NANOS Collection of Unusual Congenital Ocular Motility Disorders

Stewards:

Thomas M. Bosley, MD
Head of the Division of Neurology
Cooper University Hospital
Bosley-Thomas AT cooperhealth.edu

Elizabeth C. Engle, MD
Children's Hospital Boston, Program in Genomics
elizabeth.engle AT childrens.harvard.edu

NANOS would like to assist in collecting patients and families with unusual congenital ocular motility abnormalities. These individuals occur so uncommonly that it is difficult to collect enough individuals or families from one center for a comprehensive evaluation. We hope that the NANOS membership as a whole may be able to help collect both recognized and unrecognized congenital ocular motility problems for phenotypic description and genetic analysis. Your stewards in this process are Thomas M. Bosley, MD, who developed an interest in this area while working in Saudi Arabia, and Elizabeth C. Engle, MD, whose laboratory at Children's Hospital Boston has discovered the genes known to be mutated in these syndromes.

We are interested in collecting and evaluating patients and families with the less common types of congenital ocular motility disturbances that we refer to as the congenital cranial dysinnervation disorders (see below), and patients with unclassified eye movement disorders. We are also interested in more common types of strabismus such as comitant esotropia or exotropia of childhood, but only if the motility abnormality is familial (three or more first degree family members). We will use Dr. Engle's data collection form and, if appropriate, her informed consent form (vide infra), both of which are approved by the Children's Hospital Boston IRB.

To enroll a patient, what you have to do is:

1. Download and fill out the data form; [Data Collection Form]
2. Call Caroline Andrews, the senior research specialist in Dr. Engle's lab at 617 919-2168 to discuss whether your local IRB will require expedited review and approval of the Children's Hospital Boston protocol and consent form. She will provide both to you on request.
3. Talk to the patient and available family members about the informed consent (either Dr. Engle's [Participant Questionnaire] or yours) and address their questions. Once these issues are satisfied, ask each individual or guardian to sign the informed consent.
4. Obtain blood or saliva from proband and family that will be used for DNA extraction. In general, it is better to obtain samples from proband, available siblings and parents. We can provide collection tubes and will undertake the DNA extraction. And finally,
5. Send the informed consents, data forms, and samples to Dr. Engle's laboratory. We will confirm receipt.

We will be in touch with additional questions about phenotyping and with notification about any manuscripts including individuals whom you have phenotyped and enrolled that may approach publication. Our aim is to be inclusive in this process. . For all disorders, the Engle lab can provide research-based genetic screening for mutations in candidate genes. Keep in mind that IRB rules prohibit you from informing your patients about the outcome of genetic analysis done for research purposes. However, genetic analyses, once perfected, are commonly moved to CLIA (Clinical Laboratory Improvement Act) federally approved certified laboratories For many of the syndromes for which the disease gene has been identified, we can also offer diagnostic genetic testing in a CLIA-approved laboratory, either free through EyeGene or via insurance (or self-pay) at Children's Hospital Boston. Caroline Andrews will be available to discuss the options when questions arise.

The following is a description of the congenital cranial dysinnervation disorders
(Gutowski et al., 2003). This list is not intended to be comprehensive; rather, we provide it to give you some idea of the sort of congenital ocular motility problems that have been recognized. With luck, you will recognize some syndrome not yet described, but keep in mind that we are also interested in studying patients with recognized disorders.

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; MIM # 135700) usually presents with ptosis OU and with both eyes infraducted. Patients have an upgaze paralysis OU and bilateral asymmetric restriction of ocular motility OU in other directions (Engle et al., 2002). This is an autosomal dominant syndrome in which heterozygous missense mutations in KIF21A (Yamada et al., 2003) cause dysinnervation of extra-ocular muscles (Demer et al., 2005).

Congenital fibrosis of the extraocular muscles type 2 (CFEOM2; MIM # 602078) looks like bilateral absence of the oculomotor and trochlear nerves with no adduction, elevation, or depression OU and with incomplete abduction (Bosley et al., 2006). It is an autosomal recessive disorder in which mutations in PHOX2A cause absence of the nuclei of cranial nerves 3 and 4 bilaterally (Nakano et al., 2001).

Congenital fibrosis of the extraocular muscles type 3 (CEOM3; MIM %600638) is another congenital cranial dysinnervation disorder (CCDD) in which patients have asymmetric restriction of ocular motility in all directions OU, generally without the severe restriction of upgaze that is typical of CFEOM1. This is an autosomal dominant syndrome that, in most families, maps to chromosome 16 (Doherty et al., 1999).

Horizontal gaze palsy and progressive scoliosis (HGPPS; MIM # 607313) is marked neurologically by severe congenital bilateral horizontal gaze restriction, but the major clinical impact is the severe scoliosis that develops in the first or second decade of life (Bosley et al., 2005). It is an autosomal recessive syndrome caused by homozygous mutations in ROBO3. ROBO3 permits decussation of a number of neuronal tracts in the developing brainstem, so these individuals also have asynchronous blinking and lack decussation of the long motor and sensory tracts (Jen et al., 2002; Jen et al., 2004).

The HOXA1 Spectrum (MIM # 601536) is made up of the Bosley-Salih-Alorainy syndrome (Bosley et al., 2007) and the Athabascan Brainstem Dysgenesis syndrome (Holve et al., 2003), both of which are caused by autosomal recessive mutations in the HOXA1 gene (Tischfield et al., 2005). Clinical hallmarks of the syndrome are bilateral type 3 Duane retraction syndrome (or horizontal gaze palsy OU), bilateral deafness, variable cerebrovascular and cardiovascular dysplasia, and autism in some (Bosley et al., 2008).

DURS2-Duane retraction syndrome (DURS2-DRS; MIM %126800) is isolated Duane syndrome that can be inherited as an autosomal dominant trait and results from gain-of-function mutations in CHN1, which encodes a cell signaling molecule, alpha2-chimerin, believed to be essential for correct axon targeting of the abducens motor neurons to the lateral rectus muscle (Appukuttan et al., 1999; Miyake et al., 2008).

Duane-Radial Ray syndrome (Okihiro syndrome; DRRS; MIM #607323) is an autosomal dominant syndrome in which DRS is inherited together with hand and upper limb anomalies, and less frequently with deafness. It is caused by heterozygous mutations in SALL4 (Al-Baradie et al., 2002).

Wildervanck syndrome (MIM 314600) in which DRS occurs in association with congenital deafness and Klippel-Feil anomaly.

Moebius syndrome is the combination of abduction defects and facial weakness; we have identified individuals with CFEOM-like Moebius syndrome as well as Duane-like Moebius syndrome. It can be associated with limb anomalies and developmental deficits. It is most commonly sporadic.

Congenital ptosis. Isolated congenital ptosis can be inherited as an autosomal dominant and an X-linked trait. Several genetic loci have been mapped but disease genes have yet to be identified.

Common strabismus. Esotropia and exotropia are influenced by genetics but appear to be complex traits rather than Mendelian traits. Enrollment of families with three or more affected members will assist in the identification of strabismus susceptibility genes.

References