Etiology
- CPEO, OPMD, and myotonic dystrophy are all due to genetic alterations (Allen, 2013).
- CPEO is caused by mutations in genes that are involved in mitochondrial function (Biousse and Newman, 2003). This has traditionally been described as mutations in the mitochondrial genome; however, it is also recognized that mutations in genes that are encoded in the nucleus and involved in mitochondrial function can cause CPEO. This results in there being three potential inheritance patterns: maternal, autosomal dominant, and autosomal recessive. CPEO caused by mtDNA mutations reveals rearrangement of segments of mtDNA in the form of deletions and duplications and, less commonly, point mutations. There are currently seven genes from the nuclear genome known, mutations in which cause CPEO. Autosomal dominant: ANT1, C10orf2, POLG, POLG2, RRM2B, and DNA2. Autosomal recessive: TYMP and POLG.
- Myotonic dystrophy is an autosomal dominant disease caused by mutations in the DMPK gene. The gene contains a noncoding trinucleotide repeat (CTG) that is expanded in affected individuals. Normal individuals have 5 to 37 repeats, while mildly affected individuals have 50-150 repeats, classically affected individuals have 100-1000 repeats, and congenital onset is associated with more than 2000 repeats (Harley et al., 1993). The repeat can lengthen as it is passed through the generations, a phenomenon known as anticipation.
- OPMD is an autosomal dominant disease caused by mutations in the PAPBN1 gene (Brais et al., 1998). The most common mutation identified is a small triplet repeat expansion. Due to the relative stability of this repeat and the fact that it is short, there is no significant correlation of disease severity with repeat length, and there is no anticipation.
Figure 1. CPEO retinopathy. Courtesy Raymond Cho, MD.
Figure 2. CPEO. Courtesy Raymond Cho, MD.
Figure 3. CPEO ptosis. Courtesy Anne Barmettler, MD.
Figure 4. CPEO. Courtesy Brett Davies, MD.
Figure 5. CPEO. Courtesy Michael J. Hawes, MD.
Figure 6. OPMD. Courtesy Richard C. Allen, MD, PhD, FACS.
Figure 7. OPMD. Courtesy Richard C. Allen, MD, PhD, FACS.
Epidemiology
- Due to the genetic character of these diseases, there are no risk factors other than having parents who carry the mutations.
- In CPEO, there can be significant variability within families who carry mtDNA mutations due to the fact that in each cell, there are multiple mitochondria, and in each mitochondrion, there are multiple copies of the circular DNA. Due to this, within a family, there can be variability with regards to the proportion of mitochondria that carry a mutation and the proportion of circular DNA in each mitochondrion that have the mutation (Biousse and Newman, 2003).
- In OPMD, there are significant geographic clusters of patients in Quebec (French descent), Northern New Mexico (Hispanic descent), and Israel (Bukhara Jewish descent) (Becher et al., 2001) (Blumen et al., 2000).
Pertinent elements of history
Family history is an important piece of information to obtain in these patients. However, due to the variability of penetrance and expression in CPEO and myotonic dystrophy, the family history might not be informative. For OPMD, recognition of French Canadian or Hispanic New Mexican descent is useful.
Clinical features
For each of these diseases, ptosis should be noted with evidence of subnormal levator strength. The subnormal levator strength can sometimes be difficult to elicit early in the disease. Traditionally, levator function is used to determine levator strength; however, early in the disease levator function can still be "normal" (15 mm) (Frueh and Musch, 1996). Looking at the velocity of the lid from downgaze to upgaze can be helpful, noting a slower velocity in these patients even though LF is normal. The age of onset of CPEO and myotonic dystrophy is variable; however, earlier onset is associated with more severe ocular and systemic disease (Harley et al., 1993). The age of onset of OPMD is around the age of 50, with 99% of patients with the mutation having symptoms by the age of 70 (Brais et al., 1999).
- CPEO
- Reduced extraocular motility
- Reduced orbicularis strength
- Poor Bells phenomenon (related to reduced extraocular motility)
- Kearns-Sayre syndrome
- Retinal pigmentary changes
- Cardiac conduction disorders
- Cerebellar ataxia
- High CSF protein
- Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
- Mutations in TYMP
- Autosomal recessive
- Autosomal recessive cardiomyopathy ophthalmoplegia (ARCO)
- Mutations in POLG
- Autosomal recessive
- Myotonic dystrophy
- Reduced extraocular motility (not as much as CPEO)
- Reduced orbicularis strength (more than CPEO)
- Significant meibomian gland dysfunction
- Poor Bells phenomenon (related to reduced extraocular motility)
- Myotonia
- Cardiac conduction abnormalities
- Polychromatic (Christmas tree) cataracts
- Hypogonadism
- Frontal balding
- OPMD
- Reduced supraduction (not as much as CPEO or myotonic).
- Intact orbicularis strength
- Intact Bells phenomenon
- Dysphagia
- Can precede or follow ptosis symptoms
- Patients might describe choking on food.
- Patients take longer to finish meals.
- Aspiration pneumonia later in the disease
- Some patients will eventually have a feeding tube.
- Dysphonia
- Patients can almost be diagnosed by the sound of their voice.
- Proximal muscle weakness
- Later in the disease
- Not recognized in the textbooks
Testing and evaluation for establishing diagnosis
- CPEO
- Due to the multiple potential genes involved and multiple different potential mutations, genetic testing has not become standard for CPEO.
- Muscle biopsy remains the mainstay of diagnosis.
- Easily accessible muscles such as the vastus lateralis or deltoid are the most commonly biopsied muscles.
- Some have advocated orbicularis oculi biopsy during eyelid surgery (Roefs et al., 2012).
- Pathology
- Ragged-red fibers
- Partial cytochrome C oxidase deficiency
- MRI has shown the EOMs to be smaller (Carlow et al., 1998).
- Myotonic dystrophy
- Genetic testing is appropriate to evaluate the triplet repeat length in the DMPK gene.
- Neurology consultation
- EMG can be helpful in diagnosis to demonstrate myotonia.
- OPMD
- Genetic testing is appropriate to evaluate the triplet repeat length in the PABPN1 gene.
- Muscle biopsy is no longer appropriate.
- Pathology showed intranuclear inclusions (INIs).
Evaluation to determine staging or impairment level
- Clinical examination
- Margin reflex distance 1 (MRD1)
- Palpebral fissure height (PF)
- Levator function (LF)
- Lid crease
- Orbicularis strength
- Extraocular motility
- Photographs
- To document level of impairment
- Ptosis visual fields
- With lids untapped and taped
- To document level of impairment