Myopathy, CPEO and Kearns–Sayre syndrome

Ocular Myopathies & Mitochondrial Disorders

When progressive ptosis and ophthalmoplegia develop symmetrically without diurnal fluctuation, pupillary involvement, or pain, primary mitochondrial and muscular dystrophies must be investigated.

Chronic Progressive External Ophthalmoplegia (CPEO)

CPEO is the most common mitochondrial myopathy affecting the visual system:

• Genetics: Most commonly caused by sporadic, single large-scale deletions of mitochondrial DNA (mtDNA), such as the common 4,977-base-pair deletion. Autosomal dominant and recessive familial forms occur secondary to mutations in nuclear genes controlling mtDNA replication (e.g. POLG, TWNK, SLC25A4).
• Clinical Presentation: Insidious, slowly progressive, symmetrical bilateral ptosis, followed years later by symmetrical limitation of ocular ductions in all directions of gaze.
• The Diplopia Paradox: Despite near-complete external ophthalmoplegia (the eyes may become completely fixed in primary position), patients rarely complain of diplopia. Because the myopathic process progresses in a remarkably symmetrical fashion between both orbits, alignment remains parallel.
• Diagnostic Hallmarks: Normal pupils and normal accommodation; accompanying severe orbicularis oculi weakness; negative myasthenic serology; modified Gomori trichrome staining of skeletal muscle biopsy demonstrates ragged-red fibers (subsarcolemmal accumulations of structurally abnormal mitochondria) and cytochrome c oxidase (COX)-negative fibers.

Kearns-Sayre Syndrome (KSS)

Kearns-Sayre syndrome is a severe, multisystem mitochondrial deletion syndrome defined by a strict clinical triad:

1. Onset before age 20 years;
2. Chronic Progressive External Ophthalmoplegia (CPEO);
3. Atypical Pigmentary Retinopathy: Bilateral, diffuse, fine 'salt-and-pepper' retinal pigment epithelium atrophy and pigment clumping, characteristically involving the macula and mid-periphery. Unlike classical retinitis pigmentosa, arteriolar attenuation and waxy disc pallor are absent, and electroretinography (ERG) demonstrates only mild or diffuse photoreceptor dysfunction.

In addition to the triad, diagnosis requires at least one of the following systemic manifestations:

• Cardiac conduction disease: KSS requires cardiac assessment and surveillance because conduction failure can be life-threatening. Pacing is selected by established disease and specialist risk, not automatically in every patient at diagnosis.
• Cerebrospinal Fluid (CSF) Protein $>100\text{ mg/dL}$ ($>1.0\text{ g/L}$);
• Cerebellar Ataxia.

Oculopharyngeal Muscular Dystrophy (OPMD)

OPMD is an autosomal dominant, late-onset muscular dystrophy characterized by distinct genetic and clinical features:

• Genetics: Caused by an expanded (GCN)11-18 trinucleotide repeat expansion in the PABPN1 gene (polyadenylate-binding protein nuclear 1) on chromosome 14q11.
• Clinical Presentation: Characteristically manifests in the fifth or sixth decade (age 50 to 60 years) with progressive, symmetrical bilateral ptosis and severe, progressive dysphagia (pharyngeal muscle involvement). Patients suffer from choking episodes, nasal regurgitation, severe aspiration pneumonia, and cachexia.
• Ophthalmoplegia: Limitation of ocular motility occurs late in the disease course and is milder than in CPEO.
• Muscle Biopsy: characteristic intranuclear filamentous inclusions measuring 8.5 nm in diameter on electron microscopy and rimmed vacuoles on light microscopy.

Master Summary: Neuromuscular & Myopathic Motility Disorders

The following master table synthesizes the immunological, genetic, clinical, and histopathological criteria distinguishing these disorders:

Test and Treatment Limits

Ice and enhanced-ptosis signs support MG but are not individually definitive. Protect the skin during ice testing. Antibody sensitivity differs in ocular and generalised disease. Single-fibre EMG depends on muscle, presentation and technique; a normal study is less reassuring in isolated diplopia than in typical ptosis, and abnormal jitter is not exclusive to MG. Review medicines that may worsen weakness, and assess breathing, swallowing and voice change urgently.

Thymoma assessment is relevant, but the MGTX thymectomy evidence was for selected generalised AChR-positive disease, not every ocular or MuSK presentation. Immunotherapy is selected by neurological severity and risks; rituximab can be an option in appropriate MuSK/generalised disease rather than an automatic response to one test. CPEO may produce diplopia and Kearns–Sayre requires cardiac surveillance, with pacing according to conduction disease and specialist risk. Oculopharyngeal dystrophy can be established genetically; biopsy is not compulsory in every case.