S Afr Optom 2012 71(4) 178-189

A review of ocular genetics and inherited eye

diseases
SD Mathebula

Department of Optometry, University of Limpopo, Private Bag x1106, Sovenga, 0727 South Africa

<solani.mathebula@ul.ac.za>
Received 23 April 2012; revised version accepted 2 November 2012

Abstract Knowledge of the clinical and molecular features

of ocular genetics and inherited eye diseases is im-
During the past twenty years, there has been an portant for appropriate diagnosis and patient man-
exponential increase in the knowledge and under- agement. This article reviews the current informa-
standing of ocular genetic diseases and syndromes. tion on ocular genetics and inherited eye diseases.
The number of human eye diseases that have a The ocular conditions described in the review have
known genetic or hereditary component contin- significant visual impairment and blindness con-
ues to increase. In addition, genetic diseases are sequences. Therefore, optometrists (as the mostly
the most common cause of blindness in infants and likely first line of consultation) should be able to
children in developed countries. Optometrists are diagnose the condition appropriately first before
likely to encounter patients with inherited eye dis- they could make any management, care or referral
orders. They may be the first clinician the patient plan. Visual aids are, of course, one of the manage-
consults. Inherited eye diseases may be isolated ment options for such patients with visual impair-
(only affecting the eye) or part of a complicated ment. (S Afr Optom 2012 71(4) 178-189)
syndrome. Both isolated eye diseases and genetic
syndromes can have identifiable gene mutation Key words: Ocular genetics, gene, genome, muta-
known to cause the disease. tion, Mendelian genetics.

Introduction to provide a review of the current understanding of

ocular genetics. This may be useful to clinicians and
The interest in ocular genetics by ophthalmolo- researchers in their ability to provide accurate genetic
gists who described the patterns of inheritance of diagnosis and appropriate counselling to patients and
familiar eye diseases contributed much to the hu- their families.
man discovery of ocular genetics. The pace of genes
(units of heredity) discovery has increased a lot and Basics of genetics
we now have the Human Genome Database1-4. Of the
approximately 4000 genetic diseases and syndromes Genetics is the study of hereditary and the vari-
known to affect humans, at least one-third involve the ation of inherited characteristics6. It is a matter of
eye3-6. Over the last two decades, there has been an general observation that the cubs of a lion resem-
exponential increase in our knowledge of genetic eye ble the lion and pups of a dog resemble the dog not
diseases and syndromes. The purpose of this paper is only in shape but also in habits, strength and func-

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tional abilities. Surely, there is something common and weaker hydrogen bonds pair A with T and C
between the parents and their offspring which is re- with G between the two strands. Some sections of
sponsible for such resemblance. Many speculations bases act as assembly instructions for proteins9. All
were made but none turned out to be correct unless proteins are made from amino acids and therefore,
mode of hereditary in sexually reproducing animals DNA acts as a set of instructions for the order of
was explained. It was Mendel who gave the concept amino acids from which the protein is made. Spe-
of “factor” being transmitted from parents to off- cific triplets of bases (codons) correspond with spe-
spring3. These factors are known as genes. cific amino acids. Because there are four bases (A,
A cell is a microscopic unit surrounded by a cell C, G and T), 24 triplet combinations are possible.
membrane in animals and a true cell wall in plants2. Since there are only 20 amino acids, there is much
The inner material, cytoplasm, consists of a nucleus redundancy in the genetic code. Each set of instruc-
in the centre and many microscopic organelles such tions along the DNA strand is a gene, and so genes
as mitochondria, Golgi bodies, centrosome, endo- are expressed as to form proteins10, 11. The final re-
plasmic reticulum, et cetera, which perform special- sult of a genetic expression is known as genotype.
ized functions in the cell. The nucleus contains a sap Double-stranded DNA is replicated by breakage of
- the nucleoplasm and thread like bodies called chro- the two strands and formation of a new complemen-
mosomes. The chromosomes are the structural unit tary strand for each, resulting in two identical copies
of inheritance and carry many genes within them of the original10, 11. A single strand of DNA can also
which are the functional unit of a character or trait3. act as a template for a complementary strand ribonu-
The position where a gene rests on the chromosome cleic acid (RNA). This transcription RNA is similar
is termed a locus. Each species has a specific num- to DNA, but T is replaced by uracil (U)9.
ber of chromosomes4. Cell division and accompanying replication and
In human beings, all the genetic information or partitioning of DNA that leads to the formation of
genome is split between 23 pairs of chromosomes7-9. sperm and ova is meiosis8, 9. Meiosis is the process
Therefore, the human genome is distributed among by which one chromosome of a homologous pair is
46 chromosomes. One of the 23 pairs is the sex incorporated into gamete (sperm or ova)8, 9. During
chromosome. The other 22 pairs of chromosomes meiosis one partner of each pair of chromosomes
are found in both males and females, and are called passes into daughter cells with the result that each
autosomes. One chromosome in each of the 22 ho- daughter cell has half the number of chromosomes
mologous pairs is derived from the mother and one of the parent cell. Each gamete receives at random
from the father. The only exception is the sex chro- one member of each homologous chromosomal
mosomes, which come in two forms: X or Y. The sex pair8, 9.
chromosomes present determine the sex of the indi- In addition to the 46 (44 autosomes and two sex)
vidual. The presence of two X chromosomes gives chromosomes that make up a human nuclear DNA
birth to a female, homozygous. On the other hand, (nDNA), there is a small extrachromosomal double
the XY composition symbolizes the male, heterozy- strand circle of DNA that is essential for life - the
gous chromosomes. A condition of YY chromosomes mitochondrial genome (mtDNA)12-17. The mtDNA
does not exist. Males have only one X and therefore, consist of heavy and light strands and encodes 13
only one set of alleles for all genes on X, while fe- polypeptides, two ribosomal RNAs and 22 transfer
males have paired alleles on their sex chromosomes. RNAs12-17. The mitochondrial genome plays an im-
An allele is an alternate form of a gene found at the portant role in the process of oxidative phosphoryla-
same locus on homologous chromosome8. tion (the process of producing bulk of cellular ATP
The human genome9 is made up of deoxyribonu- in aerobically respiring cells)12-17. The mitochondrial
cleic acid (DNA), which consists of a long sequence genome possesses unique characteristics that distin-
of nucleotide bases of four types: adenine (A), cyto- guish it from Mendelian genetic rules and it is strict-
sine (C), guanine (G) and thymine (T). In the nucleus ly inherited through the maternal lineage. Paternally
of a cell, the DNA is double stranded. Strong cova- derived mtDNA is labelled with an ubiquitin, which
lent bonds bind bases together along a single strand, evokes rapid targeted proteolysis when it enters the

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oocyte18. Thus, only maternal mtDNA can be inher- Some common ocular examples of genetic dis-
ited. The mtDNA is polyploidy, with multiple copies eases
of mtDNA within each mitochondrion and several
hundreds, if not thousands of mitochondria per cell. A genetic or inherited disease is a condition that
Normally, all mtDNA within the cells of an individ- may be passed on from parent to their children
ual are identical-homoplasmy12-17. However, a muta- through the coded information contained in the
tion occurring in one copy of mtDNA can eventually genes1-6. Inherited disorders differ from the medical
result in heteroplasmy (dual populations of mutant disorders in that they tend to recur within families
and wild-type DNA coexisting within the same cell). and often, the risk of occurrence for other family
During mitosis, the mutant and wild-type mtDNA are members can be predicted1-6.
randomly segregated to each of the daughter cells18.
This random segregation affects both expression and Corneal dystrophies
inheritance of mitochondrial disease. The word “dystrophy” is derived from Greek (dys
= wrong or difficult, trophe = nourishment). Corneal
Mendelian inheritance dystrophies are a group of inherited corneal diseases
that are typically bilateral, symmetric, and slowly
Genetic eye disorders are classified according to progressive and without relationship to environment
the type of genetic abnormality. Often the abnor- or systemic factors21, 22. These autosomal dominant
mality occurs on only one gene. These single-gene diseases are characterized by progressive accumu-
defects are the types of genetic abnormality called lation of corneal deposits beginning in the first or
the Mendelian inheritance19, 20. They are subdivided second decade of life. The most common inherited
into autosomal dominant, autosomal recessive and corneal dystrophies are the granular and lattice cor-
X-linked or sex-linked19, 20. Autosomal means that neal dystrophies22. Mutations in KRT3 and KRT12
the genes involved are located on the chromosomes are the causes of dystrophies22. Meesmann corneal
numbered one to 22, rather than on the X or Y sex dystrophy is an autosomal dominant disorder that af-
chromosomes. To produce an autosomal dominant fects only the corneal epithelium23, 24.
inheritance only one copy of the defective gene is
required. The offspring of affected individuals have Anterior segment dysgenesis
a 50% chance of being affected19, but the offspring Anterior segment dysgenesis (ASD) encompasses
of unaffected individuals are not affected. Males and a spectrum of inherited autosomal dominant diseases
females are equally likely to be affected. Most auto- that results from maldevelopment of the anterior seg-
somal dominant traits involve structural defects. ment of the eye6, 9, 25. A serious clinical consequence
The term “recessive” means hidden20. In other is the increased risk of secondary glaucoma9, 25. Mu-
words, an individual can carry a single copy of a tations of PITX2 homeobox and FOXC1 forkhead
defective gene without showing any clinical signs. genes have been found in patients with a range of
Traits of autosomal recessive tend to cause meta- anterior segment dysgenesis phenotypes25. Howev-
bolic disorders, such as diabetes and hypertension19. er, mutations of these genes account for only 35% or
There is a 25% theoretical risk to offspring who have less of cases of ASD. Therefore there are other ad-
two carrier parents. The characteristics of X-linked ditional genes that may play a role in this condition.
inheritance are that males are affected and females
are usually unaffected carriers. There is no male-to- Aniridia
male transmission because the father must donate Aniridia is a condition where there is near-total
his Y chromosome to have a son. The risk to male absence of the iris6. This is an autosomal dominant
offspring is 50% if the mother is a carrier19, 20. inherited directly from a parent who has aniridia
(See appendix on page 188.) Unlike the Mendelian themselves25, 26. It is the result of a mutation in a
inheritance, multifactorial traits are polygenic20. gene called PAX6 gene. Aniridia is associated with
There is usually a significant environmental factor many serious ocular (eye) conditions, including cat-
in multifactorial inheritance. aracts, glaucoma and corneal pannus. Each child of

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a person with aniridia will have a 50% chance of inheritance pattern. The other mutation that may
inheriting the gene mutation20. cause the development of primary open-angle glau-
coma is the risk alleles36. Risk alleles do not cause
Uveal melanoma disease on their own but when combined with other
Uveal melanoma is the most frequent primary glaucoma risk alleles and environmental factors36.
malignant intraocular tumour in adults27-29. It arises
from melanocytes located in the iris, choroid and cil- Cataract
iary body, which are structures of the uveal tract27-29. The transparency of the lens depends on a highly
Cutaneous melanoma and uveal melanoma both structured arrangement of lens proteins and lens fi-
derive from melanocytes but show distinct differ- bres37, 38. About 90% of the lens proteins are crystal-
ences in tumour genesis, mode of metastic spread, lins37. The crystallins are long-lived proteins located
genetic alteration and therapeutic response27-29. Not inside lens fibres, and are essential in the mainte-
much is known about genes involved in the de- nance of transparency and refractive power37. These
velopment and progression to metastasis in uveal proteins that function in maintaining the clarity of
melanoma compared to cutaneous melanoma27-29. the lens could be the potential genes causing herita-
This could be due to the result of the lower inci- ble cataracts. According to Shiels and Hejtmancik38,
dence of uveal melanoma and the small quantities congenital or infantile cataract can be seen within
of tumour sample available for research27-29. Cuta- the first year of life, juvenile cataract occurs mostly
neous melanoma accounts for more than 90% of all within the first decade of life, presenile cataract oc-
melanomas30 whereas uveal melanoma31 is only en- curs before age 45 years and senile or age-related
countered in 5%. However, several candidate genes cataract thereafter. The hereditary congenital cata-
were proposed as causes of uveal melanoma, such racts tend to be inherited in a Mendelian fashion,
as GNA11, GNAQ and DDEF1. Van Raamsdonk et while age-related cataracts tend to be multifactorial
al32, 33 reported that more than 80% of uveal mela- with both genes and environmental factors influenc-
nomas carry mutations in either GNA11 or GNAQ. ing the phenotype37, 38. Hereditary cataracts are esti-
Furthermore, the DDEF1-gene has been described mated to account for between 8% and 25% of con-
in uveal melanoma28. The gene responsible for uveal genital cataracts39. Mendelian cataracts are inherited
melanoma is located at chromosome 8 (8q24) and more commonly as autosomal dominant than as au-
found to be mutated in 50% of uveala melanomas34. tosomal recessive or X-linked traits38. A mutation in
the αβ-crystallin gene is the possible candidate for
Glaucoma congenital cataract37-39. This means that a mutation
Glaucoma, as a heterogeneous group of disorders, that severely disrupts the protein or inhibits its func-
is a pathologic condition in which there is a progres- tion might result in congenital cataracts inherited
sive loss of retinal ganglion cells, specific visual field in a Mendelian fashion, while mutation that causes
deficit and characteristic excavative optic nerve atro- less severe damage to the same protein or impairs its
phy35, 36. The major risk factor for glaucoma is ab- function only mildly might contribute to age-relat-
normally elevated intraocular pressure35, 36. Primary ed cataracts. Mutations in the fibrillin gene (FBN1)
open-angle glaucoma is the most common type of have been reported to be the cause of ectopia lentis6.
glaucoma characterized by the presence of glauco-
matous optic neuropathy in the absence of an iden- Norrie disease
tifiable secondary cause35, 36. Approximately 5% of Norrie disease is a rare X-linked recessive neu-
primary open-angle glaucoma has a genetic basis rodevelopmental disorder characterized by vitreous
and is attributed to a single gene36. This is called opacity, retinal detachment, retinal folds and fibro-
Mendelian forms of glaucoma, that is, glaucoma vascular masses40, 41. The disease affects organs
caused by mutations in myocin (MYOC) or optineu- derived from the neuroectoderm, such as the brain,
rin (OPTN)36. These single-gene forms of glaucoma retina and inner ear. Therefore, the affected individ-
are responsible for the disease that is transmitted as ual manifests congenital blindness, which is often
a Mendelian trait often with an autosomal dominant associated with hearing loss, mental retardation and

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psychiatric problems40-42. Genetic linkage studies RPGR1P1, TULP1, CRB1 and CRX are known to be
have localized the ND gene as the cause of Norrie the cause of the condition45. Different mutations in
disease42. several of these genes have been observed to cause
retinitis pigmentosa and other retinal dystrophies45.
Retinoschisis
X-linked retinoschisis is a relatively common ju- Choroideremia
venile retinal degenerative disease that affects males Choroideremia is an X-linked, recessively inher-
early in life . It is characterized by mild to severe ited, progressive, diffuse degeneration of the cho-
43

loss in central vision and splitting of inner retinal roid, retinal pigment epithelium and retinal photore-
layers in the peripheral retina44. During the course of ceptor cells51-54. It is caused by deletion or mutation
the disease, secondary complications including reti- of the CHM gene encoding Rab escort protein-1
nal detachment and vitreous haemorrhage can occur. (REP1). Patients with choroideremia characteristi-
Retinoschisis was first described in 1898 in two af- cally experience nyctalopia, peripheral field loss
fected brothers44. Since then it has been shown to be and a characteristic fundus appearance of extensive
one of the more frequent inherited retinal diseases retinal pigment epithelium and choroidal atrophy55.
affecting macular function in males43, 44. To date 191 Virtually all mutations reported on choroideremia
different mutations in the RS1 gene are known to result in the absence of the normal protein product
cause X-linked retinoschisis44. The RS1 protein is in affected males. Carrier females exhibit signs of
expressed in the rod and cone photoreceptors. patchy chorioretinal degeneration which have been
ascribed to random X-inactivation56.
Retinitis pigmentosa
Retinitis pigmentosa is now known as a group Albinism
of clinically and genetically heterogeneous retinal Albinism may be divided into oculocutaneous al-
degenerative hereditary diseases45-47. The disease binism affecting eyes, hair and skin; and ocular al-
can display X-linked, autosomal dominant and au- binism affecting only the eyes57-59. Oculocutaneous
tosomal recessive inheritance patterns. Clinically, albinism is a syndrome that encompasses a group of
the disease is characterized by night blindness, nar- individual inborn errors, each inherited as a Mende-
rowing of the visual field and pigmentary changes lian autosomal recessive trait characterized by the
or alterations of the retina, eventually leading to absence or near absence of melanin pigmentation in
complete loss of vision45-47. Mutations in RP1 gene the skin, hair and eyes59. Ocular albinism is an X-
seem to be the cause of autosomal dominant retinitis linked trait with findings predominantly restricted
pigmentosa48. Mutations in the RPGR gene are the to the eye. It is characterized by reduction of visual
most frequent cause of X-linked retinitis pigmen- acuity, iris transillumination, nystagmus, foveal hy-
tosa49. The genes more frequently involved in au- poplasia and hypopigmentation of the uveal tract and
tosomal recessive retinitis pigmentosa are the genes retinal pigment epithelium60. At present, four genes
encoding the subunits α and β of the Cgmp Phospho- for human albinism have been mapped (OCA1,
diesterase, RHO and the cGMP gated ion channel OCA2, HPS and OA1). Pathologic mutations have
protein CNGC50. been identified on ACA1, OCA2 and OA1 genes.
Another form of retinal dystrophy is Leber’s Tyrosinase (TYR) on chromosome 11q14-21 is an
congenital amaurosis which is an inherited condi- important enzyme in melanogenesis. Tyrosinase is
tion where clinical findings commonly first appear categorized as OCA1 gene. Mutations in human
after 2-3 months of life45. Visual function is usually TYR lead to the absence or decreased synthesis of
poor and often accompanied by nystagmus, sluggish melanin and thus cause oculocutaneous albinism60.
or near-absence pupillary responses, photophobia,
high hyperopia, keratoconus and enophthalmos45. Colour vision deficiencies
In contrast to original thinking, Leber’s congenital Colour vision is a behavioural capacity which al-
amaurosis is now known to be caused by at least lows primates to discriminate variations in the spec-
seven genes. Mutations in RPE65, RetGC1, AIPL1, tral composition of light, irrespective of variations

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in intensity61, 66. In the human eye, there are rods and tic nerve dysfunction appears to be hereditable69-73.
cones photoreceptor cells that serve different func- The pathology of inherited optic neuropathies is lim-
tions. Rhodopsin and cone pigments are the light- ited to the retinal ganglion cells of the optic nerve.
sensitive molecules in rods and cones, respectively. Optic nerve dysfunction can be the presenting and
Both the rhodopsin and cone pigments are collec- only ophthalmological manifestation causing two
tively called photopigments or visual pigments. most common inherited optic neuropathies encoun-
They are composed of a protein component called tered in clinical practice - Leber’s hereditary optic
opsin and the chromophore 11-cis-retinal. Colour neuropathy and dominant optic neuropathy. The in-
vision is initiated by the absorption of light quanta herited optic neuropathies typically present symmet-
(photon) by visual pigments within the photorecep- rically and bilaterally with central visual loss69-73.
tors. Leber’s hereditary optic neuropathy (LHON) is
The human colour vision is normally trichromatic the most common mitochondrial genome disorder
and possesses three distinct classes of retinal cone that presents with rapid, painless loss of central vi-
photoreceptors. The three classes of pigment differ sion in one eye, followed by similar loss of vision
in their relative spectral sensitivities and are com- in the fellow eye within days or months in young
monly referred to as the blue or short-wave sensi- males69, 70, 72. The vast majority of cases of LHOA are
tive (S), green or middle/medium-wave sensitive due to one of three point mutation of mtDNA affect-
(M) and red or long-wave sensitive (L) photopig- ing complex I or ND genes (G11778A, G3460A and
ments63-65. Using colour names for photopigments T14484C). The Leber’s hereditary optic neuropathy
can be misleading. So people who are working in the has a non-Mendelian pattern of inheritance69-73. It is
field of colour vision prefer S, M and L to minimize maternally inherited and all maternal offspring will
confusion. inherit the mutation. This is probably because the
Red-green colour vision defects are inherited as midpiece of the sperm, which is the only part con-
X-linked recessive trait66-69. All red-green colour vi- taining mitochondria, does not penetrate the ovum
sion defects are caused by the absence of one class of during fertilization18. There is evidence for small pa-
cone photopigment. Tritan colour vision deficiency is ternal contribution but to date this does not seem to
a rare autosomal dominant trait and is characterized have any role in disease pathogenesis. Dominant optic
by blue-yellow colour confusion. Achromatopsia or atrophy (DOA) is the most common autosomal heredi-
total colour-blindness is a rare autosomal recessive tary optic neuropathy. Unlike Leber’s hereditary optic
trait68. It is also referred to as rod monochromacy neuropathy, it shows no sex predilection73, 74. Domi-
and it is characterized by loss of function of all cone nant optic atrophy typically present as slow progres-
classes, severe photophobia under daylight condi- sive, painless, bilateral, symmetric visual loss, begin-
tions and nystagmus69. Incomplete achromatopsia ning insidiously in the first two decades of life73, 74.
(blue cone monochromacy) is characterized by the Mutation in the OPA1 gene located at 3q28 has been
loss of only L and M cone functions68. identified as the cause of dominant optic atrophy73, 74.
The genes responsible for red-green colour vision
deficiency66-68 are located on the X-chromosome at Anophthalmia
xq28, and the genes causing tritanopia are located on Anophthalmia or anophthalmos (Greek word for
chromosome 7 (7q32). Achromatopsia is caused by without eye) is a rare congenital absence of one or
mutations in CNGA3 and CNGB3 genes. To the best both eyes74. In true anophthalmia, there is a complete
of our knowledge, there are no known advantages or failure of primary optic vesicle outgrowth or the op-
disadvantages to having extra genes. However, the tic vesicle has degenerated74. Clinical anophthalmia
reduction of genes to less than required leads to col-
is the absence of the globe in an orbit that otherwise
our vision defects. contains normal adnexal structures74. Bilateral ano-
phthalmia is rare. Anophthalmia is caused by a mu-
Inherited optic neuropathies tation in the SOX2 gene, which is responsible for the
The inherited optic neuropathies comprise a group production of the SOX2protein75, 76. Without SOX2
of mitochondrial disorders in which the cause of op- protein, the activity of genes that is important for the

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development of the eye are disrupted. SOX2 ano- lesions89, 90, 92. Most patients have inherited Star-
phthalmia syndrome follows an autosomal dominant gardt’s disease as an autosomal recessive trait, but in
inheritance pattern. some families it has been reported as an autosomal
dominant trait92. Stargardt’s disease92 is commonly
Keratoconus caused by mutations of the ABCA4 gene located on
Keratoconus is a bilateral and asymmetric cor- the short arm of chromosome 1.
neal degeneration characterized by localized corneal
thinning, which leads to protrusion of the thinned Pseudoexfoliation syndrome
cornea77, 78. It is the most common primary ecta- Pseudoexfoliation (PEX) syndrome is highly as-
sia 77. Corneal protrusion causes high myopia and
sociated with age93. It is rarely found in patients
irregular astigmatism, affecting visual quality. It younger than 50 years. PEX syndrome is described
usually occurs in the second decade of life and af- as a fibrillopathy that affects older patients and is
fects both genders and all ethnicities77-80. The cause marked by the production and accumulation of an
and possible mechanisms for the development of abnormal amyloid fibrillar extracellular matrix93-96.
keratoconus remains poorly understood. However, The matrix is a product of abnormal basement mem-
several hypotheses have been proposed on the ge- brane metabolism. The intraocular complications of
netic mechanism of development81-84. Heon et al82 PEX include phacodonesis and lens subluxation, an-
identified four mutations of the VSX1 gene (R166W, gle-closure glaucoma, insufficient mydriasis, blood-
L159M, D144E and H244R) in different keratocon- aqueous barrier dysfunction, posterior synechiae
ic patients. Recently, Liskova et al83 and Tang et and corneal endothelial decomposition93-96. PEX
al84 have shown that mutations of D144E, L159M, syndrome is currently acknowledged as the most
R166W and H244R are not related to keratoconus. common identifiable cause of open-angle glaucoma.
The etiology of keratoconus is complicated but the Biomicroscopically, the PEX matrix will appear as
genetic basis of the disease has started to be uncov- white deposits at the pupillary margin and anterior
ered. More recently, Guan et al81 have shown the lens surface96. Eyes with PEX typically respond
potential involvement of TGFB1 gene in the kerato- poorly to mydriatics. The possible reason for poor
conus of the Chinese population. mydriasis could be the development of subclinical
posterior synechiae. The elevated intraocular pres-
Marfan syndrome sure seen in PEX patients probably comes from PEX
Marfan syndrome is a disorder caused by herit- matrix blocking the trabecular meshwork95, 96.
able genetic defects of the connective tissue that has It has been shown that the PEX syndrome has a
an autosomal dominant mode of transmission85, 86. genetic factor that contributes to the pathogenesis93.
The defect itself has been isolated to the fibrillin-1 PEX has been suggested to be inherited as an auto-
(FBN1) gene on chromosome 15 in the q21.1 locus, somal dominant trait. Lysyl oxidase-like 1 (LOXL1)
which encodes the connective tissue protein fibril- gene has been identified as the key genetic risk fac-
lin87. Marfan syndrome is characterized by muscu- tor for PEX syndrome and PEX glaucoma94. LOXL1
loskeletal abnormalities, cardiovascular disease and is an important enzyme in extracellular matrix for-
ocular abnormalities86. Most patients with the Mar- mation94.
fan syndrome are myopic and astigmatism and have
ectopia lentis (dislocated crystalline lenses)88. Discussion
The characteristics of autosomal dominant inher-
Stargardt’s disease itance4-8 include the following: the affected person
Stargardt’s disease is the most common form has an affected parent, parents can transmit the dis-
of juvenile macular dystrophy89-92. It causes loss order to children of both sex, and males and females
of central vision in adults younger than 50 years have the same risk of inheritance. There is 50% risk
old90. The characteristic features of Stargard’s dis- of developing the disorder to any offspring of an af-
ease include progressive central visual loss, irregu- fected person and an unaffected mate (see Appendix
lar yellow-white fundus flecks and atrophic macular on page 188, Figure 1), if the affected parent has

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one normal gene and one mutant gene. If the af- X chromosome can dominate the defective X chro-
fected parent has two mutant genes, each offspring mosome and therefore manifest the phenotype. The
has a 100% chance of receiving the mutant genes male’s Y chromosome does not dominate defective
and subsequently expressing the disease clinically. X chromosome, and hence the complete disorder
(A normal offspring of an affected parent whose ge- is manifested as the phenotype. One of the clini-
netic background does not demonstrate any skipped cal diseases/ syndromes which fall in the X-linked
generations or mild expression of the disease can recessive disorder is Lowe’s (oculo-cerebro-renal)
be given 100% assurance that he will have normal syndrome characterized by nystagmus and miotic,
children.) Unaffected persons will not transmit the non-reactive pupils79. The normally white sclera
defective gene to their offspring unless they have an may appear blue and the visual acuity may be low-
expression of the trait so mild as to be of no clinical ered due to a cloudy cornea and/ or cataracts.
significance. In such a case, the trait would appear There are some defects which are due to a muta-
to skip a generation. An example of a syndrome that tion of the chromosome itself. Syndromes which are
falls under autosomal dominant disease is the Mar- due to chromosomal abnormalities include Edward’s
fan’s syndrome77. syndrome80 or Trisomy E, Down’s syndrome81 and
In autosomal recessive, the affected child has Wolf’s syndrome82. In Edward’s syndrome80 or Tri-
clinically normal parents4-8. Both males and females somy E, the number 18 chromosome is found in trip-
children have equal risk. Transmission from an af- licate. It affects females more than males (3:1). A
fected parent to offspring can only occur if the af- mother becoming pregnant after 35 years of age is
fected parent reproduces with a carrier for the same at a greater risk of giving birth to a child affected
defects. Should such occur, 50% of the children are with Trisomy E than a younger mother. The age of
at risk of developing the disease and the others will the father does not appear to be a contributing factor.
be carriers. If both parents are affected, 100% of the The child can suffer unilateral ptosis, corneal cloud-
children will be at risk. Children of an affected par- ing and poor visual acuity due to optic nerve atro-
ent who do not marry a carrier for the same defect phy. Down’s syndrome is due to an extra number 21
will not exhibit the trait but will transmit the delete- chromosome characterized by small, oblique eyelid
rious gene to future generations. Two carrier parents fissures81. Nystagmus, esotropia, keratoconus and
(heterozygotes) for the same defect can expect 25% high refractive errors have also been noted81. Wolf’s
of their offspring to be affected (see Figures 2 and syndrome is caused by a deletion of genetic material
3 in the appendix). Stargardt’s macular dystrophy is from chromosome 4 and is characterized by ocular
one example78. colobomas, strabismus, low birth weight and mental
In X-linked dominant inheritance4-8, both male retardation82. Retinoblastoma83 is due to a deletion
and female are affected; however, females are af- of chromosome 13.
fected more than males (2:1). When the male is the Another mode of hereditary transmission is the
affected one, all daughters will be affected and no polygenic and/ or multifactorial diseases which are
transmission will occur to the male offspring (see inherited only when a variety of genes combine with
Figure 4). If the female is the affected partner, 50% each other, with or without environmental influences
of the male and 50% of the female offspring is at to produce an anomaly84. Diabetes mellitus and hy-
risk for inheriting the defective gene4-8 (see Figure pertension are examples of systemic diseases which
5 on page 189). are multifactorial in their mode of inheritance. Pa-
In X-linked recessive trait, if the female is the tients with diabetes and hypertension also have ocu-
carrier she will transmit the disease to 50% of her lar manifestations, which can lead to blindness.
male offspring4-8. An affected male will not transmit
the disease to his male offspring since no X is inher- Conclusion
ited but all of his female offspring will be carriers
(figure 6). Since females have two X chromosomes, The ocular conditions described in this review
one maternal and one paternal in origin, the normal have significant visual impairment and blindness
consequences. Therefore, optometrists should be

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able to diagnose the condition appropriately first 395-404.

before they could make any management or refer- 15. McFarland R, Taylor RW, Turnbull DM. A clinical perspec-
tive on mitochondrial disease. Lancet Neurol 2010 9 829-
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netic counseling. phosphorylation system. Annu Rev Biochem 1985 54 1015-
1069.
18. Sutovsky P, Moreno RD, Ramalho-Santos J, Dominko T, Si-
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Appendix: Probability of inheritance
Tang YG, Picornell Y, Su X, Yang H, Rabinowitz YS.
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Ophthalmol 2006 51 561-575. square we put the genetic contribution of one parent
87. Dietz HC, Pyeritz RE. Mutations in human gene for fibril- (father) across the top and that of the other parent
lin-1 (FBN1) in the Marfan syndrome and related disor-
ders. Hum Mol Genet 1995 4 1799-1809.
(mother) down the left side.
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den Hallander AI, Hoyng CB. Clinical and genetic charac- Figure 1. Let A be the dominant allele for the gene. If only one
teristics of late-onset Stargardt’s disease. Ophthalmol 2012 parent has a single copy of a dominant allele for the dominant
119 1199-1210. disease, their children will have a 50% chance of inheriting the
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Figure 2. Let a be the recessive allele gene. If both parents are Figure 6. X-linked paternal recessive: There is 100% chance
carriers of the recessive allele for the disease, all of their chil- that all females will be carriers.
dren will have the following odds of inheriting it: 25% chance
of having the recessive disease (aa), 50% of being a healthy
carrier (Aa) and 25% chance of being healthy and not have the
recessive allele at all (AA).

Figure 3. Let a be the recessive allele gene. If one parent is a
carrier and the other has a recessive disease, their children will
have 50% chance of being a healthy carrier or 50% of having a
recessive disease.

Figure 4. X-linked paternal dominant: All the female (100%)
will have the mutant phenotype while no male will inherit the
disease.

Figure 5. X-linked maternal dominant: There is 25% chance

that females will not inherit the mutation, a 25% chance of hav-
ing a female who inherits the mutation, a 25% chance of having
an unaffected son and a 25% chance that males will be affected.

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