Genetics of Duane’s Retraction Syndrome Ocular Motility Journal Club June 12 th 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 with Associated 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