CFEOM1 is the 'classic' form of CFEOM, and appears to be the most prevalent form of CFEOM. An individual with CFEOM1 has bilateral ptosis and bilateral ophthalmoplegia, with the primary position (resting position) of both eyes below the horizontal midline and the inability to raise either eye above the midline point. The horizontal movements of the eyes range from normal to severely limited. Residual eye movements can be very aberrant. The individual in the photograph has CFEOM1 and is holding her head back in order to see.

Given this definition of CFEOM1, most affected individuals are easily diagnosed and there is little variability in expression. CFEOM1 is not typically accompanied by other developmental abnormalities.

For a family to be classified as a 'CFEOM1 pedigree', all affected members of the family must have CFEOM1. In addition, the inheritance pattern in the family must be autosomal dominant and the penetrance must be complete.

In 1994, we mapped a gene for CFEOM1 to the centromere of chromosome 12. Over the subsequent years, we studied additional CFEOM1 families whose gene also mapped to this location. This was done using the technique of linkage analysis and involved the work of many of our collaborators.

For more detailed information about the main CFEOM1 gene, click on KIF21A.

If you have CFEOM1, and would like KIF21A mutational analysis to be undertaken, please print off this Diagnostic testing sheet and take it to your ophthalmologist for completion. He/she can request the testing on your behalf and will need to draw 3-5cc of your blood to be placed into a purple capped (EDTA) vacutainer. A CLIA approved DNA Diagnostic Testing Laboratory based at Children's Hospital Boston will test your sample for the 'hotspot' KIF21A exons (exons 8, 20 and 21 of this 38 exon gene). If a mutation is identified results of the testing will be released to your physician who will convey the information to you. If a mutation is not identified, and you have signed this Informed Consent Form, the diagnostic laboratory will be permitted to pass an aliquot of your DNA over to the Engle lab for research analysis. We will screen your DNA sample for the remaining 35 KIF21A exons or candidate genes and, if anything is identified, it can then be confirmed by the CLIA lab.

You may either send your completed diagnostic testing sheet and blood sample directly to:
DNA Diagnostic Lab[CLIA #: 22D0001844]
Attention: Lab Control
300 Longwood Ave, Farley 7
Boston, MA 02115
Phone # 617.355.7582
Fax # 617.730.0338
or contact Caroline Andrews, who will describe the testing with you in more detail, and can organize processing of the sample. Also, please click on Diagnostic testing for individuals with CFEOM1, for answers to many questions regarding Diagnostic testing. The current cost for this mutation screening is approximately $600 and these charges should be covered by your health insurance provider. Please contact your insurance company for coverage information.

CFEOM1 PATHOLOGY:
We have examined the brain and extraocular muscles of individuals with CFEOM1 using various techniques, including pathology and neuroimaging. Our findings are summarized in the schematic lateral view of the orbit below.

Normally, the oculomotor nucleus is in the midbrain of the brainstem, and its nerve (cranial nerve III) exits the brainstem and branches into a superior and inferior division. The superior division innervates the levator palpebrae (eyelid muscle) and the superior rectus (the eye muscle that pulls the eyeball upwards).

In individuals with CFEOM1, the superior division of cranial nerve III is absent or very small (normal nerves are yellow, and these absent axons are depicted as the red dotted lines). The motoneurons in the midbrain subnuclei whose axons make up the superior division of CN III are absent (depicted as absence of black outline of the tiny midbain CN III subnuclei). The levator palpebrae superioris and the superior rectus muscles are abnormal or absent. These muscles are normally innervated by the superior division of cranial nerve III (these muscles are depicted as blue rather than the normal brown). Dysfunction of the levator palpebrae would result in bilateral ptosis, and dysfunction of the superior rectus would result in the eyes fixed downward with an inability to elevate.

These data suggest that CFEOM1 results from a neurogenic (nerve) rather than a myopathic (muscle) cause.