Kearns-Sayre Syndrome

Kearns-Sayre syndrome is a sporadic mitochondrial disease from a single large scale mitochondrial DNA deletion, with onset before age 20 years, progressive external ophthalmoplegia, pigmentary retinopathy and one of cardiac conduction block, cerebrospinal fluid protein above 1 g/L, or cerebellar ataxia.

Pathophysiology. Large scale deletion removes tRNA and respiratory chain genes, impairing oxidative phosphorylation, mostly in extraocular muscle, retina, conduction tissue and brain.

Progressive ptosis and ophthalmoplegia (often without diplopia), pigmentary retinopathy with night blindness, cardiac conduction block (heart block, sudden death), ataxia, short stature, hearing loss, endocrine disease (diabetes, hypoparathyroidism, growth hormone deficiency, hypogonadism), renal tubular dysfunction (Fanconi), proximal myopathy, dysphagia and cognitive decline.

Red flags.

• Syncope or bradycardia (heart block).
• Metabolic stress with lactic acidosis.

Muscle biopsy shows ragged red fibres and cytochrome oxidase negative fibres. Genetic testing for a single large deletion in muscle (blood may be negative). ECG and Holter monitoring, echocardiography, serum lactate, CSF protein, MRI (white matter and basal ganglia change) and endocrine tests (glucose, calcium, parathyroid hormone, growth hormone, cortisol). Ophthalmology, audiometry and renal function.

Differential diagnosis.

• Chronic progressive external ophthalmoplegia with other mitochondrial mutations.
• Myasthenia gravis, oculopharyngeal muscular dystrophy and Pearson syndrome.
• Retinitis pigmentosa syndromes and other mitochondrial disease.

Cardiac. Pacemaker for second- or third degree block, and consider implantable defibrillator for high risk patients, since sudden death is a major risk. Yearly ECG and Holter monitoring.

Endocrine. Insulin for diabetes (avoid metformin), hormone replacement for deficiencies, and calcium and vitamin D for hypoparathyroidism.

Ophthalmic. Ptosis crutches or surgery, with risk of exposure keratopathy.

Other. Cochlear implant for hearing loss, renal care, nutrition, physiotherapy and speech therapy.

Supplements. Coenzyme Q10 and folinic acid have limited evidence (folinic acid for cerebral folate deficiency with low CSF folate).

Avoid valproate, aminoglycosides and metabolic stress.

Monitoring. ECG, echocardiography, glucose, endocrine and renal function yearly.

Referral and escalation. Refer to mitochondrial disease services, cardiology and endocrinology.