26.1 Clinical Features and Laboratory Investigations
Kearns-Sayre syndrome (KSS) is a rare, sporadic disorder that affects males and females equally. Disease onset is before the age of 20 years. The sequence of manifestations is not constant, but the signs and symptoms in themselves are consistent. Early development is normal. Ptosis and chronic progressive external ophthalmoplegia are usually the initial signs. Apart from progressive external ophthalmoplegia the typical clinical triad includes pigmentary degeneration of the retina and cardiac conduction block. The fine salt-and-pepper type of atypical retinitis pigmentosa is usually associated with good visual function and follows a benign course. Incidentally, choroi-deremia is present instead of pigmentary retinopathy. The most common cardiac conduction blocks are complete atrioventricular block, bundle branch blocks, and fascicular blocks. Other frequently noted signs are short stature due to progressive growth failure, delayed psychomotor development, sensorineur-al hearing loss, cerebellar ataxia, proximal myopathy, cardiomyopathy, and sensory neuropathy. Less frequent are pyramidal dysfunction and dementia. Seizures may occur. Endocrine disease is often present and may include primary gonadal failure, delayed puberty, diabetes mellitus, growth hormone deficiency, hyperaldosteronism, hypothyroidism, hy-poparathyroidism, ACTH deficiency, and primary adrenal insufficiency. Hypomagnesemia may occur. Some patients have a mottled, hyperpigmented skin. Cardiac arrhythmias and congestive cardiomyopathy may be the cause of death. Cardiogenic embolism and stroke may also occur and contribute to the disability and the risk of death.
Incidental patients have been reported who suffered from Pearson syndrome in infancy, followed later by KSS. Pearson syndrome comprises refractory sideroblastic anemia requiring transfusions, throm-bocytopenia, neutropenia, pancreatic insufficiency, and hepatic dysfunction. Onset is in infancy and most patients die in early childhood from a combination of pancreatic, hepatic, renal, and bone marrow insufficiency. Some children survive the infantile period and no longer need repeated blood transfusions. These patients subsequently developed KSS syndrome. Incidental KSS patients have also been reported who de velop aplastic anemia without other signs of Pearson syndrome.
Laboratory investigations in KSS almost invariably reveal an increased CSF protein level, usually above the level of 1 g/l. Blood and CSF lactate and pyruvate are usually elevated. Signs of variable endocrine dysfunction are frequently found. EMG may reveal signs of a myopathy. ECG shows evidence of a disturbance of cardiac conduction. Echocardiography and chest X-ray may show cardiomegaly.
Biochemical analysis of muscle tissue reveals decreased activity of respiratory complexes I, III, and IV, individually or in combination. The diagnosis is confirmed by demonstrating a heteroplasmic, single, large-scale deletion of mitochondrial DNA or, rarely, a mitochondrial DNA duplication.
On light microscopic examination of muscle biopsies, application of the modified Gomori trichrome stain reveals the presence of ragged red fibers. With this stain the abnormal fibers demonstrate a mottled and irregular appearance with red-staining peripheral and intermyofibrillar zones. Histochemistry for ox-idative enzymes such as NADH dehydrogenase, succi-nate dehydrogenase, and cytochrome-c oxidase may yield abnormal staining patterns. On electron microscopy, the ragged red fibers display large aggregates of mitochondria, generally under the sarcolem-ma, but also between myofibrils. The mitochondria are frequently abnormal in size and structure. The mitochondrial cristae are often increased in number and irregularly oriented. The mitochondria may contain different abnormal inclusions such as crystalline or paracrystalline structures or globular bodies.
In KSS the main finding on postmortem examination is a spongy state of the cerebral white matter due to splitting of myelin sheaths. The axons are generally preserved. The white matter changes are diffusely observed in the frontal, parietal, temporal, and occipital lobes of both hemispheres. It is the hemispheric white matter that is involved, whereas the corpus cal-losum and internal capsule tend to be preserved. The U fibers are preferentially affected. The cerebral cortex is intact. The basal ganglia are involved, in particular the globus pallidus and caudate nucleus, but the putamen, thalamus, hypothalamus, subthalamic nuclei, and substantia nigra may also be affected. The basal ganglia lesions are characterized by loss of nerve cells, spongiosis, gliosis, and capillary proliferation. Within the globus pallidus perivascular depositions of calcium and intracellular depositions of iron may be seen. The same type of depositions may be seen within the caudate nucleus, dentate nucleus, and the putamen. Within the cerebellar cortex, loss of Purkinje cells may be seen. The cerebellar white matter displays spongiosis and gliosis. In the brain stem spongiosis and gliosis have been reported in white matter structures, in the pontine and midbrain tegmentum, red nucleus, substantia nigra, and other gray matter nuclei. Within the spinal cord vacuolation of tracts, in particular the dorsal columns, may be seen.
Cardiomyopathy with ragged red fibers may be found. The pancreas may display fatty infiltration. The adrenals may be atrophic and small. Glomerular and tubular abnormalities may be found in the kidneys. The lobules of the testes may be atrophic with marked overgrowth of fibrous tissue.
In most KSS patients large deletions of mitochondrial DNA are present. Large deletions of a substantial proportion of mitochondrial DNA have been described in chronic progressive external ophthalmo-plegia (CPEO), Pearson syndrome, and KSS. These syndromes are clinically overlapping: muscle weakness and chronic progressive external ophthalmople-gia form part of the symptomatology in KSS. Although the size and the position of the large deletions ranges from 1.8 to 8 kilobases, the same 4.977-kilobase deletion is known to occur most often and is therefore known as "the common 5-kb deletion." Most deletions are flanked by direct repeats, suggesting that homologous recombination or slip-replication may be responsible for the deletion. Despite the deletion, the mitochondrial genomes are usually competent for replication and transcriptionally active. Most frequently, the deleted segment encompasses some of the genes encoding the 13 proteins of the respiratory chain,but also several genes encoding tRNAs. This explains the decrease in all mitochondrial translation products demonstrated in immunological and biochemical analyses, leading to respiratory chain dysfunction. Biochemical analysis reveals decreased activity of complexes I, III, and IV, individually or in combination. Although large single deletions of mitochondrial DNA were initially thought to underlie KSS, the genetic abnormality is more complex. Mitochon-drial DNA duplications appear frequently to be present as well, and there may be multiple deletions.
In all patients the deletions are heteroplasmic. Part of the relationship between genotype and phenotype can be explained by heteroplasmy with different percentages of mutant mitochondrial DNA in different tissues and changes of percentages with course of time. An increase with time of the mutated mitochondrial DNA fraction has been reported, paralleling the progression of the disease. In patients surviving Pearson syndrome it is likely that the patient initially had a high percentage of mitochondrial DNA with a deletion in blood cells. The spontaneous recovery indicates that selection favoring normal cells may occur in vivo. The percentage of deleted mitochondrial DNA is similar in muscles of both CPEO and KSS patients, but deletions are restricted to skeletal muscle in CPEO and widely distributed in extramuscular tissues in KSS. In Pearson syndrome mitochondrial DNA defects are present in high amounts in all tissue, in particular in blood and bone marrow. The proportion in blood and bone marrow probably falls with age if the patient survives, whereas conversely an increase in proportion of deleted mitochondrial DNA has been shown in repeated investigation of muscle tissue. In KSS patients the deletion is usually present in only a small proportion of peripheral blood cells.
The deletions are sporadic. The deletions are not present in mothers of patients or in children of affected mothers. Apparently, the deletions occur in the oocyte or zygote and affect somatic rather than germ cells. An alternative explanation for not finding the deletion in offspring of KSS mothers could be that oocytes containing mitochondrial DNA deletions may not be viable for gametogenesis and fertilization. By means of unequal mitotic segregation the deletion is spread among part of the cells of the body of the embryo and fetus. Replication of genomes containing the deletion occurs more rapidly, and as a consequence selection of respiratory-deficient cells may occur in the rapid-turnover tissues.
KSS is considered a clinical diagnosis and multiple KSS patients have been reported with other mito-chondrial DNA abnormalities than those described above, including point mutations, multiple deletions, and mitochondrial DNA depletion. It is striking that as a rule these patients do not have the same abnormalities on MRI of the brain as are observed in patients with classical KSS. In most of these patients MRI of the brain is normal.
Symptomatic treatment is important in KSS. Cardiac conduction defects often require medication or the implantation of a pacemaker. Endocrine dysfunction can be treated adequately.
Administration of cofactors has often been employed in an attempt to ameliorate the course of disease. Coenzyme Q10, cytochrome c, flavin adenine dinucleotide, riboflavin, thiamine, nicotinamide,vita-min C, and vitamin K3 (menadione) have been given alone or in varying combinations and variable improvement has been reported. However, none of these has led to a consistent improvement of ocular movements, CNS symptoms, and cardiac function.
In KSS CT scan often reveals calcium deposits in the globus pallidus and caudate nucleus in addition to low density of the cerebral white matter and progressive atrophy (Fig. 26.1). In some patients the calcium deposits are more widespread and also occur in the cerebral white matter. In the absence of calcium deposition, low density of the globus pallidus may be apparent.
MRI often shows a characteristic pattern with symmetrical lesions of the globus pallidus and thalamus and subcortical white matter abnormalities (Figs. 26.2-26.4). Other central nuclei that are often involved include the caudate nucleus, substantia nigra, and red nuclei. The putamen is usually less prominently involved. The white matter abnormalities are symmetrical and tend to involve all subcortical white matter in a patchy or confluent way, sparing the periventricular white matter and corpus callo-sum, although in our experience the splenium of the corpus callosum is usually affected. The cerebellar white matter may also be involved. Often extensive brain stem abnormalities are seen, in particular involving the brain stem tegmentum. Cerebellar and to a lesser extent cerebral atrophy may occur.
The full-blown pattern in KSS is diagnostic. However, the pattern develops over time and in the earlier stages only limited abnormalities in some of the structures may be seen. In these patients,the differential diagnosis is longer. MRS shows elevated lactate in KSS, which may aid the diagnosis.
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