Seminars in Ophthalmology, 2013; 28(5–6): 313–320

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ISSN: 0882-0538 print / 1744-5205 online
DOI: 10.3109/08820538.2013.825276

Genetics of Ectopia Lentis

Mohammad Ali Sadiq and Deborah Vanderveen

Department of Ophthalmology, Boston Children’s Hospital, Boston, Massachusetts, USA

ABSTRACT
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Hereditary ectopia lentis or lens subluxation can occur with and without systemic associations. Significant
overlap can be found in the genetic mutations and pathogenesis of subluxated lenses in their isolated forms as
well as with associated syndromes. Gene mutations have been identified for lens subluxation associated with
Marfan syndrome, Weill Marchesani syndrome, Ectopia Lentis simplex, Ectopia Lentis et pupillae, Ehlers
Danlos syndrome, homocystinuria, and sulfite oxidase deficiency. Herein we describe the ocular and systemic
characteristics found in patients with ectopia lentis, as well as the gene mutations identified thus far.
Keywords: Ehler Danlos, homocystinuria, marfan, subluxated lens, sulfite oxidase deficiency, weill marchesani
For personal use only.

INTRODUCTION anterior uveal tumors, pseudoexfoliation syndrome,

Ectopia lentis is displacement of the lens from its
normal position. Subluxated lens refers to a partial
displacement of the lens, with some of the zonules
remaining intact so that part of the lens remains in the
pupillary area. Luxated or dislocated lens is the
complete separation of all zonular attachments,
causing the lens to be completely displaced from the
pupil.
Lens subluxation can lead to high refractive error,
marked astigmatism, monocular diplopia, decreased
best corrected acuity, and iridodonesis. Additional
complications may include cataract formation, dis-
placement of lens into the anterior chamber or the
vitreous. With displacement of the lens into the
vitreous, leakage of lens proteins may occur, resulting
in chronic vitritis and chorioretinal inflammation.1
Tractional changes on the retina may occur. Anterior
displacement can lead to pupillary block, with acute
and/or chronic angle closure glaucoma. Amblyopia
may occur in the pediatric population, and asymmet-
ric subluxation at an early age may cause amblyopia
that may be severe and irreversible.2
Ectopia lentis may be hereditary or secondary to
other causes. The secondary causes include trauma, a
large eye (e.g., high myopia and buphthalmos),
and hypermature cataracts. The hereditary causes
can broadly be divided into causes with systemic
associations (Marfan’s syndrome, homocystinuria,
Weill-Marchesani syndrome, Ehlers Danlos syn-
drome, sulfite oxidase deficiency syndrome, and
hyperlysinemia) and those without systemic associ-
ations (Familial Ectopia lentis, Ectopia lentis et
pupillae, and Aniridia).
This review will focus on the hereditary types of
lens subluxation. Both clinical features and the
associated genetic mutations for each syndrome
associated with ectopia lentis will be reviewed.
CAUSES WITH SYSTEMIC
ASSOCIATIONS
13
20
Marfan Syndrome
Marfan syndrome, first described by French pediatri-
cian Antoine-Bernard Marfan, is an autosomal dom-
inant systemic disorder of the connective tissue with
severe manifestations in the cardiovascular, ocular,
and skeletal systems. Its estimated incidence is 1 in
5000, affecting both sexes equally. The most striking
observations in this syndrome are the long bone

Received 11 April 2013; accepted 11 July 2013; published online 26 September 2013
Correspondence: Mohammad Ali A Sadiq, Email: sadiq.maa@gmail.com

313
 314 M. A. Sadiq and D. Vanderveen
overgrowth, leading to disproportionately long limbs
and anterior chest deformities due to rib overgrowth.
Other skeletal manifestations include arachnodactyly,
elbow contractures, scoliosis or spondylolisthesis,
protrusion acetabulae (detected by X-ray), and calca-
neal displacement resulting in pes planus with hind-
foot valgus.3 The typical facial characteristics include
down-slanting palpebral fissures, enophthalmia, ret-
rognathia, and a high arched palate with tooth
crowding. The troublesome locomotor symptoms
include muscle hypoplasia and myalgia, resulting in
fatigue and spinal pain. These increase with age and
affect up to 98% of adult patients.4
The diagnostic criteria for Marfan syndrome,
determined by international consensus, are known
as the Ghent criteria5; aortic root aneurysm and
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ectopia lentis are cardinal features. Lens subluxation
occurs in 50–80% of patients with Marfan syndrome.
This is best assessed by a slit lamp examination after
pupillary dilatation. Lens subluxation is mostly
supero-temporal and accommodation is retained.
Other ocular findings (e.g., high myopia, retinal
detachment, cataract, or glaucoma) may also cause
significant visual impairment or even blindness.6
Aortic root dilatation, dissection, and rupture
remain the leading causes of morbidity and mortality
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in Marfan syndrome patients. The aortic dilatation is
generally greatest at the sinuses of the valsalva.
Measurements of the aortic root should be normalized
to body surface area and age.7 Two-thirds of patients
have mitral valve dysfunction, with valve prolapse,
insufficiency, and calcification often associated with
myxomatous valve thickening.8 Dural ectasia is also
seen in 92% of patients and may be detected in young
children.9
Genetics
Family history and genetics play a vital role in
confirming the diagnosis of Marfan syndrome. The
disorder is inherited in an autosomal dominant
fashion in 75% of cases, and 25% cases result from
de novo mutation.
Dietz et al. reported that alterations in microfibrils,
caused most commonly by mutation of the fibrillin-1
gene (FBN1), which maps to 15q21, cause classic
Marfan syndrome.10 Fibrillin-1 is an extracellular
matrix glycoprotein essential to normal fibrinogen-
esis. It is a 350-kDa protein responsible for a head to
tail assembly of 10- to 12-nm fibrillin monomers in the
presence of calcium constituting microfibrils.11
Mutations of the fibrillin-1 gene increase the suscep-
tibility of fibrillin-1 to proteolysis in vitro, leading to
microfibrils’ fragmentation. The mutation may also
cause changes in the cell to cell signaling via latent
binding transfer protein.12 It has also been hypothe-
sized that the alterations in fibrillin result in alteration
in Transforming Growth Factor-beta (TGFB) signal-
ing.13 There has been recent identification of a
mutation in TGFB receptor 2 gene responsible for
Marfan syndrome type 2.14 These TGFB-2 mutations,
however, are also responsible for other conditions,
including Loeys-Dietz aneurysm syndrome and famil-
ial thoracic aneurysm syndromes.
Currently, more than 1200 mutations in the FBN1
gene have been identified.15 Most mutations causing
severe disease are found to be clustered in exons
24–32, which encodes a central stretch of 12 cbEGF
repeats. This stretch is important in the formation of a
rigid rod-like structure, which might be involved in
the formation of microfibril assembly.16 So far, no
correlation between a specific type of mutation and
the clinical phenotype has been recognized.17
Interestingly, among Marfan syndrome patients with
ectopia lentis, a higher frequency of cysteine substi-
tution was observed opposed to the premature
termination codon mutations.18 The ocular manifest-
ations in a Pakistani family carrying mutations in
exon 19 of FBN1 were also severe.11
Due to the mutation in fibrillin-1 gene-causing
conditions other than Marfan-like disorder, and
the fact that the current methods used to find
mutations in the fibrillin-1 gene cannot identify all
the mutations that cause this syndrome, the diagnosis
continues to depend primarily on clinical features that
have been codified into the Ghent diagnostic
nosology.5
Homocystinuria
Cognitively delayed patients in Northern Ireland and
Wisconsin and patients with dislocated lenses seen at
the Wills Eye Hospital in Philadelphia19 were found to
have homocystinuria as well as elevation of plasma
methionine in 1962.19,20
Clinically, these patients have marfanoid-like
appearance, and the most frequent clinic abnormal-
ities in such patients are cognitive delays, dislocation
of crystalline lenses (mostly infero-nasal), early
thromboembolic events, and skeletal abnormalities
including osteoporosis, genu valgum, and thinning
and lengthening of the long bones. Mudd et al.21
demonstrated that 86% of patients have been diag-
nosed on the basis of ectopia lentis.
Barber and Spaeth were able to demonstrate the
metabolic abnormality of some patients decreasing
during administration of pharmacological doses of
vitamin B6 (B6-responsive), while other patients did
not demonstrate this response (B6-non-responsive).22
The median IQ in B6-non-responders was found to be
markedly lower than in B6-responders. Lens sublux-
ation occurred in 50% of B6-non-responders by the
age of six years and 50% of B6 responders by the age
of 10 years. Thromboembolic event in both groups
Seminars in Ophthalmology

occurred in 25% of patients by the age of 16 years, and
by 50% by age of 29 years.
In homocystinuria, lens subluxation is the result of
degenerative changes in the zonular fibers. These
fibers are composed of fibrillin microfibrils which are
rich in half-cystine residues with the total zonular
protein containing from 38 to 83 such half-cystine per
1000 amino acid. It was recently demonstrated that
treatment of fibrillin-1 with homocysteine led to the
formation of disulfide bonds and made the protein
more susceptible to proteolytic degradation.23
The reduction of disulfide bonds within fibrillin-1
cbEGF domains by elevated homocysteine, resulting
in the loss of native structure and protein misfolding,
may play a role in the bony changes seen in
homocysteinuria.24 Osteoporosis may be the result of
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interference by homocyseine with the collagen
crosslinks.
Genetics
Homocystinuria has an autosomal recessive inherit-
ance pattern, and is associated with a cystathionine
beta-synthase (CBS) deficiency.25 Using the newborn
screening programs, CBS deficiency overall has been
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found at rates of 1:344,000.26 CBS is a pyridoxal
5’-phosphate-dependent tetramer composed of sub-
units, each 63 kDa in size,27 551 amino acids long, and
organized in a three-domain structure.28 The human
CBS gene has been located in the subtelomeric region
of band 21q22.3 of chromosome 21, where the gene for
alpha-crystallin, a major structural protein of the
ocular lens, is also found.29
Studies have shown that misfolding plays an
important role in the pathogenesis of CBS muta-
tions.30 More than 150 human mutations are now
known. Many are private or have been rarely found,
but several are more common and/or regional.
The mutation that accounts for close to a quarter of
all homocystinuric alleles is the c.833T4C transition
mutation, p.1278T.31 This is generally associated with
B6-responsiveness and a milder phenotype. The
c.919G4A transition, p.G307s mutation, having a
more severe clinical phenotype, is also very prevalent
and is mainly found in patients of Celtic origin.32
C.572C4T transition, p.T191 M, is a common muta-
tion in the Iberian peninsula and Latin American
countries and has been reported to be B6-non-
responsive with a low vascular disease prevalence.33
D444 N mutation has been found in homozygous
Venezuelan patients with vascular involvement as the
main feature and a marfanoid habitus.34 The com-
pound heterozygous T3553 M mutation associated
with B6-non-responsive phenotype has been found in
Georgia (USA)35 as well as in Korean patients.36
Additionally, 24 mutations in the MTHFR gene
have been found in patients with homocysteinuria.
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Genetics of Ectopia Lentis 315
The C677T mutation is associated with an increased
risk of cardiovascular disease as well as neural tube
defects and the development of cancers and leukemia
as well as predisposition to schizophrenia.37
B6-responsiveness (i.e., whether B6 administration
will lead to substantial lowering of homocysteine
and its derivatives) requires the presence of at least a
small amount of CBS activity. It is also dependent
on the particular CBS mutations(S) present in an
individual. However, Kruger and coworkers, through
comparisons of mutations R266K and 1278T, exem-
plified that multiple mechanisms may be involved
in responsiveness to B6.38 Therefore despite the
availability of results of extensive and informative
studies characterizing a wide variety of mutations,
it appears that at this time no set of criteria have
emerged upon which predictions of the B6 respon-
siveness of novel missense CBS mutations might be
firmly based.
Weill Marchesani Syndrome
The rare syndrome Weill-Marchesani syndrome was
first described by Weill in 1932 and then delineated by
Marchesani in 1939. It is a generalized connective
tissue disorder characterized by short stature, brachy-
dactyly, thick skin and stiff joints,39 and occasional
heart defects.40
The primary clinical manifestation is ocular, with
the mean age of recognition being 7.5 years.40 The lens
is spherical, frequently small, and lacks evidence of
microfibrils around its equator.41 Micropsherophakia
causes lenticular myopia and lack of microfibrils
results in downward displacement of the lens.40
Glaucoma develops at an early age, which severely
compromises the vision eventually.42 Presenile vitre-
ous liquefaction has been described in a large family
with the syndrome.43
Genetics
Two modes of inheritance have been described for this
clinically homogenous syndrome: autosomal domin-
ant inheritance44 and autosomal recessive inheritance
with occasional brachymorphism in heterozygotes.45
Mutation in ADAMTS10 (A Disintegrin-like And
Metalloproteinase domain, reprolysin type, with
Thrombospondin type 1 repeats) causes the auto-
somal recessive form of Weill-Marchesani syn-
drome,46 while a mutation in FBN1 was found in a
large family with autosomal dominant inheritance.47
Weill-Marchesani-like syndrome with ocular mani-
festations and short stature, but without stiffness of
the distal joints, brachydactyly, and cardiac valvular
anomalies, has been reported to result from
ADAMTS17 mutations.48
 316 M. A. Sadiq and D. Vanderveen
The FBN1 mutation causing Weill-Marchesani syn-
drome is an in-frame deletion of eight amino acids
within exon 41 affecting the TB5 module.47 A second
mutation has been reported in abstract from in an in-
frame deletion near the N-terminus that removed the
TB1 module, the proline-rich region and EGF-like
domain 4.
Clinical evidence has suggested that ADAMTS
proteins interact with fibrillin-1 in some way to
contribute to both the structural and regulatory roles
of microfibrils. It has also been suggested that the
relevant ADAMTS proteins bind directly to fibrillin-1,
providing a starting point for defining the molecular
mechanisms underlying each phenotype.41 It has been
established that in vitro, ADAMTS10 not only bound
specifically to fibrillin-1 with high affinity but was
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also associated with dermal and zonule fibrillin
microfibrils.49 ADAMTS10 also cleaves fibrillin-1
inefficiently, since it is activated by furin, whereas
conditioned medium containing ADAMTS10 acceler-
ates the assembly of fibrillin-1 microfibrils by fibro-
blast culture.49 This role of being involved in
microfibril assembly explains the ectopia lentis result-
ing from the loss of fibrillin-1 microfibrils in the
zonule.
An influence on the regulatory role of fibrillin is
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suggested as a cause of other organ anomalies and
dysmorphism as a consequence of ADAMTS10,
ADAMTS17, and ADAMTS2 mutations. The high
levels of active TGF-beta and evidence of TGF-beta
signaling in GD dermal fibroblasts provide a convin-
cing example of this function.50
Ehlers Danlos Syndrome
Ehlers Danlos syndrome is estimated to be approxi-
mately 1 in 5000 births, with no racial predisposition.
The main clinical features present in all subtypes
including skin hyperextensibility, delayed wound
healing with atrophic scarring, joint hypermobility,
easy bruising, and generalized fragility of the soft
connective tissues.3
The ocular features associated with Ehler Danlos
syndrome include scleral fragility, keratoconus, and
myopia with ectopia lentis occurring occasionally.
Genetics
In 50% of classic types of Ehler Danlos syndrome,
mutations in the COL5A1 and COL5A2 genes encod-
ing the alpha1- and alpha2-chains of type V collagen
are found. In approximately one-third of all classic
Ehler Danlos syndrome patients, the mutation leads to
non-functional COL5A1 allele, resulting in a dimin-
ished amount of type V collagen that is available
for collagen fibrillogenesis. In a smaller number of
patients, a mutation of COL5A1 or COL5A2 is found
which results in production of structurally altered and
functionally defective type V collagen protein.51
The relatively low detection rate for mutations in
COL5A1/A2 genes suggests genetic heterogeneity.
Mutations in non-collagenous protein, tenascin-X
leads to complete lack of serum tenascin-X. This
mutation is the cause of an autosomal recessive
phenotype with great similarities to classic Ehler
Danlos syndrome but without the atrophic scars.52
The cardiac valvular subtype has been observed to
have a complete deficiency of pro alpha2- chain of
type 1 collagen.53
The vascular type of EDS results from a wide
spectrum of COL3A1 mutations, the majority of
which are point mutations leading to substitution
for the obligatory glycine in the triple helical region of
collagen molecule.
Mutations in CoL1A1 or the COL1A2 gene result in
the distinct Ehler Danlos/Osteogenesis Imperfecta
overlap phenotype.54
Homozygous mutations in PLOD1 (procollagen-
lysine, 2-oxoglutarate 5-dioxygenase, or lysyl-hydro-
genase-1) are found in patients with the kyphoscoliotic
type of syndrome while a deficient activity of pro-
collagen-N-proteinase due to mutations in the
ADAMTS-2 gene encoding the lysyl hydroxylase-1
enzyme is responsible for the dermatosparaxis type of
Ehler Danlos Syndrome.55
Hyperlysinemia
Hyperlysinemia, an inborn error of metabolism of
the amino acid lysine, is associated with ectopia
lentis. Affected individuals show mental retardation,
recurrent emesis, hypotonia, lethargy, diarrhea, and
developmental delay.
Genetics
Familial hyperlysinemia, an autosomal recessive dis-
order that was first reported in individuals with
physical and mental retardation, was found to be
due to a bifunctional enzyme.56 Subsequent studies
identified hyperlysinemia in normal individuals, sug-
gesting that hyperlysinemia alone may not be involved
with a clinical phenotype.57 The disorder was found to
be associated not only with a defect in lysine-
ketoglutarate reductase (LKR) activity but also with a
defect in saccharopine dehydrogenase (SDH) activity,
suggesting the existence of a single locus encoding for
both of these activities.58 In the yeast saccharomyces
cerevisiae, these two activities are encoded by two
separate genes – LYS1 and LYS9, respectively.59
However, in humans, a mutation in the AASS gene
encoding the alpha-aminoadipate semialdehyde
Seminars in Ophthalmology

synthase, the bifunctional protein that contains both
the LKR activity and SDH activity, has been found to
be responsible for this disorder.60
The AASS gene includes 24 exons that span approx
68 kb and is localized to chromosome 7q31.3.
Homozygous 9-bp deletion in exon 15 has been
identified in a patient with hyperlysinemia. The 9-bp
deletion is out of frame and results in the formation of
a stop codon across the deletion, resulting in a
predicted protein that lacks the 393 C-terminal
amino acids and most of the putative SDH domain.
This premature stop codon affects AASS mRNA
processing or stability and thus causes reduction in
the activities of both LKR and SDH.60
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Sulfite Oxidase Deficiency Disorder
This rare syndrome’s first case was reported by
Irrevere in 1967. The case reported was opisthotonic
at birth and had a poor suck and was hypertonic in all
four limbs by one month of age. No motor or verbal
skills were ever developed and ectopia lentis was
observed at one year of age. Urine samples showed
sulfite, S-sulfocysteine, and thiosulfate. Urinary inor-
ganic sulfate levels were reduced and serum uric acid
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levels were normal. Measuring sulfite oxidase activity
in post-mortem samples of liver, brain, and kidney
from the patient confirmed that the metabolic defect
was in the sulfite oxidase enzyme.61
Only 21 cases of sulfite oxidase deficiency have
been reported in the literature to date. Neurologic
abnormalities have been prominent in the presenta-
tion of all reported cases, ranging from abnormal
muscle tone, seizures, abnormal movements includ-
ing choreoathetosis and dystonia, and global devel-
opmental delay.62 Cerebral edema without any
evidence of ventricular dilatation has been seen
early in the disease with both CT and MR scans.63
Ventirculomegaly can be seen on MRI scans as early as
12 days.63 Cerebral and cerebellar atrophy and cystic
changes has also been observed neuroradiologically
as well as on postmortem reports.
Respiratory distress has been reported as a symp-
tom of this disorder, presenting in the first 24 hours
of life.64
Ectopia lentis has been reported in 53% of patients;
the age of detection ranges from 3 months to 3.5 years.
The pathophysiology of ectopia lentis in sulfite
oxidase deficiency is unknown. However, increase in
the proteolytic activity of matrix along with a reduc-
tion in the activity of tissue inhibitor of metallopro-
teinases (TIMP) was reported in a case of isolated
ectopia lentis.65 Those authors suggested that an
increase in the activity of MMPs might result in
increased fibrillin degradation and hence dislocation
of the lens. The binding of TIMP and MMPs involves
the formation of disulfide bonds.66 Because sulfites
! 2013 Informa Healthcare USA, Inc.
Genetics of Ectopia Lentis 317
are thought to interact with disulfide bonds in vivo
to form S-sulfonates,66 it is possible that an accumu-
lation of sulfites might inhibit the binding of TIMP to
MMPs, leading to excess MMP activity and lens
subluxation.
Genetics
Human sulfite oxidase gene (SUOX) is the gene
implicated in this disorder. This gene is located in
chromosome 12q13.13. At least 16 different patho-
genic mutations and 1 polymorphism (2012C4G)
have been reported for this gene.62 Most of the
mutations are private, but the 479G4A mutation,
resulting in R160Q substitution, occurs at a CpG
hotspot in the gene and has been identified for at least
four patients.67 Patients with missense mutation
experienced severe developmental delay.67 Two
patients have been seen with deletions in the sulfite
oxidase gene that result in a truncated protein. Both
died at an early age with one at 10 weeks of age68 and
the other at 32 months of age.69
CAUSES WITHOUT SYSTEMIC
ASSOCIATIONS
Ectopia Lentis Simplex and Ectopia Lentis et
Papillae
Ectopia lentis simplex is usually inherited as an
autosomal dominant trait, but the existence of an
autosomal recessive form also has been reported.70
Dominantly inherited ectopia lentis is usually bilateral
and symmetrical, with the lenses dislocated upward
and laterally, but without ectopia papillae.
Ectopia lentis pupillae is inherited as an autosomal
recessive trait. Enlarged corneal diameters71 and
microspherophakia72 have been described as features
of ectopia lentis et papillae. Usually the lenses and
pupils are displaced in the opposite direction in this
bilateral condition.
Genetics
A novel FBN1 mutation, E2447K, in exon 59 of FBN1
was first described in 1994.73 The mutation occurs in
cb-EGF motif no. 38 of FBN1, resulting in the
substitution of a highly conserved glutamic acid for
a lysine residue, and is predicted to affect calcium
binding. This phenotypic spectrum for this mutation
ranged from mild isolated skeletal features of Marfans
syndrome in some, to skeletal features and ectopia
lentis and/or severe ocular involvement (myopia,
peripheral iris atrophy, retinal lattice degeneration,
retinal detachment and glaucoma) in others. None of
 318 M. A. Sadiq and D. Vanderveen
these patients had the cardiovascular symptoms and
none had aortic root dilatation on echocardiography.
It was postulated that this might have a different
phenotypic effect than the more usual alterations of a
highly conserved cysteine residue associated with
Marfans syndrome.74
Autosomal dominant isolated ectopia lentis is
associated with FBN1 gene mutation, R240C, which
involves the substitution of a non-conserved arginine
residue for a cysteine. The mutations, which have
previously been reported in Marfans syndrome, have
mutations occurring in exons 2, 6, or 13 of the gene.
According to one report, 62% of mutations occur
between exons 1 and 15, 17% between exons 16 and
49, and 21% between exons 49 and 64. Almost half the
mutations involve substitution of a non-conserved
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arginine for a cysteine, and 24% involve substitution
of a cysteine for another amino acid.75
R240C mutation can thus cause purely isolated
ectopia lentis, ectopia lentis with involvement of
integument, or classic Marfans syndrome.75
SUMMARY
Genetic studies of syndromes associated with sub-
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luxated lenses have enabled us to better understand
the pathophysiology behind ectopia lentis. Defects in
microfibril assembly are a major mechanism contri-
buting to these subluxations. Mutations in the FBN1
gene, essential for normal fibrinogenesis, are found in
Marfans and Weill-Marchesani syndrome as well as
Ectopia lentis simplex and Ectopia lentis pupillae.
Mutations in the ADAMTS protein, which interacts
with fibrillin-1, is found in Weill-Marchesani and
Ehler Danlos syndrome. COL5A1 and 2 mutations
found in Ehler Danlos syndrome are involved in
encoding alpha 1 and 2 of type V collagen, which is
required for collagen fibrillogenesis. Homocystinuria
has CBS and MTHFR mutation; hyperlysinemia has
mutation in the bifunctional enzyme, AASS, while
sulfite oxidase deficiency syndrome has mutation in
SUOX gene. Further research into the genetics and
gene therapy may help us to develop treatments for
the consequences of these syndromes in the future.
DECLARATION OF INTEREST
The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of
the paper.
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