Miopatias Metabólicas.pptx

Metabolic myopathies
A practical review
Fellowship Doenças neuromusculares e eletroneuromiografia (FAMERP)
03 de Abril de 2023
Laura Alonso Matheus Montouro

Introduction
● Set of rare disorders that disrupt energy metabolism.
● Defects of enzymatic pathways involved in myocyte metabolism (inborn errors
of metabolism)
● MMs can affect the skeletal muscle exclusively, or the muscle plus other
organs or tissues (metabolic myopathy plus (MM+), collateral myopathy)

Introduction
● Muscle → high energy demand.
● Adenosine triphosphate (ATP) is the primary source of the energy required for
muscle contraction and relaxation.
● The main sources of ATP are glycogen, glucose, and free fatty acids.

Introduction
● The most frequently disturbed metabolic pathways in muscle cells
leading to MM are:
○ Mitochondrial pathways, such as the respiratory chain
(oxidative phosphorylation), or beta-oxidation,
○ Cytoplasmic pathways, including glycolysis (Krebs cycle),
glycogen synthesis, or
○ Lysosomal pathways, such as glycogen degradation and fat
metabolism.

Introduction
● Skeletal muscle contains a mixture of type 1 and 2 fibers.
● Type 1 fibers are referred to as slow red muscle fibers, which depend
on aerobic glycolysis for energy production and are resistant to
fatigue on continuous contraction.
● Type 2 fibers are referred to as fast white muscle fibers.
● Type 2A fibers rely on aerobic and anaerobic glycolysis for energy and
are relatively more resistant to continuous exercise than type 2B fibers,
which rely exclusively on anaerobic glycolysis for energy and show easy
fatigability on continuous exercise.

Rest and rest-to-exercise
● At rest, fatty acids (FAs) are the primary source of fuel for skeletal muscle.
● The transition from rest-to-exercise requires immediate utilization of
ATP, sourced from the phosphocreatine shuttle, which is
independent of oxygen supply.
● This provides energy for 8 to 10 seconds, after which other metabolic
pathways are activated, depending on the intensity of activity, type of
exercise, duration of exertion, and physical conditioning and diet of
the individual.

Rest → Beta-oxidation of fatty acids
● The aerobic lipolysis system is your most heavily relied upon
energy pathway.
● Day to day activities and is incredibly economical.
● High energy density → beta-oxidation.
● Beta oxidation is a multi-step process that is repeated multiple
times to metabolize fat into ATP and it yields a net average of
106 molecules of ATP per 1 molecule of fat.
● The capacity of this pathway is indefinite; as long as we
provide the fuel source, it will continue to produce energy.

Phosphocreatine shuttle
● This is part of phosphocreatine
metabolism.
● In mitochondria, ATPlevels are very high
as a result of glycolysis, TCA cycle,
oxidative phosphorylation processes,
whereas creatine phosphate levels are
low.
● This makes conversion of creatine to
phosphocreatine a highly favored
reaction.
● Phosphocreatine is a very-high-energy
compound → mitochondria to myofibrils.

Phosphocreatine shuttle
a form of transportation that travels regularly between two places.
8 to 10
seconds of
energy

Anaerobic Glycolysis
● High-intensity exercise at submaximal HR
requiring short bursts of power relies on
anaerobic glycolysis.
● ↑85% of max HR - 70% VO2 max
● Glycogen is broken.
● 200m sprint, for example.
● Only 2 ATPs / cicle
● Lactic acid production → Fadigue.
10 to 60
seconds of
energy

Anaerobic Glycolysis
● Lactic acid:
○ ↓Glycolytic enzyme activity (PFK)
○ Fadigue - neuromuscular junction
■ Lower release of ACETYLCHOLINE by
nerve endings, due to acidification of the
interstitial fluid and alteration of protein
structures (acetylcholine receptors) by the
action of H+.
■ Acidosis alters the permeability of the
reticulum, decreasing Ca++ conductance.
○ Acidosis stimulates type "C" (slow) fibers
causing "burning" type pain.

Aerobic glycolisis
● Glycolysis: anaerobic phase to form pyruvate
● Krebs cycle → The tricarboxylic acid (TCA) cycle.
● Oxidative phosphorylation is a more efficient mechanism for producing
ATP.
○ metabolizes glycogen, glucose, and FAs to produce NADH and
FADH2, which donate electrons in the mitochondrial electron
transport chain to produce ATP.

Energy system
● Submaximal low-intensity aerobic
exercise favors metabolism of FA
and glycogen.
● High-intensity exercise favors
glycogen as a primary source of
energy.
● Aerobic glycolysis contributing in
both instances.
● As the duration of submaximal
exercise increases, FAs become
the primary source of energy.

Muscle metabolic disorders
Glycogenoses
● glycogen or glucose degradation or glycogen synthesis (glycogenesis)
and lead to an abnormal accumulation of glycogen;
● GSD: glycogen storage disorders.
Disorders of lipid metabolism primarily include FA oxidation disorders (FAODs),
which are defects of beta-oxidation or carnitine cycle disorders, but also
include other pathways.
Mitochondrial diseases can result from many defects including those that affect
respiratory chain proteins.

Clinical presentation
● Exercise intolerance, fatigue, myalgias, and/or weakness.
● At clinical presentation, individuals may be asymptomatic without
fixed weakness.

Laboratory studies
● Blood serum and urine studies should be obtained.
● CK:
○ Although CK levels are not specific, abnormal values may help
identify potential mimics or suggest a specific diagnosis.
○ False positive CK elevations can be caused by exercise, statin
use, or normal variations.
● Serum lactic acid: elevations → mitochondrial myopathy;
● Lipidic storage disorders: plasma acylcarnitine profile, plasma total
and free carnitine levels, and urine organic acid levels should be
measured
● If biochemical studies suggest a particular class of disorders, then
next-generation sequencing (NGS) of DNA.

Genetics
● Although NGS is useful when pathogenic variants are found, variants
of unknown significance (VUS) are common, as are potentially false-
negative results.
● Mitochondrial myopathies.
○ Blood or saliva mtDNA testing is helpful for identifying point
mutations; however, given the wide range of genetic
abnormalities causing mitochondrial myopathies, muscle is the
ideal tissue for analysis, especially for mtDNA deletions and
heteroplasmy—given accessibility and yield if blood or saliva
testing is negative.

Electrophysiology and Exercise Testing
● EMGs may be normal or show myopathic units. Spontaneous activity
is typically absent.
● Exercise testing → useful when genetic testing and/or biopsy results
are nondiagnostic.
○ Nonischemic forearm exercise testing, as opposed to ischemic
testing, is recommended to evaluate for GSDs because it
provides similar sensitivity and specificity without the added risk of
rhabdomyolysis or acute compartment syndrome.
○ Ischemic forearm exercise testing.

Electrophysiology and Exercise Testing
● Aerobic cycling exercise testing is typically
performed using a standard Bruce protocol with a
gradual increase in workload on a cycle ergometer.
○ A hallmark of mitochondrial dysfunction is
reduced VO2max, reduced peripheral
oxygen extraction (arteriovenous oxygen
difference), and a hyperkinetic circulation
(elevated baseline cardiac output).
○ Falsely reduced VO2max can be seen in
people who are physically inactive, which leads
to loss of mitochondrial enzyme activity.

Muscle biopsy
● A muscle biopsy can be of use in identifying mimics, performing
enzyme analysis, or running tissue-specific sequencing.
● Biopsy with electron microscopy is particularly helpful for
mitochondrial myopathies.
● In FAODs, muscle biopsy may show abnormal lipid accumulation.
The degree of FA accumulation can narrow the differential diagnosis.
○ More FA accumulation suggests MADD, primary carnitine
deficiencey, or neutral lipid storage disease,
○ Whereas the other FAODs have less FA accumulation.

Glycogen Storage Disorders – GSD
● MMs due to impaired carbohydrate metabolism
○ With glycogen storage with or without the additional deposition of
polyglucosan (glycogenoses - GSD), of which 16 are currently
known,
○ Without glycogen storage (aglycogenoses), of which two are
currently known.

● Deposition of abnormally structured glycogen in myocytes
● Disrupting contractile functions or reduced substrate turnover below
the enzymatic block.
● The most common is McArdle’s disease.
● The only GSD that is treatable is Pompe disease (PD).

● “Light” GSD: second or third decade of life but often have attributable
symptoms in childhood.
● Seconds to minutes: cramps and exercise intolerance.
● Intermittent rhabdomyolysis is a common feature, particularly in
McArdle (GSD5) and Tarui (GSD7) disease.
● Whereas Pompe (GSD2) disease is characterized by myopathy
without rhabdomyolysis.

GSD5: McArdle Disease
● The most common disorder of carbohydrate metabolism.
● Autosomal recessive mutation in the glycogen phosphorylase
(PYGM) gene
● Myophosphorylase deficiency.

GSD5: McArdle Disease - Genetics
○ Mutations
■ Recessive: Loss of function
■ > 170 different mutations identified
● Types: May be missense, stop, destruction of start codon or small
deletion with frameshift
● Missense most frequent (50%)
● Splice site (11%)
● Hotspots: Exons 1 & 17;
■ Common mutations
● US, Britain, Germany, France, Italy: Arg50Stop in exon 1
○ Most common mutation
○ Type: Nonsense
● W798R
● Gly205Ser: 10%; North American & Spanish
○ Allelic disorder: PYGM myopathy, Dominant

GSD5: McArdle Disease - Pathology
https://neuromuscular.wustl.edu/pathol/phosphorylase.htm
Phosphorylase stain From: S Moore Subsarcolemmal cytoplasmic vacuoles
(Blebs)
Most contain diffuse pale-staining material
May contain myonuclei

GSD5: McArdle Disease - Pathology
https://neuromuscular.wustl.edu/pathol/phosphorylase.htm
Blebs: Subsarcolemmal
Contain Glycogen granules

● Onset age
○ Usual: < 15 years;
○ Often early childhood (< 10 years)
○ May be > 50 years
● Exercise intolerance & Fatigue (99%)
○ Especially brief & intense exercise
● Moderate exercise: Usually well tolerated
● Cramping & Muscle swelling: May last for hours
● Myoglobinuria (50%)
● Discomfort: Muscle → Cramps and pain: Especially proximal legs

● Weakness
○ Severity → Usually Mild
○ Frequency: 11% to 30%; More common in older patients → Usually > 40
years
○ Fixed
○ Distribution: Variable
■ Proximal > Distal
■ Symmetric or Asymmetric
● Asymmetric: Scapular winging or FSH phenotype common 12
■ Arm > Leg
■ No clear relation to genotype

● ‘Second wind’ phenomenon → improvement in exercise tolerance after
approximately 10 minutes of low intensity exercise (a ‘warm-up’ period), is
pathognomonic.
● Some people can also develop fixed proximal muscle weakness.
● Sucrose intake before exercise mitigates symptoms

GSD5: McArdle Disease - Laboratory and other exams
● CK
○ Elevated even at rest (> 90%): Up to 12,000
○ May be normal in pregnancy
● Hyperuricemia
● High K+ during exercise
● EMG: Myopathic
● Muscle biopsy

GSD5: McArdle Disease - Ischemic forearm exercise test
● Patient’s non-dominant arm have the antecubital vein
cannulated and then a blood pressure cuff on the
same arm is inflated (>20 mm Hg above systolic
pressure) to occlude venous return.
● The arm is then maximally exercised to exhaustion
using intermittent anisometric maximal forearm
contractions.
● The blood pressure cuff is released.
● Blood samples are taken at baseline and then serially
(1, 3, 5, and 10 minutes) after exercise.

● Normal Values: at least a 3x increase in
serum lactate and ammonia levels without
an increase in CPK or potassium.
● Abnormal Values: McArdle disease show
an increase in ammonia levels but not in
serum lactate.
● >90% sensitive with glycogen storage
disorders
● Adverse Effects: Cramping, myalgia,
contractures, and, rarely, myoglobinuria or
rhabdomyolysis are seen.
● Cost: Approximately $1400

Adenylate kinase pathway:
● Two ADP molecules combine to
regenerate ATP, and adenosine
monophosphate (AMP) is
produced as a by-product.
● This reaction is coupled with
AMP deamination, resulting in
the production of IMP and
ammonia (NH3).

GSD5 - Nonischemic forearm exercise test

GSD7: Tauri Disease
● Autosomal recessive mutation in the phosphofructokinase (PFKM) gene
● Genetics
○ Many different mutations: ~ 20 identified
○ Types: Missense, Splicing change & Deletions
○ More severe disease may occur with simultaneous mutations in AMPD gene
○ Allelic disorders
■ Fatal infantile
■ Adult onset: Exercise intolerance
● PFK protein
○ Phosphorylates fructose-6-phosphate to fructose-1,6-bisphosphate
○ Commits glucose to glycolysis
○ Rate limiting step in glycolysis

GSD7: Tarui Disease
● Clinical features: Some features similar to McArdle's
○ Onset: 2nd to 4th decade
○ Exercise intolerance
■ Muscle cramps & Myoglobinuria after vigorous exercise
■ Cramps relieved by rest
■ Pain may be associated with nausea & vomiting
■ Second wind phenomenon: Less common than in McArdle's
■ High carbohydrate meals exacerbate exercise intolerance
○ Weakness: Late-onset with fixed myopathy in some patients
○ Systemic features
■ Gout: Hyperuricemia
■ Gastric ulcer

GSD7: Tarui Disease
● Epidemiology
○ Male predominence (9:1)
○ Prevalence high: Ashkenazi Jews (US) / Italy / Japan
● Diet (vs McArdle's)
○ High carbohydrate meal: More symptoms
■ ‘Out-of-wind’ phenomenon: when sugar is taken before
exercise, worsening symptoms.
○ Prolonged fasting: Milder symptoms
● Myoglobinuria: Less frequent than in McArdle's

GSD7: Tarui Disease
● Pathology
○ Subsarcolemmal vacuoles
○ Glycogen may be normal or high
○ Abnormal polysaccharide may acumulate
■ Stains with PAS but not digested by diastase
■ Polyglucosan: Older patients
○ Myopathic change in children

GSD7: Tarui Disease - Laboratory
○ Serum CK
■ During episodes: High
■ Between episodes: Often normal
○ Hyperuricemia
○ Hyperbilirubinemia
○ Hemolytic anemia → phosphofructokinase in erythrocytes
○ Exercise test: No lactate rise
○ Repetitive nerve stimulation (20 Hertz for 1 minute):
Decrement
○ EMG: Myopathy ± Irritability
○ Biochemistry
■ PFK activity reduced to < 40%
■ Accurate only if muscle is rapidly frozen after biopsy

GSD7: Tarui Disease- PFK variants
● Fatal infantile: Severe myopathy + CNS & Systemic
○ Epidemiology: 5 families
○ Genetics - Inheritance: Recessive
○ Clinical
■ Age: Infants & young children
■ Motor: Hypotonia, Develop fixed weakness, Respiratory failure.
■ Cardiomyopathy
■ Arthrogryposis
■ CNS
■ Seizures
■ Cortical blindness
■ Corneal opacification
■ No hemolysis
■ Course
■ Rapidly progressive
■ Death < 2 years

Glycogen Storage Disorders – GSD: Treatment
● Exercise training in the various types of GSD can be beneficial
regarding exercise tolerance and increasing fatty acid oxidation.
● Oral galactose treatment may have a beneficial effect for some of
the clinical manifestations in PGM1-associated GSD.
● For GSD III, a high protein diet has been reported to improve
cardiomyopathy.
● McArdle: Creatine intake/ oral sucarose

GSD2: Pompe Disease - Introduction
● Autosomal recessive mutations in the alpha-glucosidase (GAA) gene
cause an enzymatic deficiency in acid maltase.
● Limb-girdle weakness, ventilatory failure and cardiomyopathy are
possible.
● Late-onset acid maltase deficiency can result in early respiratory
insufficiency with proximal muscle weakness and scapular winging with
exercise intolerance caused primarily by dyspnea.
● In Pompe disease, myotonic discharges may be seen in the paraspinal
muscles.
● Enzyme replacement is an available treatment option for Pompe
disease.

GSD2: Pompe Disease - Epidemiology
● Epidemiology
○ Disease incidence
■ Overall: 1 in 40,000 to 57,000 live births
○ More common in
■ Afro-Americans: Arg854X; 1 in 14,000; Infant onset
■ Dutch: del525T & del exon 18; Infant onset
■ Taiwan: Asp645Glu; Infant onset
■ Caucasians: 1 in 100,000
● Frequency: 5,000 to 10,000 cases world-wide
● Carrier frequency: 1 in 85 to 100

GSD2: Pompe Disease - Genetics
● Gene features: Mutations
○ > 500 identified
■ Types: Point; Deletions; Splicing
○ Some hot spots
■ IVS1AS-13T>G: Common
mutation in adults but not
children
■ Most patients compound
heterozygotes

GSD2: Pompe Disease - Genetics
● Level of residual enzyme activity correlates with
○ Severity of disease
■ Infant onset (< 1 year): < 1% GAA activity
■ Childhood & Juvenile onset 2% to 6% GAA activity
■ Adult onset (> 2nd decade): 1% to 29% activity
○ Age of disease onset
○ Location of mutations
● Exon 18: deletion → No enzyme formed → Infant onset.
● Intron 1: Transversion of acceptor splice site (IVS1(-13T->G))
○ Results in splicing out of exon 2
○ Splicing is "leaky"; Some functional enzyme is produced
○ Common (> 70%) in adult onset weakness & later respiratory failure

GSD2: Pompe Disease - Genetics: c.32-13T>G

https://neuromuscular.wustl.edu/pathol/acidmalt.htm

GSD2: Pompe Disease - Clinical Features: Infant Onset
● Infant onset: Multisystem; Severe
○ Onset
■ Age: < 6 months
■ Hypotonia
○ Systemic
■ Cardiac (> 90%)
■ Cardiomegaly
■ Congestive heart failure
■ Arrhythmia
■ Variant with no cardiac involvement: Longer survival
■ Liver involvement
■ Pulmonary: Pneumonia
○ Motor
■ Hypotonia (88%)
■ Respiratory distress (80%)
■ Weakness (60%)

GSD2: Pompe Disease - Clinical Features: Infant Onset
● Anesthesia
○ Succinylcholine: Increased risk
■ Arrhythmia
■ Hyperkalemia
■ Rhabdomyolysis
○ Possibly safer anesthetics: Ketamine; Etomidate
○ Other
■ EKG: Monitor intra-operative
■ Serum K+ & CK: Monitor post-operative
● Death
○ < 1 year: 80% to 95%
○ Median: 6 to 8 months
○ Shorter survival: Earlier onset
● Glycogen accumulation: In most tissues

GSD2: Pompe Disease - Clinical Features: Childhood Onset
○ Clinical
■ Weakness: Proximal; Symmetric
■ Muscle size: Calf hypertrophy
■ Subgroup < 15 years with more severe & rapidly progressive
disease
■ Death: 3 to 24 years: Due to respiratory failure
○ Laboratory
■ Glycogen accumulation: Mainly in muscle
■ Acid maltase: Low but residual levels of activity

GSD2: Pompe Disease - Clinical Features: Juvenile Onset
Juvenile onset (LGMD 2V): Spine + Axial
● Mutation: Common leaky IVS splice site on one allele
● Onset age: 12 to 21 years
● Spine
○ Rigid spine: Childhood onst; Incomplete
○ Scoliosis
○ Lumbar hyperlordosis
● Joints
○ Contractures: Distal
○ Pes equinus
● Low body mass: Small muscles
● Muscle
○ Scapular winging
○ Respiratory insufficiency
○ Axial: Neck & Trunk > Limbs
○ Swallowing: Normal

GSD2: Pompe Disease
Patient D., 9 years old with late-onset Pompe
disease. Clinical examination: а -due to weakness
of mm. gluteus, erector spinae the patient uses
the extra support of the hand on the thigh, trying
to stand upright, б -severe hyperlordosis and
weakness of the deltoid muscles, в -atrophy of
the back muscles, clearly visible when leaning
forward; г -weakness of the muscles holding the
scapula, asymmetric syndrome of «pterygoid»
scapula, more pronounced on the left
Clinical examination of patients with late-onset Pompe disease: typical and not typical symptoms and signs - Scientific Figure on ResearchGate. Available from:
https://www.researchgate.net/figure/Patient-D-9-years-old-with-late-onset-Pompe-disease-Clinical-examination-a-due-to_fig1_338551965 [accessed 26 Mar, 2023]

GSD2: Pompe Disease
Fig. 2. Patient D, 9 years old. Diagnosis:
Pompe disease with a late onset.
A characteristic technique used additional
support on the arm when climbing stairs due
to weakness of the muscles of the pelvic
girdle and hips
Clinical examination of patients with late-onset Pompe disease: typical and not typical symptoms and signs - Scientific Figure on ResearchGate. Available from:
https://www.researchgate.net/figure/Patient-D-9-years-old-with-late-onset-Pompe-disease-Clinical-examination-a-due-to_fig1_338551965 [accessed 26 Mar, 2023]

Pompe Disease - Adult Onset: Myopathy and other features
○ Initial symptoms
■ Age
● Mean 29 years; Range 1st to 6th decade
● Often some history of weakness or fatigue during 2nd decade
■ Fatigue: Young adults
■ Weakness: Older adults; Legs & Trunk; Running & Sports
■ Muscle discomfort: Cramps
■ May present with high CK but normal strength

● Weakness:
● Symmetric
● Respiratory failure
○ Presenting feature in 5% to 30%: Often with other signs
○ Symptoms: Headache; Somnolence; Dyspnea
○ Course
■ Onset usually several years after leg weakness
○ Diaphragm involvement: Common & Early; More symptomatic when supine
○ Sleep disordered breathing: Common
○ Expiration more involved than inspiration
○ Secondary features
■ Basilar atelectasis
■ Pulmonary hypertension
○ Treatment: Nocturnal ventilation

● Weakness:
● Axial: Abdominal & Paraspinal muscles
● Proximal > Distal
● Legs > Arms: Hip flexors & extensors, adductors & abductors
● Paraspinous muscles (Atrophy)
● Bulbar: Tongue; Dysphagia & Dysarthria
● Relatively spared: Quadriceps; Distal muscles
● Disease course: Progression 30
○ Slow, over years
○ Severity related to disease duration, not patient age 17
○ More rapid with
■ Respiratory involvement
■ Longer disease duration

● Cardiac: Usually normal
● Other
○ Skeletal
■ Spine: Disease onset < 21 years
1. Lordosis (50%)
2. Scoliosis (10% to 33%)
3. Rigid spine
■ Fractures: Vertebral; Long bones
■ Back pain
■ Contractures (40%): Shoulders; Hips; Knees; Neck
○ GI: Diarrhea; Abdominal pain
○ Weight loss
○ Smooth muscle: Urinary or Fecal incontinence
○ Hearing loss
○ Cognitive impairmant, mild

● Course
○ Progressive
■ Disability related to disease duration
■ Eventual respiratory involvement common
■ Many need wheelchair or walking devices
○ Some patients remain independent & employed
○ Death: Due to respiratory failure
● Serum CK: Mean 440 - Range 270 to 1040
● MRI of Muscle
○ Early involvement
■ Paraspinous & Trunk (Abdominal)
■ Thigh: Adductor magnus; Semimembranosus
○ Later selective involvement
■ Long head of biceps femoris; Semitendinosus; Anterior thigh; Psoas
○ Spared: Sartorius; Rectus; Gracilis
○ Pattern of muscle abnormality: Atrophy; Abnormal signal

GSD2: Pompe Disease
Clinical features in Pompe disease.
Atrophy of the quadriceps muscle (A),
scapular winging / deltoid atrophy (B),
and ptosis (C)
van der Beek, Nadine A. M. E.; de Vries, Juna M.; Hagemans, Marloes L. C.;
Hop, Wim C. J.; Kroos, Marian A.; Wokke, John H. J.; de Visser, Marianne; van
Engelen, Baziel G. M.; Kuks, Jan B. M.; van der Kooi, Anneke J.; Notermans,
Nicolette C. (2012-11-12). "Clinical features and predictors for disease natural
progression in adults with Pompe disease: a nationwide prospective
observational study". Orphanet Journal of Rare Diseases. 7: 88.
doi:10.1186/1750-1172-7-88. ISSN 1750-1172. PMC 3551719. PMID
23147228.

GSD2: Pompe Disease
Laforêt, P., Doppler, V., Caillaud, C., Laloui, K., Claeys, K. G., Richard, P., … Eymard, B. (2010). Rigid spine syndrome revealing late-onset Pompe disease.
Neuromuscular Disorders, 20(2), 128–130. doi:10.1016/j.nmd.2009.11.006
Fig. 1. Clinical and histopathological findings in
patient. (A and B) The patient has rigid spine,
thoracolumbar scoliosis, severe paraspinal
muscular atrophy and mild bilateral scapular
winging. (C–E) Serial transverse sections in the
biopsy of the left deltoid muscle. Small vacuoles
in the sarcoplasm and subsarcolemmal area are
observed in 0.5% of fibers on hematoxylin and
eosin (HE) stain (C).PAS activity is increased in
the vacuoles
(D). The vacuoles show a positive reaction for
acid phosphatase (red staining of the vacuoles)
(E). The inset in (E) shows the affected fiber,
containing vacuoles that stain positive for acid
phosphatase, at a larger magnification. The
asterisk
indicates the same fiber containing vacuoles in
the serial sections.
(F) Ultrastructural analysis shows accumulations
of both free (1) and membrane-bound (2)
normally
structured glycogen, between the myofibrils and
underneath the sarcolemma.

Pompe Disease - Adult Onset: Cardio-cerebrovascular
● Onset age: Mean 38 years; Range 18 to 62 years
● Vascular
○ Cardic arrhythmias: Sick sinus syndrome / Wolff–
Parkinson–White
○ Aneurysm: Cerebral (Basilar or Aortic); Aortic
○ Aorta: Stiff
○ Cerebral atherosclerotic angiopathy
■ Mutations: Ala237Val; Gly293Arg
○ Dolichoectasia: Basilar & Internal carotid arteries
○ Stroke
○ Other
■ Eye: Unilateral ptosis; Diplopia
■ Migraine
○ Cardiac ultrasound: Right ventricular hypertrophy
● Weakness
https://neuromuscular.wustl.edu/msys/glycogen.html#am

GSD2: Pompe diseae - Laboratory and EMG
● Serum CK
○ Infants: High (< 10x); Highest in infants
○ Rarely normal in adults (5%)
● EMG: Irritative myopathy
○ Myopathy
○ Fibrillations
○ Complex repetitive discharges
○ Myotonic discharges

GSD2: Pompe diseae - Bx
● Vacuolar Myopathy
○ Muscle fiber sizes: Varied
○ Vacuoles in muscle fibers
○ Locations: Subsarcolemmal & Internal
H&E.

GSD2: Pompe diseae - Bx
Glycogen Storage
● Diffuse, or patchy,
increase in glycogen
staining in muscle fiber
cytoplasm
● Variably present in
muscle fibers
● Vacuoles: Not clearly
delineated; Many have no
staining
● Aggregates: PAS+

GSD2: Pompe Disease - Treatment
● GSD II is the only MM for which an effective therapy is available.
● It is an enzyme replacement therapy (ERT) in which a
recombinant human alpha glucosidase (rhGAA; 20 mg/kg
intravenously every two weeks) is applied.
● The earlier ERT is initiated, the more effective it is.
● A number of studies using rhGAA alone or in combination with
chaperones are currently ongoing.

Fatty acid metabolism
(1) entrance of fatty acids into the cytoplasm through proteins of
the sarcoplasmic membrane;
(2) storage or breakdown of FA of lipid droplets;
(3) transportation of FA into the mitochondria, from external to
internal mitochondrial membrane;
(4) FA release in mitochondria matrix to enter in beta-oxidation.

● The carnitine protein is
mainly responsible for
the FA entrance trough
cell membrane.

● FA entry the mitochondria thanks to the action of Carnitine
Palmitoyl Transferase I (CPT I), Mitochondrial Trifunctional
Protein (MTP), Carnitine- Acylcarnitine Translocase (CACT)
and Carnitine Palmitoyl Transferase II (CPT II).
● The FA are metabolized in mitochondria by Electron-Transfer
Flavoprotein (ETF) and beta-oxidation enzymes

Lipid Myopathies
● Rare
● Plus forms → heart, live etc.
Clinically LM can show stable and progressive weakness
or episodic asthenia with rhabdomyolysis crisis, triggered
by metabolic stress, fever, physical exercise.

Lipid Myopathies
● In the forms with fixed myopathy, dosage of Creatin Kinase (CK) ranges
from 2 to 5 times the normal value.
● Crisis → rhabdomyolysis and myoglobinuria can cause, during the acute
onset, the rise of CK to up to several thousands of units, provoking the
risk of renal failure.
● Excess of lipid in the cytoplasm of muscle fibers can be visible, in the
majority of the cases, in muscle biopsy, with Oil Red O (O.R.O.) or
Sudan Black staining.
● Type I fibers are more affected than type II fibers, because of their
major utilization of lipids in cellular metabolism.

Lipid Myopathies
A normal muscular biopsy does not rule out lipid
myopathy, because some of these diseases do not
cause excessive lipid storage, as in CPTII deficit, so
the term of lipid storage myopathies could be
inappropriate to define all type of lipid myopathies.

Carnitine palmitoyl-transferase-II deficiency
● The most common of the FAUDs
(Fatty Acid Uptake Disorders)
● Homozygous mutations in the
CPT2 gene
● Three clinical presentations: a
lethal neonatal form, a severe
infantile form, and a more
common and mild myopathic
form.

● Long chain fatty acid
through inner
mitochondrial membrane
requires carnitine and
carnitine palmitoyl
transferase.
● The first report appeared in
1973

● Mild myopathic form: myoglobinuria, exercise intolerance and
recurrent attacks of muscle weakness, muscle cramps, and
myoglobinuria precipitated by certain drugs, prolonged exercise,
episodes of fasting, or stress.
○ Males are usually more severely affected than females.
● The frequency of crisis ranges from one or two attacks during the life
to several attacks weekly

● The EMG and ECG are normal.
● Usually liver is asymptomatic.
● The onset of disease is in 60% of patients in childhood (1–12 years).
● Muscle biopsy between the attacks is normal. During the crisis, muscle
shows only nonspecific myopathic changes and isolated necrotic
fibers.
● Serum CK and serum C12 and C18 acyl-carnitines are elevated
during such episodes.

CPTII deficiency, in contrast with carnitine deficiency
that cause a fixed myopathy, is characterized by
recurrent attacks of myalgia, cramps, muscle
stiffness or tenderness, transient weakness and
rhabdomyolysis.

Disorders of Lipid Metabolism
Carnitine (100 mg/kg at once) and feeds may be given orally, in
line with British Inherited Metabolic Diseases Group
recommendations.
Glucose infusion is of benefit during or after myoglobinuria, but oral
glucose does not achieve the same effects, probably because of its
low penetration in muscle.
Avoid drugs including non-steroidal anti-inflammatory drugs
Reducing dietary long-chain fats and extra carbohydrate intake
before and during sustained exercise and frequent meals.

Primary Carnitine Deficiency (PCD)
● a low concentration of plasma and
tissue carnitine due to recessive
mutations in SLC22A5
● gene which encodes Organic
Cation/Carnitine Transporter 2 (OCTN2)
● OCTN2 is expressed in several tissues,
including muscle, heart and kidney, but not
liver.
● Urinary loss of carnitine

● The low levels of plasma free carnitine
are an indirect effect of the
dysregulation in glucose aerobic
oxidation, gluconeogenesis and
ketogenesis, as well as other
metabolic pathways, which has been
reported to result in metabolic disorders
and organ damage.

● a wide spectrum of clinical symptoms:
○ asymptomatic patients,
○ episodic exertional rhabdomyolysis,
○ hypertrophic or dilated early onset cardiomyopathy,
○ generalized muscle weakness,
○ severe infantile Reye-like syndrome mainly
characterized by recurrent hypoglycemic hypoketotic
encephalopathy

The principal clinical manifestations include
hypoketotic hypoglycemia, encephalopathy,
cardiomyopathy and skeletal muscle weakness.

Figure 2 - Brain MRI scans of the patient with primary carnitine deficiency and intractable epilepsy in November 2015. The brain MRI indicated a low signal in
the right cerebral hemisphere on the T1-weighted image (right) and a high signal on the T2-weighted image (left), indicated by arrows.

Cardiac magnetic resonance (CMR) examples of cardiac fibrosis involvement in primary carnitine deficiency (PCD). Arrows shows late gadelineum involvement representing
cardiac fibrosis.

● Muscle biopsy in PCD
frequently shows a massive
lipidosis, particularly evident in
type 1 fibers, whereas type 2
could result atrophic.

● The diagnoses of PCD in the present case report were based
on the low levels of plasma free carnitine (<5 µmol/l).
● normal esterified fractions and
● high carnitine loss in urine

● Supplementation treatment with of high-dose of oral carnitine
(100 mg/Kg/day) in four daily doses, dramatically improves
myopathy and cardiomyopathy during the first weeks and
prevents the development of phenotype in neonates

Secondary causes of carnitine deficiency

Secundary causes of carnitine deficiency

Neutral Lipid Storage Disease (NLSD)
● The enzymatic inborn errors
affecting the lipase ATGL and
his coactivator CGI58 cause
neutral lipid storage diseases
(NLSD)

● Two rare autosomal
recessive disorders
characterized by the
excessive, non-lysosomal
accumulation of neutral
lipids in multiple tissues.

Myopathy, ichthyosis and cardiomyopathy

● 2 forms:
● Neutral Lipid Storage Disease with Myopathy (NLSD-M)
○ mutation in PNPLA2 gene mainly cause heart and skeletal
muscle symptoms
● Neutral Lipid Storage Disease with Ichthyosis (NLSD-I)
○ mutations in CGI58 cause also ichthyosis and severe hepatic
symptoms, associated with myopathic symptoms.
○ Chanarin-Dorfman syndrome

In NLSD lipids accumulate in several tissues such as
skin, skeletal muscle, liver, heart, thyroid, pancreas,
central nervous system, and leukocytes.

Muscle pathology and peripheral blood
smear of NLSDM.
a Muscle biopsy showing massive
vacuoles of various size within myofibers,
including some rimmed vacuoles under
hematoxylin & eosin staining.
b Oil red O staining revealed
accumulations of a large number of lipid
droplets within myofibers.
c Modified Gomori trichrome staining
confirmed rimmed vacuoles.
d Peripheral blood smear revealed
Jordan’s anomaly under Wright’s stain.
Scale bar = 50 μm (a-c); Scale bar =20 μm
(d).

● Myopathy is fixe, with muscular hypotrophy, generally bulbar and
respiratory muscles are not involved.
● Hearing loss, ataxia, cognitive impairment etc

Jordan’s anomaly - a) neutrophils , (b) eosinophils, and (c) basophils

Lower leg muscle and cardiac MRI
characteristics in NLSDM patients. a
MRI revealed diffuse fatty
infiltration, predominantly
involving the gluteus maximus at
the pelvic level.
b, d The long head of the biceps
femoris, semimembranosus and
adductor magnus were moderately-to-
severely affected. The rectus femoris,
gracilis and sartorius were relatively
preserved.
c, e The soleus and medial head of the
gastrocnemius were severely affected.
The anterior and posterior tibialis were
relatively preserved.
(f) Cardiac MRI showed dilated
cardiomyopathy

● No effective treatment exists to date for NLSD

Phosphatidic Acid Phosphatase Deficiency (Lipin Deficiency)
● Lipin 1 gene (LPIN1) is
expressed in adipose
tissue and skeletal
muscle.
● LPIN1 had phosphatase
function in cytosol and
with transcriptional
regulatory function in
nucleus.

Autosomal recessive LPIN1 deficiency is one of
the most common causes of severe recurrent
rhabdomyolysis in childhood

● Episodic weakness with rhabdomyolysis is suspected caused
by LPIN1 deficiency in particular in early age.
● Exercise, febrile illness, anesthesia or fasting caused crisis.
● The disease can cause death in 33% of cases, for
hyperkalemia or cardiac arrest.
● In a study of 141 patients with rhabdomyolysis, about 13%
were found to have homozygous Lipin1 mutations, 89%
were aged 2–6 years;

● Has been proposed a therapeutic strategy maintaining high
caloric intake during viral infections or excessive
physical activity and treating the rhabdomyolysis
episodes with intravenous high-concentration glucose.

Resumo
● CPT-II: Crises de rabdomiólise e fraqueza, biópsia normal, CK e
C12/C8 acetil carnitina elevados na crise, gene CPT2.
● Deficiência de carnitina: miopatia fixa com comprometimento de
outros órgãos → encefalopatia, cardiomiopatia e hipoglicemia.
● Doença de armazenamento de lipídios neutros: ictiose, anomalia
de Jordan, cardiomiopatia.
● Deficiência de Lipin1: criança entre 2 a 6 anos com episódios de
rabdomiólise, fraqueza e febre.

Referências Bibliográficas
1. Salman Bhai. Diagnosing Metabolic Myopathies. Neuromuscular Notes. (2021)
2. Josef Finsterer. Update Review about Metabolic Myopathies. Life (2020), 10, 43;
doi:10.3390/life10040043
3. A non-ischemic forearm exercise test for the screening of patients with exercise
intolerance J.-Y. Hogrel, P. Laforêt, R. Ben Yaou, M. Chevrot, B. Eymard, A.
Lombès. Neurology Jun 2001, 56 (12) 1733-1738; DOI: 10.1212/WNL.56.12.1733
4. Kitaoka, Yu. 2014. "McArdle Disease and Exercise Physiology" Biology 3, no. 1:
157-166. https://doi.org/10.3390/biology3010157
5. Lipid myopathies. J. Clin. Med. 2018, 7, 472; doi:10.3390/jcm7120472
6. Angelini, C. (2018). Neutral Lipid Storage Disease with Ichthyosis, Chanarin-
Dorfman Syndrome. In: Genetic Neuromuscular Disorders. Springer, Cham.
https://doi.org/10.1007/978-3-319-56454-8_81

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