Aches, cramps, pain during or immediately after exercise Þ Phosphorylase, PFK, CPT defic.
Poor tolerance to intense exercise Þ Phosphorylase, PFK
Poor tolerance after prolonged exercise Þ CPT deficiency
Early weakness of respiratory muscles and ventilatory insufficiency Þ Acid Maltase deficiency (Pompe’s Disease)
Why?
Glycogenolysis defects – during brief intense exercise glycogen is main source of energy. Diseases block glycogen Þ glucose.
Pompe’s Disease – inborn lysosomal enzyme defect. Though purpose of this pathway is unknown, a defic causes accumulation of glycogen in vacuoles in cytosol.
Lipid Metabolism defects – during prolonged exercise of moderate intensity free FAs become most important source of energy. Without carnitine to transport FAs into the mitochondria, FA oxidation does not occur.
Laboratory Clues:
Fasting Hypoglycemia in kids Þ Debrancher, Carnitine
is variably increased in most metabolic myopathies.
Ischemic Forearm Exercise Test
– patient squeezes fist rhythmically and vigorously for one minute while wearing a BP cuff to stop blood flow. Cuff is then released and venous blood is drawn after 1, 3, 6, and 10 minutes. An increase in lactic acid and ammonia should be seen. Test should be positive (i.e. flat venous lactate response) in glycogenolysis or glycolysis (phosphorylase defic, debrancher defic, PFK defic).
Mitochondrial Myopathies
Mitochondrial myopathies are caused by defects in the mitochondrial genes (not nuclear genes coding for mitochondrial proteins).
Why are mitochondrial genes so susceptible?
Mitochondrial DNA is almost all introns. Therefore, any mutation will be expressed.
Mitochondrial repair machinery is not efficient; also lacks protective histones.
Mitochondria is an oxidative environment. Free radicals
Þ mtDNA damage.
mtDNA does not recombine
Þ mutations accumulate sequentially through maternal lineages.
Maternal inheritance
– mitochondria are derived from the oocyte.
Polyplasmy
– there are multiple mitochondria in each cell, each contains multiple genomes. This as opposed to cells that contain only one genome.
Heteroplasmy
– in normal tissues, all mtDNA molecules are identical (homoplasmy). A mutation in mtDNA can lead to coexistence of two populations of mtDNA in the same tissue. This is called heteroplasmy. Most pathogenic mutations are heteroplasmic.
Threshold effect
– Number of mutant mtDNA needed to cause cell dysfunction. Depends on specific tissue demands