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GLYCOGEN & GLUCOSE METABOLIC DISORDERS

Acid Maltase Deficiency: 17q23 Aldolase A: 16q22 Branching enzyme deficiency: 3p12 Debrancher: 1p21 β-Enolase: 17pter Glycogen synthase 1: 19q13 Hexokinase 1 (HMSNR): 10q22 Lactate dehydrogenase A: 11p15 Lafora disease: Laforin, 6q24 Lamp-2: Xq24 Phosphofructokinase: 12q13 Phosphoglucomutase 1: 1p31 Phosphoglycerate Kinase: Xq13 Phosphoglycerate Mutase: 7p12 Phosphorylase (McArdle's): 11q13 Phosphorylase b Kinase   X-linked: Xq12   Recessive: 16q12 Polyglucosan body (Branching enzyme)   Myopathy   Syndrome Triosephosphate isomerase: 12p13 General principles Glycolytic reactions Metabolic pathways

From D Driemeier19 Brahman calf with glycogenosis

MUSCLE METABOLISM: SUBSTRATES USED BY MUSCLE

• Rest: Fatty acids
• Intense exercise, Isometric
  • Metabolic pathway: Anaerobic glycolysis
  • Disease examples: Phosphorylase deficiency
• Submaximal exercise
  • Low intensity
    • Metabolic pathways: Blood glucose; Free fatty acids
    • Disease example: Phosphoglycerate Mutase, M (muscle) subunit deficiency
  • High intensity: Aerobic metabolism of glycogen
• Mild exercise
  • Short term (0 to 1 hour): Free fatty acids progressively more than Glucose
  • Intermediate term (1 to 4 hours): Increasing Free fatty acid uptake
  • Longer term (> 4 hours): Fatty acid oxidation
  • Disease example: CPT deficiency
• Starvation: Amino acids

Muscle Glycogenoses: General Principles⁴

• Glycogenoses causing: Exercise intolerance, Cramps & Myoglobinuria
  • General
    • Usually occurs after intense exercise
    • Usually due to muscle specific enzyme defects: Exception is PGK deficiency
  • Specific enzyme defects
    • Phosphorylase b Kinase
      
      • X-linked: Xq12
      • Recessive: 16q12
    • Phosphorylase (McArdle's): 11q13
    • Phosphofructokinase: 1cen-q32
    • Phosphoglycerate Kinase: Xq13
    • Phosphoglycerate Mutase: 7p12
    • β-Enolase: 17pter
    • Lactate dehydrogenase: 11p15
  • Differential diagnosis of exercise intolerance
    • CPT II deficiency
      • Most common cause of recurrent myoglobinuria
      • Myoglobinuria occurs after moderate exercise or prolonged fasting
    • Mitochondrial disorders
      • Complex III, or I or IV
      • Premature fatigue or breathlessness after normal activities of daily living
      • Myalgias but no cramps
      • Laboratory: Lactic acidosis at rest or after mild exercise
• Glycogenoses causing: Fixed weakness
  • General
    • Weakness may be associated with degree of glycogen storage in muscle
    • Usually due to generalized enzyme defects: Exception is aldolase A deficiency
  • Specific defects
    • Acid Maltase Deficiency: 17q23
    • Aldolase A: 16q22
    • Branching enzyme deficiency: 3p12
    • Debrancher: 1p21
    • Lamp-2: Xq24
    • Phosphorylase (McArdle's), severe phenotype: 11q13
    • Triosephosphate isomerase: 12p13
      

Acid Maltase Deficiency (Glycogenosis type 2; Pompe disease)

• Epidemiology
  • Disease incidence
    • Overall: 1 in 40,000 to 50,000 live births
    • More common in
      • Afro-Americans: Arg854X; 1 in 14,000; Infantile onset
      • Dutch: del525T & del exon 18; Infantile onset
      • Taiwan: Asp645Glu; Infantile onset
    • Caucasians: 1 in 100,000
  • Frequency: 5,000 to 10,000 cases world-wide
  • Carrier frequency: 1 in 85 to 100
• Gene features: Mutations
  • Many identified
  • Types: Point; Deletions; Splicing
  • Some hot spots
    • IVS1AS-13T-G: Common mutation in adults but not children
  • Most patients compound heterozygotes
  • External links: Mutation databases
    • AC
    • Pompe center
• Acid α-1,4-glucosidase protein
  • Location: Present in all tissues, "Housekeeping enzyme"
  • Subcellular location: Lysosomal
  • Action
    • Hydrolyzes linear α1-4 glucosidic linkages on carbohydrates
    • Catalytic site: Asp-518
  • Mutation effects on acid α-1,4-glucosidase protein: Varied
    • Enzyme protein absent: Most infantile disease
    • Enzyme protein & activity proportionately reduced: Adult onset
    • Enzyme protein present but has little catalytic activity: May occur in infants, children or adults
    • Abnormal enzyme maturation & transport
    • Trp481Arg: Absent catalytic activity; Normal synthesis & posttranslational modification
    • Some mutations prevent protein secretion
• Clinical-genetic correlations⁹
  • Level of residual enzyme activity correlates with
    • Severity of disease
      • Infantile onset (&lgt; 1 year): < 1% GAA activity
      • Childhood & Juvenile onset (1 year to teens): 2% to 6% GAA activity
      • Adult onset (> 2nd decade): 1% to 29% activity
        • No clear correlation with residual activity within adult population
    • Age of disease onset
    • Location of mutations
  • Exon 18: deletion
    • No enzyme formed
    • Often in infantile onset
  • 525delT: Exon 2; Single base pair deletion
    • Glu176fsTer44
    • Frameshift
    • Prohibits formation of mature enzyme
    • Hot spot
  • 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
    • Uncommon in children
  • Tyr455Phe: Juvenile onset
  • Missense: Most other mutations
    • Many allow precursor formation
    • But prevent intracellular transport & maturation to a catalytically active enzyme
  • Splice site
    • Often leaky
    • Associated with mild phenotypes
  • Nonsense & Frame shift
    • Predictably deleterious at N-terminal of protein
    • C-terminal mutatons may also have severe effect
• Clinical features
  • General
    • Several syndromes: Vary with age of onset
    • Intrafamilial features: Homogeneous
  • Infantile onset
    • 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%)
    • Anesthesia¹⁸
      • Succinylcholine: Increased risk
        • Arrhythmia
        • Hyperkalemia
        • Rhabdomyolysis
      • Propofol: ? Increased risk
      • 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
  • Atypical infantile onset
    • Onset: < 1 year
    • Death: 1st decade
  • Childhood onset

    From: Anne Connolly MD Acid maltase deficiency Mildly enlarged tongue

    • 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
  • Adult onset: Variable features¹¹
    • Common mutations
      • European Caucasians
        • -45T>G (IVS1-13t>g)
        • Location: Intron 1
        • Leaky splice site: Produces reduced amounts of normal protein
      • Japan: Arg672Gln (Juvenile); Ser529Val (Adult-onset)
    • 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
    • Weakness
      • Respiratory failure
        • Presenting feature in 5% to 30%: Often with other signs
        • Symptoms: Headache; Somnolence; Dyspnea
        • Course
          • Onset usually several years after leg weakness
          • Eventually occurs in 100%
        • 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 ventilation¹⁶
      • Proximal > Distal
      • Legs > Arms
      • Paraspinous muscles (Atrophy)
      • Patchy
        • Pectoralis: Sternal > Clavicular head
        • Thigh adductors
        • Scapular winging
      • Disease course
        • Progression: Slow, over years
        • Severity related to disease duration, not patient age¹⁷
    • Other muscle features
      • Pain: Legs > Arms
      • Fatigue
      • Cramps: Proximal muscles
      • Muscle size
        • Atrophy: Proportionate to weakness
        • May be mild calf hypertrophy
    • Tendon reflexes: Reduced in proportion to weakness
    • Other
      

      Basilar aneurysm: Fusiform

      • Vascular
        • Cerebral aneurysm (Basilar)
        • Cerebral atherosclerotic angiopathy
          • Mutations: Ala237Val; Gly293Arg¹³
      • Cardiac: Usually normal
      • Skeletal
        • Spine: Disease onset < 21 years
          • Lordosis (50%)
          • Scoliosis (10%)
        • Back pain
      • Contractures (40%): Shoulders; Hips; Knees; Neck
      • Weight loss
    • Course
      • Progressive
        • Disability related to disease duration¹⁴
        • Disability not predictable based on age of disease onset
        • Eventual respiratory involvement common
        • Many need wheelchair or walking devices
      • Some patients remain independent & employed
      • Death: Due to respiratory failure
    • MRI of muscle
      • Early involvement: Adductor magnus; Semimembranosus
      • Later selective involvement: Long head of biceps femoris; Semitendinosus; Anterior thigh; Psoas; Paraspinal
      • Spared: Sartorius; Rectus; Gracilis
      • Pattern of muscle abnormality: Atrophy; Abnormal signal
• Laboratory
  • Serum CK
    • Infants: High (< 10x); Highest in infants
    • Rarely normal in adults (5%)
  • EMG: Irritative myopathy
    • Myopathy
    • Fibrillations
    • Complex repetitive discharges
    • Myotonic discharges
  • Muscle pathology
    • Vacuoles
      • Cytoplasmic (Lysosomal)
      • Perimeter may stain for: Dystrophin, Spectrin, Laminin
      • Acid phosphatase staining
      • May be more frequent in type I fibers in adult-onset disease
      • Contain: Glycogen & Metachromatic staining material; Cell debris
      • Muscle fibers with vacuoles become enlarged
    • Type 1 muscle fibers more involved than type 2
    • Little muscle fiber degeneration or increased connective tissue
    • Glycogen storage: PAS stains most fibers darkly in childhood forms
    • Severity
      • More severe in childhood-onset
      • Adult onset: Variable among muscles; Some may be normal
    • Electron microscopy
      • Glycogen in cytoplasm, single membrane-bound, autophagic (Lysosomal) vacuoles
      • Occasional abnormal mitochondria with crystalloid inclusions
  • Muscle biochemistry
    • Glycogen
      • Increased in childhood forms
      • May be normal in adults
    • Acid maltase
      • Activity: Absent in infants; Residual activity in later onset forms
      • Mutation effects: Variable; Altered enzyme stability, phosphorylation or processing/degradation
  • Skin fibroblasts
    • α-glucosidase activity & lysosomal glycogen content: Predictors of age of onset¹⁵
• Treatment: Enzyme replacement¹⁰
  • Recombinant α-glucosidase: Intravenous
  • May benefit infantile disease & ? Late onset
    • Strength
      • Improved: Distal weakness more improved than proximal
      • Better pulmonary function
    • Cardiomyopathy: Improved
    • Course: Over months
  • Side effects: Infusion reactions
  • Predictors of good histologic response to treatment of infantile type²¹
    • Low glycogen levels
    • Mild ultrastructural damage
    • High proportion of type I muscle fibers
    • Young age at baseline
• Animal models
  • Acid maltase-deficient Japanese quails
  • Lapland dog
  • Australian cattle

Debrancher deficiency (Glycogenosis type 3) ¹

• Genetics
  • Normal AGL mRNAs: Multiple tissue-specific isoforms differing only at 5'-end
  • ~ 16 different mutations identified
  • Mutation types: Most commonly nonsense, small deletions or insertions, or splice site change
  • Mutation effects: Usually ® premature truncation by carboxy terminal amino acids
  • Mutation locations
    • North African Jewish: 4455delT
    • Caucasian: Mutations in exon 3
    • Japanese: Heterogeneous mutations
• Amylo-1,6-glucosidase protein
  • Enzyme catalyzes 2 reactions
    • Oligo-1,4-1,4-glucantransferase: Transferase
    • Amylo-1,6-glucosidase: Hydrolysis
    • Degrades phosphorylase-limit dextrin: Product of phosphorylase degradation of glycogen
  • Mutation biochemical variants
    • Transferase deficiency
    • Transferase + Hydrolase deficiency: In liver & muscle
    • Transferase + Hydrolase deficiency: In liver but not muscle
• Clinical features
  • General
    • Male more frequent than Female (~3:1)
    • Disease types: Related to somewhat different mutations in AGL gene
      • GSD IIIa (85%): Liver & muscle involvement
      • GSD IIIb (15%)
        • Only liver involvement
        • Common mutation: Trp680Ter
  • Infantile
    • Liver & muscle storage
    • Hypoglycemia: Recurrent
    • Seizures
    • Cardiomegaly: Severe
    • Hepatomegaly
    • Death: 4 years
  • Childhood:
    • Weakness: Resolves at puberty
    • Liver dysfunction & Hepatomegaly (100%)
    • Growth retardation
    • Hypoglycemia ± Seizures
  • Adult
    • Onset: 3rd to 6th decade
    • Weakness
      • Distal: Calves & peroneal muscles
      • Proximal
      • Respiratory failure
        • May have subacute onset related to fasting
        • ? Associated with more severe cardiomyopathy
      • Progression: Slow
    • Exercise intolerance (50%)
    • Fatigue & Myalgia: Occasional patient
    • Muscle hypertrophy: Calves
    • Rhabdomyolysis: Occasional patient
    • Systemic
      • Hepatic dysfunction (50%)
      • Cardiomyopathy: Mild or None
    • Serum CK: Increased at rest; 5x to 45x normal
  • Neuropathy
    • Axonal loss
    • Glycogen storage in endoneurial cells ± axons
  • Laboratory
    • Cardiac: EKG changes (90%); Ventricular Hypertrophy (5% to 20%)
    • Ischemic lactate test: Insufficient rise in venous lactate
    • EMG: Irritative myopathy; Mild neuropathy (Axonal)
    • Muscle pathology
      • Myopathy
      • Glycogen storage: Subsarcolemmal & intermyofibrillar vacuoles
  • Treatment
    • Hypoglycemia in children: Frequent feeding
    • Weakness (Subacute in adults): ? High protein diet

Phosphorylase deficiency (McArdle's; GSD 5)

• Gene mutations
  • > 65 different mutations identified
    • Types: May be missense, stop, destruction of start codon or small deletion with frameshift
    • Rare mutation in intron causes abnomal gene splicing
    • Missense mutations usually in highly conserved residues
  • Allelic heterogeneity common
  • Common mutations
    • US, Britain, Germany, France
      • Most common mutation is Arg50Stop in exon 1
      • Type: Nonsense
      • Previous nomenclature: Arg49X
    • Japan: Skipped codon 708/709 is common
    • G204S: 10%
  • Many ethnic or familial private mutations
• Glycogen phosphorylase: Disease biochemistry
  • Impaired ATP generation from
    • Aerobic glycogenolysis: Reduction of glycogen metabolized to carbon dioxide and water
    • Anaerobic glycogenolysis: Reduction of glycogen metabolized to lactic acid
  • Reduced production of pyruvate
  • See: Glycogenolysis pathways
• Clinical-genetic correlations
  • Pseudodominant transmission in a few families due to:
    • Manifesting heterozygote with low residual enzyme activity, or
    • Mating of homozygote with heterozygote⁶
  • Most mutations result in complete loss of protein production
  • Clinical interfamilial & intrafamilial variability
    • No correlation of clinical features with site or type of mutation
    • No clinical differences between truncating & non-trunctaion mutations
    • Contrasts with biochemical homogeneity
  • Phenotype modulators⁵
    • Myoadenylate deaminase (AMPDA) gene
      • No effects of partial defect on phenotype
      • 1 patient with complete loss of activity and severe phenotype
    • Angiotensin-converting enzyme (ACE) (2 alleles): I allele longer & D allele shorter
      • Severe phenotype: More D alleles; Higher ACE activity
      • Milder phenotype: More I alleles
      • Normals: Subjects with I allele respond much more efficiently to muscle training
        • D alleles more common in athletes engaged in intense, short-duration sports
        • I alleles more common in endurance athletes
• Clinical features
  • Onset
    • Usual: < 15 years
    • May be > 50 years
  • Male predominance
  • Exercise intolerance
    • Especially brief & intense: Moderate exercise usually well tolerated
    • Cramping & Muscle swelling: May last for hours
  • "Second wind" phenomenon: Brief rest after myalgias allows further activity⁷
    • Sudden, marked improvement in exercise capacity
    • Exercise that previously produced muscle fatigue, tachycardia & breathlessness becomes easily tolerated
    • Two types: Spontaneous; Induced by carbohydrate & lipid fuels
    • Biochemistry
      • Due to substrate-dependent increases in muscle oxidative capacity
      • Reduced or eliminated by residual myophosphorylase activity
        • Normalizes oxidative deficit of complete myophosphorylase deficiency
  • Myoglobinuria (50%)
  • Weakness: Variable patterns
    • Frequency: 11% to 30%
    • Onset age: Usually > 40 years
    • Fixed
    • Distribution
      • Proximal > Distal
      • Symmetric or Asymmetric
        • Similar frequencies
        • Asymmetric: Scapular winging or FSH phenotype common¹²
      • Leg or Arm predominant
      • No clear relation to genotype
    • Frequency: More common in older patients
  • Muscle size change
    • Wasting: 12%
    • Calf hypertrophy: 9%
  • Renal failure: Males > Females; Acute with rhabdomyolysis
  • Rare clinical presentations
    • Fatigability: Mild
    • 49 to 74 years with proximal weakness: Arms & Legs; Asymmetric or Symmetric
    • Infantile with severe weakness & respiratory failure
    • Mild congenital weakness
    • Association with adenylate deaminase (AMPD) deficiency: More prominent myoglobinuria
    • Malignant hyperthermia susceptibility: May have positive contracture test
• Laboratory
  • Serum
    • CK elevated even at rest (> 90%)
    • Hyperuricemia
    • High K⁺ during exercise
  • EMG: Myopathic
  • Exercise test (hazardous): Reduced lactate production with ischemic exercise
  • Pathology
    • Subsarcolemmal vacuoles
    • Type 1 muscle fiber atrophy
    • Linearization of internal architecture on NADH
    • Occasional necrotic & regenerating muscle fibers
    • Regenerating muscle fibers may express phosphorylase: Not with homozygous Arg49Stop mutation
• Possible treatments
  • High protein diet
  • Pyridoxine
  • Creatine monohydrate
  • ACE inhibitors: Ramipril (2.5 mg qd) may improve disability in D/D allele patients²³
  • Gene therapy
• External link
  • Genetic testing (Buffalo): Common mutations

Phosphorylase b Kinase

• Phosphorylase b Kinase protein
  • Function: Activates glycogen phosphorylase in response to neuronal or hormonal stimuli
  • Structure: Decahexameric protein composed of 4 subunits
    • α & β subunits: Regulatory
    • γ subunit: Catalytic
    • δ subunit: Identical to calmodulin; Confers Ca⁺⁺ sensitivity to enzyme
• X-linked syndrome (GSD9D)
    l Phosphorylase kinase, α subunit (muscle) (PHKA1) ; Chromosome Xq12-q13; Recessive
  • Genetics: Several αM mutations identified
    • Nonsense: Glu1112Ter; 695delC
    • Missense: Asp299Val
    • 5' Splice junction mutation in intron ® Skipping of previous exon
  • α Subunit (PHKA1) protein
    • Muscle & liver isoforms
    • Disease mutations produce loss of function
  • Clinical features
    • Onset: Childhood to 5th decade
    • Weakness: Distal > Proximal
    • Exercise intolerance & cramps
    • Myoglobinuria: Occasional
  • Laboratory
    • Forearm ischemic exercise test: Normal or Reduced rise in lactate
    • Serum
      • CK: High, 2x to 10x normal
      • Hyperuricemia
    • EMG: May be normal
    • Muscle histology
      • Subsarcolemmal vacuoles
      • Mild accumulation of glycogen: May be subsarcolemmal
      • Occasional muscle fiber necrosis
    • Biochemistry
      • Phosphorylase kinase levels
        • Low or absent in muscle
        • Normal in erythrocytes & liver
      • Total phosphorylase levels: Normal
      • Muscle glycogen: Increased
• Autosomal recessive syndrome (GSD9B)
    l Phosphorylase kinase, β subunit (PHKB) ; Chromosome 16q12-q13
  • Protein: Enzyme deficiency in both muscle & liver
    
  • Clinical features
    • Myalgia, cramps & weakness with exercise
    • Myoglobinuria
    • Onset in childhood or adolescence
    • Some forms with hepatomegaly
  • Normal exercise test
• Liver & renal phosphorylase b kinase deficiency (GSD9A)
    l Liver PHK, α-2 subunit; Chromosome Xp22.2-p22.1
  • Normal muscle
  • Also caused by mutations in glucose permease (GLUT2; SLC2A2)
• Liver phosphorylase kinase deficiency (GSD9C)
    l Phosphorylase kinase, testis/liver, γ-2 (PHKG2); Chromosome 16p12.1-p11.2
• Cardiomyopathic forms of phosphorylase kinase deficiency
    l Protein kinase, AMP-activated, noncatalytic, γ-2 (PRKAG2); Chromosome 7q36
  • Lethal, congenital glycogen storage disease of heart
  • Cardiomyopathy, familial hypertrophic, with Wolff-Parkinson-White syndrome

Phosphofructokinase, M (muscle) subunit (PFKM; Tarui's disease; Glycogen storage disease VII; GSD 7)

• Genetics
  • Many different mutations: ~ 20 identified
  • Types: Missense, Splicing change & Deletions
  • Most Ashkenazi Jews have deletions: Exon 5 splicing defect or Exon 22 frameshift
  • More severe disease may occur with simultaneous mutations in AMPD gene
• Epidemiology
  • Male predominence (9:1)
  • Prevalence high
    • Ashkenazi Jews (US)
    • Italian families
• 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
  • Myoglobinuria: Less frequent than in McArdle's
  • Weakness: Late-onset with fixed myopathy in some patients
  • Variants
    • Severe myopathy in infants & young children
      • Develop fixed weakness
      • Respiratory failure & cardiomyopathy reported
      • Arthrogryposis
      • CNS: Seizures; Cortical blindness
      • Systemic: Corneal opacification; Cardiopathy
    • Adult onset myopathy: History of exercise intolerance in younger years
  • Systemic features
    • Compensated hemolytic anemia: Hemolysis without myopathy (Unstable M subunits)
    • Gout: Hyperuricemia
    • Gastric ulcer
• Laboratory
  • Serum CK: High
  • Hyperuricemia
  • Hyperbilirubinemia
  • Compensated hemolytic anemia: High reticulocyte count
  • Exercise test: No lactate rise
  • Repetitive nerve stimulation (20 Hertz for 1 minute): Decrement
  • EMG: Myopathy ± Irritability
  • Biochemistry: Accurate only if muscle is rapidly frozen after biopsy
• 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 changechange in children

Phosphoglycerate Kinase

• Genetics
  • Mutation types: Missense, Deletion & Splice site
  • Mutation locations: All along gene except myopathic form
  • > 20 mutations described
• Protein
  • Ubiquitous expression except in sperm
  • Glycolytic pathway
  • Generates ATP through conversion of 1,3-DPG to 3-PGA
• Clinical features: Only rarely (6%) all in same patient
  • Hemolytic anemia (34%): Non-spherocytic
  • CNS dysfunction
    • Mental retardation
    • Seizures
    • Behavioral abnormalities
    • Strokes
    • Usually associated with anemia
  • Muscle
    • Myopathy (Slowly progressive)
    • Cramps
    • Myalgia: Exercise induced
    • ± Myoglobinuria
• Laboratory
  • Serum CK: High or normal
  • Ischemic exercise: No rise in lactate; High rise in ammonia
  • Muscle Pathology
    • Histology: Normal
    • No glycogen accumulation
    • PGK activity: 1% to 11% of control mean; Similar to erythrocyte levels
• PGK deficiency: Myopathic form (27%)²⁴
  • Genetics
    • Mutations: Cluster in C terminal domain near substrate binding pocket
    • G213C; E252A; D315N; T378P; Del 206-709
  • Clinical
    • Cramps
    • Myalgia: Exercise induced
    • Myoglobinuria
    • No anemia or CNS dysfunction
  • Resting CK: High; 1000 to 3000
• Heterozygous females
  • May have Hemolytic anemia: ? Associated with skewed X-inactivation
  • PGK activity 50% to 100% in asymptomatic carriers
• Hemizygous asymptomatic male: 2% of control mean PGK activity

Phosphoglycerate Mutase deficiency (Glycogen storage disease X; GSDX; GSD 10) ²⁰

• Epidemiology
  • ~14 patients described
  • US: Predominantly African-Americans (Trp78X; Glu89Ala)
  • Italian (Arg90Trp; Del532G), Danish, Pakistani (R180X) & Japanese (Gly97Asp) families identified
  • Japanese family: ? Manifesting heterozygotes
• Genetics
  • Mutations: Missense, Deletion & Nonsense
  • Most in exon 1; Some in exon 2
• PGAM protein
  • Most active enzyme in glycolytic pathway
  • Tissue expression: Muscle & Heart
  • Reaction catalysed: 2-phospho-D-glycerate <=> 3-phospho-D-glycerate
  • Enzymatic activity
    • Increased in muscles with higher glycolytic activity
    • Hypothyroidism & Denervation: Decreased PGAM activity in fast twitch muscles
  • Activity in other tissues (red blood cells, liver, brain) due to PGAMB, a different gene
  • Mutations: Remaining PGAM activity may be related to presence of BB enzyme
• Clinical features:
  • General
    • Usually mild or no symptoms at rest
    • Only muscle
  • Onset age
    • Usually adolescence
    • Up to 5th decade
  • Exercise intolerance: May be otherwise asymptomatic
  • Cramps
    • Exercise related
    • Electrically silent contractures
    • ? Related to Increased sarcoplasmic Ca⁺⁺
  • Myalgia
  • Myoglobinuria: Some patients; With intense exercise
  • Strength: Normal
  • Clinical course: Benign
• Laboratory
  • Serum CK: High
  • Exercise test
    • Lactate: Rise reduced but present
    • Ammonia: Increased rise
  • EMG: Normal or Myopathic
  • Muscle Pathology
    • Subsarcolemmal glycogen
    • Tubular aggregates
      • NADH: Strong staining
      • Ultrastructure: Atypical; Variably sized SR tubules
      • Present in 30% of patients
      • Ca⁺⁺ & Ca⁺⁺ adenine triphosphate activity increased in muscle
• Treatment: Dantrolene may reduce cramps
• Variants
  • 1 patient with symptoms associated with statin use
  • Manifesting heterozygotes described

Lactate dehydrogenase A deficiency (GSD 11)

• Genetics: Frame shift deletions & Nonsense mutations
• LDH protein
  • Tetrameric
  • Composed of varying proportions of muscle specific & cardiac subunits
  • Expressed in muscle
• Clinical features
  • Muscle
    • Exercise intolerance
    • Myoglobinuria: Some patients
    • Strength: Normal
  • Erythematous rash
  • Difficulties in childbirth (uterine stiffness)
• Laboratory
  • Serum CK: High
  • Exercise test: Rise in pyruvate but not lactate
  • Serum LDH: Low
• See: Lactate metabolism

Branching enzyme deficiency (GSD 4)

• Nosology: Andersen disease; Glycogen storage disease IV (GSD IV)
• Genetics
  • > 20 mutations identified
  • Types: Nonsense, Missense, Deletion, Insertion & Splice-site
• Clinical features (Several presentations)
  • Congenital forms
    • Genetics: Associated with Nonsense or other severe mutations
    • Severe hypotonia
    • Muscle wasting
    • Arthrogryposis
    • Neuronal involvement
    • Hepatic failure
    • Death: Infancy
  • Childhood systemic disorder
    • Onset: 1 year
    • Hepatomegaly; Liver failure
    • Hypotonia
    • Some milder cases with cardiomyopathy or myopathy²
    • Death: < 4 years
    • Treatment: Liver transplantation
  • Myopathy: Childhood
    • Clinical
      • Onset: 1st decade
      • Weakness
      • Exercise intolerance
      • Cardiomyopathy
    • Laboratory
      • Serum CK: Normal
      • Muscle
        • Polyglucosan bodies (PAS positive)
        • Ultrastructure: Non-membrane bound vacuoles containing filamentous & finely granular material
  • Myopathy: Adult onset
    • Genetics & Protein
      • Mutation: Missense, G149A; Heterozygous
      • Mutant protein: No branching activity
    • Weakness
      • Proximal
      • Legs > Arms
    • Muscle pathology
      • Polyglucosan bodies
        • PAS positive
        • Only partially digested by diastase
      • Branching activity: Partially reduced
      • Accumulation of abnormal glycogen: Few branch points; Linear long peripheral chains
  • Polyglucosan body syndrome : Diffuse CNS & PNS dysfunction
• Animal disorders: Norwegian Forest cats: Other dogs & cats

Aldolase A (muscle) deficiency

• Genetics: Glu206Lys mutation impairs thermostability of molecule
• Protein: Present in erythrocytes & muscle
• Clinical features
  • Onset: Childhood
  • 1st year
    • Jaundice
    • Anemia: Nonspherocytic, hemolytic
  • Proximal weakness
  • Episodic myalgias & hemolysis: ? Related to fever
• Laboratory
  • CK: High after exercise & anesthesia; Near normal otherwise
  • Muscle pathology
    • Variable fiber size
    • EM: Distorted mitochondria; Lipid accumulations

β-Enolase deficiency ³ (GSD 13 )

• Genetics: Missense mutations, Gly156Asp & Gly374Glut
• β-Enolase protein
  • Interconverts 2-phosphoglycerate & phosphoenolpyruvate
  • Localization: Skeletal muscle
• Epidemiology: 1 patient
• Clinical
  • Onset: 3rd decade
  • Exercise intolerance: Fatigability
  • Myalgias: After heavy exercise; No cramps
  • Strength: Normal
  • Muscle bulk: Normal
  • Course: Increasing intensity of myalgiass over decades
  • No extramuscular involvement
• Laboratory
  • Serum CK: Episodic elevations; Reduced with rest
  • Lactate: No rise with ischemic exercise
  • Enolase activity: 5% of normal
  • EMG: Myopathic
  • Muscle
    • Fiber size: Mild variability
    • PAS: Normal
    • β-enolase immunoreactivity: Reduced or absent
    • Ultrastructure
      • Sarcoplasmic glycogen β granules
      • Similar to Aldolase A, PGAM, LDH-M deficiencies

Triosephosphate isomerase (TIM) deficiency

• Genetic
  • Common mutation Glu104Asp
  • Heterozygote frequency: 1 to 5 per 1,000
• Biochemistry: Reduced Triosephosphate isomerase activity in many tissues
• Clinical: Most severe clinical disorder fo fo glycolysis
  • Onset: < 2 years
  • Hemolytic anemia: Chronic; Non-spherocytic; Crises
  • Recurrent infections
  • CNS
    • Mental retardation
    • Dystonia
    • Cerebellar
    • Tremor
    • Upper motor neuron: Extensor plantar responses
    • Cognitive: Probably normal
  • Muscle weakness
    • Proximal; Facial
    • Slowly progressive
  • Tendon reflexes
    • Early: Reduced
    • Late: Increased with Spasticity
  • Peripheral nerve: Some patients⁸
    • Weakness: Distal
    • Sensory loss: Large fiber modalities
    • Electrophysiology: Axonal loss
    • Nerve biopsy: Loss of myelinated axons; Regeneration
  • Joint contractures: Ankles
• Course
  • Onset < 2 years
  • Majority die < 6 years
  • Respiratory failure; Cardiomyopathy
• Muscle pathology: Variable severity
  • Myopathy: Fiber degeneration & Regeneration
  • Increased glycogen in muscle fibers
  • Mitochondria
    • Increased Size & Number
    • Abnormal shape & structure
    • No ragged red fibers
  • Vessels: Degenerating endothelial cells & pericytes
  • Normal connective tissue
• CNS Neuropathology
  • Neuronal loss in dentate & olive
  • Hypothalamus & Cerebellar cortex: Hyaline cell bodies & Axonal spheroids
  • Anterior horn cell loss

Lafora's disease (Progressive myoclonic epilepsy 2)

• Laforin protein: ? Role in phosphorylation/dephosphorylation reactions controlling glycogen metabolism
• Clinical
  • Onset: Adolescence
  • Cortical: Seizures; Myoclonus; Dementia
  • Other: Ataxia; Spasticity; Rigidity
  • Course: Rapid progression; Death < 25 years
• Pathology: Lafora bodies
  • Characteristics: Round, Basophilic, PAS + inclusions
  • Location: Neurons; Liver, Heart, Skin, Skeletal muscle & Retina

Glycogen storage disease, Muscle, Type 0 ²²

• Epidemiology: Syrian family
• Genetics: Homozygous stop mutation (Arg462Ter)
• GYS1 protein
  • Muscle glycogen synthesis: Accounts for disposal of up to 90% of ingested glucose
  • Muscle & Heart glycogen: Rrovidesl energy during bursts of activity & sustained muscle work
• Clinical
  • Onset: 1st decade
  • Cardiomyopathy: Hypertrophic
  • Fatigue: Reduced exercise capacity
  • Muscle strength: 50% reduced
• Laboratory
  • Muscle biopsy
    • Reduced PAS staining
    • Type I fiber predominance
    • Mitochondrial proliferation
    • Glycogen synthase protein: Absent from muscle
  • Glucose tolerance test: Normal

Phosphoglucomutase 1 Deficiency (GSD 14)

• Epidemiology: Single patient
• Genetics
  • Heterozygous mutations: Thr114Ala; c.1145-1G-C (IVS7DS,G-C,-1) in an intron 7-8 splicing donor site
• PGM1 protein
  • Catalyzes transfer of phosphate between 1 and 6 positions of glucose
  • PGM1 is major isozyme in most tissues
• Clinical
  • Cramps: Exercise induced
  • Rhabdomyolysis: 2 probable episodes
  • Weakness: Mild; Proximal
• Laboratory
  • Serum CK: Mildly high at rest; 10x to 20x after exercise
  • EMG: Myopathic
  • Exercise test: Lactate rise normal; Ammonia rise 4x normal
  • Muscle biopsy: Subsarcolemmal & Sarcoplasmic glycogen accumulation

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