardiomyopathy

• Hyaline bodies

image stain with ATPase
image negative for oxidative stains
image EM shows unstructured fine granular material

CYLINDRICAL SPIRALS MYOPATHY

• Rare
• Myopathy with cylindrical spirals on electron microscopy
• Most sporadic

image familial cases recognized

• Red plaques on Gomori trichrome
• Electron microscopy

image aggregates of spirals located beneath sarcoplasmic membrane

REDUCING BODY MYOPATHY

• Rare myopathy associated with FLH-1 gene mutations (Schessl et al 2008)
• Characterized by presence of reducing bodies
• May present as severe childhood myopathy or adult onset disease
• Reducing bodies

image stain with menadione NBT

• Electron microscopy

image granular and tubular material close to nucleus

TUBULAR AGGREGATE MYOPATHY

• Tubular aggregates

image red in Gomori trichrome
image positive in NADH-TR stains
image negative in mitochondrial stains

• Electron microscopy

image collections of tubular structures
image often with double layered membrane

• May occur in number of settings

image periodic paralysis
image alcoholic myopathy
image congenital myasthenic syndrome
image familial disorder

SARCOTUBULAR MYOPATHY

• TRIM32 mutations

image same gene as limb girdle muscular dystrophy 2H

• Myopathy with dilated sarcoplasmic reticulum

MYOPATHY WITH FINGERPRINT BODIES

• Rare congenital myopathy
• Fingerprints

image red on H&E
image green on Gomori
image parallel lamellae on electron microscopy

• Similar changes may be seen in other contexts

image eg central core disease

CAP BODY MYOPATHY

• Mutations in tropomyosin 2 (TPM2)
• Rare
• Caps present

image crescent shaped granular areas
image dark on Gomori
image stain for NADH and wide range of immunohistochemistry

– including desmin

image EM-Z-band material

• May contain rods

ZEBRA BODY MYOPATHY

• Very rare
• Zebra body

image Z-band material separated by thin filaments

MYOFIBRILLAR/DESMIN MYOPATHIES AND RELATED DISORDERS

MYOFIBRILLAR (DESMIN) MYOPATHIES

• Heterogeneous group characterized by myofibrillar disorganization extending from the Z-band and myofibrillar protein accumulation (Selcen 2008)

image traditionally desmin but many others proteins accumulate

Genetics

• Heterogeneous

image desmin mutations
image αB-Crystallin mutations
image myotilin
image ZASP
image filamin-C
image Bag-3 (Selcen et al 2009)

• Some authors include myosin gene mutations (MYHC2A and MYH7) and inherited inclusion body myopathies in this group

Clinical features

• Usually adult onset
• Rare in pediatric practice

image childhood cases reported associated with Bag-3 and desmin mutations

Histopathological features

• Inclusion bodies

image often best seen on Gomori

– areas more darkly stained

image not always present
image cytoplasmic bodies

– red on Gomori trichrome

image spheroid bodies
image sarcoplasmic bodies
image hyaline structures
image Congophilic material
image rimmed vacuoles

• Myopathic features

image atrophy and hypertrophy
image focal necrosis
image endomysial collagen
image fiber type grouping
image type 1 predominance

– some cases

• Oxidative stain (SDH, NADH, COX) and ATPase often absent from regions of protein accumulation
• Minicore type lesion may be seen

Immunohistochemical staining

• Desmin deposits in cytoplasm
• Many other proteins co-localize with the desmin deposits

image cytoskeletal proteins
image amyloidogenic proteins

Electron microscopy

• Myofibrillar disruption
• Amorphous granular electron dense deposits
• Filaments

image mixed with granular deposits

– granulofilamentous component

image surrounds electron granular dense core

– cytoplasmic bodies

HEREDITARY INCLUSION BODY MYOPATHIES

• Rare group of diseases associated with rimmed vacuoles

image similar to those seen in inclusion body myositis

– inclusion body myositis affects adults and is not discussed here

image lack inflammation

Genetics

• Multiple syndromes are described
• Overlap with myofibrillar myopathies
• UDP-N-acetylglucosamine 2 epimerase-N-acetylmannosamine kinase (GNE) (Argov et al 2008)
• Myosin heavy chain IIA (MyH2A)
• Other adult-onset syndromes

Clinical features

• Limb weakness predominates
• Onset typically in adolescence or early adulthood

Histopathological features

• As sporadic inclusion body myositis but no inflammation
• Rimmed vacuoles

image small vacuoles lined by basophilic granular material
image purple-red granules on Gomori trichrome stain
image variable numbers of vacuoles
image variable shape

– rounded, cleft-like

image occasional eosinophilic inclusions at edge of vacuole
image poorly preserved in paraffin tissue

• Myopathic or neurogenic changes
• Amyloid

Immunohistochemical staining

• Inclusions stain for range of proteins associated with neurodegeneration in adults

image eg amyloid precursor protein, β-A4, α-synuclein

Electron microscopy

• Tubulofilaments

image 15–21nm
image cytoplasmic

– may be near vacuole
– may see nuclear

image characteristic

• Vacuoles

image non-membrane bound
image contain myeloid debris

METABOLIC MYOPATHIES AND RELATED DISEASES

ALPHA-GLUCOSIDASE DEFICIENCY / ACID MALTASE DEFICIENCY / POMPE’S DISEASE / TYPE II GLYCOGEN STORAGE DISEASE

• Glycogen storage disease due to deficiency of lysosomal enzyme (acid) α-glucosidase (Van der Ploeg et al 2008; Figs 17.26–17.29)
image

Fig 17.26 Photomicrograph of a muscle biopsy from a patient with Pompe’s disease. There are large vacuoles in many of the fibers.

image

Fig 17.27 Photomicrograph of a muscle biopsy (same case as Fig 17.26) from a patient with Pompe’s disease. The large vacuoles show positive staining for acid phosphatase (red).

image

Fig 17.28 Electron micrograph of a muscle biopsy from a patient with Pompe’s disease. There are large collections of sarcoplasmic glycogen (see also Fig 17.29).

image

Fig 17.29 Electron micrograph of a muscle biopsy from a patient with Pompe’s disease. There are large collections of membrane-bound glycogen (see also Fig 17.28).

Genetics

• Autosomal recessive

Clinical features

• Infantile form (Pompe’s disease)

image severe hypotonia
image progressive cardiomegaly
image hepatomegaly
image death in the first year from cardio-respiratory failure

• Non-classical infantile form

image as infantile but less severe cardiac involvement
image survival can be prolonged with respiratory support

• Childhood form

image 2–3 years
image difficulty walking
image wheel chair bound and respiratory failure in late childhood

• Juvenile form

image onset in late childhood/adolescence
image muscle weakness
image respiratory failure

• Adult form

image onset in 20s or 30s
image muscle weakness/wasting
image respiratory failure

Histopathological features

• Infantile form (Pompe’s disease)

image massive irregular vacuoles fill many fibers

– contain PAS-positive material
– acid phosphatase positive
– some Alcian blue material

• Later onset forms

image smaller PAS positive vacuoles

– particularly type 1 fibers

Immunohistochemical staining

• Not diagnostic
• Periphery of vacuoles may show staining for variety of proteins

image dystrophin and spectrin

Electron microscopy

• Excess glycogen in vacuoles and in the sarcoplasm
• Vacuoles have single membrane

image may contain membranous material and cellular debris

Differential diagnoses and pitfalls

• LAMP-2 deficiency (Danon’s disease)

image in Pompe’s the vacuoles generally lack labeling for lectins (UEA-1) in contrast to Danon’s disease

• X-lined myopathy with excessive autophagy
• Other causes of vacuolar myopathy (see below)

LAMP-2 DEFICIENCY / DANON’S DISEASE / LYSOSOMAL GLYCOGEN STORAGE DISEASE WITH NORMAL ACID MALTASE

• Lysosomal vacuolar disorder of skeletal and cardiac muscle

image resembling α-glucosidase (acid maltase) deficiency

– but normal α-glucosidase activity

Genetics

• Associated with mutations in lysosomal associated membrane protein 2 (LAMP-2)
• X-linked, probably dominant

Clinical features

• Cardiomyopathy

image hypertrophic
image onset in teenage years
image arrhythmia common

• Myopathy

image usually mild

• Cognitive problems

Histopathological features

• Multiple small vacuoles

image may appear as small basophilic nodules on H&Es

Special stains

• Vacuoles may be positive for acetyl cholinesterase

Immunohistochemical staining

• Vacuoles may stain with various membrane-associated proteins

image eg dystrophin, sarcoglycans and laminins

Electron microscopy

• Autophagic vacuoles containing

image myelin bodies
image electron dense material
image cellular debris

• Vacuoles may be lined by basement membrane

Differential diagnoses and pitfalls

• Vacuoles may be inconspicuous on H&E
• α-glucosidase deficiency

image see above

• X-lined myopathy with excessive autophagy
• Other causes of vacuolar myopathy

X-LINKED MYOPATHY WITH EXCESSIVE AUTOPHAGY

• X-linked myopathy associated with sarcoplasmic vacuoles (Malicdan et al 2008)

Clinical features

• Onset early childhood
• Proximal muscles

image lower limbs more than upper limbs

• No cardiac or CNS manifestations
• EMG characteristic

image includes myotonia

Histopathological features

• Small sarcoplasmic vacuoles

image positive for acid phosphatase

• Fiber size variation often marked
• Fibrosis and fatty replacement late in disease

Immunohistochemical staining

• Vacuoles often lined by membrane-associated proteins

image eg laminin and dystrophin

• May show complement deposition

image C5-9 (membrane attack complex)

Electron microscopy

• Vacuoles surrounded by basal lamina and contain cellular debris

image degenerate organelles
image granular material
image membranous whorls

• Duplication of the basement membrane

Differential diagnoses and pitfalls

• α-glucosidase deficiency
• Danon’s disease
• Other causes of vacuolar myopathy

VACUOLAR MYOPATHY

• Differential diagnosis:

• Glycogen storage disorders
• Lipid storage myopathy
• Drugs

image autophagy/lysosomal

– eg chloroquine

image T-tubules derives

– hypokalemia

· diuretics

• Periodic paralysis
• Rimmed vacuoles

image hereditary inclusion body myopathies

• Lysosomal disorders

image alpha glucosidase deficiency
image Danon’s disease
image X-linked myopathy with excessive autophagy

• Artefacts

image ice crystal
image excess saline in transport media

DEBRANCHER DEFICIENCY / GLYCOGEN STORAGE DISEASE TYPE III / CORI–FORBES DISEASE

• Clinical – variable combination

image myopathy
image liver disease
image cardiomyopathy

• Histopathological features in muscle may be mild

image peripheral glycogen accumulation

GLYCOGEN STORAGE DISEASE IV / POLYGLUCOSAN DISEASE / ANDERSEN’S DISEASE

• Mutations in glycogen branching enzyme 1 (GBE1) (Nolte et al 2008)
• See also Chapter 10
• Neuromuscular presentation

image fetal akinesia deformation syndrome
image congenital form

– hypotonia

image childhood form

– neuromuscular presentation
– cardiac presentation

image adult form

– limb girdle weakness

• Polyglucosan bodies in muscle

image cf Lafora body

MCARDLE’S DISEASE / GLYCOGEN STORAGE DISEASE TYPE V

• Rare
• Autosomal recessive
• Usually adult onset
• Exercise induced myalgia or myoglobinuria
• Muscle wasting

image later in life

Histopathological features

• Glycogen accumulation may be subtle

image cytoplasmic
image subsarcolemmal blebs

• Histochemistry for myophosphorylase

image diagnostic
image non-regenerating extra-fusal fibers are negative
image muscle spindles and regenerating fibers may remain positive

Electron microscopy

• Subsarcolemmal glycogen accumulation

TARUI’S DISEASE / GLYCOGEN STORAGE DISEASE TYPE VII

• Phosphofructokinase (PFK) deficiency

Clinical

• Myopathy

image muscle cramps
image exercise intolerance
image myoglobulinuria

• Hemolytic anemia
• Infantile form

image severe disease

Histopathological features

• Sarcoplasmic glycogen accumulation

image may not be pronounced

• PFK deficiency may be demonstrated histochemically and biochemically

DISORDERS ASSOCIATED WITH EXCESS LIPID DEPOSITION ON MUSCLE BIOPSY

• Excess lipid deposition occurs in wide range of clinical contexts
• Interpretation of lipid stains (Figs 17.30–17.32) on muscle biopsy is subjective and depends on

image stain used
image normal levels seen in each laboratory
image metabolic state of the patient
image patient age

– normal levels of stainable lipid increase with age

• Differential diagnosis of excessive lipid deposition include

image defects in fatty acid metabolism

– myopathy is common in fatty acid oxidation defects

· presenting feature in 40%

– non-membrane bound lipid

· very variable in size and quantity
· more prominent in type 1 fibers than type 2
· destructive features present only when recent rhabdomyolysis
· lipid accumulation may be slight or absent in some fatty acid disorders (eg carnitine palmitoyltransferase (CPT) deficiency)

– secondary mitochondrial abnormalities may occur

· increased size, number
· inclusions
· indistinct cristae
· however, excess lipid deposition may occur in primary mitochondrial myopathies (ie disorders of oxidative phosphorylation)

image mitochondrial disorders

– oxidative phosphorylation defects

image nutritional abnormalities
image ischemia
image drugs

image

Fig 17.30 Photomicrograph showing large vacuoles due to excess lipid deposition (see Figs 17.31 and 17.32).

image

Fig 17.31 Photomicrograph showing large vacuoles due to excess lipid deposition (Oil red O) (see Figs 17.30 and 17.32).

image

Fig 17.32 Electronmicrograph showing excess lipid deposition (see Figs 17.30 and 17.31).

MITOCHONDRIAL DISORDERS (DISORDERS OF OXIDATIVE PHOSPHORYLATION)

• Heterogeneous group of disorders of oxidative phosphorylation (Filosto et al 2007; Figs 17.33–17.38)
image

Fig 17.33 Photomicrograph showing the appearances of a ragged red fiber by H&E staining. A granular basophilic rim surrounds the fiber in the center of the field.

image

Fig 17.34 Photomicrograph showing ragged red fibers characterized by peripheral red staining indenting the sarcoplasm on three sides (Gomori trichrome stain).

image

Fig 17.35 Photomicrograph showing a cytochrome-oxidase negative fiber from a patient with a mitochondrial myopathy (cytochrome oxidase histochemistry).

image

Fig 17.36 Photomicrograph showing a ragged blue fiber from a patient with a mitochondrial myopathy (SDH histochemistry).

image

Fig 17.37 Electronmicrograph of a muscle biopsy from a patient with a mitochondrial myopathy showing a subsarcolemmal accumulation of mitochondria.

image

Fig 17.38 Electronmicrograph of a muscle biopsy from a patient with a mitochondrial myopathy showing abnormal mitochondrial with a whorled architecture.

Genetics

• Mitochondrial genome defects

image maternal inheritance
image heteroplasmy

– single cell carry multiple different copies of the mitochondrial genome

• Nuclear genome defects

Clinical features

• Surgical biopsies usually come with history of undiagnosed complex multi-system neurological disorder
• Large range of specific clinical syndromes recognized

image chronic progressive external ophthalmoplegia (CPEO)
image CPEO plus

– ophthalmoplegia
– variable involvement of other organs

image Kearns–Sayre syndrome

– ophthalmoplegia
– onset in first two decades
– cardiac conduction defects
– cerebellar ataxia
– diabetes mellitus
– retinitis pigmentosa
– multi-system neurodegeneration

image Pearson’s syndrome

– pancytopenia
– dysfunction of exocrine pancreas

image neuropathy, ataxia, retinitis pigmentosa (NARP)
image Leigh’s syndrome

– subacute necrotizing encephalomyelopathy
– can be associated multiple different genetic defects

image myopathy with myoglobinuria
image mitochondrial encephalomyelopathy, lactic acidosis and stroke-like episodes (MELAS)
image myoclonic epilepsy with ragged red fibers (MERRF)
image mitochondrial myopathy and cardiomyopathy
image aminoglycoside-induced non-syndromic deafness
image cardiomyopathy
image MtDNA depletion syndrome
image myoneurogastrointestinal encephalopathy (MNGIE)
image Wolfram syndrome

– DIDMOAD (diabetes insipidus diabetes mellitus optic atrophy deafness)

image infantile hypertrophic cardiomyopathy with encephalopathy
image benign infantile myopathy

Histopathological features

• Main diagnostic features for this group are

image ragged red fibers

– accumulation of mitochondrial staining (red) on Gomori trichrome

· accumulated mitochondria should indent the sarcoplasm on three sides of the muscle (‘ragged’)

– lesser degrees of mitochondrial staining may be seen
– may be visible on H&E

· peripheral irregular basophilia

image ragged blue fibers

– same phenomena as ragged red fibers

· demonstrated on SDH histochemistry

– similar accumulation may be seen on the NADH-TR stain
– some laboratories combine SDH with COX stains

· show ragged blue fibers as COX negative

image cytochrome oxidase negative fibers

– truly negative fibers lack any granular COX staining
– some negative fibers are a normal finding in later adulthood

• Associated features

image variable myopathic or neurogenic changes may be present
image lipid and glycogen accumulation may be seen

Special diagnostic investigations

• A wide range of mitochondrial abnormalities may be seen ultrastructurally

image increased size/frequency of mitochondrial
image abnormalities of architecture of crista
image mitochondrial inclusions

– ‘parking lot’ inclusions

· classical inclusion of mitochondrial cytopathy
· relatively uncommon in young children

• Biochemistry for respiratory chain function
• Genetics

Differential diagnoses and pitfalls

• Little difficulty when clear ragged red/blue fibers or COX negative fibers present

image in many cases in early childhood, morphological features are more subtle and not diagnostic

– histochemistry needs to be accompanied by enzyme biochemistry and genetics

image not all mitochondrial disorders produce ragged red fibers or cytochrome oxidase negative fibers
image ragged red fibers have been reported as a secondary change

MYOADENYLATE DEAMINASE DEFICIENCY

• Deficiency of adenylate deaminase
• Common

image population frequency of homozygotes 1–2%

• Deficiency affects AMP metabolism
• May be asymptomatic or present with exercise-induced muscle pain
• Deficiency can be demonstrated by histochemistry
• Muscle is usually structurally normal
• Significance of co-incident deficiency with other metabolic defects is unproven

INFLAMMATORY MYOPATHIES

JUVENILE DERMATOMYOSITIS

• Overall is rare but is the commonest inflammatory myopathy of childhood (Figs 17.39–17.42)
• Consider as overlapping but not identical to adult disease
image

Fig 17.39 Photomicrograph of a muscle biopsy from a patient with juvenile dermatomyositis. There is extensive perimysial inflammation. In addition, inflammatory cells are in the wall of a perimysial vessel.

image

Fig 17.40 Photomicrograph of a muscle biopsy from a patient with juvenile dermatomyositis showing infiltration of the wall of a vessel by inflammatory cells.

image

Fig 17.41 Photomicrograph of a muscle biopsy from a patient with juvenile dermatomyositis (left hand panel) and a control muscle (right hand panel) stained for MHC. The control biopsy only shows significant staining on the vessels. In contrast in the patient’s biopsy, there is significant sarcolemmal staining.

image

Fig 17.42 Photomicrograph of a muscle biopsy from a patient with juvenile dermatomyositis (left hand panel) and a control muscle (right hand panel) stained for the membrane attack complex (C5–C9). In the control muscle, staining is restricted to the wall of large vessels (top right) but the capillaries are negative. In the patient’s biopsy there is patchy staining of capillaries (arrows).

Clinical features

• Presentation 5–15 years
• Proximal muscle weakness
• Raised CK
• Heliotrope rash
• Systemic complications
• May show overlap with other connective tissue disorders
• Not associated with malignancy

Histopathological features

• Features of destructive myopathy

image necrosis
image regeneration
image atrophy

– classically perifascicular distribution

image internal nuclei
image fibrosis

• Inflammation

image lymphocytes

– perifascicular and perivascular
– may be variable

· patchy nature of disease

– necrotizing vasculitis unusual
– infiltration of vessels by lymphocytes may be seen
– focal muscle necrosis very rare

Immunohistochemical staining

• Immunophenotyping shows infiltrate to be predominantly T-cells
• Sarcolemmal staining by major histocompatibility complex class I (MHC) may be present even in the absence of inflammatory cells

image not entirely specific to inflammatory myopathies
image important to include negative control (ie a non-expressing muscle) to exclude over-staining
image may be up-regulated in regenerating fibers irrespective of underlying diagnosis

• Membrane attack complex may stain the capillaries

image not always present

• Endothelial markers (CD31) will show a reduction in capillary density

image may be difficult to assess

• Staining for dystrophy related proteins may be necessary to exclude a dystrophy with inflammatory component

Classification and staging

• A validated scoring system has been developed (Wedderburn et al 2007)

Electron microscopy

• Tubuloreticular inclusions may be seen in endothelium

Differential diagnoses and pitfalls

• Dystrophies with an inflammatory component

image eg facioscapulohumeral dystrophy or Miyoshi dystrophy

• Due to the patchy nature of the disease biopsies maybe appear relatively minimal

JUVENILE POLYMYOSITIS

• Controversy as to whether juvenile form of polymyositis exists

image if it does exist, then it is very rare

• Need to exclude inflammatory component of a dystrophy

INFECTIOUS MYOPATHIES

• Inflammatory myopathies may occur in wide range of infectious disease

image not normally biopsied

• Differential diagnosis includes:
• Viral infections

image may cause acute myositis, rhabdomyolysis or subacute myopathy
image myositis

– influenza
– parainfluenza
– adenovirus

image rhabdomyolysis

– influenza
– coxsackie
– echovirus
– adenovirus
– herpes simplex

image subacute

– HIV myopathy

· endomysial inflammation (HIV polymyositis)
· necrosis without inflammation
· rarely nemaline rods

– HIV wasting syndrome

· type 2 atrophy

– HTLV-1 myositis
– echovirus

· may cause dermatomyositis pattern in immunoglobulin deficient patients

• Bacterial infection

image Pyomyositis
image Most frequently Staphylococcus aureus
image Clostridium myositis
image Necrotizing fasciitis/myonecrosis

• Fungal infection

image Rare
image Associated with immunosuppression

• Protozoa

image Toxoplasma
image Trypanosomiasis (African and South American)
image Microsporidosis
image Malaria
image Cysticercosis
image Trichinosis
image Hydatid disease

MISCELLANEOUS MYOPATHIES

TOXIC AND DRUG ASSOCIATED MYOPATHIES

• Multiple patterns of muscle damage may be seen with toxins and drugs (Klopstock 2008)
• Patterns in which toxic agents enter differential diagnosis include

image necrosis/rhabdomyolysis
image vacuolar myopathy

– lysosomal vacuoles, ‘autophagic’ vacuoles
– T-tubule derived vacuoles

image mitochondrial defects

– eg AZT in HIV treatment

image type 2 fiber atrophy
image inflammatory myopathies
image heavy chain myosin loss
image focal myopathy

NEUROGENIC DISORDERS

• Changes occurring following damage to motor neurone or axon innervating a muscle (Fig 17.43–17.45)
• Muscle biopsies taken in this context to support a clinical diagnosis of anterior horn cell disease

image in pediatric practice one of the most important contexts is spinal muscular atrophy (SMA) (see below)

image

Fig 17.43 Photomicrograph showing an angular atrophic fiber (arrow) from a patient with neurogenic muscular atrophy.

image

Fig 17.44 Photomicrograph showing target fibers (one example arrowed) from a patient with neurogenic muscular atrophy (NADH-TR preparation).

image

Fig 17.45 Photomicrograph showing fiber type grouping in the context of a neurogenic muscle disorder. There are enclosed groups of type 2 fibers (dark) and type 1 fibers (pale) (ATPase histochemistry; pH9.4).

Histopathological features

• General histopathological features of neurogenic changes

image atrophy

– fibers often angular

· may be rounded in young children eg SMA

– may occur individually but group atrophy suggests a neurogenic cause
– nuclear clumps
– both type 1 and type 2 fibers affected

image fibrosis and hyperplasia as later events
image target fibers

– central area of pallor on oxidative stains

· may be surrounded by area of increased staining
· limited longitudinal extent (cf central cores)

image fiber type grouping

– normal muscle biopsies show intermixed fiber typing
– following denervation

· axon sprouting leads to groups of adjacent fibers being of one type
· subsequent injury to the sprouting fiber, leads to group atrophy

– criteria for ‘a group’

· minimum is a fiber surrounded on all sides by fibers of the same type

– to distinguish neurogenic changes from a simple predominance of one fiber type

· need to see grouping of all three fiber types

Denervation in infants

• Most important clinical context is type 1 spinal muscular atrophy

image SMA type 1, Werdnig–Hoffman disease

• Features of denervation in infants with SMA type 1 show some distinctive features

image rounded atrophic fibers
image hypertrophy of type 1 fibers
image groups of atrophic type 2 fibers
image type 1 predominance
image atrophic fibers may co-express fast and slow myosin heavy chains
image may show relatively little grouping

TYPE 2 FIBER ATROPHY

• Selective atrophy of type 2 fibers (usually type 2b; Fig 17.46) is common manifestation of several insults

image disuse atrophy
image endocrine disorders

– especially corticosteroid excess

image paraneoplasia
image vitamin D deficiency
image drugs
image

Fig 17.46 Photomicrograph showing type 2b fiber atrophy. There are multiple small type 2b fibers (intermediate staining) in contrast to the larger type 1 fibers (dark) and type 2a fibers (pale) (ATPase histochemistry; pH4.6).

MYOSIN HEAVY CHAIN DEFICIENCY SYNDROME

• Acute quadriplegia

image commonest pathological basis for ‘critical illness neuropathy’ or ‘critical illness myopathy’

• Patients treated with corticosteroids and neuromuscular blockade in intensive care units

image on withdrawal of treatment, patient is unexpectedly paralyzed
image days to months to recover
image may not have always had corticosteroids

– especially severe sepsis

image old age and low protein intake are risk factors
image rare in childhood

• Associated with loss of thick myofibers from the A-band of the sarcomere
• Gomori trichrome – smudgy increased purple staining
• Reduced myosin ATPase staining
• Milder attenuation of myosin heavy chain
• EM shows loss of thick myofilament

image remaining sarcomere structure is preserved

MARINESCO–SJÖGREN SYNDROME

• Rare neurodegenerative disease
• Mutations in SIL1 gene
• Muscle biopsy

image variable myopathic features

• Ultrastructure

image double membrane associated with nuclei

– useful diagnostic feature

MALIGNANT HYPERTHERMIA

• Complication of anesthesia
• Clinical syndrome

image raised temperature
image generalized muscular rigidity
image tachycardia, tachypnea, cyanosis

• Muscle biopsy may show non-specific features
• Functional testing of muscle is undertaken in some centers but controversial
• Genetic susceptibility

image prediction of affected individuals may be difficult
image autosomal dominant
image two loci

– ryanodine receptor (RYR1)
– CACNA1S

· α1 subunit of dihydropyridine receptor

• Several primary muscle diseases have been associated with risk of malignant hyperthermia

image central core disease
image King–Denborough’s syndrome
image Becker and Duchenne muscular dystrophy
image multiple additional associations

RHABDOMYOLYSIS

• Clinical syndrome due to massive muscle breakdown

image raised CK
image myoglobinuria
image renal failure

• Biopsy at time

image muscle necrosis and regeneration
image or surprisingly subtle changes

• Muscle biopsy should be taken after the event

image secondary changes are no longer present
image effects of a primary muscle disease can be identified

ION CHANNEL DISORDERS

• Ion channel disorders are relatively rare biopsy specimens

image diagnosis is rarely dependent on histology

MYOTONIA AND PARAMYOTONIA

• Myotonia

image slow muscle relaxation
image ameliorated by exercise
image worsened by rapid movement

• Paramyotonia

image worsened by cold and exercise
image followed by prolonged weakness

• Classification generally dependent on

image genetic transmission
image potassium sensitivity

Histopathological features

• Chloride channel myotonias – Becker & Thomsen

image biopsy

– may be normal
– mild myopathic features
– type 2A hypertrophy
– type 2B reduction/absence

• Potassium aggravated myotonia

image myotonia fluctuans and permeans
image variable myopathic features
image sarcoplasmic vacuoles on electron microscopy

• Paramyotonia congenita

image similar features on light microscopy to chloride channel myotonia
image may see

– myofibril degeneration with

· myelin bodies
· lipid deposits
· subsarcolemmal vacuoles
· tubular aggregates

– fatty replacement and macrophage infiltration

PERIODIC PARALYSIS

• Disorders associated episodic weakness
• Two forms

image hyperkalemic periodic paralysis

– attacks associated with raised serum potassium
– exacerbated by potassium, rest after exercise and relieved by glucose
– earlier onset
– more frequent attacks
– milder course
– sodium channel mutations

image hypokalemic periodic paralysis

– attacks associated with low serum potassium
– exacerbated by glucose and exercise and relieved by potassium
– can be associated with progressive myopathy
– mutations in sodium, potassium or chloride channels

• Histology

image tubular aggregates
image vacuoles

BRODY’S DISEASE

• Autosomal recessive

image ATP2A1 gene

– encodes for SERCA1
– expressed in fast fibers

• Painless cramps
• Slow muscle relaxation during exercise
• Immunohistochemistry

image loss of SERCA1 from fast fibers in some patients

• Brody’s syndrome

image similar clinical syndrome
image no ATP2A1 mutations

NEUROMUSCULAR JUNCTION DEFECTS

MYASTHENIA GRAVIS

• Autoimmune disease
• Characterized by failure of neuromuscular transmission

image worsens with exercise

• Associated with antibodies against acetylcholine receptor
• Usually disease of adulthood
• Diagnosis depends on clinical, electrophysiological and serological criteria
• Surgical pathology

image thymectomy performed for therapy

– thymoma
– thymic hyperplasia

· depends on age-specific weights

image very rarely motor point biopsies may be taken to include the neuromuscular junction

– not part of routine diagnostic investigation

• Eaton–Lambert myasthenia syndrome

image paraneoplastic disease of adulthood

CONGENITAL MYASTHENIC SYNDROME

• Broad group of disorders

image characterized by failure of neuromuscular transmission

• Variable change in end plate on motor point biopsies

image not a routine investigation

• Routine muscle biopsy

image non-specific changes

NERVE BIOPSY

• Nerve biopsies rarely undertaken in children

image should be reported in a specialist center
image outline only presented here

• Processing of nerve biopsies varies but reasonable minimum is

image fix portion in formalin and process for paraffin embedding

– split and embed longitudinally and in cross-section

image fix a portion in glutaraldehyde

– for resin sections/EM

· important for diagnosis

– for teased nerve fibers

· limited diagnostic value

• As with muscle biopsies close discussion with the clinical team is necessary for accurate interpretation
• Changes in nerve biopsy with age include

image fiber number
image fiber size
image myelin thickness

• Initial distinction between axonal neuropathies and demyelinating/dysmyelinating neuropathies

image features favoring axonal neuropathy

– myelin ovoids/degenerating axon profiles

· macrophage infiltration

– loss of axon profiles
– bands of Bunger on EM

· Schwann cells lacking axon profiles

– regenerating sprouts

· thin axon profiles
· clusters of axons within one Schwann cell
· thin myelin sheath
· short inter-nodal space

image features favoring demyelinating neuropathy

– segmental demyelination on teased fibers

· unmyelinated internodes

– remyelination

· thinly myelinated fibers
· short internodes
· onion bulbs

• Second step to screen for specific diagnoses on biopsy

image inflammation

– vasculitis

image demyelinating disorders

– chronic inflammatory demyelinating polyneuropathy (CIDP)
– metachromatic leukodystrophy

· metachromatic granules

image hereditary disorders

– giant axonal neuropathy
– neuroaxonal dystrophy
– Charcot–Marie–Tooth
– metabolic disorders

· Fabry’s (osmophilic inclusions, endothelium and perineurium)
· Krabbe’s (inclusions in Schwann cells and macrophages, straight or slightly curved)
· metachromatic leukodystrophy (metachromatic inclusions)

image systemic disease

– amyloid
– sarcoid
– leprosy

REFERENCES

Argov Z, Mitrani-Rosenbaum S. The hereditary inclusion body myopathy enigma and its future therapy. Neurotherapeutics. 2008;5:633-637.

Brown SC, Piercy RJ, Muntoni F, Sewry CA. Investigating the pathology of Emery–Dreifuss muscular dystrophy. Biochem Soc Trans. 2008;36:1335-1338.

Filosto M, Tomelleri G, Tonin P, et al. Neuropathology of mitochondrial diseases. Bioscience Reports. 2007;27:23-30.

Guglieri M, Straub V, Bushby K, Lochmüller H. Limb-girdle muscular dystrophies. Curr Opin Neurol. 2008;21:576-584.

Jungbluth H, Wallgren-Pettersson C, Laporte J. Centronuclear (myotubular) myopathy. Orphanet J Rare Dis. 2008;3:26.

Klopstock T. Drug-induced myopathies. Curr Opin Neurol. 2008;21:590-595.

Laing NG. Congenital myopathies. Curr Opin Neurol. 2007;20:583-589.

Malicdan MC, Noguchi S, Nonaka I, Saftig P, Nishino I. Lysosomal myopathies: an excessive build-up in autophagosomes is too much to handle. Neuromusc Disord. 2008;18:521-529.

Muntoni F, Torelli S, Brockington M. Muscular dystrophies due to glycosylation defects. Neurotherapeutics. 2008;5:627-632.

Nolte KW, Janecke AR, Vorgerd M, Weis J, Schroder JM. Congenital type IV glycogenosis: the spectrum of pleomorphic polyglucosan bodies in muscle, nerve, and spinal cord with two novel mutations in the GBE1 gene. Acta Neuropathol. 2008;116:491-506.

Oldfors A. Hereditary myosin myopathies. Neuromusc Disord. 2007;17:355-367.

Schessl J, Zou Y, McGrath MJ, et al. Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy. J Clin Invest. 2008;118:904-912.

Selcen D. Myofibrillar myopathies. Curr Opin Neurol. 2008;21:585-589.

Selcen D, Muntoni F, Burton BK, et al. Mutation in BAG3 causes severe dominant childhood muscular dystrophy. Ann Neurol. 2009;65:83-89.

Sewry CA, Jimenez-Mallebrera C, Muntoni F. Congenital myopathies. Curr Opin Neurol. 2008;21:569-575.

Tawil R. Facioscapulohumeral muscular dystrophy. Neurotherapeutics. 2008;5:601-606.

Treves S, Jungbluth H, Muntoni F, Zorzato F. Congenital muscle disorders with cores: the ryanodine receptor calcium channel paradigm. Curr Opin Pharmacol. 2008;8:319-326.

Van der Ploeg AT, Reuser AJ. Pompe’s disease. Lancet. 2008;372:1342-1353.

Wedderburn L, Varsani H, Li CK, et al. International consensus on a proposed score system for muscle biopsy evaluation in patients with juvenile dermatomyositis: a tool for potential use in clinical trials. Arthritis Rheum. 2007;57:1192-1201.

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