Genetics ofDuane’s Retraction Syndrome

Ocular Motility Journal Club

June 12th 2007

Amy Cohn

Early Studies

• Primary myopathic aetiology of lateral and medial recti– Fibrosis– Abnormal insertions– Adhesions

Early Studies

• Careful postmortems revealed absence of abducens nuclei and VI nerve on affected side

• Partial aberrant innervation of LR via III nerve

Other studies

• EMG showed simultaneous activation of MR and LR is associated with co-contraction and globe retraction

• MRI verified absence of VI nerve in pons and demonstrated co-contraction of LR and MR

• Thus led to terminology of DRS being one of the congenital cranial dysinnervation disorders (CCDDs)

Genetics of DRS

• Most commonly sporadic

• 2-8% of probands have at least one family member with DRS

• Higher incidence of other forms of strabismus

• Alternatively reports of family memebers with normal eye movements but other anomalies known to be associated – Suggests variable expressivity

Genetics of DRS withAssociated Anomalies

• DRS commonly occurs with other congenital anomalies– Especially those involving the skeleton, ear,eye

and kidney

• These associated findings can either be sporadic or part of a genetic syndrome

• These syndromes overlap and most show variable penetrance and expressivity

DRS and congenital anomalies

• Pfaffenbach et al looked at 186 cases of DRS– 33% had at least 1 associated congenital anomaly– 17% at least 2– 8% at least 3

• Hypothesised that incidence could be higher – 40% did not have a physical examination– 20% had spine Xrays or hearing tests

Associated Anomalies

• Limb/skeletal– Hypoplasia– Polydactyly– Absent radius/thumb– Cleft palate– Scoliosis– Spina bifida

• Ear– Malformed pinna– Inner ear appendage– Sensorineural deafness

• Ocular– Additional ocular

abnormalities occurred in 19%

– Amblyopia in 10%– Nystagmus– Ptosis– Microphthalmia– Coloboma– Heterochromia iridis– cataract

DRS and Syndromes

• Radial Dysplasia Syndrome

• Holt-Oram Syndrome

• Acro-Renal-Ocular Syndrome

• IVIC Oculo-acoustic-radial syndrome

• Marfinoid Hypermobility

• Klippel-Feil Anomaly

DRS and SALL4 mutations

• Chromosome

• Mutations have segregated in families with Okihiro disease, acro-renal-ocular syndrome and IVIC– Proving they are allelic entities

• Co-ordinates with SALL1 during embryogeneis in anorectal, heart, brain and kidney development

DRS and HOXA1 mutations

• Chromosome 7

• Responsible for hindbrain segmentation

• Mutations in two separate consanguineous families with DRS, deafness, ICA malformations, autism, facial weakness, vocal cord paralysis

DRS and chromosome 4

• Single case report

• De novo deletion 4q27-31

• Boy with bilateral blepharoptosis, bilateral DRS type 1 and learning difficulty

• Lies close to EGF gene on chromosome 4q25 responsible for Riegers syndrome

Sporadic DRS

• Less is known about the genetic basis for sporadic DRS

• IOVS Jan 2007; Engle et al

• Two AD DRS pedigrees mapped to DURS2 locus

• Chromosome 2

Sporadic DRS

• Most but not all have bilateral DRS (either type I or III)

• No patients linked to DURS2, HOXA1 or SALL4 have DRS II– Maybe a genetically distinct disorder

DURS2

• Members of the pedigrees were analysed with MP-MRI

• Showed that it is a diffuse CCDD not limited to abducens nucleus and cranial nerve 6

• Therefore maybe a different phenotype to true sporadic or unilateral cases