blepharoptosis

Spinocerebellar Ataxia 3

Clinical Characteristics
Ocular Features: 

External ophthalmoplegia in some form is usually present and there may be a supranuclear component.  Smooth horizontal movements are impaired and saccades are dysmetric.  Gaze-evoked nystagmus is a common finding.  The eyes are often described as 'bulging' and this has been attributed to eyelid retraction.  With time the abnormal saccadic movements slow resulting in ophthalmoparesis with restriction of upgaze.

Systemic Features: 

This form of spinocerebellar ataxia is considered to be the most frequent.  It is a progressive disease in all aspects which accounts for some of the considerable clinical heterogeneity reported.  Onset is likewise highly variable depending upon the number of repeats but usually sometime between the second to fifth decades.  In a large cohort of Azorean individuals the mean age of onset was reported to be 37 years.

An unsteady gait, dysarthric speech, general clumsiness, and diplopia are among the early symptoms.  Nystagmus, spasticity, and various autonomic signs including reduced bladder control may also be noted.  Chronic pain, sleep disturbances, impaired mental functioning, and memory deficits are often present and some authors have labelled these as indicative of dementia.

Virtually all clinical signs progress with ambulation difficulties requiring the need for assistive devices about a decade after the onset of disease.  Eventually signs of brain stem involvement appear with facial atrophy, perioral twitching, tongue fasciculations and atrophy, and dysphagia. Some degree of peripheral polyneuropathy with muscle wasting and loss of sensation are often present.  Tremors and other signs of Parkinsonism may be present.  Dystonic movements are often seen.

Imagining of the brain has revealed pontocerebellar atrophy and enlargement of the 4th ventricle but this is variable.  Nerve conduction studies documents involvement of the sensory nerves.  Neuropathologic studies show widespread neuronal loss in the CNS and spinal cord.

Genetics

This is considered to be an autosomal dominant disorder caused by an excess of heterozygous trinucleotide repeats in the ataxin3 gene (14q32) encoding glutamine.  The number in normal individuals is up to 44 repeats whereas patients with SCA3 have 52-86 repeats.  However, clinical signs of SCA3 have been found in patients with as few as 45 glutamine repeats.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Physical and occupational therapy combined with regular exercise has been reported to slow the progression of symptoms.

References
Article Title: 

Machado-Joseph disease

Sudarsky L, Coutinho P. Machado-Joseph disease. Clin Neurosci. 1995;3(1):17-22. Review.

PubMed ID: 
7614089

3MC Syndromes

Clinical Characteristics
Ocular Features: 

The major ocular features involve the periocular structures.  These result in the typical facial dysmorphism and include hypertelorism, blepharoptosis, blepharophimosis, and highly arched eyebrows. Ptosis, unilateral or bilateral, can be present.

One patient was reported to have unilateral aniridia and a corneal leucoma.  Tear duct atresia was reported in another individual.

Systemic Features: 

Systemic features are highly variable in their presence and severity.   Facial clefting, growth deficiency, cognitive impairment, and hearing loss are present about half the time in some combination while craniosynostosis, urogenital anomalies, and radioulnar synostosis are seen in about a third of individuals.  More rare features include cardiac defects and abdominal midline defects (omphalocele and diastasis recti).

Genetics

This condition (3MC) is now postulated to include at least 3 disorders (Malpuech-Michels-Mingarelli-Carnevale syndromes) and considered here as a single autosomal recessive disease complex with overlapping clinical features that requires genotyping for diagnostic separation.  These are: 3MC1 syndrome (257920) resulting from homozygous mutations in the MASP1 gene (3q27.3), 3MC2 syndrome (265050) caused by mutations in the COLEC11 gene (2p25.3) and 3MC3 (248340) with mutations in the COLEC10 gene (8q24.12).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective general treatment has been reported.

References
Article Title: 

COLEC10 is mutated in 3MC patients and regulates early craniofacial development

Munye MM, Diaz-Font A, Ocaka L, Henriksen ML, Lees M, Brady A, Jenkins D, Morton J, Hansen SW, Bacchelli C, Beales PL, Hernandez-Hernandez V. COLEC10 is mutated in 3MC patients and regulates early craniofacial development. PLoS Genet. 2017 Mar 16;13(3):e1006679. doi: 10.1371/journal.pgen.1006679. eCollection 2017 Mar.

PubMed ID: 
28301481

Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome

Rooryck C, Diaz-Font A, Osborn DP, Chabchoub E, Hernandez-Hernandez V, Shamseldin H, Kenny J, Waters A, Jenkins D, Kaissi AA, Leal GF, Dallapiccola B, Carnevale F, Bitner-Glindzicz M, Lees M, Hennekam R, Stanier P, Burns AJ, Peeters H, Alkuraya FS, Beales PL. Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome. Nat Genet. 2011 Mar;43(3):197-203.

PubMed ID: 
21258343

Fibrosis of Extraocular Muscles with Synergistic Divergence

Clinical Characteristics
Ocular Features: 

This is an ocular motility disorder with restrictive ophthalmoplegia and anomalous eye movements.  Some individuals exhibit Marcus Gunn jaw winking and downgaze fixation along with ptosis.  MRI imaging may reveal hypoplasia of the oculomotor nerve and absence of the abducens nerve.  Sometimes one or more extraocular muscles are replaced with fibrous tissue.  Globe retraction may accompany the abduction movement.  Forced duction testing may reveal severe restriction and Bell's phenomenon may be absent.  Vertical nystagmus and jerky eye motions may accompany attempted fixation.  There is considerable asymmetry to the extraocular movements of the two eyes. 

Systemic Features: 

Some patients have oculocutaneous hypopigmentation.

Genetics

No specific mutation has been identified.  Several examples of parent to child transmission have been reported suggesting autosomal dominant inheritance.

Other nonsyndromal forms of congenital fibrosis of extraocular muscles include: CFEOM1 (135700), CFEOM2 (602078), CFEOM3C (609384), and CFEOM5 (616219), although the eye movement phenotype may vary.  See also Tukel CFEOM syndrome (609428).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Ptosis and strabismus surgery may be of benefit.

References
Article Title: 

Fibrosis of Extraocular Muscles, CFEOM1

Clinical Characteristics
Ocular Features: 

Hereditary CFEOM is a congenital, nonprogressive condition.  The eyes are usually fixed in the infraducted position about 20-30 degrees below the primary position.  Horizontal movement is absent or severely restricted.  Blepharoptosis is almost always present and patients exhibit a marked chin-up position of gaze.  Binocularity is usually absent.  Some patients have large amounts of astigmatism.  Amblyopia has been reported to occur on a refractive or strabismic basis.  However, careful examination of the optic nerve may reveal anomalies such as increased cupping, asymmetric cupping and hypoplasia and could be responsible for the reduced vision in some patients.

Neuropathologic studies in rare patients have shown defects in brainstem neural development including in one case absence of the superior division of the oculomotor nerve.  Fibrosis of extraocular muscles and Tenon's capsule as well as adhesions to the globe and between muscles have been described.   Anomalous insertions of EOMs may also occur.  An MRI can reveal atrophy of the levator palpebrae and the superior rectus muscles as well as absence or hypoplasia of the oculomotor and sometimes abducens nerves.  It is now considered that CFEOM disorders result from primary neuronal disease resulting in secondary myopathy. 

Systemic Features: 

Late onset gait abnormalities associated with MRI documented vermis atrophy have been reported in a single autosomal dominant pedigree.  The diagnosis of CFEOM1 was confirmed with molecular studies but only two older individuals aged 79 and 53 years had the cerebellar atrophy while a 33 year old in the same family had only CFEOM with no gait difficulties and no neuroimaging abnormalities.

Genetics

CFEOM1 is an autosomal dominant disorder caused by mutations in the KIF21A gene located at 12q12.  This is considered the classic form of congenital, restrictive strabismus but other types such as CFEOM2 (602078) and CFEOM3 (600638, 609384) have also been reported.  CFEOM3 is a clinically heterogeneous autosomal dominant condition and the label is usually applied to individuals who do not meet the criteria for the other two types.  A rare subtype (CFEOM3B) is also due to mutations in the KIF21A gene.  CFEOM3A (600638) is caused by mutations in the TUBB3 gene (16q24) while CFEOM3C (609384) maps to 13q.

The CFEOM2 (602078) phenotype is due to mutations in the PHOX2A (ARIX) gene and inherited in an autosomal recessive pattern.

Other nonsyndromal forms of congenital fibrosis of extraocular muscles include: CFEOM3C (609384), CFEOM5 (616219), and CFEOM with synergistic divergence (609612).  See also Tukel CFEOM syndrome (609428).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Normal ocular movements cannot be restored but large recessions of the inferior recti followed by frontalis suspension of the upper eyelids can improve severe ptosis and the compensatory chin-up gaze. Corneal lubrication must be maintained.  Refractive errors and amblyopia should be corrected.  

References
Article Title: 

Blepharoptosis, Myopia, Ectopia Lentis

Clinical Characteristics
Ocular Features: 

A mother and 2 daughters with ectopia lentis, myopia, and blepharoptosis have been reported.  The axial length of the globes was increased in the mother and one of the daughters while the myopia in the other daughter with ectopia lentis was presumably lens-induced as the equator bisected the visual axis (axial length approximately 25mm).  The upper lid creases were considered to be abnormally high but levator function was good, consistent with levator aponeurosis disinsertion.  Extraocular movements were normal.  

Systemic Features: 

No systemic abnormalities were present.  More specifically, there was no evidence of Ehlers-Danlos (225400) or Marfan syndrome (154700).

Genetics

The presence of similar findings in a mother and 2 daughters suggests autosomal dominant inheritance but no locus has been identified. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Displaced lenses may need to be removed. 

References
Article Title: 

Smith-Lemli-Opitz Syndrome

Clinical Characteristics
Ocular Features: 

A large number of ocular anomalies have been found in SLO syndrome but the most common is blepharoptosis of some degree.  No consistent pattern of ocular abnormalities has been reported.  Atrophy and hypoplasia of the optic nerve, strabismus, nystagmus, and cataracts may be present.   Abnormally low concentrations of cholesterol and cholesterol precursors have been found in all ocular tissues studied.

Systemic Features: 

This is a syndrome of multiple congenital anomalies.  Among these are dwarfism, micrognathia, hard palate anomalies, hypotonia, anomalies of the external genitalia, polysyndactyly, microcephaly, and mental retardation.  It has been suggested that many individuals have a characteristic behavioral profile consisting of cognitive delays, hyperreactivity, irritability, language deficiency, and autism spectrum behaviors.  Some individuals exhibit aspects of self destructive behavior.  Tissue levels of cholesterol are low.

Genetics

SLO syndrome is an autosomal recessive disorder resulting from mutations in the sterol delta-7-reductase  (DHCR7) gene mapped to 11q12-q13. The result is a defect in cholesterol synthesis.

The clinical features significantly overlap those seen in Meckel (249000) and Joubert (213300) syndromes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

A high cholesterol diet has been reported to have a beneficial effect on behavior and general well-being.

References
Article Title: 

Strømme Syndrome

Clinical Characteristics
Ocular Features: 

The core complex of Stromme syndrome consists of intestinal atresia and ocular abnormalities of the anterior segment.  The ocular anomalies consist of variable amounts of angle dysgenesis, anterior synechiae, corneal leukoma, iris colobomas and hypoplasia, sclerocornea, cataracts, and sometimes microcornea.  However, microphthalmia, tortuous retinal vessels, and optic nerve hypoplasia may also be present.  Hypertelorism and deep-set eyes have been described.  Glaucoma has not been reported.  Only about 10 cases have been reported since Stromme 's first report in 1993.  Most patients have been too young for reliable acuity testing. 

Systemic Features: 

The phenotype is highly variable.  The ears are often large and low-set.  Microcephaly is often present along with a cleft palate and micrognathia.  The intestinal atresia seems to involve the jejunum primarily and is usually surgically correctable.  The duodenum may also be involved and intestinal malrotation has been described.  Myopathic changes in the myocardium have been seen along with small cardiomyoctes.  Microcephaly seems to be progressive.  Short stature has been noted and the amount of developmental delay is highly variable.  Renal hypodysplasia and hydronephrosis have been described.

Some patients seem to develop and function almost normally while more severely affected individuals may not live beyond early infancy or childhood.

Genetics

Compound heterozygous mutations in the CENPF gene (1q41) segregate with this condition. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Infants do well following intestinal surgery.  Ocular surgery has not been reported.

References
Article Title: 

Stromme Syndrome: New Clinical Features

Stromme Syndrome: New Clinical Features Bayram Ali Dorum, Irmak Tanal Sambel, Hilal Ozkan, Irfan Kiristioglu, Nilgun Koksal APSP J Case Rep. 2017 Mar-Apr; 8(2): 14. Published online 2017 Mar 18.

PubMed ID: 
5371687

Stromme Syndrome is a Ciliary Disorder Caused by Mutations in CENPF

Filges I, Bruder E, Brandal K, Meier S, Undlien DE, Waage TR, Hoesli I, Schubach M, de Beer T, Sheng Y, Hoeller S, Schulzke S, Rosby O, Miny P, Tercanli S, Oppedal T, Meyer P, Selmer KK, Stromme P. Stromme Syndrome is a Ciliary Disorder Caused by Mutations in CENPF. Hum Mutat. 2016 Jan 28. doi: 10.1002/humu.22960. [Epub ahead of print].

PubMed ID: 
26820108
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