Ophthalmoplegia, autosomal dominant progressive external (adPEO)

Material

2 ml EDTA blood

2 ml serum

OMIM

606075, 604983, 174763, 103220

Methods

Verification of mutations in the POLG, SLC25A4, C10orf2, and POLG2 genes by PCR, DNA sequencing, MLPA

Clinical relevance

Mutation analysis for differential diagnosis in cases of

 

- external ophthalmoplegia

- ptosis

- mitochondrial myopathy of unknown origin

- elevated lactate levels in the serum of unknown origin (> 2.2 mmol/l)

- increased pyruvate levels in the serum of unknown origin (> 150 mmol/l)

- elevated creatine kinase levels in the serum of unknown origin

(women: > 167 U/l, men: > 190 U/l)

- for risk assessment in familial clustering of adPEO or adPEO-like

conditions

General notes

Ophthalmoplegias may have various causes. Often they present as mitochondrial diseases with different molecular defects, mostly deletions of mitochondrial DNA, especially Kearns-Sayre syndrome (KSS, see Kearns-Sayre syndrome), chronic progressive external ophthalmoplegia (CPEO, see Ophthalmoplegia, chronic progressive external (CPEO)), sensory ataxic neuropathy, dysarthria and ophthalmoplegia (SANDO syndrome, see SANDO syndrome).

 

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a disease that affects the mitochondria. It is characterised by an increased rate of deletions in mitochondrial DNA (mtDNA deletions). Secondary, in a subset of patients, a reduced number of mitochondria and mitochondrial DNA (mtDNA) is also observed. This phenomenon is known as depletion (mtDepletion, mitochondrial depletion syndrome). Characteristic symptoms include paralysis of the external eye muscles, ptosis, and mitochondrial myopathy. Paralysis is usually symmetrically in both eyes. Ophthalmoplegia may occur at any age. The earlier it occurs, the more severe its course. Associated diseases include: hearing loss, depression, sensory axonal neuropathy, spinocerebellar ataxia, cataract, optic atrophy, Parkinson's disease, hypogonadism, and familial hypertrophic cardiomyopathy.

 

adPEO is caused by nuclear mutations in the genes POLG, C10orf2, SLC25A4, and POLG2. Approximately 45% of cases of adPEO are based on mutations in the POLG gene. Furthermore, mutations in the POLG gene may also trigger autosomal recessive progressive external ophthalmoplegia (arPEO, see Ophthalmoplegia, autosomal recessive progressive external (arPEO)) and Alper's syndrome (see Alpers' syndrome). Approximately 35% of cases of adPEO are caused by mutations in the C10orf2 gene. In rare cases, a mutation in the POLG2 gene may also cause adPEO. The genes POLG and POLG2 encode two subunits of DNA polymerase γ, which is involved in the replication of mitochondrial DNA. Mutations in this gene lead to increased mitochondrial deletions, but may also reduce the activity of polymerase γ during replication. The C10orf2 gene (PEO1, TWINKLE) encodes a hexameric DNA helicase, which plays a key role in the mitochondrial DNA replication. Mutations lead to both deletions and to depletion. Laboratory values of patients with adPEO show elevated levels of creatine kinase, lactate, and pyruvate in the blood serum. Furthermore, mutations in the POLG, POLG2, and C10orf2 genes lead to cytochrome c oxidase (COX) negative skeletal muscle fibres.

 

The POLG gene is located on the long arm of chromosome 15 (more precise localisation: 15q25). So far, 135 mutations in the POLG gene have been identified (The Human Gene Database, as of 09.2010). Approximately 95% of currently known mutations can be detected with the molecular genetic analysis. The C10orf2 gene is located on the long arm of chromosome 10 (more precise localisation: 10q24). So far, 41 mutations in the C10orf2 gene have been identified (The Human Gene Database, as of 09.2010). Approximately 95% of currently known mutations can be detected with the molecular genetic analysis. The POLG2 gene is located on the long arm of chromosome 17 (more precise localisation: 17q23-q24). So far, one mutation is known affecting the POLG2 gene (The Human Gene Mutation Database, as of 09.2010). Approximately 95% of currently known mutations can be detected with the molecular genetic analysis.

Last update: 18.06.2018

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