Transcript Genetics of Duane’s Retraction Syndrome

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
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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
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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