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GLYCOGEN & GLUCOSE METABOLIC DISORDERS

Acid Maltase Deficiency (GSD2): 17q25
Aldolase A (GSD12): 16p11
Branching enzyme deficiency (GSD4): 3p12
Debrancher (GSD3): 1p21
β-Enolase (GSD13): 17p13
G6PD: Xq28
Glycogen synthase 1 (GSD0B): 19q13
Glycogenin (GSD15): 3q24
Hexokinase 1 (HMSNR): 10q22
Lactate dehydrogenase A (GSD11): 11p15
Lafora disease: Laforin, 6q24
Lamp-2: Xq24
Phosphofructokinase (GSD7): 12q13
Phosphoglucomutase 1 (GSD14): 1p31
Phosphoglycerate Kinase: Xq21
Phosphoglycerate Mutase (GSD10): 7p13
Phosphorylase (McArdle's) (GSD5): 11q13
Phosphorylase b Kinase
  PHKA1 (GSD9D): Xq13
  PHKB (GSD9B): 16q12
  PRKAG2: 7q36
Polyglucosan body
  Branching enzyme (GBE1)
    Myopathy (GSD4): 3p12
    Syndrome
  Myopathy (PGBM)
    1: RBCK1; 20p13
    2: GYG1; 3q24
Triosephosphate isomerase: 12p13
SMGMQTL: PRKAG3; 2q35

General principles
Glycolytic reactions
Metabolic pathways
Muscle biopsy results

From D Driemeier 19
Glycogenosis Type 2: Brahman calf



MUSCLE METABOLISM: SUBSTRATES USED BY MUSCLE


Muscle Glycogenoses: General Principles 4


Acid Maltase Deficiency (Glycogen storage disease 2 (GSD2); Pompe disease)

  Acid α-1,4-glucosidase (GAA) ; Chromosome 17q25.3; Recessive

Clinical syndromes
  Infant
  Infant treated
  Child
  Juvenile
  Adult
  Vascular & Systemic
Epidemiology
GAA protein
Genetics
  Clinical-Genetic relations
Laboratory
Muscle pathology
  Child
  Adult
Treatment

From: Anne Connolly MD
Acid maltase deficiency
Mildly enlarged tongue
Pompe disease: Cardiomyopathy

Debrancher deficiency (Glycogenosis type 3; GSD3) 1

  Amylo-1,6-glucosidase, 4-α-Glucanotransferase (AGL; GDE) ; Chromosome 1p21.2; Recessive
  • Nosology
    • Cori disease
    • GSD 3a & 3b
  • Epidemiology
  • Genetics
    • Normal AGL mRNAs: Many tissue-specific isoforms differing at 5'-end
    • > 20 different mutations identified
    • Mutation types: Nonsense, Small deletions, Insertions, or Splice site
    • Mutation effects: 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 varied mutations in AGL gene
        • GSD IIIa (85%): Liver & Muscle involvement
        • GSD IIIb (15%)
          • Only liver involvement
          • Common mutation: Trp680Ter
    • Infant onset
      • Storage: Liver & Muscle
      • Seizures
      • Cardiomegaly: Severe
      • Hepatomegaly
      • Metabolic
        • Hypoglycemia: Recurrent
        • Hyperlipidemia
        • Hyperketonemia
      • 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: Rare
      • Axon loss
      • Glycogen storage in endoneurial cells ± axons
    • Treatment
      • Hypoglycemia in children: Frequent feeding
      • Weakness (Subacute in adults): ? High protein diet
  • 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 40
      • Myopathy
        • Nuclei: Internal
        • Endomysial connective tissue: Increased
        • p62+ aggregates: In vacuoles & subsarcolemmal
        • Necrosis: Uncommon
      • Glycogen storage
        • PAS
          • Increased stain in cytoplasm & vacuoles
          • Ring fibers seen
        • Vacuoles
          • Location: Subsarcolemmal & Intermyofibrillar
          • Present in fiber types I & II
        • Deposit types
          • Sarcoplasmic deposits: Large; Non-membrane bound
            • Contents: Normal glycogen
          • Autophagosomes
            • Sac structures
              • Smaller
              • Rounded
              • Lined by: Continuous double membrane
            • Contents: Glycogen
      • Acid phosphatase: Normal


Phosphorylase deficiency (McArdle; GSD 5) 26

  Glycogen phosphorylase (Muscle) (PYGM) ; Chromosome 11q13.1; Recessive

Epidemiology
Genetics
PYGM protein
Clinical
Laboratory
PYGM: Myopathy, Dominant

Phosphorylase b Kinase

Several syndromes

Glycogen storage disease VII (GSD 7; Tarui's disease)

  Phosphofructokinase, M (muscle) subunit (PFKM; 6-Phosphofructokinase) ; Chromosome 12q13.11; Recessive

Phosphoglycerate Kinase Deficiency

  Phosphoglycerate kinase 1 (PGK1) ; Chromosome Xq21.1; Recessive

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

  Phosphoglycerate mutase M (muscle) subunit (PGAMM; PGAM2) ; Chromosome 7p13; Recessive

Lactate dehydrogenase A deficiency (GSD 11)

  L-lactate dehydrogenase, M (muscle) subunit (LDHA) ; Chromosome 11p15.1; Recessive

Branching enzyme deficiency (GSD 4)

  1,4-α-Glucan Branching Enzyme (GBE1) ; Chromosome 3p12.2; Recessive

Polyglucosan body myopathy 1 (PGBM1) 28

  RANBP-type and C3HC4-type Zinc finger-containing 1 (RBCK1; HOIL-1L) ; Chromosome 20p13; Recessive

Aldolase A (Muscle) deficiency (GSD 12) 35

  Fructose-biphosphate aldolase (ALDOA) ; Chromosome 16p11.2; Recessive

β-Enolase deficiency (GSD 13) 3

  Enolase-3 (ENO3) ; Chromosome 17p13.2; Recessive

Triosephosphate isomerase deficiency (TPID) (Hemolytic anemia)

  Triosephosphate isomerase 1 (TPI1) ; Chromosome 12p13.31; Recessive

Lafora's disease (Progressive myoclonic epilepsy 2A & 2B)

  Laforin tyrosine phosphatase (EPM2A) ; Chromosome 6q24.3; Recessive
  NHL repeat-containing 1 gene (NHLRC1; Malin; EPM2B) ; Chromosome 6p22.3; Recessive

Glycogen storage disease, Muscle, Type 0 (GSD0B) 22

  Glycogen synthase 1 (GYS1) ; Chromosome 19q13.33; Recessive

Phosphoglucomutase 1 Deficiency (GSD 14; CDG1T)

  Phosphoglucomutase 1 (PGM1) ; Chromosome 1p31.3; Recessive

Polyglucosan body myopathy 2 (PGBM2) 25

  Glycogenin-1 (GYG1) ; Chromosome 3q24; Recessive

Glucose-6-phosphate dehydrogenase (G6PD) Deficiency 38

  Glucose-6-phosphate dehydrogenase (G6PD) ; Chromosome Xq28; Dominant
Glycolysis flow charts
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9/12/2022