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GLYCOGEN & GLUCOSE METABOLIC DISORDERS

Acid Maltase Deficiency (GSD2): 17q25 Aldolase A (GSD12): 16p11 Branching enzyme (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 (GSD2b): 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 & Pathways 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
• Glycogen & Glucose pathways
  • Glycogen synthesis
    • Glycogen synthase 1 (GSD0B): 19q13
    • Branching enzyme (GSD4): 3p12
    • Glycogenin (GSD15): 3q24
  • Glycogen breakdown
    • Debrancher (GSD3): 1p21
    • Phosphorylase (McArdle's) (GSD5): 11q13
      
    • PHKA1 (GSD9D): Xq13
    • Phosphoglucomutase 1 (GSD14): 1p31
      
  • Glycolysis
    • Phosphofructokinase (GSD7: 12q13
    • Phosphoglycerate Mutase (GSD10): 7p13
    • Lactate dehydrogenase A (GSD11): 11p15
    • Aldolase A (GSD12): 16p11
    • β-Enolase (GSD13): 17p13
    • Phosphoglucomutase 1 (GSD14): 1p31
  • Lysomal glycogenoses
    • Acid Maltase Deficiency (GSD2): 17q25
    • Lamp-2 (GSD2B): Xq24

Muscle Glycogenoses: General Principles ⁴

• 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
      
      • PHKA1: Xq12
      • PHKB: 16q12
    • Phosphorylase (McArdle's) (GSD5): 11q13
    • Phosphofructokinase (GSD7): 12q13
    • Phosphoglycerate Kinase: Xq13
    • Phosphoglycerate Mutase (GSD10): 7p12
    • Phosphoglucomutase 1 (GSD14): 1p31
      
    • β-Enolase (GSD13): 17pter
    • Lactate dehydrogenase (GSD11): 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 (GSD2): 17q25
    • Aldolase A (GSD12): 16q22
    • Branching enzyme (GSD4): 3p12
    • Debrancher (GSD3): 1p21
    • Glycogen synthase 1 (GSD0B): 19q13
      
    • Glycogenin (GSD15): 3q24
      
    • Lamp-2 (GSD2B): Xq24
    • Phosphorylase (McArdle's), severe phenotype (GSD5): 11q13
    • Triosephosphate isomerase: 12p13
      
• Cardiomyopathy
  • Glycogen synthase 1 (GSD0B): 19q13
  • Acid Maltase Deficiency (GSD2): 17q25
  • Lamp-2 (GSD2B): Xq24
  • Debrancher (GSD3): 1p21
  • Branching enzyme (GSD4): 3p12
  • Phosphoglucomutase 1 (GSD14): 1p31
  • Glycogenin (GSD15): 3q24
• Liver Involvement ⁴³
  • 0, I , III, IV, VI , IX, XI

Acid Maltase Deficiency (Glycogen storage disease 2 (GSD2); Pompe disease) ⁴⁸

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

From: Anne Connolly MD Acid maltase deficiency Mildly enlarged tongue

Pompe disease: Cardiomyopathy

• Nosology: LGMD 2V
• Epidemiology
  • Disease incidence
    • Overall disease: 1 in 4,400 to 37,000 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
  • Frequency: 5,000 to 10,000 cases world-wide
  • Carrier frequency: 1 in 85 to 100
• 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
  • External links: Mutation databases
    • Human Gene Mutation Database
    • Pompe center
• Clinical-Genetic correlations ⁹
  • Level of residual enzyme activity correlates with
    • Severity of disease
      • Infant onset (< 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 infant 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
  • Pseudodeficiency
    • Asians: c.1726G>A , G576S; c.2065G>A, E689K
  • Phenotype modulators ³²
    • Angiotensin-converting enzyme (ACE) allele: DD genotype
      • Disease onset: Earlier onset
      • Creatine kinase levels: Higher at diagnosis
      • Muscle pain: More frequent
      • Disease progression: Faster
      • Also modulates: Phosphorylase deficiency phenotype
    • ACTN3: R577X polymorphism
      • Disease progression: More rapid
      • Disease onset: Earlier
• Acid α-1,4-glucosidase (GAA) protein
  • Precursor protein
    • Modified in rough ER & Golgi
    • ER: N-glycosylated
    • Golgi: Mannose 6-phosphate added; Targets GAA to lysosome
  • Location (Tissue): Present in all tissues, "Housekeeping enzyme"
  • Subcellular location: Lysosome
  • Action
    • Catalytic site: Asp-518
    • Hydrolyzes terminal linear α1-4 glucosidic linkages on carbohydrates
      • α-D-glucose released
      • Oligosaccharides: Hydrolyzed quickly by α-Glucosidase (GAA)
      • Polysaccharides
        • Hydrolyzed slowly, if at all, by α-Glucosidase
        • Hydrolyzed by: Glucan 1,4-α-glucosidase with release of β-D-Glucose
  • Mutation effects on acid α-1,4-glucosidase protein: Varied
    • Absent Enzyme protein: Most infant disease
    • Proportionate reduction of Enzyme protein & Activity: Adult onset
    • Catalytic activity reduced, but Enzyme protein present: May occur in infants, children or adults
      • Trp481Arg: Absent catalytic activity; Normal protein synthesis & posttranslational modification
    • Abnormal Enzyme maturation & transport: Protein may be synthesized but not efficiently delivered to lysosome
    • Some mutations prevent protein secretion
• Clinical features
  • General
    • Several syndromes: Vary with age of onset
    • Intrafamilial features: Homogeneous
  • 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%)
    • Anesthesia ¹⁸
      • 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
  • Infant onset: Atypical
    • Onset: < 1 year
    • Death: 1st decade
  • Infant onset: Treated with enzyme replacement ³¹
    • Disease course
      • Progression after early improvement
    • Weakness: Common features different or more severe vs Late-onset disease
      • Face: Weakness; Ptosis
      • Neck flexors
      • Distal: Dorsiflexors, Foot (Myopathic)
      • Hip extensors
      • Posture: Anterior pelvic tilt; Forward trunk lean
      • Relatively spared muscles
        • Hip flexors
        • Spinal extensors
      • Muscle pathology: Myopathy, vacuolar
    • Neuropathy
      • Sural nerve: Axon loss
      • NCV: CMAPs small amplitude
      • EMG: Complex repetitive discharges
      • Skin biopsy: Intraepidermal axons reduced
    • Skeletal
      • Contractures
        • Hip flexors
        • Iliotibial bands
        • Plantar flexors: Foot
        • Posterior tibial
        • Plantar fascia
      • Scoliosis: Less than untreated patients
      • Bone issues: Osteopenia (55%)
    • CNS
      • Cognitive impairment
      • Brain MRI ³⁷
        • Pre-Rx
          • Ventricular enlargement
          • Myelination delay
          • May improve with treatment
        • Post-Rx
          • White matter signal
          • Deep frontoparietal cerebral changes: > 10 years of age
  • Acid Maltase deficiency variant: Childhood onset; Weakness
    • 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
  • Acid Maltase deficiency variant: 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
  • Acid Maltase deficiency variant: Adult onset Myopathy + Variable features ¹¹
    • 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
      • 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
          • 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 ventilation ¹⁶
      • Axial: Abdominal & Paraspinal muscles
      • Proximal > Distal
      • Legs > Arms: Hip flexors & extensors, adductors & abductors
      • Paraspinous muscles (Atrophy)
      • Bulbar: Tongue; Dysphagia & Dysarthria
      • Patchy
        • Pectoralis: Sternal > Clavicular head
        • Thigh adductors
        • Scapular winging (33%): With other shoulder girdle muscle weakness
      • Other
        • Ptosis (23%): Normal EOM; May be asymmetric
        • Bulbar (28%)
      • Relatively spared: Quadriceps; Distal muscles
      • Disease course: Progression ³⁰
        • Slow, over years
        • Severity related to disease duration, not patient age ¹⁷
        • Average decline: 1.3% to 2.6% per year
        • More rapid with
          • Respiratory involvement
          • Longer disease duration
          • 10% of patients
    • 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
    • Cardiac: Usually normal
    • Other
      • Skeletal
        • Spine: Disease onset < 21 years
          • Lordosis (50%)
          • Scoliosis (10% to 33%)
          • 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 ¹⁴
        • 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
    • 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
  • Acid Maltase deficiency variant: Adult onset, Cardio-Cerebrovascular ²⁹
    

    Basilar aneurysm: Fusiform

    • Onset age: Mean 38 years; Range 18 to 62 years
    • Vascular
      • Cardic arrhythmias
        • Sick sinus syndrome
        • Lown IVb ventricular arrhythmia
        • Wolff–Parkinson–White
      • Aneurysm: Cerebral (Basilar or Aortic); Aortic
      • Aorta: Stiff
      • Cerebral atherosclerotic angiopathy
        • Mutations: Ala237Val; Gly293Arg ¹³
      • Dolichoectasia: Basilar & Internal carotid arteries
      • Stroke
      • Other
        • Eye: Unilateral ptosis; Diplopia
        • Migraine
      • Cardiac ultrasound: Right ventricular hypertrophy
      • Pathology: Smooth muscle damage & glycogen accumulation
    • Weakness
• 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
      • Common in quadriceps
    • 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
    • Lysosomes: Increased
    • Lipofuscin ³³
      • Acumulates in lysosomes (LAMP-positive) & autolysosomes (LC3 positive)
      • Especially in later onset patients
    • 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 onset ¹⁵
  • Other organs
    • Glycogen in smooth muscle of vessels, heart, bladder, intestine, esophagus
    • Peripheral nervous system (PNS): Glycogen storage in dorsal root ganglia, Schwann cell cytoplasm
    • Autonomic: Myenteric plexus neurons, Parasympathetic neurons
    • CNS: Cerebral capillaries, Basilar arteries, Choroid plexus
• Treatment: Enzyme replacement ¹⁰
  • Recombinant α-glucosidase: Intravenous
  • Does not cross Blood-Brain barier
  • May benefit
    • Cardiomyopathy: Improved more than myopathy
    • Infant-onset & Adult-onset disease
    • Strength
      • Improved: Distal weakness more improved than proximal
      • Better pulmonary function
      • Some muscles remain weak
    • Late onset: Mild improvement or disease stabilization reported
    • Course after treatment
      • Improvement
        • Course: Over months
        • Degree: Mild
        • Sensitive measure: 6 minute walk test
      • May develop new weakness after initial small improvement ⁴¹
        • Face
        • Bulbar: Dysarthria; Dysphagia
        • Respiratory: Progressive loss begins especially after 1 to 2 years of treatment
  • Side effects: Infusion reactions
  • Predictors of good histologic response to treatment of infant onset type ²¹
    • Low glycogen levels
    • Mild ultrastructural damage
    • High proportion of type I muscle fibers
    • Young age at baseline
  • Albuterol (8 mg bid): May improve response to enzyme replacement treatment ³⁴
• Animal models: Acid maltase deficiency
  • Japanese quails
  • Lapland dog
  • Australian cattle

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 3rd most prevalent muscle glycogenosis After: McArdle (GSD5) & Acid maltase deficiency (GSD2) 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

Gerty Cori

Phosphorylase deficiency (McArdle; GSD 5) ²⁶

• Epidemiology
  • Incidence: 1 in 10,000 to 100,000 in North Americans of European descent
  • Male predominance
• Genetics
  • Mutations
    • Recessive: Loss of function
    • > 206 different mutations identified
      • Types: May be missense, stop, destruction of start codon or small deletion with frameshift
      • Missense most frequent (50%)
      • Splice site (11%)
      • Missense mutations usually in highly conserved residues
      • Hotspots: Exons 1 & 17; Nonsense mutations more common
    • Allelic heterogeneity: Common
    • Common mutations
      • US, Britain, Germany, France, Italy: Arg50Stop in exon 1
        • Most common mutation
        • Type: Nonsense
        • Previous nomenclature: Arg49X
      • Japan: Skipped codons 708/709
      • Gly205Ser: 10%; North American & Spanish
      • Other: L542T; W798R
    • Many ethnic or familial private mutations
  • Allelic disorders
    • PYGM myopathy, Dominant
    • Schizophrenia: Altered energy metabolism; Low PYGM in astrocytes
    • Neoplasm: Altered levels in cancers
• Clinical-Genetic correlations: Inconsistent
  • Pseudodominant transmission in a few families due to:
    • Manifesting heterozygote with low residual enzyme activity, or
    • Mating of homozygote with heterozygote ⁶
  • 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 modulators ⁵
    • 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
      • Also modulates: Acid maltase deficiency phenotypes
• Glycogen phosphorylase (PYGM) protein ⁴⁷
  • Glycogenolysis pathway
  • Catalyzes release of: Glucose-1P from Glycogen
  • Types: Myophosphorylase A & B
    • Phosphorylation of Ser-15 converts Phosphorylase B (unphosphorylated) to Phosphorylase A
    • Myophosphorylase B: Requires AMP for interconversion to active form
    • Myophosphorylase A: Independent of AMP
  • Location: Cytosol
  • Cofactors
    • Pyridoxal 5'-phosphate (PLP; Active form of vitamin B6)
    • Ras-related C3 botulinum toxin substrate 1 (Rac1)
  • Activators
    • AMP
    • Inosine 50-monophosphate (IMP)
  • Activated when phosphorylated by: Phosphorylase kinase
  • Inhibitors
    • ATP
    • G1P
    • Metabolites
  • Enzyme stops glycogen breakdown at 4th residue away from an alpha-1,6 branching point
    • Leaves highly branched core (Limit dextrin)
  • Other functions
    • Insulin & glucagon signaling
    • Phototransduction pathway
      • Interaction with recoverin (RCVRN) & CALM1
      • Connection with Ca⁺⁺ cellular level regulation
      • Impaired glycogen metabolism in retinal pigment epithelium & Cone photoreceptors
    • Necroptosis
      • Interaction with receptor interacting serine/threonine kinase (RIPK)
      • RIPK3: Activates glycogen phosphorylase; Influences glycogenolysis
    • T-cells: Immune functions
  • Disease biochemistry
    • Impaired ATP generation from
      • Aerobic glycogenolysis: Reduction of glycogen metabolized to carbon dioxide & water
      • Anaerobic glycogenolysis: Reduction of glycogen metabolized to lactic acid
    • Reduced production of pyruvate
• Clinical features
  • 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
  • "Second wind" phenomenon: Brief rest after myalgias allows further activity ⁷
    • 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
    • Frequency: 78%
  • Myoglobinuria (50%)
  • Discomfort: Muscle
    • Cramps
    • Pain: Especially proximal legs
  • Weakness
    • Severity
      • Usually Mild
      • Limitations of activities of daily living: 25%
    • Frequency: 11% to 30%; More common in older patients
    • Onset age: Usually > 40 years
    • Fixed
    • Distribution: Variable
      • Proximal > Distal
      • Symmetric or Asymmetric
        • Similar frequencies
        • Asymmetric: Scapular winging or FSH phenotype common ¹²
      • Leg or Arm predominant
      • Arm > Leg
      • No clear relation to genotype
  • Muscle size change
    • Wasting
      • Frequency: 12%
      • Age: > 40 years
      • Distribution: Shoulder girdle; Axial
    • Hypertrophy
      • Frequency: 9% to 24%
      • Muscles: Deltoid; Biceps; Calves; Thighs
  • Other systems involved
    • Renal failure: 11%; Males > Females; Acute with rhabdomyolysis
    • Retinopathy
  • 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
    • Compartment syndrome: Older ages
  • Possible treatments
    • Sucrose before exercise
    • Diet: High protein or High carbohydrate
    • Pyridoxine (B₆): Oral; 60mg to 90 mg/day ²⁷
    • Creatine monohydrate: Low dose
    • ACE inhibitors: Ramipril (2.5 mg qd) may improve disability in D/D allele patients ²³
    • Gene therapy
• Laboratory
  • Serum
    • CK
      • Elevated even at rest (> 90%): Up to 12,000
      • May be normal in pregnancy
    • Hyperuricemia
    • High K⁺ during exercise
  • EMG: Myopathic
  • Exercise tests
    • Ischemic exercise (hazardous): Reduced lactate production
    • Non-ischemic exercise test
      • Test: Exercise limb (forearm) for 2 to 3 minutes
      • Results
        • McArdle & glycolytic disease: Reduced Lactate production with normal Ammonia increase
        • AMPDA deficiency: Reduced Ammonia production with normal Lactate increase
        • Insufficient exercise: No rise in lactate or ammmonia
    • 12 minute walking: 50% of normal
  • Muscle Pathology
    • Muscle fiber pathology
      • Subsarcolemmal vacuoles or blebs: May be regional
      • Necrosis & Regeneration: Occasional
      • Regenerating muscle fibers may express phosphorylase: Not with homozygous Arg50Stop mutation
      • Linearization of internal architecture on NADH
      • Type 1 muscle fiber atrophy
      • Rare: Rimmed vacuoles
    • Chronic myopathic changes: Unusual
    • Muscle glycogen level: High; 2- to 4-fold
• PYGM variant: PYGM myopathy, Dominant ³⁹
  • Epidemiology: 1 family; 13 patients
  • Genetics
    • Inheritance: Dominant
    • Mutation: c.1915G>C transversion; p.Asp639His
      • Missense; Heterozygous
      • Impairs AMP-independent, but not AMP-dependent Myophosphorylase activity
  • Clinical
    • Onset age: Adult; Range 40 to 55 years
    • Weakness
      • Initial: Proximal legs
      • Disease progression: Proximal arms; Then Distal legs
      • Respiratory: Normal
      • Course: Progressive to need gait aids over decade
  • Laboratory
    • Serum CK: 105 to 346
    • EMG: Myopathic
    • Oxidative capacity: Normal
    • Muscle pathology
      • Fiber types: I predominance
      • Sizes: Varied
      • PAS: Central & Sub-sarcolemmal deposits, digested by α-amylase; NADH-
      • Aggregates: Contain PYGM & Desmin
      • Phosphorylase
        • Stain: Present; Myophosphorylase activity in fiber periphery
        • Protein: Present
      • Glycogen levels: Normal
      • Myophosphorylase protein: Abnormal folding conformation
      • Ultrastructure
        • Free glycogen particles
        • Subsarcolemmal glycogen aggregates (Honeycomb structures)

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
    • α1, α2 & β subunits: Regulatory
    • γ subunit: Catalytic
    • δ subunit: Identical to calmodulin; Confers Ca⁺⁺ sensitivity to enzyme
• Exercise intolerance, X-linked (GSD9D) ⁴⁴
    ● Phosphorylase kinase, α subunit (muscle) (PHKA1) ; Chromosome Xq13.1; Recessive
  • Epidemiology: 16 patients
  • Genetics: Several αM mutations identified
    • Nonsense: Y511*; 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 age: Childhood to 5th decade
    • Weakness: Distal > Proximal
    • Exercise intolerance, Myalgia & Cramps
    • Myoglobinuria: Occasional
    • Camptocormia: 1 patient
    • Course: Slow progression
  • Laboratory
    • Forearm ischemic exercise test: Normal or Reduced rise in lactate
    • Serum
      • CK: High, 2x to 20x normal
      • Hyperuricemia
    • EMG: Normal or Myopathic
    • Muscle histology
      • Subsarcolemmal vacuoles
      • Glycogen: Mild accumulation: May be subsarcolemmal
      • Necrosis & Regeneration: Few muscle fibers
    • Biochemistry
      • Phosphorylase kinase levels
        • Low or absent in muscle
        • Normal in erythrocytes & liver
      • Total phosphorylase levels: Normal
      • Muscle glycogen: Increased
• Myalgia & Myoglobinuria: Recessive (GSD9B)
    ● Phosphorylase kinase, β subunit (PHKB) ; Chromosome 16q12.1
  • Genetics
    • Mutations: Ala117Pro; Tyr418Ter; Gln656Ter; Exon 14 insertion; Splice
  • Protein
    • β-subunit of Phosphorylase kinase (PHK)
    • Regulatory functions controlled by phosphorylation
    • Disease: Enzyme deficiency in both muscle & liver
  • Clinical
    • Myalgia, cramps & weakness with exercise
    • Myoglobinuria
    • Onset age: Childhood or Adolescence
    • Hepatomegaly: Some forms
    • Growth retardation
  • Normal exercise test
• Liver & renal phosphorylase b kinase deficiency (GSD9A1)
    ● Liver PHK, α-2 subunit (PHKA2) ; Chromosome Xp22.13; Recessive
  • Normal muscle
  • Also caused by mutations in glucose permease (GLUT2; SLC2A2)
• Liver phosphorylase kinase deficiency (GSD9C)
    ● Phosphorylase kinase, testis/liver, γ-2 (PHKG2) ; Chromosome 16p11.2; Recessive
• Phosphorylase kinase deficiency: Cardiomyopathic forms
    ● Protein kinase, AMP-activated, noncatalytic, γ-2 (PRKAG2) ; Chromosome 7q36.1; Dominant
  • Glycogen storage disease of heart, Lethal, Congenital
    • Epidemiology: 8 patients
    • Genetics
      • Mutations: Arg531Gln; Arg384Thr
      • Allelic disorders
        • Phosphorylase kinase deficiency: Cardiomyopathic forms
        • Glycogen storage disease of heart, lethal congenital
        • Cardiomyopathy, familial hypertrophic, with Wolff-Parkinson-White syndrome (CMH6)
        • Wolff-Parkinson-White syndrome
    • PRKAG2 protein
      • γ2 subunit of AMP-activated protein kinase
      • Dominant isoform in regulatory γ subunit
      • AMPK protects cells from ATP depletion
        • Activates glycolysis & fatty acid uptake during hypoxic stress or metabolic demand
      • Non-lysosomal cardiac glycogenosis
    • Clinical
      • Onset: Neonatal
      • Cardiac
        • PR interval: Short
        • Congestive heart failure
        • Cardiomyopathy: Vacuolar; Cardiomegaly, Biventricular hypertrophy
        • Glycogen: Increased in myocardium
        • Phosphorylase kinase activity: Absent in myocardium
      • Respiratory
        • Failure
        • Pulmonary edema
      • Macroglossia: Some patients
      • Death: 3 weeks to 5 months of age
    • Laboratory
      • Muscle
        • Vacuoles
        • Glycogen: Increased
        • Phosphorylase kinase activity: Normal
      • Hypoglycemia: Neonatal
• Skeletal Muscle Glycogen content & metabolism, Quantitative Trait Locus (SMGMQTL)
    ● Protein kinase, AMP-activated, noncatalytic, γ-3 (PRKAG3) ; Chromosome 2q35; Recessive
  
  • Epidemiology: Mutation found in 2 (of 760) obese patients
  • Genetics
    • Mutation: Missense; Arg225Trp
    • Allelic disorder
      • Hampshire pigs: R200Q; Muscle glycogen increased
  • PRKAG3 protein
    • AMPK γ-3 subunit: Regulatory
    • Muscle specific
    • Mutation effect: Increased AMPK activity
  • Clinical: No phenotype described
  • Laboratory
    • Muscle
      • PAS stain increased x2
      • Intramuscular triglyceride: Reduced by 30%

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

• Epidemiology
  • Male predominence (9:1)
  • Prevalence high
    • Ashkenazi Jews (US)
    • Italy
    • Japan
• 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
  • 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
• 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
  • Diet (vs McArdle's)
    • High carbohydrate meal: More symptoms
    • Prolonged fasting: Milder symptoms
  • Myoglobinuria: Less frequent than in McArdle's
  • Weakness: Late-onset with fixed myopathy in some patients
  • Systemic features
    • Gout: Hyperuricemia
    • Gastric ulcer
• Laboratory
  • Serum CK
    • During episodes: High
    • Between episodes: Often normal
  • Hyperuricemia
  • Hyperbilirubinemia
  • Hemolytic anemia
    • Compensated
    • High reticulocyte count
    • Hemolysis without myopathy (Unstable M subunits)
  • 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
• 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
• 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
    • Laboratory
      • Serum CK: Normal to 350
      • Skeletal muscle
        • Varied fiber sizes
        • Vacuoles
        • PAS+ storage
        • More pathology with later biopsy
      • Heart & Liver: Extralysosomal glycogen storage
  • Myopathy: Adult onset
    • Exercise intolerance: History in younger years

Phosphoglycerate Kinase Deficiency

• 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 (HNSHA) (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 variant: 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
    • CNS dysfunction
      • Parkinsonism, juvenile: In some patients with same mutation (T378P)
  • 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
  • ~15 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
  • Allelic with: CDG1T
• 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
  • Treatment: Dantrolene may reduce cramps
• 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
• Heterozygotes: Manifesting patients described
• Variant syndrome
  • Symptoms associated with statin use: 1 patient

Lactate dehydrogenase A deficiency (GSD 11) ⁴⁵

• Epidemiology: 15 families
• Genetics: Frame shift deletions & Nonsense mutations
• LDH protein
  • Tetrameric
  • Composed of varying proportions of muscle specific & cardiac subunits
  • Expressed in muscle
• Clinical features
  • Onset ages: 1st & 2nd decade
  • Muscle
    • Exercise intolerance
    • Cramps
    • Myoglobinuria: Some patients
    • Strength: Normal
  • Skin: May be only feature
    • Erythematous rash
    • Desquamating erythematosquamous lesions
    • Pustular psoriasis-like lesions
    • Often appear in Spring & resolve after Fall
  • Difficulties in childbirth: Uterine stiffness & pain
• Laboratory
  • Serum CK: High
  • Exercise test: Rise in pyruvate but not lactate
  • Serum LDH: Low
• See: Lactate metabolism
• LDHB deficiency : No clinical features

GSD4: Branching enzyme deficiency

• Nosology: Andersen disease; Glycogen storage disease IV (GSD IV; GSD 4)
• Genetics
  • Mutations
    • > 20 mutations identified
    • Types: Nonsense, Missense, Deletion, Insertion & Splice-site
    • Milder disease: Misasense mutations
  • Allelic disorders
    • Congenital
    • Congenital + Arthrogryposis (Fetal akinesia)
    • Childhood
      
    • Myopathy, childhood
    • Myopathy, adult
    • Polyglucosan body syndrome, Adult - Diffuse CNS & PNS dysfunction
    • Animal: Norwegian Forest cats; Other dogs & cats
• GBE1 protein
  • Glycogen biosynthesis
  • Converts amylose into amylopectin
  • Transfers segment of (1->4)-α-D-glucan chain to primary hydroxy group in similar glucan chain
  • Activity also reduced with: c2orf69 mutations
• Clinical features (Several presentations)
  • Congenital forms
    • Genetics: Associated with Nonsense or other severe mutations
    • Clinical
      • Severe hypotonia
      • Muscle wasting
      • Arthrogryposis: Congenital contracture syndromes (LCCS)
      • Neuronal involvement
      • Hepatic failure
      • Cardiomyopathy: Dilated
      • Death: Infancy
      • Most severe forms: Fetal akinesia deformation sequence (FADS)
    • Muscle
      • Abnormal staining for membrane proteins
      • Polyglucosan bodies: PAS positive
      • Ultrastructure: Myofibril fragmentation; Z-band patchy absence
  • Childhood systemic disorder
    • Onset: 1 year
    • Liver: Hepatomegaly; Failure; Cirrhosis
    • Hypotonia
    • Some milder cases with cardiomyopathy or myopathy ²
    • 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
      • Chitotriosidase levels: May be high
  • 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, Adult - Diffuse CNS & PNS dysfunction

Polyglucosan body myopathy 1 (PGBM1) ²⁸

• Nosology: Polyglucosan body myopathy ± Immunodeficiency (PBMEI)
• Epidemiology: 27 patients
• Genetics
  • Mutations: Missense or Truncating
  • Allelic disorders & Clinical associations
    • Truncating mutations: Cardiomyopathy
    • Missense mutations: Milder course; Less weakness & cardiomyopathy
    • N-terminal mutations: Failure to thrive, Chronic autoinflammation, Immunodeficiency & Recurrent sepsis
    • Middle or C-terminal region: Cardiomyopathy or Neuromuscular
• RBCK1 protein
  • E3 ubiquitin-protein ligase
  • Interacts with
    • EYA1 phosphatase: Involved in myogenesis (High in nuclei of fast-twitch muscle fibers)
    • Iron regulatory protein 2 (IRP2)
    • Forms: Linear Ubiquitin Assembly Complex (LUBAC) with HOIP (RNF31) & Sharpin
• Clinical
  • Onset
    • Age: Infancy to 17 years
    • Weakness: Proximal legs
  • Weakness
    • Proximal
    • Legs > Arms
    • Ptosis (40%)
    • Course: Slow progression; Ambulation difficulties
    • Vital capacity: 40% to 90%
  • Cardiomyopathy (80%)
    • Especially with: Truncating mutations
    • Dilated
    • Course: Rapidly progressive; May require transplant
  • Liver involvement (20%): Hepatomegaly
  • Skeletal
    • Growth retardation (40%)
    • Scoliosis (30%)
  • Immunodeficiency (Some patients)
    • Recurrent infections
    • Hyperinflammatory state
    • IgA: Increased
    • Memory B cells: Decreased
    • Lymphadenopathy
• Laboratory
  • Muscle
    • NADH: Irregular internal architecture
    • Normal glycogen: Depleted in 50% of muscle fibers
    • Polyglucosan accumulation: Inclusions
      • Incompletely digested by alpha-amylase
      • Partially resistant to proteinase K treatment
      • Ubiquitinated
      • Contents ⁴²
        • Sequestosome-1 (p62): Ubiquitin-binding protein
        • Glycogen metabolism components
        • Protein control pathway components
      • Ultrastructure: Granular & Partly fibrillar structure; Variable electron density
      • Desmin aggregates
  • Cardiac muscle
    • Hypertrophy
    • Polyglucosan bodies: alpha-amylase resistant PAS-positive inclusions
  • Serum CK: Normal to 5x High

Aldolase A (Muscle) deficiency (GSD 12) ³⁵

• Nosology: Fructose-1,6-bisphosphate aldolase
• Genetics
  • Mutations: Glu206Lys; Ala279Val
• ALDOA Protein
  • Present in erythrocytes & muscle
  • Mutation effects: Impair thermostability of ALDOA
• Clinical features
  • Onset: Childhood
  • 1st year
    • Jaundice
    • Anemia: Nonspherocytic, hemolytic
  • Weakness: Proximal
  • Episodes: Related to fever
    • Myalgias
    • Rhabdomyolysis: Childhood onset
    • Hemolysis: Some patients
  • Learning disabilities: Some patients
  • ? Treatment: Arginine
• Laboratory
  • CK: High after exercise & anesthesia; Near normal otherwise
  • EMG: Normal
  • Muscle pathology
    • Fiber size: Variable
    • Lipid: Increased
    • EM: Distorted mitochondria; Lipid accumulations
    • Aldolase A activity: Reduced

β-Enolase deficiency (GSD 13) ³

• Epidemiology: 3 patients
• Genetics
  • Mutations: Missense - Asn151Ser, Gly156Asp, Glu187Lys, Gly374Glut
• β-Enolase protein
  • Interconverts 2-Phosphoglycerate (PGA) & Phosphoenolpyruvate
  • Localization: β-subunit of enolase prevalent in Skeletal muscle
• Clinical
  • Onset age: Childhood to 3rd decade
  • Exercise intolerance: Fatigability; Myalgias; Cramps
  • Myalgias: After heavy exercise
  • Rhabdomyolysis: Episodic
  • Strength: Normal
  • Muscle bulk: Normal
  • Course: Increasing intensity of myalgiass over decades
  • No extramuscular involvement
• Laboratory
  • Serum CK: Episodic elevations; Reduced or normal with rest
  • Lactate: No rise with ischemic exercise
  • Enolase activity: 5% of normal
  • EMG: Myopathic
  • Muscle pathology
    • Fiber size: Mild variability
    • PAS: Normal
    • No vacuoles
    • β-enolase
      • Immunoreactivity: Reduced or absent
      • Activity: 5% to 20% residual
    • Ultrastructure
      • Sarcoplasmic glycogen β granules
      • Similar to Aldolase A, PGAM, LDH-M deficiencies

Triosephosphate isomerase deficiency (TPID) (Hemolytic anemia) ⁴⁶

• Epidemiology: > 50 patients
• Genetic
  • Common mutation: Glu105Asp
  • Glu105Asp homozygotes: Severe disease
  • Heterozygote frequency: 1 to 5 per 1,000
• TPI1 protein
  • Glycolytic pathway
    • Catalyzes glyceraldehyde 3-phosphate (GAP) & dihydroxyacetone phosphate (DHAP) interconversion
    • TPI1 deficiency: Accumulation of DHAP
    • DHAP transforms spontaneously into cytotoxic by-product methylglyoxal
  • Biochemistry: Reduced Triosephosphate isomerase activity in many tissues
  • Target for NO-mediated post-translational modifications in neurodegenerative diseases
  • Mutations: Abnormal synaptic vesicle recycling
• Clinical: Most severe clinical disorder of glycolysis
  • Onset: Neonatal to < 2 years
  • Hemolytic anemia: Chronic; Non-spherocytic; Crises
  • Recurrent infections
  • CNS
    • Mental retardation
    • Dystonia
    • Cerebellar
    • Tremor
    • Upper motor neuron
      • Extensor plantar responses
      • Tone increased
    • Cognitive: Probably normal
  • Muscle weakness
    • Proximal
    • Face
    • Slowly progressive
  • Tendon reflexes
    • Early: Reduced
    • Late: Increased with Spasticity
  • Peripheral nerve: Some patients ⁸
    • Weakness: Distal
    • Sensory loss: Large fiber modalities
    • Electrophysiology: Axonal loss
    • Nerve biopsy: Loss of myelinated axons; Regeneration
  • Joint contractures: Ankles
  • Course
    • Onset < 2 years
    • Death: Majority < 6 years; Longest survival 20 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 2A & 2B)

• Laforin protein
  • ? Role in phosphorylation/dephosphorylation reactions controlling glycogen metabolism
  • Mutation: Leads to hyperphosphorylated glycogen and polyglucosan formation
• NHLRC1 protein: E3 ubiquitin ligase
• 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 (GSD0B) ²²

• Epidemiology: 3 families
• Genetics
  • Homozygous stop mutations; Arg462Ter, 2-bp Del 162AG
  • Allelic with: PSSM1
• GYS1 protein
  • Muscle glycogen synthesis: Accounts for disposal of up to 90% of ingested glucose
  • Muscle & Heart glycogen: Provides energy during bursts of activity & sustained muscle work
• Clinical
  • Onset: 1st decade
  • Cardiomyopathy
    • Hypertrophic
    • May produce sudden death
  • Fatigue: Reduced exercise capacity
  • Muscle strength: 50% reduced
• Laboratory
  • Muscle biopsy
    • PAS stain: Reduced
    • Glycogen: Reduced
    • Type I fiber predominance
    • Mitochondrial proliferation
    • Glycogen synthase protein: Absent from muscle
  • Glucose tolerance test: Normal
• GYS1 variant: Equine Polysaccharide Storage Myopathy Type 1 (PSSM)
  • Epidemiology: Historical selection in Belgian, but not Quarter horse breeds
  • Genetics
    • Inheritance: Dominant
    • Gys1 Mutation: Arg309His
  • GYS1 protein: Glycogen synthase activity increased in mutant
  • Clinical
    • Rhabdomyolysis: Painful recurrent episodes after exercise
    • Treatment: Low carbohydrate diet; Regular exercise
  • Skeletal muscle
    • Abnormal glycogen accumulation: Coarse granular, Amylase-resistant, Cytoplasmic
    • Vacuoles: Subsarcolemmal; Some rimmed
    • Internal nuclei
    • Inclusions: Desmin+
    • Polyglucosan bodies

Phosphoglucomutase 1 Deficiency (GSD 14; CDG1T)

• Epidemiology: Two patients
• Genetics: Mutations
  • Heterozygous
  • Thr115Ala, Gly121Arg; Arg503Ter; c.1145-1G-C (IVS7DS,G-C,-1) in intron 7-8 splicing donor site
  • Allelic disorder: CDG1T
• PGM1 protein
  • Catalyzes transfer of phosphate between 1 and 6 positions of glucose
  • PGM1: Major isozyme in most tissues
  • Binds to heart-muscle-cell–specific splice variant of ZASP
  • Function: N-glycosylation pathway
    • α-D-glucose 1-phosphate → α-D-glucose 6-phosphate
  • Mutations: Hypogalactosylation
• Clinical
  • Onset age: Childhood
  • Cramps
    • Exercise induced
    • Electrically silent
  • Rhabdomyolysis: Episodes
  • Weakness
    • Mild
    • Proximal
    • 2nd wind phenomenon
• 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
    • Total glycogen: Normal or Low
• PGM1 Variant syndrome: Congenital disorder of glycosylation, Type It (CDG1T)
  • Epidemiology: > 50 patients
  • PGM1 genetics
    • Inheritance: Recessive
    • Mutations: Missense, Splice, Stop
    • Allelic with: PGM1 deficiency
  • Clinical
    • Onset age: Infant or Childhood
    • Cardiomyopathy (30%): Dilated; Tachycardia
    • Hypotonia
    • Myopathy (60%)
      • Weakness: Some patients
      • Fatigue & Exercise intolerance
      • Rhabdomyolysis (20%)
    • Bifid uvula (85%)
    • Skeletal: Pierre Robin sequence, Cleft palate, Short stature
    • CNS
      • Seizures
      • Intellectual disability
      • Cerebral thrombosis
    • Liver disease
    • Hypogonadotropic hypogonadism: Few patients
    • Coagulation disorders
    • Growth delay
    • Eye: Blue sclera
    • Treatment: Dietary D-galactose supplementation
  • Laboratory
    • Liver enzymes: High (100%)
    • Hypoglycemia: Episodic
    • Serum CK: 300 to 10,000
    • Transferins: Abnormal
      • N-glycosylation
      • Monosialo- & trisialotransferrin
    • PGM activity: 7% to 8% residual
    • Brains: Normal

Polyglucosan body myopathy 2 (PGBM2; GSD15) ²⁵

• Epidemiology: 10 patients
• Genetics
  • Mutations: Missense (Ala16Pro; Thr83Met); Stop; Splice site
  • Allelic with: Glycogenin Deficiency (GSD 15) ²⁵
• GYG Protein
  • Involved in initiation reactions of glycogen synthesis
  • Self glucosylating
  • Glycosyltransferase
  • Catalyzes formation of short glucose polymer of approximately 10 glucose residues
    • From uridine diphosphate glucose
    • Autoglucosylation reaction
  • Glycogenin-Oligosaccharide molecule
    • Constitutes primer for glycogen synthesis: Catalyzed by
      • Glycogen synthase
      • Branching enzyme
• Clinical
  • Onset
    • Age: Childhood to 65 years
    • Weakness
  • Weakness
    • Symmetric
    • Proximal > Distal: 1 patient with only hand weakness
    • Specific muscles involved
      • Neck flexion
      • Shoulder abduction: May be asymmetric
      • Elbow flexion & extension
      • Abdominal muscles
      • Foot dorsiflexion
      • Scapular winging: Mild; May be asymmetric
      • Respiratory: Mild
    • Face & Eyes: Normal
    • Course: Slow progression
  • Cardiomyopathy: Some patients; Ventricular tachycardia
• Laboratory
  • Serum CK: Normal to 977
  • Cardiac enzymes: Mild elevation
  • EMG: Myopathic
  • EKG: Often normal
  • Muscle MRI ³⁶
    • Early involvement of deltoid & gluteus
    • Legs: Adductor longus, Biceps femoris (Long), Vasti
  • Muscle pathology
    • Glycogen: Reduced in muscle fibers in 1 patient
    • Type I predominance
    • Atrophy
    • SDH stain: Increased around rim of fibers
    • Glycogenin-1: Unglucosylated; Reduced in amount
    • Polyglucosan bodies: Central in fibers
    • Inclusions: Desmin; p62; Ubiquitin
    • No necrosis
    • Ultrastructure: Storage material, subsarcolemmal & central
  • Cardiac pathology: Cardiomyocytes
    • Hypertrophic
    • Enlarged nuclei
    • Vacuoles: Large, Central, Contain PAS-positive material (Polyglucosan bodies)

Glucose-6-phosphate dehydrogenase (G6PD) Deficiency ³⁸

• Epidemiology
  • Frequency: 400 million people worldwide
  • Highest prevalence: Africa
  • Most common genetic cause of chronic & drug-, food-, or infection-induced hemolytic anemia
• Genetics
  • Mutations: 300 described
  • Often missense
  • Mild mutations: Amino terminal
  • Severe mutations: Carboxy end; Between amino acids 362 & 446
  • G6PD: Hemizygosity & Heterozygosity confers resistance against malaria
• G6PD protein
  • Production of ribose 5-phosphate
  • Generation of NADPH in hexose monophosphate pathway
  • Only NADPH-generation process in mature red cells
  • Antioxidant
  • Present in many tissues including RBCs & muscle
• Clinical
  • Neonatal: Jaundice
  • Hemolytic anemia, acute
    • Common precipitants
      • Drugs: Primaquine; Vitamin K
      • Fava beans (Contain vicine & convicine)
      • Infection
  • Muscle: Reports of myalgia, cramps, rhabdomyolysis
• Laboratory
  • Anemia

• Indiana State