Duane’s syndrome ¹

Birth

Patients have deficiency of abduction and/or adduction with associated co-contraction of the medial and lateral recti causing globe retraction and narrowing of the palpebral aperture on lateral gaze. Symptoms occur secondary to a cranial nerve III-VI synkinesis. Blepharoptosis can occur secondarily.

Nonprogressive

Majority sporadic

5–10% inherited AD

Rarely AR

Sporadic mutations involve CHN1 gene (chimerin 1, GTP-ase-activating protein)

Surgical correction of strabismus and blepharoptosis where indicated

Marin-Amat syndrome, “Inverted Marcus Gunn phenomenon” ⁷

Typically acquired after facial nerve palsy, rarely congenital

Synkinesis of cranial nerves V and VII, whereby jaw opening leads to eyelid closure

Nonprogressive

Can be acquired or inherited (rare); unknown genetics

Unknown

Facial neuromuscular retraining and in select cases, botulinum toxin

Blepharophimosis-ptosis-epicanthus inversus syndrome ^{8 ,​ 9}

Birth

Classically, patients have severe bilateral blepharoptosis, blepharophimosis, epicanthus inversus, and telecanthus. Other periorbital findings include lower lid ectropion, hypertelorism, superior orbital rim hypoplasia, and lacrimal system abnormalities, present in varying degrees. Type I is associated with ovarian insufficiency

Nonprogressive, possible improvement of telecanthus with growth

AD

FOXL2 (forehead box protein 2) is responsible for types I and II

Surgical correction of blepharoptosis and phimosis

Monocular elevation deficiency, formerly “double elevator palsy” ¹² ID#b282a672_13 ^{– 14}

Present at birth, or acquired

Unilateral syndrome, in which the eye is not able to supraduct in all fields of gaze. Hypotropia is present in primary position. Can be associated with blepharoptosis

Nonprogressive

Sporadic

N/A

Surgical correction of strabismus, followed by surgical correction of blepharoptosis

Autosomal dominant optic atrophy plus syndrome (Treft Sanborn Carey syndrome) ¹⁵

Childhood

Bilateral optic atrophy, sensorineural hearing loss, myopathy leading to ophthalmoplegia, blepharoptosis, ataxia, and peripheral neuropathy

Progressive

AD

OPA1 (OPA1 protein, a mitochondrial dynamin like GTPase)

Supportive measures

Surgical correction of strabismus and blepharoptosis where indicated

Centronuclear myopathy, X-linked myotubular myopathy (XLMM)^{a, 18 ,​ 19}

Infancy, early childhood

Facial and neck muscle weakness, including ocular (blepharoptosis, ophthalmoparesis), limb weakness, diaphragmatic weakness

Often progressive

XLR, AD, or AR

More common: DNM2 gene (dynamin 2), BIN1(bridging integrator 1), TTN (Titin)

Less common: CCDC78 gene (coiled-coil domain containing 78), SPEG (A member of the myosin light chain kinase family, required for myocyte cytoskeletal development), RYR1 (skeletal muscle ryanodine receptor, calcium channel in the sarcoplasmic reticulum)

XLMM: MTM1 (myotubularin)

Supportive care

Surgical correction of strabismus and ptosis where indicated

Congenital fiber-type disproportion^{a 22} ID#b282a672_23 ^– ID#b282a672_24 ²⁵

Birth

Floppiness, limb and facial weakness; ptosis, ophthalmoplegia, bulbar weakness and diaphragmatic weakness

Usually non-progressive or may show improvement over time

AD, AR, or XLR

ACTA1 (skeletal muscle actin), SEPN1 (Selenoprotein N), TPM3 (Tropomyosin 3)

Supportive care

Surgical correction of strabismus and blepharoptosis where indicated

Kugelberg-Welander syndrome^{a, 27}

After 1 year

Hypotonia and weakness proximal >distal. 50% have scoliosis and restrictive lung disease. Diaphragmatic weakness may occur late in the disease. May have blepharoptosis.

Progressive

AR

SMN (survival motor neuron protein), NAIP (neuronal apoptosis inhibitory protein)

Supportive care

Surgical correction of blepharoptosis

Lymphedema-distichiasis-syndrome ³¹ ID#b282a672_32 ^{– 33}

Variable

Lymphedema, distichiasis, blepharoptosis in 30% of patients. Possible systemic associations include cardiac defects, cleft palate, spinal cord cysts, and scoliosis

Lymphedema develops by age 40, distichiasis occurs in 94%, presentation of blepharoptosis is variable

AD; 25% sporadic

FOXC3 gene (forkhead box C2, a transcription factor)

Treatment of lymphedema and distichiasis by conventional methods.

Surgical correction of blepharoptosis

Multiminicore myopathy^{a, 17 ,​ 35 ,​ 36}

Birth, infancy

Hypotonia, generalized muscle weakness (predominately axial), facial weakness, blepharoptosis, ophthalmoplegia

Static or progressive

AR

RYR1 gene in atypical cases (skeletal muscle ryanodine receptor, Calcium channel in the sarcoplasmic reticulum), SELENON gene in classic cases (Selenoprotein N)

Supportive care

Surgical correction of strabismus and blepharoptosis

Myotubular myopathy^{a, 17}

Birth to childhood

Severe weakness, hypotonia, facial weakness, bulbar weakness, diaphragmatic weakness

Frequently fatal in childhood

XLR (most severe form), AD (least severe and does not affect eyes), AR

MTM1 gene (myotubularin)

Supportive care

Surgical correction of blepharoptosis where indicated

Noonan syndrome ⁴⁰

Birth

Distinct facies notable for hypertelorism, epicanthal folds, blepharoptosis, micrognathia, webbed neck, low posterior hairline, pectus carinatum, short stature, kyphosis/scoliosis, cardiac anomalies, platelet deficiency, cryptorchidism

Nonprogressive

AD

PTPN11 (50%)

SOS 1(10–13%)

RAF1(5%)

RIT1

(these genes encode proteins important in the RAS/MAPK cell signaling pathway important for cell division, growth, differentiation and migraine)

KRAS (<5%)

Less frequent:

NRAS

BRAF

MEK2

RRAS

RASA2

A2ML1

SOS2

LZTR1

Surgical correction of blepharoptosis in indicated cases

Sensory ataxic neuropathy, dysarthria and ophthalmoplegia (SANDO) ^{42 ,​ 43}

Variable (5–17 years of age)

Sensory ataxic neuropathy, dysarthria, ophthalmoparesis. Hearing loss, seizures, myopathy may occur and lead to blepharoptosis.

Progressive

AR (nuclear coded mitrochondrial DNA)

POLG (DNA polymerase gamma gene)

Supportive care

Surgical correction of strabismus and blepharoptosis in indicated cases

Vertebral fusion posterior lumbosacral blepharoptosis ⁴⁵

Birth

Congenital blepharoptosis, posterior fusion of lumbosacral vertebrae

Nonprogressive

AD

Unknown

Treatment of lumbosacral vertebral fusion by conventional methods; surgical correction of blepharoptosis

Chronic progressive external ophthalmoplegia ^{17 ,​ 46}

Early adulthood

Generalized weakness, blepharoptosis, ophthalmoplegia, facial weakness including orbicularis; Plus syndrome includes sensorineural hearing loss, ataxia, parkinsonism

Progressive

AR, AD, MM

Nuclear DNA (AD):

POLG

TWNK

SLC25A4

Nuclear DNA (AR):

POLG

RRM2B

Mutation in these genes leads to large deletions of mtDNA in muscle cells; mechanism unclear

Mitochondrial DNA:

MT-TL1 (disrupt tRNA function, thus interrupting production of proteins involved in oxidative phosphorylation)

Surgical correction of strabismus, followed by surgical correction of blepharoptosis where indicated

Myotonic dystrophy type I and II (DMI, DMII)^{b, 28 ,​ 49}

Congenital, juvenile, and adult forms

Hypotonia, blepharoptosis, diaphragmatic weakness, atrophy, myotonia, cardiac conduction abnormalities. DMII is less severe.

Progressive

AD

DMI: DMPK

DMII: CNBP

Leads to expanded microsatellite sequences and intranuclear accumulation of mutated transcripts

Supportive care; surgical correction of blepharoptosis where indicated

Oculopharyngodistal myopathy ^{28 ,​ 50 ,​ 51}

Adulthood

Blepharoptosis, external ophthalmoplegia, dysphagia, and distal weakness.

Progressive

AD, AR

Unknown

Supportive care

Surgical correction of strabismus and blepharoptosis in indicated cases