Excerpt from Kearns-Sayre Syndrome

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Background

Kearns-Sayre syndrome is characterized by a triad of features including (1) onset in persons younger than 20 years; (2) chronic, progressive, external ophthalmoplegia; and (3) pigmentary degeneration of the retina. In addition, Kearns-Sayre syndrome may include cardiac conduction defects, cerebellar ataxia, and raised cerebrospinal fluid (CSF) protein levels (>100 mg/dL).

Additional features associated with Kearns-Sayre syndrome may include myopathy, dystonia, endocrine abnormalities (eg, diabetes, growth retardation/short stature, hypoparathyroidism), bilateral sensorineural deafness, dementia, cataracts, and proximal renal tubular acidosis. Thus, Kearns-Sayre syndrome may affect many organ systems.

Pathophysiology

Kearns-Sayre syndrome occurs secondary to deletions in mitochondrial DNA (mtDNA) that cause a particular phenotype. The gene in which deletions occur is identified as Online Mendelian Inheritance in Man number 530000. An understanding of some aspects of mitochondrial genetics is important to understanding Kearns-Sayre syndrome.

mtDNA differs from nuclear DNA in several ways. The 16.5-kilobase (kb) mitochondrial genome is circular. The genome contains 13 structural genes that encode peptides, all of which are components of respiratory chain complexes, and contains genes that encode transfer RNA and mitochondrial ribosomal RNA. Inherited abnormalities of mtDNA demonstrate maternal inheritance because, during formation of the zygote, all mitochondria come from the ovum. In addition, each cell contains hundreds of mitochondria.

In certain diseases, including Kearns-Sayre syndrome, mtDNA displays heteroplasmy, a mixture of wild-type and mutant mtDNA within a single cell. The ratio of mutant DNA to wild-type DNA is important in determining the phenotype in a mitochondrial disorder. mtDNA continues to replicate, even in a nondividing cell, which may cause the mutated form to accumulate in nondividing tissues. As a result of common involvement in mitochondrial disorders, the relative replication rates of mutant and nonmutant mtDNA may also be an important factor in the pathogenesis of mitochondrial disorders. Mutant DNA appears to accumulate primarily in nondividing tissues. Not all genes needed for mitochondrial function are found within mtDNA; some are contained within nuclear DNA.

Because mitochondrial disorders affect respiratory chain function, the disorders may be expected to have the greatest effect on cells or organ systems with the highest energy requirements (eg, brain, skeletal and cardiac muscle, sensory organs, kidneys).

In patients with Kearns-Sayre syndrome, mtDNA deletions occur, most of which are sporadic and are believed to occur as germ-cell mutations or very early in new embryo development. Deletions vary in size (1.3-8 kb) and position within the mitochondrial genome; however, the single most common site is between positions 8469 and 13147 (deletion hotspot) on the gene. This 4.9-kb mutation accounts for one third of cases of Kearns-Sayre syndrome. Deletions are found in all tissues, and, occasionally, tandem duplications of DNA occur rather than deletions. Duplications may lead to disease via the formation of deletions. Although deletion size varies, the deletions produce a similar phenotype.

How can a heterogeneous group of mitochondrial deletions lead to a similar phenotype? The proposed mechanism is based on the knowledge that transcription of mtDNA is polycistronic, which means that all genes encoded on the heavy and light strands are transcribed as 2 large precursor RNA strands. These subsequently cleave into separate RNA strands, including transfer RNA strands. A deletion anywhere in the mitochondrial genome may affect transcription or translation of genes that were not affected by the deletion.

An identical deletion has been identified in patients with 2 other conditions: Pearson syndrome, which is composed of sideroblastic anemia of childhood, pancytopenia, and exocrine pancreatic failure, and chronic progressive external ophthalmoplegia (CPEO), which is composed of external ophthalmoplegia, bilateral aponeurogenic ptosis, and a mild proximal myopathy. Mitochondrial deletions in CPEO tend to be localized in muscle tissue.

Neither size nor location of the deletion alone determines clinical phenotype. Instead, the phenotype appears to be determined by the relative amounts of deleted and wild-type mtDNA. Very high levels of deleted mtDNA in all tissues are likely to cause Pearson syndrome, in which the dominant feature is pancytopenia. Lower levels of deleted mtDNA cause Kearns-Sayre syndrome. In CPEO, deleted mtDNA may be detected only in muscle tissue. Exceptions are recognized, and survivors of the pancytopenic crisis of Pearson syndrome can also develop Kearns-Sayre syndrome.

Differences in mutant DNA content occur in different tissues and organs. In addition to mutated (ie, deleted) mtDNA accumulating in postmitotic tissues, vegetative segregation (ie, segregation of the mtDNA of the parent [dividing] cell between its 2 offspring cells) may also occur, and this segregation may be unequal.

Tanji et al suggested that a disconnection of Purkinje cells at the dentate nucleus may play a role in the pathogenesis of cerebellar ataxia in patients with Kearns-Sayre syndrome;¹ however, the study investigated only 2 patients with Kearns-Sayre syndrome.

Harvey and Barnett hypothesized that the spongiform changes (seen frequently throughout the brain) may be responsible for short stature.² Dynamic endocrine testing indicates that the pituitary glands of patients with Kearns-Sayre syndrome are responsive to gonadotropin-releasing hormone (GnRH); hence, the defect in the pituitary-gonadal axis occurs at the hypothalamic level.

Frequency

International

Kearns-Sayre syndrome is a rare disorder. Marked heterogeneity and various types of inheritance have been observed. By 1992, authors had described 226 cases.

Mortality/Morbidity

Although Kearns-Sayre syndrome probably reduces life expectancy, no numerical data are available. Morbidity depends on severity and the number of systems or organs involved, which widely varies from patient to patient. Heart block is a significant and preventable cause of mortality.

Race

Kearns-Sayre syndrome has no known racial predilection.

Sex

Kearns-Sayre syndrome has no known sex predilection.

Age

Part of the characterization of Kearns-Sayre syndrome is onset in individuals younger than 20 years.

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