Alternative titles; symbols
SNOMEDCT: 240096000, 25792000, 77835008; ICD10CM: H49.81; ORPHA: 480; DO: 12934;
A number sign (#) is used with this entry because Kearns-Sayre syndrome is caused by various mitochondrial deletions.
Kearns (1965) reported 9 unrelated patients with ophthalmoplegia, pigmentary degeneration of the retina, and cardiomyopathy as leading features. Less consistent features were weakness of facial, pharyngeal, trunk and extremity muscles, deafness, small stature, electroencephalographic changes, and markedly increased cerebrospinal fluid protein. In none of the 9 was a positive family history present. Shy et al. (1967) described a 21-year-old black woman with progressive ptosis, external ophthalmoplegia, retinitis pigmentosa, ataxia, absent deep tendon reflexes, elevated cerebrospinal fluid protein, and histologic features compatible with either Hurler syndrome (MPS I; see 607014) or Refsum disease (266500). Neither phytanic acid nor mucopolysaccharide was found in excess in the tissues, however. Hurwitz et al. (1969) described affected brother and sister. They and both parents had amino aciduria which was of uncertain relationship to the myopathy. Clinically the myopathy most resembled that described by Batten and Turner (see congenital myopathy; 255300). Ophthalmoplegia and floppiness also occur with myotubular myopathy (see centronuclear myopathy; 255200), but this entity was excluded by the muscle biopsy in the cases of Hurwitz et al. (1969). Ross et al. (1969) described the association of chronic progressive external ophthalmoplegia and complete heart block, and noted 4 earlier reports of the same. Rosenberg et al. (1968) reviewed syndromes involving ophthalmoplegia.
Iannaccone et al. (1974) observed progressive ophthalmoplegia in females in 4 successive generations and demonstrated ragged-red fibers in skeletal muscle from the extremities. Electron microscopy showed subsarcolemmal clusters of mitochondria containing paracrystalline inclusions. Nonfamilial cases were reported by Olson et al. (1972) and others. The great difficulty in classification of cases of external ophthalmoplegia was noted by many authors. Butler and Gadoth (1976) reported a 17-year-old man and found reports of 19 cases in the literature, all of which were sporadic. Berenberg et al. (1977) reviewed 5 new cases and 30 others from the literature. They suggested that a 'persistent viral infection' may be causal. Drachman (1975) gave a classification of disorders associated with progressive external ophthalmoplegia, which he termed 'ophthalmoplegia plus' (Drachman, 1968). Bastiaensen et al. (1978) described 4 patients who had chronic progressive external ophthalmoplegia with retinal, neurologic, endocrine, and auditory anomalies. Three had signs of cardiomyopathy, with abnormalities confirmed by histologic study of a cardiac biopsy in one. Biochemical studies showed disturbances in pyruvate and lactate metabolism and in respiratory control. Biopsy of skeletal muscle in all 4 showed aggregates of abnormal mitochondria. The pedigrees of 2 families with many affected members in an autosomal dominant pattern, including several instances of male-to-male transmission, were diagrammed. Bertorini et al. (1978) referred to this condition as 'childhood oculocraniosomatic neuromuscular disease with ragged-red fibers.' Mitochondrial abnormalities were present. In some cases Bertorini et al. (1978) demonstrated the presence of a major, diffuse leukoencephalopathy by means of computerized axial tomography. Robertson et al. (1979) reported an 8-year-old girl who had electron-microscopically abnormal mitochondria in skeletal muscle and, by computerized axial tomography, cerebellar and brainstem atrophy and calcification in the region of the basal ganglia. With the possibility of mitochondrial inheritance in mind, Egger and Wilson (1983) studied the pedigrees of 6 affected families whose members they had examined personally and of 24 families described in the literature. In 27 families maternal transmission occurred exclusively; in 3 there was also paternal transmission in 1 generation. Altogether, 51 mothers and only 3 fathers had transmitted the condition, which the authors referred to as mitochondrial cytopathy. They concluded that mitochondrial inheritance is very likely.
Fine (1978) outlined the characteristics expected of mitochondrial inheritance, based on the fact that the mitochondria are probably derived exclusively from the mother. The complete nucleotide sequence of the mitochondrial chromosome, which might be called man's 25th chromosome or chromosome M, has been determined (Anderson et al., 1981)--all 16,569 basepairs. Lestienne and Ponsot (1988) described a 5-kb deletion in the mitochondrial DNA from muscle of a patient with Kearns-Sayre syndrome. The deletion was observed only in muscle mitochondria and not in DNA from lymphocytes or fibroblasts. The deletion was mapped to the region including the sequence for 4 subunits of complex I, 2 subunits of complex IV and V, and 5-to-8 tRNA genes. Holt et al. (1988) analyzed 25 patients with mitochondrial myopathy associated with various neurologic symptoms, some of which included the ophthalmoplegia and ptosis characteristic of Kearns-Sayre syndrome. Nine cases were found to harbor heteroplasmic deletions OH and OL. Moraes et al. (1989) surveyed mitochondrial encephalomyopathy patients for mitochondrial DNA deletions. Deletions were found in 78% of Kearns-Sayre patients, 56% of chronic progressive external ophthalmoplegia-plus patients, but none of the patients with MERRF (545000), MELAS (540000), Leigh syndrome, or infantile mitochondrial myopathy (551000). Egger and Wilson (1983) referred to homochondrial and heterochondrial persons; homoplasmic and heteroplasmic were later preferred terms. Ogasahara et al. (1985) described a KSS patient with reduced levels of coenzyme Q(10) in serum and in the mitochondrial fraction of skeletal muscle. The patient had been well until age 12 when progressive ophthalmoparesis and ptosis were first observed. Bilateral atypical degeneration of the retina and hearing loss were noted at age 18. After administration of coenzyme Q(10), 60-120 mg daily for 3 months, serum levels of lactate and pyruvate became normal, with improvement of a previously existing first-degree atrioventricular block and improvement in ocular movements. Bernal et al. (1986) found clear autosomal recessive inheritance of the Kearns-Sayre syndrome in an inbred kindred in Colombia. Whitaker et al. (1987) restudied the pituitary from one of the cases of Kearns and Sayre (1958) and labeled the patient's disorder as Laurence-Moon syndrome. Jankowicz et al. (1977) reported a father and son with pigmentary retinopathy, chronic progressive external ophthalmoplegia (CPEO), myopathy, and ataxia, associated with a cardiac conduction defect in the son, who had mitochondrial abnormalities on muscle biopsy. A similar but variable spectrum of clinical features was observed by Leveille and Newell (1980) in a pedigree that appeared to support autosomal dominant inheritance. In this family, 1 male with CPEO and limb weakness had a daughter with CPEO, retinopathy, cardiac arrhythmias, and proximal myopathy. The father had ragged-red fibers on muscle biopsy but his daughter did not. Scorza Smeraldi et al. (1983) presented a family with 5 affected in 3 generations and transmission only by females. Close linkage to HLA was excluded.
Moraes et al. (1989) found deletions in muscle mitochondrial DNA of 32 of 123 patients with various mitochondrial myopathies or encephalopathies. All patients had progressive external ophthalmoplegia. Some patients had only ocular myopathy, whereas others had Kearns-Sayre syndrome. Deletions ranged in size from 1.3 to 7.6 kb, but in 11 patients, an identical 4.9-kb deletion was found in the same location. Zeviani et al. (1988) found large-scale deletions in muscle mitochondrial DNA in all 7 patients with KSS studied. Deletions ranged in size from 2.0 to 7.0 kb and did not localize to any single region of the mitochondrial genome. The proportion of mutated chromosomes in each KSS patient ranged from 45 to 75% of total mtDNA. Channer et al. (1988) reported a 21-year-old man in whom the Kearns-Sayre syndrome was associated with rapid development of progressive congestive cardiac failure requiring cardiac transplantation. Rowland et al. (1988) described concordantly affected monozygotic twins with KSS. Johns et al. (1989) found that in each of 4 patients with chronic progressive external ophthalmoplegia and a large deletion of mitochondrial DNA, the deletion breakpoint occurred within a directly repeated sequence of 13-18 basepairs, present in different regions of the normal mitochondrial genome. In 2 of the patients the deletions were identical. Partially deleted and normal mitochondrial DNAs were found in all tissues examined, but in very different proportions, indicating that these mutations originated before the primary cell layers diverged. Comparison of the repeated sequences showed a consensus of 11 nucleotides, suggesting involvement of a recombinational event in the development of the deletions.
Rivner et al. (1989) reported a 25-year-old woman with Kearns-Sayre syndrome and isolated complex II deficiency (see 252011). She had short stature, complete external ophthalmoplegia, pigmentary retinopathy, ataxia, and cardiac conduction defects. Muscle biopsy showed ragged-red fibers and increased number of mitochondria with abnormal structure and paracrystalline inclusions.
Larsson et al. (1990) found heteroplasmy for mtDNA deletions in muscle of 3 patients with KSS. The deletions were mapped to the same region of mtDNA but were of different sizes. Two of the 3 deletions may have included nucleotide 8993 which has been demonstrated to be the site of mutation in NARP syndrome (551500; 516060.0001). The same type of deletion could also be detected in fibroblasts in all 3 cases, but the percentage was considerably lower. In 2 cases, the fraction of mtDNA increased with time in muscle and this increase paralleled the progression of the disease. One case spontaneously recovered from an infantile sideroblastic anemia before the development of KSS. The anemia was of the type seen in Pearson marrow-pancreas syndrome (557000). There have been rather numerous examples of children surviving the pancytopenic crisis of Pearson syndrome and subsequently developing progressive symptoms of KSS (Norby et al., 1994).
Poulton et al. (1991) described a patient with Kearns-Sayre syndrome and 2 asymptomatic relatives, the mother and a maternal aunt, all of whom were found to carry the same mtDNA mutation. This was the first report of deletion of mtDNA in the germline. Larsson et al. (1992) described a woman with Kearns-Sayre syndrome and a high percentage of deleted mtDNA in muscle. Although the mtDNA deletion was detected in fibroblasts, bone marrow, and peripheral blood cells by Southern blot analysis, it was detected in all tissues examined when polymerase chain reaction (PCR) was used. The patient had healthy parents and 9 healthy sibs. No deleted mtDNA was detected in the blood of the patient's mother. The patient delivered a healthy daughter in whom no mtDNA deletion was detected by PCR. The presence of deleted mtDNA was excluded at a fractional level of less than 1:100,000 in all examined tissues.
Fischel-Ghodsian et al. (1992) pointed out that the same 4,977-bp deletion has been identified in patients with 2 very different diseases: KSS and Pearson marrow-pancreas syndrome. Thus it is not possible to predict the clinical phenotype from the size or location of the deletion; instead, differential tissue distribution of the deletion is probably a critical determinant of phenotype. For example, in KSS the deletion has not been detected by Southern blotting in blood, whereas in Pearson syndrome it is easily detectable. However, Fischel-Ghodsian et al. (1992) described an 11-year-old boy with clinically characteristic KSS and a 7.4-kb mitochondrial DNA deletion between nucleotides 7194 and 14595. Southern blotting demonstrated that 75% of the mitochondrial DNA molecules from peripheral blood had the deletion. Thus, the molecular distinction between KSS and Pearson syndrome was blurred and it was necessary to question whether tissue distribution is a sufficient explanation for the difference in phenotype.
In a case of Kearns-Sayre syndrome, Remes et al. (1993) found a deletion in the mitochondrial chromosome comprising 3,236 bp starting from nucleotide 10170. The deletion was bracketed by direct repeats that were unusual in that one of them was located 11-13 nucleotides from the deletion site and both were conserved, which should not occur in slip replication or illegitimate elongation. The deleted region was demarcated on the deletion side by sequences that could be predicted to form hairpin structures. The arrangement around the deletion bore some resemblance to that described by Rotig et al. (1991) in association with Pearson marrow-pancreas syndrome.
Identical deletions have been reported in KSS, Pearson syndrome, and CPEO. The tissue distribution of mutant mtDNA is, however, different. In Pearson syndrome, high levels of mutant mtDNA are present in all tissues, particularly blood. In KSS, they are more localized to muscle and the central nervous system. In CPEO, the mutant mtDNA is probably still more localized. It is not known what determines the subsequent clinical course: Pearson syndrome may evolve into KSS and this seems to be associated with a change in the distribution of abnormal mtDNA, which decreases in blood and accumulates in muscle. Poulton et al. (1994) suggested that the mitochondrial chromosome rearrangements that have previously been thought to represent simple deletions have, in fact, a more complex genetic abnormality and that the failure to recognize the complexity results from the use of inappropriate restriction enzymes to linearize mtDNA. The finding of families of rearranged mtDNA molecules in 3 patients with KSS prompted Poulton et al. (1994) to investigate a further 18 patients with KSS/CPEO who had previously documented mtDNA deletions, 1 of whom had a history of Pearson syndrome. They detected mtDNA duplication in 10 of 10 patients with KSS, while deletion monomers were the only recombinant mtDNA easily detectable in 8 of 8 patients with CPEO. Deletion dimers were found only in cases having duplications. Thus, duplications of mtDNA seem to be a hallmark of KSS, including the patient where Pearson syndrome was the first manifestation. Poulton et al. (1994) suggested that duplication of mtDNA is characteristic of early-onset KSS and that the balance of mtDNA rearrangements may be central to the pathogenesis of this unique group of disorders.
Replicative segregation of mtDNA can produce large differences in the proportions of wildtype and mutant mtDNAs in different cell types of patients with mitochondrial encephalomyopathy. Shoubridge et al. (1997) noted that these differences are particularly striking in the skeletal muscle of patients with KSS, a sporadic disease associated with large-scale mtDNA deletions, and in sporadic patients with tRNA point mutations. Although the skeletal muscle fibers of these patients invariably contain a large proportion of mutant mtDNAs, mutant mtDNAs are rare or undetectable in satellite cells cultured from the same muscle biopsy specimens. Since satellite cells are responsible for muscle fiber regeneration, restoration of the wildtype mtDNA genotype might be achieved in these patients by encouraging muscle regeneration. To test this concept, Shoubridge et al. (1997) rebiopsied a patient with the KSS phenotype and an mtDNA point mutation in the MTTL2 gene (590055.0001) and analyzed muscle fibers regenerating at the site of the original muscle biopsy. Regenerating fibers were identified by morphologic criteria and by expression of neural cell adhesion molecule (116930). All such fibers were positive for cytochrome c oxidase (COX) activity by cytochemistry and essentially homoplasmic for wildtype mtDNA, while the majority of non-regenerating fibers were COX-negative and contained predominantly mutant mtDNAs. These results demonstrated that it may be possible to improve muscle function in similar patients by methods that promote satellite cell incorporation into existing myofibers.
In postmortem examination of 2 patients with KSS, Tanji et al. (1999) found a moderate loss of Purkinje cells and spongiform degeneration of the cerebellar white matter. The dentate nuclei showed spongiform degeneration and capillary proliferation, but no significant loss of neurons. Immunostaining of neurons in the dentate nuclei showed a marked reduction of mitochondrial-encoded proteins. Tanji et al. (1999) concluded that the findings likely underlie the cerebellar dysfunction in KSS.
Wang et al. (1999) reproduced the biochemical, morphologic, and physiologic features of the dilated cardiomyopathy of Kearns-Sayre syndrome in the mouse by heart-specific inactivation of mitochondrial DNA gene expression through disruption of the gene encoding mitochondrial transcription factor A (TFAM; 600438).
Lertrit et al. (1999) found a 3.5-kb deletion of mtDNA by Southern blot analysis. The deleted position was localized to nucleotides 10208-13765 or nucleotides 10204-13761, spanning the coding area of subunits 3 (ND3; 516002), 4L (ND4L; 516004), 4 (ND4; 516003), and 5 (ND5; 516005). Of the respiratory chain enzyme complex I, as well as the tRNA genes for histidine, serine, leucine, and arginine. The sequence flanking the deletion was a 4-bp repeat of TCCC. All 4 patients, who were not known to be related, had exactly the same 3,558-bp mtDNA deletion. Although they had the same deletion, clinical features were different: 2 had experienced onset during childhood, whereas the other 2 came to the hospital at ages greater than 30 years. The clinical symptoms that presented since childhood, such as hypotonia, epilepsy, and ataxia, involved the neuromuscular system. Both adult patients presented with chronic progressive external ophthalmoplegia, ptosis in both eyes, and pigmentary retinopathy. All 4 patients were heteroplasmic for the deletion. As with several other reported deletions, the defect in this case preserved the promoters of transcription of heavy and light strands, the 12-S and 16-S ribosomal RNA genes, and the origin of heavy strand replication. Thus, the affected mtDNA must be competent for replication to account for the high proportion of genomes with deletions. The deletion was found in heteroplasmic form in muscle samples from the 4 patients but not in their leukocytes. Two patients had KSS and ragged-red fibers on muscle biopsy.
Lertrit et al. (1999) reported that the 3.5-kb deletion appears to be unique to Thai patients and that the common 4977-bp deletion (nucleotides 8470-13446) found elsewhere in Asia, in Japanese (Goto et al., 1990; Anan et al., 1995), Taiwanese (Lee et al., 1994), and Chinese, had not been found in Thai patients.
Although endocrinopathies (e.g., growth hormone deficiency, hypogonadism, diabetes mellitus, and hypoparathyroidism) are common in KSS, Boles et al. (1998) appeared to have provided the first report of nonautoimmune Addison disease in KSS. The patient had a 4.9-kb deletion extending from approximately 2 o'clock in the ND5 gene to 6 o'clock in the ATP8 gene (516070).
Barshop et al. (2000) reported a patient who presented with 2-oxoadipic aciduria and 2-aminoadipic aciduria (204750) at 2 years of age with manifestations typical of organic acidemia, episodes of ketosis and acidosis, progressive to coma. This resolved and the key metabolites disappeared from the urine and blood. At 9 years of age, she developed typical Kearns-Sayre syndrome with complete heart block, retinopathy, and ophthalmoplegia. Southern blot revealed a deletion in the mitochondrial genome.
Puoti et al. (2003) reported a mother and son with KSS who both carried an identical large heteroplasmic mtDNA rearrangement detected in muscle and blood lymphocytes. The rearrangement was present in 2 forms: an mtDNA deletion in skeletal muscle, and a combination of partially deleted and partially duplicated mtDNA molecules in blood. Puoti et al. (2003) emphasized that, although rare, mother-to-offspring transmission of large mtDNA rearrangements is possible.
Pineda et al. (2006) reported a child with an incomplete form of KSS and a large mtDNA deletion. The patient had a profound decrease of cerebrospinal fluid folate levels with normal serum folate levels, suggesting a transport defect across the blood-brain barrier. Oral folinic acid treatment resulted in marked clinical improvement, particularly with regard to near normalization of white matter lesions.
Poulton et al. (1989) described a duplication of about 8 kb in the mitochondrial genome in several tissues in 2 patients with mitochondrial myopathy and multisystem involvement. Both patients were heteroplasmic.
Anan, R., Nakagawa, M., Miyata, M., Higuchi, I., Nakao, S., Suehara, M., Osame, M., Tanaka, H. Cardiac involvement in mitochondrial diseases: a study on 17 patients with documented mitochondrial DNA defects. Circulation 91: 955-961, 1995. [PubMed: 7850981] [Full Text: https://doi.org/10.1161/01.cir.91.4.955]
Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. H., Staden, R., Young, I. G. Sequence and organization of the human mitochondrial genome. Nature 290: 457-465, 1981. [PubMed: 7219534] [Full Text: https://doi.org/10.1038/290457a0]
Barshop, B. A., Nyhan, W. L., Naviaux, R. K., McGowan, K. A., Friedlander, M., Haas, R. H. Kearns-Sayre syndrome presenting as 2-oxoadipic aciduria. Molec. Genet. Metab. 69: 64-68, 2000. [PubMed: 10655159] [Full Text: https://doi.org/10.1006/mgme.1999.2946]
Bastiaensen, L. A. K., Joosten, E. M. G., de Rooij, J. A. M., Hommes, O. R., Stadhouders, A. M., Jaspar, H. H. J., Veerkamp, J. H., Bookelman, H., van Hinsbergh, V. W. M. Ophthalmoplegia-plus, a real nosological entity. Acta Neurol. Scand. 58: 9-34, 1978. [PubMed: 212920] [Full Text: https://doi.org/10.1111/j.1600-0404.1978.tb02856.x]
Berenberg, R. A., Pellock, J. M., DiMauro, S., Schotland, D. L., Bonilla, E., Eastwood, A., Hays, A., Vicale, C. T., Behrens, M., Chutorian, A., Rowland, L. P. Lumping or splitting? 'Ophthalmoplegia-plus' or Kearns-Sayre syndrome. Ann. Neurol. 1: 37-54, 1977. [PubMed: 889288] [Full Text: https://doi.org/10.1002/ana.410010104]
Bernal, J. E., Winz, O., Tamayo, M. The Kearns-Sayre syndrome in three members of a consanguineous Colombian family. (Abstract) 7th International Congress of Human Genetics, Berlin 1986. P. 280.
Bertorini, T., Engel, W. K., Di Chiro, G., Dalakas, M. Leukoencephalopathy in oculocraniosomatic neuromuscular disease with ragged-red fibers: mitochondrial abnormalities demonstrated by computerized tomography. Arch. Neurol. 35: 643-647, 1978. [PubMed: 697605] [Full Text: https://doi.org/10.1001/archneur.1978.00500340019004]
Boles, R. G., Roe, T., Senadheera, D., Mahnovski, V., Wong, L. J. C. Mitochondrial DNA deletion with Kearns Sayre syndrome in a child with Addison disease. Europ. J. Pediat. 157: 643-647, 1998. [PubMed: 9727847] [Full Text: https://doi.org/10.1007/s004310050902]
Butler, I. J., Gadoth, N. Kearns-Sayre syndrome: a review of a multisystem disorder of children and young adults. Arch. Intern. Med. 136: 1290-1293, 1976. [PubMed: 791168] [Full Text: https://doi.org/10.1001/archinte.136.11.1290]
Channer, K. S., Channer, J. L., Campbell, M. J., Rees, J. R. Cardiomyopathy in the Kearns-Sayre syndrome. Brit. Heart J. 59: 486-490, 1988. [PubMed: 3370184] [Full Text: https://doi.org/10.1136/hrt.59.4.486]
Drachman, D. A. Ophthalmoplegia-plus: the neurodegenerative disorders associated with progressive external ophthalmoplegia. Arch. Neurol. 18: 654-674, 1968. [PubMed: 5652994] [Full Text: https://doi.org/10.1001/archneur.1968.00470360076008]
Drachman, D. A. Ophthalmoplegia plus; a classification of the disorders associated with progressive external ophthalmoplegia. In: Vinken, P. J.; Bruyn, G. W. (eds.): Handbook of Clinical Neurology. Vol. 22. Part II. System Disorders and Atrophies. New York: American Elsevier Publishing Co., Inc. 1975. Pp. 203-216.
Egger, J., Wilson, J. Mitochondrial inheritance in a mitochondrially mediated disease. New Eng. J. Med. 309: 142-146, 1983. [PubMed: 6866014] [Full Text: https://doi.org/10.1056/NEJM198307213090304]
Fine, P. E. M. Mitochondrial inheritance and disease. Lancet 312: 659-662, 1978. Note: Originally Volume 2. [PubMed: 80581] [Full Text: https://doi.org/10.1016/s0140-6736(78)92764-2]
Fischel-Ghodsian, N., Bohlman, M. C., Prezant, T. R., Graham, J. M., Jr., Cederbaum, S. D., Edwards, M. J. Deletion in blood mitochondrial DNA in Kearns-Sayre syndrome. Pediat. Res. 31: 557-560, 1992. [PubMed: 1635816] [Full Text: https://doi.org/10.1203/00006450-199206000-00004]
Gonatas, N. K. A generalized disorder of nervous system, skeletal muscle and heart resembling Refsum's disease and Hurler's syndrome. II. Ultrastructure. Am. J. Med. 42: 169-178, 1967. [PubMed: 4163597] [Full Text: https://doi.org/10.1016/0002-9343(67)90016-2]
Goto, Y., Koga, Y., Horai, S., Nonaka, I. Chronic progressive external ophthalmoplegia: a correlative study of mitochondrial DNA deletions and their phenotypic expression in muscle biopsies. J. Neurol. Sci. 100: 63-69, 1990. [PubMed: 1965208] [Full Text: https://doi.org/10.1016/0022-510x(90)90014-e]
Gross, M. L. P., Teoh, R., Legg, N. J., Pallis, C. Ocular myopathy and Marfan's syndrome: a family study. J. Neurol. Sci. 46: 105-112, 1980. [PubMed: 7373340] [Full Text: https://doi.org/10.1016/0022-510x(80)90047-7]
Holt, I. J., Harding, A. E., Morgan-Hughes, J. A. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331: 717-719, 1988. [PubMed: 2830540] [Full Text: https://doi.org/10.1038/331717a0]
Hurwitz, L. J., Carson, N. A. J., Allen, I. V., Chopra, J. S. Congenital ophthalmoplegia, floppy baby syndrome, myopathy and aminoaciduria: report of a family. J. Neurol. Neurosurg. Psychiat. 32: 495-508, 1969. [PubMed: 5364721] [Full Text: https://doi.org/10.1136/jnnp.32.6.495]
Iannaccone, S. T., Griggs, R. C., Markesbery, W. R., Joynt, R. J. Familial progressive external ophthalmoplegia and ragged-red fibers. Neurology 24: 1033-1038, 1974. [PubMed: 4153849] [Full Text: https://doi.org/10.1212/wnl.24.11.1033]
Jankowicz, E., Berger, H., Kurasz, S., Winogrodzka, W., Eljasz, L. Familial progressive external ophthalmoplegia with abnormal muscle mitochondria. Europ. Neurol. 15: 318-324, 1977. [PubMed: 902666] [Full Text: https://doi.org/10.1159/000114820]
Johns, D. R., Rutledge, S. L., Stine, O. C., Hurko, O. Directly repeated sequences associated with pathogenic mitochondrial DNA deletions. Proc. Nat. Acad. Sci. 86: 8059-8062, 1989. [PubMed: 2813377] [Full Text: https://doi.org/10.1073/pnas.86.20.8059]
Kearns, T. P., Sayre, G. P. Retinitis pigmentosa, external ophthalmoplegia, and complete heart block: unusual syndrome with histologic study in one of two cases. Arch. Ophthal. 60: 280-289, 1958.
Kearns, T. P. External ophthalmoplegia, pigmentary degeneration of the retina, and cardiomyopathy: a newly recognized syndrome. Trans. Ophthal. Soc. U.K. 63: 559-625, 1965.
Larsson, N.-G., Eiken, H. G., Boman, H., Holme, E., Oldfors, A., Tulinius, M. H. Lack of transmission of deleted mtDNA from a woman with Kearns-Sayre syndrome to her child. Am. J. Hum. Genet. 50: 360-363, 1992. [PubMed: 1734716]
Larsson, N.-G., Holme, E., Kristiansson, B., Oldfors, A., Tulinius, M. Progressive increase of the mutated mitochondrial DNA fraction in Kearns-Sayre syndrome. Pediat. Res. 28: 131-136, 1990. [PubMed: 2395603] [Full Text: https://doi.org/10.1203/00006450-199008000-00011]
Lee, H. C., Pang, C. Y., Hsu, H. S., Wei, Y. H. Differential accumulations of 4,977 bp deletion in mitochondrial DNA of various tissues in human ageing. Biochim. Biophys. Acta 1226: 37-43, 1994. [PubMed: 8155737] [Full Text: https://doi.org/10.1016/0925-4439(94)90056-6]
Lertrit, P., Imsumran, A., Karnkirawattana, P., Devahasdin, V., Sangruchi, T., Atchaneeyasakul, L., Mungkornkarn, C., Neungton, N. A unique 3.5-kb deletion of the mitochondrial genome in Thai patients with Kearns-Sayre syndrome. Hum. Genet. 105: 127-131, 1999. [PubMed: 10480366] [Full Text: https://doi.org/10.1007/s004399900062]
Lestienne, P., Ponsot, G. Kearns-Sayre syndrome with muscle mitochondrial DNA deletion. (Letter) Lancet 331: 885 only, 1988. Note: Originally Volume I. [PubMed: 2895391] [Full Text: https://doi.org/10.1016/s0140-6736(88)91632-7]
Leveille, A. S., Newell, F. W. Autosomal dominant Kearns-Sayre syndrome. Ophthalmology 87: 99-108, 1980. [PubMed: 7383548] [Full Text: https://doi.org/10.1016/s0161-6420(80)35262-7]
Moraes, C. T., DiMauro, S., Zeviani, M., Lombes, A., Shanske, S., Miranda, A. F., Nakase, H., Bonilla, E., Werneck, L. C., Servidei, S., Nonaka, I., Koga, Y., Spiro, A. J., Brownell, A. K. W., Schmidt, B., Schotland, D. L., Zupanc, M., DeVivo, D. C., Schon, E. A., Rowland, L. P. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. New Eng. J. Med. 320: 1293-1299, 1989. [PubMed: 2541333] [Full Text: https://doi.org/10.1056/NEJM198905183202001]
Norby, S., Lestienne, P., Nelson, I., Nielsen, I.-M., Schmalbruch, H., Sjo, O., Warburg, M. Juvenile Kearns-Sayre syndrome initially misdiagnosed as a psychosomatic disorder. J. Med. Genet. 31: 45-50, 1994. [PubMed: 8151637] [Full Text: https://doi.org/10.1136/jmg.31.1.45]
Ogasahara, S., Yorifuji, S., Nishikawa, Y., Takahashi, M., Wada, K., Hazama, T., Nakamura, Y., Hashimoto, S., Kono, N., Tarui, S. Improvement of abnormal pyruvate metabolism and cardiac conduction defect with coenzyme Q(10) in Kearns-Sayre syndrome. Neurology 35: 372-377, 1985. [PubMed: 3974895] [Full Text: https://doi.org/10.1212/wnl.35.3.372]
Olson, W., Engel, W. K., Walsh, G. O., Einaugler, R. Oculocraniosomatic neuromuscular disease with 'ragged-red' fibers: histochemical and ultrastructural changes in limb muscles of a group of patients with idiopathic progressive external ophthalmoplegia. Arch. Neurol. 26: 193-211, 1972. [PubMed: 4400816] [Full Text: https://doi.org/10.1001/archneur.1972.00490090019001]
Piccolo, G., Cosi, V., Scelsi, R., Marchetti, C. A case of progressive external ophthalmoplegia (Kiloh-Nevin type) with abnormal mitochondria: clinical, histochemical and ultrastructural findings. Europ. Neurol. 15: 325-332, 1977. [PubMed: 902667] [Full Text: https://doi.org/10.1159/000114821]
Pineda, M., Ormazabal, A., Lopez-Gallardo, E., Nascimento, A., Solano, A., Herrero, M. D., Vilaseca, M. A., Briones, P., Ibanez, L., Montoya, J., Artuch, R. Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion. Ann. Neurol. 59: 394-398, 2006. [PubMed: 16365882] [Full Text: https://doi.org/10.1002/ana.20746]
Poulton, J., Deadman, M. E., Gardiner, R. M. Duplications of mitochondrial DNA in mitochondrial myopathy. Lancet 333: 236-240, 1989. Note: Originally Volume I. [PubMed: 2563411] [Full Text: https://doi.org/10.1016/s0140-6736(89)91256-7]
Poulton, J., Deadman, M. E., Ramacharan, S., Gardiner, R. M. Germ-line deletions of mtDNA in mitochondrial myopathy. Am. J. Hum. Genet. 48: 649-653, 1991. [PubMed: 2014792]
Poulton, J., Morten, K. J., Weber, K., Brown, G. K., Bindoff, L. Are duplications of mitochondrial DNA characteristic of Kearns-Sayre syndrome? Hum. Molec. Genet. 3: 947-951, 1994. [PubMed: 7951243] [Full Text: https://doi.org/10.1093/hmg/3.6.947]
Puoti, G., Carrara, F., Sampaolo, S., De Caro, M., Vincitorio, C. M., Invernizzi, F., Zeviani, M. Identical large scale rearrangement of mitochondrial DNA causes Kearns-Sayre syndrome in a mother and her son. J. Med. Genet. 40: 858-863, 2003. [PubMed: 14627683] [Full Text: https://doi.org/10.1136/jmg.40.11.858]
Remes, A. M., Peuhkurinen, K. J., Herva, R., Majamaa, K., Hassinen, I. E. Kearns-Sayre syndrome case presenting a mitochondrial DNA deletion with unusual direct repeats and a rudimentary RNAase mitochondrial ribonucleotide processing target sequence. Genomics 16: 256-258, 1993. [PubMed: 7683627] [Full Text: https://doi.org/10.1006/geno.1993.1170]
Rivner, M. D., Shamsnia, M., Swift, T. R., Trefz, J., Roesel, R. A., Carter, A. L., Yanamura, W., Hommes, F. A. Kearns-Sayre syndrome and complex II deficiency. Neurology 39: 693-696, 1989. [PubMed: 2710360] [Full Text: https://doi.org/10.1212/wnl.39.5.693]
Robertson, W. C., Jr., Viseskul, C., Lee, Y. E., Lloyd, R. V. Basal ganglia calcification in Kearns-Sayre syndrome. Arch. Neurol. 36: 711-713, 1979. [PubMed: 508131] [Full Text: https://doi.org/10.1001/archneur.1979.00500470081017]
Rosenberg, R. N., Schotland, D. L., Lovelace, R. E., Rowland, L. P. Progressive ophthalmoplegia: report of cases. Arch. Neurol. 19: 362-376, 1968. [PubMed: 4175668] [Full Text: https://doi.org/10.1001/archneur.1968.00480040028002]
Ross, A., Lipschutz, D., Austin, J., Smith, J., Jr. External ophthalmoplegia and complete heart block. New Eng. J. Med. 280: 313-315, 1969. [PubMed: 5762373] [Full Text: https://doi.org/10.1056/NEJM196902062800607]
Rotig, A., Cormier, V., Koll, F., Mize, C. E., Saudubray, J.-M., Veerman, A., Pearson, H. A., Munnich, A. Site-specific deletions of the mitochondrial genome in the Pearson marrow-pancreas syndrome. Genomics 10: 502-504, 1991. [PubMed: 1712754] [Full Text: https://doi.org/10.1016/0888-7543(91)90342-c]
Rowland, L. P., Hausmanowa-Petrusewicz, I., Bardurska, B., Warburton, D., Nibroj-Dobosz, I., DiMauro, S., Pallai, M., Johnson, W. G. Kearns-Sayre syndrome in twins: lethal dominant mutation or acquired disease? Neurology 38: 1399-1402, 1988. [PubMed: 3412586] [Full Text: https://doi.org/10.1212/wnl.38.9.1399]
Schnitzler, E. R., Robertson, W. C. Familial Kearns-Sayre syndrome. Neurology 29: 1172-1174, 1979. [PubMed: 572507] [Full Text: https://doi.org/10.1212/wnl.29.8.1172]
Scorza Smeraldi, R., Fabio, G., Vanoli, M., Bonara, P., Moggio, M., Pellegrini, G., Scarlato, G. Discordant HLA haplotype segregation in a family with progressive extrinsic ophthalmoplegia and ragged red fibres. (Letter) J. Neurol. Neurosurg. Psychiat. 46: 787-788, 1983. [PubMed: 6886725] [Full Text: https://doi.org/10.1136/jnnp.46.8.787]
Seigel, R. S., Seeger, J. F., Gabrielsen, T. O., Allen, R. J. Computer tomography in oculocraniosomatic disease (Kearns-Sayre syndrome). Radiology 130: 159-164, 1979. [PubMed: 758643] [Full Text: https://doi.org/10.1148/130.1.159]
Shoubridge, E. A., Johns, T., Karpati, G. Complete restoration of a wild-type mtDNA genotype in regenerating muscle fibres in a patient with a tRNA point mutation and mitochondrial encephalomyopathy. Hum. Molec. Genet. 6: 2239-2242, 1997. [PubMed: 9361028] [Full Text: https://doi.org/10.1093/hmg/6.13.2239]
Shy, G. M., Silberberg, D. H., Appel, S. H., Mishkin, M. M., Godfrey, E. H. A generalized disorder of nervous system, skeletal muscle and heart resembling Refsum's disease and Hurler's syndrome. I. Clinical, pathologic and biochemical characteristics. Am. J. Med. 42: 163-168, 1967. [PubMed: 4163596] [Full Text: https://doi.org/10.1016/0002-9343(67)90015-0]
Tanji, K., Vu, T. H., Schon, E. A., DiMauro, S., Bonilla, E. Kearns-Sayre syndrome: unusual pattern of expression of subunits of the respiratory chain in the cerebellar system. Ann. Neurol. 45: 377-383, 1999. [PubMed: 10072053] [Full Text: https://doi.org/10.1002/1531-8249(199903)45:3<377::aid-ana14>3.0.co;2-m]
Wang, J., Wilhelmsson, H., Graff, C., Li, H., Oldfors, A., Rustin, P., Bruning, J. C., Kahn, C. R., Clayton, D. A., Barsh, G. S., Thoren, P., Larsson, N.-G. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Nature Genet. 21: 133-137, 1999. [PubMed: 9916807] [Full Text: https://doi.org/10.1038/5089]
Whitaker, M. D., Scheithauer, B. W., Kovacs, K. T., Randall, R. V., Campbell, R. J., Okazaki, H. The pituitary gland in the Laurence-Moon syndrome. Mayo Clin. Proc. 62: 216-222, 1987. [PubMed: 3821182] [Full Text: https://doi.org/10.1016/s0025-6196(12)62445-8]
Zeviani, M., Moraes, C. T., DiMauro, S., Nakase, H., Bonilla, E., Schon, E. A., Rowland, L. P. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 38: 1339-1346, 1988. [PubMed: 3412580] [Full Text: https://doi.org/10.1212/wnl.38.9.1339]
Zeviani, M., Moraes, C. T., Shanske, S., Lombes, A., Nakase, H., Schon, E. A., Bonilla, E., Rowland, L. P., DiMauro, S. Deletion of mitochondrial DNA in Kearns-Sayre syndrome. (Abstract) Am. J. Hum. Genet. 43: A100, 1988.