CASE-CONFERENCE
Ap.박신혜/R3 김수아
CASE 1. F/24 박O정

C/C : Nystagmus
white hair and skin, since birth
DM/HBP(-/-)
 Ocular op/trauma(-/-)
 Gls (-) Eye drop (-)
 Family Hx.

Ocular Exam
 BCVA : OD 0.125 (N-C x -1.00Ds=-7.00Dc Ax180)
OS 0.125 (N-C x -1.25Ds=-5.00Dc Ax180)
OU 0.2
 Orthophoria at F and N /sc

Nystagmus (++)
: manifest nystagmus
: pendular type
: AHP (+/-) : Rt. Head turn
• White eyelashes
• Iris hypopigmentation
• Foveal hypoplasia and visible choroidal
vasculatures
 Impression
Oculocutaneous albinism (OCA)

Plan
Gene mutation analysis
Genetic counseling
Dermatology consultation
MUTATION IDENTIFY
OCA type
OCA1
Gene
Alteration in
cDNA
Alteration in
protein
TYR
c.832C>T
(nonsense)
R278X
c.929dupC
(frameshift)
R311KfsX7
SLC45A2
(MATP)
OCA2
GENETIC COUNSELLING
Pt’s mother
Parents : Carrier of single copy of a disease-causing mutation
Patient : compound heterozygosity
Pt’s father
AFTER 1YR LATER

She visited our clinic with her fiance for genetic
counselling.
Gene analysis of him was done.
 The result showed that no relevant gene mutation was
found.

According to the principle of
autosomal recessive condition,
All of their children will be a carrier
of single copy,
it is unlikely that any of their
children could have albinism.
They were happy with the
counselling
CASE 2. M/19 김O권

C/C : Low vision, reading difficulty
yellow hair
DM/HBP(-/-)
 Ocular op/trauma(-/-)
 Gls (-) Eye drop (-)


Family Hx.
Ocular Exam
 BCVA : OD 0.1(0.25 x +4.00 Ds -5.25 Dc Ax178)
OS 0.1(0.2 x +2.75 Ds -4.00 Dc Ax167)
OU (0.25)
 Orthophoria at F and N /sc

Nystagmus (+)
: manifest nystagmus
: jerky to Rt.
• Blond hair, light-colored skin
• Iris transillumination(+)
• Hypopigmentation and foveal hypoplasia
 Impression
Oculocutaneous albinism (OCA)

Plan
Gene mutation analysis
Genetic counseling
Low vision device
Dermatology consultation
MUTATION IDENTIFY
OCA type
Gene
Alteration in
cDNA
Alteration in
protein
c.1784+1G>A2
-
c.1842G>T
(missense)
K614N
TYR
SLC45A2
(MATP)
OCA2
OCA2
CASE 3. F/45 김O미

C/C : Inward deviation of Rt.eye
white hair and skin, since birth
DM/HBP(-/-)
 Ocular op/trauma(-/-)
 Gls (-) Eye drop (-)
 Family Hx.

Ocular Exam
 BCVA : OD 0.08(0.125 x -13.00Ds=-3.00Dc Ax180)
OS 0.1(0.16 x -14.00Ds)


RET > 50△, RhoT /sc
Nystagmus (++)
: pendular type
• White eyelashes
• Iris hypopigmentation
• Foveal hypoplasia and visible choroidal
vasculatures
 Impression
Oculocutaneous albinism (OCA)

Plan
Gene mutation analysis
Genetic counseling
Muscle op. counseling
Dermatology consultation
MUTATION IDENTIFY
OCA type
Gene
Alteration in
cDNA
Alteration in
protein
c.469G>A
D157N
c.686G>A
C229Y
TYR
OCA4
SLC45A2
(MATP)
OCA2
CASE REVIEW
OCULO-CUTANEOUS ALBINISM
Ap.박신혜/R3 김수아
OCULOCUTANEOUS ALBINISM(OCA)


A group of inherited disorders of melanin biosynthesis
that exhibits congenital hypopigmentation of ocular and
cutaneous tissues.
The degree of skin and hair hypopigmentation varies with
the type of OCA
INTRODUCTION


Melanocytes deriving from the neural crest migrate to and
settle in the skin, hair, and eye (choroid).
Melanocytes in the RPE originate from the outer layer of
neuroectoderm that makes up the optic vesicle.
FUNCTION OF MELANINS
FUNCTION OF MELANINS




Melanin granules are located in the
apical portion of the RPE cells , adjacent
to ROS(rod outer segments)
Reduce light scattering and block light
absortion via the sclera, resulting in a
better image received by the retina.
Absorbs radiant energy(visible and
ultraviolet spectrum) and modifying the
energy by the degree of melanin
aggregation and redox state.
Melanin can bind redox-active metal ions
and sequester them in an inactive state
 preventing oxidative damage to the
retina.
OCA CLASSIFICATION




OCA1A
: most severe type, complete lack of melanin production
OCA1B, OCA2, OCA3, OCA4 : milder form, some pigment
accumulation over time
It is hard to identify the correct type according to only the
clinical findings because their clinical phenotypes usually
overlap.
Molecular study is a useful tool for the typing and diagnosis of OCA.
Gene
Gene product
Chr. Localization
Size
Disease name
TYR
Tyrosinase (TYR)
11q14.3
65kb (529aa)
OCA1
OCA2
OCA2
15q11.2-q12
345kb (838aa)
OCA2
TYRPI
Tyrosinase-related protein
I (TYRP1)
9p23
17kb (536aa)
OCA3
SLC45A2
Membrane-associated
transporter protein (MATP)
5p13.3
40kb (530aa)
OCA4
CLINICAL DESCRIPTION

In OCA1A (white albino)


In OCA1B (leaky mutation)


Newborn nearly always have blond or red hair.
Visual acuity is usually better than in OCA1
In OCA3 (TRP1 Albino) rare



the hair and skin may develop some pigment with time
In OCA2 (Ty-pos Albino) M/C



hair, lashes, eyebrows and skin are white and does not tan.
Irises are light blue to almost pink, and fully translucent.
Who have red hair and reddish brown skin (xanthism).
Very rare, African population
In OCA4


cannot be distinguished from OCA2 on clinical findings.
Rarer than OCA2, except in the Japanese population.
OCULOCUTANEOUS ALBINISM TYPE 4 IS ONE OF THE
MOST COMMON TYPES OF ALBINISM IN JAPAN.
Inaqaki K. Et el
Am J Hum Genet. 2004 Mar;74(3)
Of 75 unrelated patients that were screened, 18 individuals (24%) were
identified as having OCA4; they harbored seven novel mutations,
including four missense mutations (P58S, D157N, G188V, and V507L)
and three frameshift mutations (S90CGGCCArGC, V144insAAGT, and
V469delG), showing that MATP is the most frequent locus for tyrosinasepositive OCA in Japanese patients. We discuss the functional
melanogenic activity of each mutant allele, judging from the
relationship between the phenotypes and genotypes of the patients.
This is the first report on a large group of patients with OCA4.
OCULAR FINDINGS

Nystagmus
 abrupt onset during the first 3 months
 pendular initially but can become jerk type as fixation
improves

Strabismus d/t reduced stereopsis

Iris transillumination





Macular hypoplasia
Loss of melanin pigmentation within the RPE
Prominence of choroidal vessels
High refractive error, astigmatism
VA 20/100-20/200
OCULAR FINDINGS

Abnormal decussation of temporal optic nerve
misrouting of the optic nerves & excessive crossing of the fibers in
the optic chiasma
 Normal : contralateral : ipsilateral = 53:47
 Axons from the temporal retina are routed contralaterally rather
than ipsilaterally
 Reduction of uncrossed retino-geniculo-cortical projection

OCULAR FINDINGS
Using a pattern stimulus, the VEP asymmetry
can be detected
 Crossed asymmetry

GENETIC COUNSELLING




All four types of OCA are inherited as AR
disorders.
Thus, the parents of an affected child are
obligate carriers, the recurrence risk for
another affected child is 25%, and healthy
sibs are at 67% risk of being carriers.
Carrier detection and prenatal diagnosis
are possible when the disease causing
mutations have been indentified in the
family.
Under the clinical impression of OCA, the
correct subtyping was made on the basis
of genetic analysis of the chromosomes.
GENETIC COUNSELLING
Gene
Exon#
reference
Base Change
AA Change
Mutation Type/Effect
5’UTR
NG_008748.1:
g.4782C>T
NA
SNP (rs4547091)
c.832C>T
p.R278X
Nonsense(reported)
Exon2
NM_000372.4
TYR (OCA1A)
c.929insC
MATP(SLC45A2))
OCA2
Exon4
c.987G>A
P.T329T
SNP (rs2287949)
Exon10
c.1065G>A
p.A355A
SNP(rs1800404)
Exon14
c.1441G>A
p.A480T
Missense(novel)
possibly benign
c.1844A>G
p.H615R
SNP(rs1800414)
IVS21
c.2244+25C>G
N/A
SNP(rs7175046)
Exon22
c.2328T>C
p.A776A
SNP(rs1800419)
Exon23
c.2364G>A
p.S788S
SNP(rs12592307)
Exon18
NM_016180.3
Frameshift(reported)
NM_000275.2
MOLECULAR ANALYSIS OF KOREAN
PATIENTS WITH
OCULOCUTANEOUS ALBINISM
Shin Hae Park, Hyojin Chae, Yonggoo Kim, Myungshin Kim
Jpn J Ophthalmol (2012) 56:98–103
The OCA1A subtype(14 patients, 66.7%) was the most common, and 70% of the patients were
heterozygotes for two different mutational alleles. c.929dupC (54.8%) and R77Q (16.1%)
followed by OCA1B (4 patients, 19.0%), OCA4 (2 patient, 9.5%) and OCA2 (1 patient, 4.8%)
Identification of the mutational spectrum of Koreans with albinism may be valuable for correct
subtyping, prenatal diagnosis, carrier detection and genetic counseling in patients and their
families
DIFFERENTIAL DIAGNOSIS
Several disorders with characteristic of OCA in addition to
other symptoms have been identified
Hermansky-Pudlak syndrome (HPS)
: hypopigmentation and severe immunologic deficiency

Chediak-Higashi syndrome (CHS)
: hypopigmentation and increased susceptibility to bacterial
infections, prolonged bleeding time, easy bruisability


Waardenburg Syndrome type II
In Ocular Albinism(OA)
: the hypopigmentation is limited to the eyes,
The gene OA1 is localized on the X chromosome and only
boys are affected

PROGNOSIS

Lifespan in patients with OCA is not limited, and medical
problems are generally not increased compared to those in
the general population.

Development and intelligence are normal.

Persons with OCA have normal fertility.

Skin cancers may occur and regular skin checks should be
offered.
 OCAla are at high risk for skin cancers, especially squamous
cell carcinomas.
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