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Transcript
Genetics of Duane’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 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