cellular energy deficit manifests most readily in tissues that rely heavily upon aerobic metabolism such as the brain, skeletal and cardiac muscles, sensory organs, and kidneys. This is one factor involved in the presentation of mitochondrial diseases. There are other factors involved in the manifestation of a mitochondrial disease besides the size and location of a mutation. Mitochondria replicate during each cell division during gestation and throughout life. Because the mutation in mitochondrial disease most often occurs early in gestation in these diseases, only those mitochondria in the mutated lineage are defective. This results in an uneven distribution of dysfunctional mitochondria within each cell, and among different tissues of the body. This describes the term heteroplasmic which is characteristic of mitochondrial diseases including KSS. The distribution of mutated mtDNA in each cell, tissue, and organ, is dependent on when and where the mutation occurs. This may explain why two patients with an identical mutation in mtDNA can present with entirely different phenotypes and in turn different syndromes. A publication in 1992 by Fischel-Ghodsian et al. identified the same 4,977-bp deletion in mtDNA in two patients presenting with two entirely different diseases. One of the patients had characteristic KSS, while the other patient had a very different disease known as Pearson marrow pancreas syndrome. Complicating the matter, in some cases Pearson's syndrome has been shown to progress into KSS later in life. More recent studies have concluded that mtDNA duplications may also play a significant role in determining what phenotype is present. Duplications of mtDNA seem to be characteristic of all cases of KSS and Pearson's syndrome, while they are absent in CPEO. Deletions of mtDNA in KSS vary in size (1.3–8kb), as well as position in the mitochondrial genome. The most common deletion is 4.9kb and spans from position 8469 to position 13147 on the genome. This deletion is present in approximately ⅓ of people with KSS Diagnosis A neuro-ophthalmologist is usually involved in the diagnosis and management of KSS. An individual should be suspected of having KSS based upon clinical exam findings. Suspicion for myopathies should be increased in patients whose ophthalmoplegia does not match a particular set of cranial nerve palsies (oculomotor nerve palsy, fourth nerve palsy, sixth nerve palsy). Initially, imaging studies are often performed to rule out more common pathologies. Diagnosis may be confirmed with muscle biopsy, and may be supplemented with PCR determination of mtDNA