MUSCLE AND NERVE PATHOLOGY

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

Related posts:

  1. METABOLIC DISEASE PATHOLOGY
  2. BONE PATHOLOGY
  3. DERMATOPATHOLOGY
  4. RENAL PATHOLOGY

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Jun 18, 2016 | Posted by in PEDIATRICS | Comments Off on MUSCLE AND NERVE PATHOLOGY

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