A small introduction to congenital cataract genetic approach

1. Dr Ebin Roshan Paul

2. Lens anatomy and development
 Surface ectoderm not from Neuroectoderm
 Embryonic nucleus 6 weeks GA
 Birth “embryonic + fetal”

3. Lens structure
Equatorial area
Cuboidal lens epithelium
Transparent BM synthesised from lens epithelium
1. Lens capsule
2. Lens epithelium
3. Lens fibers

4. Lens fibers
 Long thin transparent cells firmly placed “laminae”
 Bulk of lens
 Linked by “gap junction”
 No organelle and no nucleus

5. Lens fibers
 Central part oldest fibers 
 Primary lens fibers  posterior epithelium in embryogenesis
 Nucleus of lens
 Secondary lens fibers  germinative cells in equatorial regions
 Lens cortex, throughout life
Embryonic
Fetal
Infantile
Adult
Cortex

7. Crystallins
 Water soluble proteins, 90% of proteins in lens and cornea
 50% familial NS cataract mutation in crystallin genes
 RI of lens (refractive proteins )
 δ seen in avian and reptile lens
Type Percentage
α 40%
β 35%
γ 25%

8. α Crystallin
 “Chaperone” like property – esp C terminal
 Px the precipitation of denatured protein and ↑ cell
tolerance and prevent apoptosis.
 2 subunits
 Similar to “sHSPs” evolved from gene duplication and
divergence allowing adaptation to novel functions.
αA subunit ~ AD and AR cataract
αB subunit – precipitation of protein under stress, myopathy

10. CRYAB gene
 αβ crystallin gene product also expressed in muscles
 Spectrum of condition ranging from isolated cataract to
mild cataract with myopathy.

11. Gap junction (GJ) proteins
 Connexins 46 (GJA3) and Connexin 50 (GJA8): “functional
hemi channels”
 Nutrition and IC communication in avascular lens 
microcirculation
 Mutation  AD Nuclear cataract
 CX46 usually with “microcornea” association.

14. Lens Membrane proteins
 AQPO: members of “aquaporin” family
“major intrinsic protein” (MIP)
Lamellar and Polymorphic Cx
AD inherited
 LIM2: Lens membrane junction protein
adhesive function of lens fibers and
transparency : “Presenile cataract”
AR inherited
(5%)

16. Other lens membrane proteins
 EPHA2 : membrane bound protein TK
AD post polar cataract
 DNMBP : protein bind tight junction protein 1
AR cataract + pupil anomalies, strabismus
and nystagmus

17. Beaded Filament proteins (BFP)
 Intermediate Filaments (IF) unique to lens fibers
development and differentiation.
 2 types
 not seen in anterior Epi cells: “nuclear/lamellar/sutural” Cx
BFSP1 ( filensin)
BFSP2 (phakinin)
(combine with α crystallin to form beaded structures)

18. Growth and TF in lens
 HSF4 : “heat shock protein” regulators esp αβ crystallin
: needed in high temp and increased stress
: mutation cataract
2 types
AD : early childhood (Lamellar)
AR: Congenital Cx (Nuclear)

19. Lens Patellar Fossa (Hyaloid fossa)
 “Saucer depression” in anterior surface of vitreous body
 If dislocated causes 2◦ cataract. Ex: WMS, MS

20. Congenital cataract
 Cataract  Opacification of lens and disruption of micro
architecture.
 Based on age
 Incidence 1-15/10000 birth
 20000-40000 birth/year
 “treatable blindness”
Type Age
Congenital At birth
Infantile <1 yr
Juvenile 1st decade
Pre-senile <45 yrs
Senile / Age related >45 yrs

21. Congenital cataract
Static  bad
Progressive  good
Syndromic
(15%)
Non syndromic
Isolated anomaly
(70%)
with other ocular
features (complex) (15%)
Unilateral (isolated
and sporadic)
Bilateral (inherited and
associated conditions )
Mutation detected and
AD is most common
Other systemic features

22. Other association
 Systemic involvement
 Mental retardation
 Deafness
 Renal disease
 Heart disease

23. Causes of CC
 1/3rd sporadic, ~50% CC are due to mutations in gene coding for
lens structure.
 IUI- rubella(MCC), TORCH, EBV, Influenza, Syphilis
 Irradiation
 Medication induced
 Trauma
 Genetic / Metabolic causes

24.  NS B/L Cong Cat : 1/3rd genetic mutations
: ~ 50% crystalline genes
: ~ 25% connexins
rest are genes associated with structural proteins and TF

25. Morphological classification by
Merin
 Polar cataract  Anterior, Posterior, Bipolar
 Posterior sub capsular cataract (PSC)  steroid use
 Zonular cataract  Nuclear and Cortical
Merin S, Crawford JS. The etiology of congenital cataracts. A survey of 386 cases. Can J Ophthal 1971
Embryonic Fetal

28.  Pulverulent (dusty) and Dense
 Sutural (Stellate) : sutural area of fetal nucleus
 Cerulean (Blue dot): small blue opacities in nucleus and
cortex
 Capsular (Membranous) : resorbtion of lens proteins
Merin S, Crawford JS. The etiology of congenital cataracts. A survey of 386 cases. Can J Ophthal 1971

29. Genetics in Cong cataract
 Esp in bilateral cataract, ~115 genes, 90% detection rate
 AD is most common
 Mainly with lens structural proteins ( crystallins )
 Why ? testing needed  etiology
 inheritance
 recurrence risk
 other system association

30. genes associated Cx
Genes Association
FOXE3 ASMD
PAX6 AS defect
EYA1 ASMD ± BORS
PITX3 ASMD
CHX10 Microopthalmia
Iris defect
MAF ASD

37. Genetic syndromes with CC
 Accounts 15% of CC
 Other systemic involvement seen

38. Condition Trait Features
Hyper ferritenemia cataract syndrome AD Raised ferritin
Warburg micro syndrome (1/2/3) AR Microcephaly, hypogonadism, DD, ID
Martsolf syndrome AR Less severe form WMS
Hallerman steriff syndrome AR Short stature, hypotrichosis, dental
Rothmund Thomson syndrome AR Poikiloderma, radial defect
SLOS AR Dysmorphism, limb, DD, ID, genital
Lathosterolosis AR Dysmorphism, limb, DD, ID, genital

39. Condition Trait Features
Norrie disease XLR HL, ID, DD, facial dysmorphism
Nance Hooran syndrome XLD Dental anomalies, dysmorphism, ID
Lowe syndrome XL Hypotonia, ID, renal association
Cockayne syndrome AR Premature aging, SNHL, Cut PS

40. Work up in a CC case
 U/L cataract extensive work up not recommended
 Why ?  mostly sporadic and isolated
 Non hereditary
 usually with PFV
 without systemic or genetic association
Zena Lim Pediatric Cataract: The Toronto Experience—Etiology, AJO,Volume 149, Issue 6,2010,

41. Approach in CC
Detailed History
Antenatal and natal h/o
Febrile illness with rash
Drug intake
Irradiation
Birth h/o
Birth weight
Birth asphyxia
family h/o with 3G pedigree
Development h/o
Metabolic cause
Systemic cause
Opthal history
Onset
Laterality
Progression

42. Examination
 “Preverbal” checking for acuity: Fixation behaviour,
Fixation preference, Objection to occlusion
 “Glare” test: Central posterior cataract.
Significant reduction in acuity in bright light.
esp while driving at night

44. White reflex ( Leukocoria )
 60% associated with CC
 18% U/L and 42% B/L
 Other DD  RB
 RD
 B/L PHPV
 Coats disease
 ROP
J Pediatr Ophthalmol Strabismus. 2008 May-Jun;45(3)

45. Other CF
 Abnormal visual behaviour
 Strabismus
 Nystagmus
Risk factors of poor visual outcome

46. Associated ocular pathology
 Torch examination, Direct/ Indirect-scopy, Retinoscopy
 VEP
 ERG
 Association
Anterior Segments  corneal clouding
 micro opthalmos
 glaucoma
 PFV
 Iris changes
Posterior Segments  CR
 ON hypoplasia
 Lebers Amaurosis

47. Cataract
 Location
 Colour
 Density
 Shape

48. Visually significant cataract
 Very dense, obscuring Fundus
 Central cataract > 3mm in diameter
 U/L cataract with Strabismus
 B/L cataract with Nystagmus
 Cataract
Static  anterior pole, nuclear Cx
Progressive  Better prognosis. Start to obscure vision after
“critical period” of vision development.
Can be missed in examination
Absolute
indication for surgery

49. Basic work up
 1. Serology for IUI ( TORCH, VDRL)
 2. FBS
 3. LFT & RFT
 4. Calcium, Phosphorous
 5. Plasma AA profile
 6. GPUT / Galactokinase
 7. Opthal evaluation – Indirect & Slit lamp

50.  Family  Slit lamp examination
 female carriers also may have lenticular changes
Genetic work up
50% cases genetic  AD is MC trait
>110 gene
Detection rate : 70-80% isolated Cx
63% Syndromic cases
15% IEM

52. Vision screening
 UK National screening committee 2020
 1st examination : all newborns red reflex (within 72hrs)
 2nd examination: 6-8 weeks (~vaccination time)
 All positive seen by ophthalmologist by 2 weeks
Examination NAIP. Newborn and infant physical examination: Program Handbook,2020.

53. Treatment options
 Surgery and IOL placement depend on age
 IATS 2020 (Infant Aphakia Treatment Study) 114 sample
size
 Surgery time
U/L dense CC  6-8 weeks (4-6 weeks, 2019)
B/L dense CC  6-10 weeks ( 8 weeks, 2019)
Cataract management in children: a review of the literature and
current practice across five large UK centres. 2020

54.  Less than 1month  high chance of aphakic glaucoma
Vishwanath M, Cheong-Leen R, Taylor D, et al. Is early surgery for
congenital cataract a risk factor for glaucoma? Br J Ophthalmol. 2004; 88: 905-910.
high chance of < 4 weeks ---6 weeks---- 8 weeks> high chance of
aphakic glaucoma deprivation amblyopia
sensory

55. Post surgery refractory correction
 IOL  2 types
 Contact lenses
 Eye glasses
Hydrophobic Acrylic: foldable / rigid IOL
PMMA : foldable / rigid IOL

56. IOL placement
 <2 years : no IOL recommended why ? (<1 year, 2019)
1. No improvement in vision outcome
2. Small capsule to hold IOL
3. ↑ Chance of reopacification of visual axis
4. No added protection 2◦ glaucoma
5. High reoperation rate compared to aphakic group
“Secondary IOL is better than Primary IOL”
Cataract management in children: a review of the literature and
current practice across five large UK centres. 2020

57. Visual Rehabilitation
 Start asap to Px  amblyopia, nystagmus, poor fusion

58. Ectopia lentis
Dislocation lens Lens patellar fossa
Luxation Outside
Subluxation Within
Ex: Marfan, HC, WMS, HEL without systemic features
Sulfite oxidase def, hyperlysinemia, Refsum disease

61. Galactosemia
 Elevated galactose  galactonate and galactitol
 CF: poor feeding/FTT/ Hypoglycemia, seizures, HSM,
cataract, sepsis (Ecoli sepsis)
 Early galactose free diet can reverse lens clouding
Deposit in lens
“oil drop cataract”
(nuclear cataract)
Type Enzyme
I G 1 PO4 UT (GALT)
II GK (GALK1)
III UDP G 4 epimerase (GALE)

62. Dr Ebin Roshan Paul

63. Condition Trait Features
Hyper ferritenemia cataract syndrome AD Raised ferritin
Warburg micro syndrome (1/2/3) AR Microcephaly, hypogonadism, DD, ID
Martsolf syndrome AR Less severe form WMS
Hallerman steriff syndrome AR Short stature, hypotrichosis, dental
Rothmund Thomson syndrome AR Poikiloderma, radial defect
SLOS AR Dysmorphism, limb, DD, ID, genital
Lathosterolosis AR Dysmorphism, limb, DD, ID, genital

64. Condition Trait Features
Norrie disease XLR HL, ID, DD, facial dysmorphism
Nance Hooran syndrome XLD Dental anomalies, dysmorphism, ID
Lowe syndrome XL Hypotonia, ID, renal association
Cockayne syndrome AR Premature aging, SNHL, Cut PS

65. Hyperferritinemia Cx syndrome
 Over translation “ferritin mRNA”
 FTL gene (19 q 13.33)
 Hyperferritinemia (Ferritin L) without Iron overload
 Crystallisation of ferritin in lens
 “bread crumb like opacity” nucleus and cortex

68. Warburg Micro syndrome
 AR
 Rab 3 GTPase
 “micro”
Cephaly
Opthalmia
+ Congenital Cataract
Cornea
Genitalia

70. Martsolf syndrome
 Less severe form WMS 2
 Spasticity limited to LL only.
RAB 18 gene
Severe Mild
WMS 2 Martsolf

71. Hallerman steriff syndrome (HSS)
 Brachycephaly with frontal bossing, “bird like facies”,
proportionate short stature, hypotrichosis, dental defects.
 Eye: micro opthalmia, bilateral cataract, blue sclera.
 Etiology and inheritance: not clearly identified

72. Hallerman steriff syndrome

73.  Cong poikiloderma and cataract syndrome
 RECQL4 gene
 Poikiloderma, cataract, radial ray defect
Rothmund Thomson syndrome

74. Sparse hair
Poikiloderma
Cataract
RR defect
Short stature
Mx in future

75. Condition RRD CSO Poikilo
derma
Alopecia Absence of eye lashes
and eye brows
Short
stature
RTS + - + + + +
BGS + + + - - +
RAPADILINO + - - - - +
RECQL4 gene & REC Q Helicase

76. SLO Syndrome (RSH syndrome)
 DHCR7 gene (11q13.4) : final step in cholesterol synthesis
 Other features: Microcephaly
Cleft palate
Dysmorphism
FTT hypotonia
Polydactyly & Syndactyly
CHD
Hypogenitalism & sex reversal
Skin HSN

78. Lathosterolosis (LATHOS)
 SC5D gene  3 β OH steroid δ 5 desaturase
 Enzyme needed for Lathosterol 7 OH cholesterol
 CF similar to SLOS

80. Norrie disease (ND)
 XLR
 NDP gene (Xp11.3)  norrin  WNT signalling
vascular development of “eyes and ears”
Hearing loss and eye issues
Other features: DD, ID, behaviour issues

82. Nance Hooran syndrome
 XLD
 NHS gene
 Dysmorphism, cataract, dental anomaly
NHS protein with 3 Isoforms
NHS A
NHS B
NHS C

83.  Eye Cong cataract (100%), microcornea (96%), micro
opthalmos, nystagmus, strabismus, RD
 Dental  diastema, supernumerary teeth, “screwdriver
shaped teeth”, “mulberry molars” (bud molars)
 Short fingers, short metacarpals

85. Nance Hooran syndrome

86. Lowe syndrome
 OCRS , XLR , OCRL gene (inositol polyPO4 phosphatase)
 Female carriers : lens opacity in cortex (radial fashion)
without systemic features ( slit lamp examination)
 Clinical features
Brain  Hypotonia, DD, seizures, ID+
Eyes  cataract (100%), glaucoma (50%)
Renal  Fanconi syndrome, aminoaciduria, rickets

87.  30% are denovo, 4.5% are germline and somatic mosaicism
 Genetic counselling and Prenatal in all cases advised

88. Cockayne syndrome
 “progeroid nanism”
 DNA repair proteins
 Cachexia, microcephaly, photo HSN, hypertonia, FTT, SS, severe
dental carries, HL, VL, enopthalmos
 Life span 12 yrs
CSA ERCC8 Chrm 5 25%
CSB ERCC6 Chrm 10 75%

90. Adams Oliver syndrome
 AD/AR depend on gene involved
 Aplasia Cutis congenita
 TTLD, oligo/ brachy / Syndactyly
 Microopthalmia, cataract
 NB: cutis marmorata telengiectasia congenita