Achromatopsia

AchromatopsiaBy:

Yousuf Kamran

BS-Biotechnology (2010-14)

IMBB, BZU Multan

1.Introduction2.Signs & Symptoms

3.Diagnosis & Testing

4.Types 5.Causes6.Differential

Diagnosis

7.Treatments/Management

8.Molecular Genetics

9.Molecular Genetic Testing

10.Molecular genetic

Pathogenesis

11.Achromatopsia in Pakistani Families

CONTENTS

What is Achromatopsia?

Achromatopsia simply means “loss of color vision”

We can define it as “total inability to see colors”

A rare, non-progressive inability to distinguish any colors as a result of absent or nonfunctioning retinal cones

Persons with achromatopsia see everything in black, white and shades of grey

They have little or no cone vision

In normal eyes there are 6 million cone cells and 100 million rod cells

Patients have to rely just on rods which do not provide color vision and “saturate” at higher levels of illumination

So an achromat (person having achromatopsia) has impaired color discrimination and is either totally colorblind or almost totally colorblind

The severity varies between individuals

Achromatopsia is rather a syndrome because it exhibits symptoms of five different related disorders

(1) Hemeralopia (2) Amblyopia (3) Photophobia

(4) Nystagmus (5) Reduced visual acuity

Other names of achromatopsia are ACHM, Complete or incomplete color blindness, Rod monochromacy, Total color blindness etc

Usually autosomal recessive

Prevalence is 1 in 30,000 people (0.0033%)

SIGNS AND SYMPTOMS

Little or no color perception

Hemeralopia: severe day blindness

Amblyopia: reduced visual acuity

Nystagmus: uncontrolled oscillatory movement of eyes

Photophobia: aversion from light

Diagnosis and Testing

Color Vision Test The color perception of individuals

with achromatopsia (achromats) is unreliable

In general, all achromats have anomalous (impaired) color discrimination along all three axes of color vision corresponding to the three cone classes

(1) the protan or long-wavelength-sensitive cone axis (red)

(2) the deutan or middle-wavelength-sensitive cone axis (green)

(3) the tritan or short-wavelength-sensitive cone axis (blue)

Electrophysiology In the single-flash electroretinogram (ERG), the photopic

(high light levels) response is absent or markedly diminished while the scotopic (low light levels) response is normal or mildly abnormal.

Visual Fields Small central scotomas can be demonstrated in some

individuals by careful testing

Fundus Appearance Many affected individuals have a normal-appearing

fundus

Complete inability to see colors

Lack of function of all three types of cone (or photopic) photoreceptors of the eye

Characterized with:

greatly reduced visual acuity

Hemeralopia

Nystagmus

Severe photophobia

Ability to see colors partially

one or more cone types may be partially functioning

Symptoms are less severe than complete achromatopsia

Reduced visual acuity with or without nystagmus or photophobia

Also called dyschromatopsia

CompleteAchromatopsia

IncompleteAchromatopsia

Types

Causes

AcquiredCongenita

l

Thalamic Cerebral

malfunction of the retinal

phototransduction pathway

Causes

Acquired Thalamic Achromatopsia: caused by damage to

the thalamus

Most frequently caused by tumor growth

Cerebral Achromatopsia: caused by damage to the cerebral cortex

Most frequently caused by physical trauma, hemorrhage or tumor tissue growth

Causes

Congenital Congenital forms of achromatopsia are due to

malfunction of the retinal photo transduction pathway

Result from the inability of cone cells to properly respond to light input by hyperpolarizing

Known genetic causes of this are mutations in the cone cell cyclic nucleotide-gated ion channels CNGA3 (ACHM2) and CNGB3 (ACHM3) as well as the cone cell transducin, GNAT2 (ACHM4)

Differential Diagnosis

As achromatopsia is characterized with severely reduced visual acuity, pendular nystagmus, increased sensitivity to light, and reduced or complete loss of color discrimination and other psychophysical and electroretinographic findings

The following retinopathies may be confused with achromatopsia


Blue cone monochromatism Also called S-cone monochromacy or X-chromosome-linked

achromatopsia

Like achromatopsia, it is also characterized with reduced visual acuity, nystagmus, normal fundus and poor or no color discrimination

BUT in patient with BCM the peak of the photopic luminosity function is near 440 nm not 507nm

Actually 440nm is the peak sensitivity of the S cones and 507nm is the peak sensitivity of rods

Which means that S cones are also functioning alongwith rods

A special four-color plate test or a two-color filter test can clinically distinguish blue-cone monochromats from achromats (rod monochromats)


Cone Monochromatism Complete achromatopsia with normal visual acuity

Achromatopsia is less often confused with two other extremely rare forms of cone monochromatism which are L or red cone monochromacy and M or green cone monochromacy

In these nystagmus and light aversions are not present and the visual acuity and the cone ERG are normal:

Red cone monochromacy: in this only red cones may be functioning in addition to rods

Green cone monochromacy: in this only green cones may be functioning along with rods


Cone Dystrophies In cone dystrophy, cone function is normal at birth and symptoms

appear later

These include reduced visual acuity, photophobia, increased sensitivity to glare, and abnormal color vision

The age of onset of vision loss may be as early as childhood or as late as the seventh decade

Differentiating between achromatopsia and cone dystrophy can be difficult, particularly in individuals with onset in early childhood

But best clinical discriminator between achromatopsia & cone dystrophy is progression

Cone dystrophy is progressive in nature while achromatopsia is not

Treatments/Management

Generally there is no as such treatment to cure achromatopsia

But to cope with achromatosia there are

Dark or special filter glasses

Red tinted contact lenses

Eyeborg: it is a device that help people to percieve colors through sound waves

Molecular GeneticsLocus name

Gene Symbol

Chromosomal locus

Protein Name

ACHM2 CNGA3 2q11.2 Cyclic nucleotide-gated cation channel alpha 3

ACHM3 CNGB3 8q21.3 Cyclic nucleotide-gated cation channel beta 3

ACHM4 GNAT2 1p13.3 Guanine nucleotide binding protein G subunit alpha 2

ACHM5 PDE6C 10q23.33 Cone cGMP specific 3’,5’ cyclic phosphdiesterase subunit alpha

ACHM6 PDE6H 12p12.3 Retinal cone rhodopsin sensitive cGMP 3’,5’ –cyclic phosphodiesterase subunit gamma

Molecular Genetic TestingGenes Proportion of

Achromatopsia Attributed to Mutations in This Gene

Test Method Mutations detected

Test availability

CNGB3 ~40-50% Targeted mutation analysis

c.1148delC Clinical

Sequence analysis

Sequence variants

Deletion/duplication analysis

Unknown

CNGA3 ~25% Sequence analysis

Sequence variants Clinical


unknown

GNAT2 <2% Sequence analysis



Exonic or whole-gene deletions

PDE6C <2% Sequence analysis


PDE6H ~0.3% Sequence analysis


Molecular Genetic Pathogenesis

Molecular pathomechanism of ACHM is either the inability to properly control or respond to altered levels of cGMP

Levels of cGMp controls the opening of cyclic nucleotide-gated ion channels (CNGs)

Mutation in any of the described genes disturb this pathomechanism

In normal eye this pathway is as follows:

Light excites cone visual pigment molecules

GDP is converted into GTP at the guanosine binding site of the transducin alpha subunit (GNAT2)

This activated GTP transducin is released from the inhibitory beta/gamma subunits binds and activates the alpha’-subunit of the cone phosphodiesterase (PDE6C) by retracting the inhibitory gamma-subunit (PDE6H)

PDE hydrolyzes cGMP and effectively reduces its intracellular concentration

This results in the closure of the hetero-tetrameric cGMP-gated cation channels (CNGA3/CNGB3) and, subsequently, membrane hyperpolarization


CNGA3

Normal allelic variants: CNGA3 consists of eight coding exons

Only a few normal allelic variants

Mostly occurring in non coding region and do not result in amino acid substitution

Pathologic allelic variants: More than 80 different mutations have been reported

Majority of mutations are missense (<80%)

Few nonsense mutations, insertions, and deletions have been observed.

Nucleotide mutation

Protein mutation

Functional? (known or predicted)

Effect

c.C67T p.R23X NO

c.A542G p.Y181C NO Does not properly traffic out of the endoplasmic reticulum

c.C1106G p.T369S Yes Increased calcium influx

c.G830A p.R277H

c.C556T p. L186F No Does not properly traffic out of the endoplasmic reticulum

c.T1565C p. I522T

c.G580A p.E194K NO Does not properly traffic out of the endoplasmic reticulum

c.A485T p.D162V

c.934_936del p. 312delI

http://en.wikipedia.org/wiki/Endoplasmic_reticulum


GNAT2 Normal allelic variants: GNAT2 consists of eight

coding exons

Only a few polymorphisms and rare variants are observed; most occur within non-coding regions or do not result in an amino acid substitution.

Pathogenic allelic variants: Only 10 different disease-associated mutations

1 nonsense mutation, 7 deletions/insertions, one large deletion of exon 4, and a mutation c.461+24G>A activating a cryptic splice site and resulting in frame-shift

Nucleotide mutaion protein Functional? (predicted)

c.C235T p.Q79X No?

c.285_291del p.Y95fsX61 No?

IVS3+365_IVS4+974del

p.A101fsX12 No?

c.503_504insT p. L168fsX3 No?

c.802_803insTCAA p. L268fsX9 No?

c.955del p. I319SfsX5 No?


CNGB3 Normal allelic variants: CNGB3 consists of 18 coding

exons

Only a few polymorphisms and rare variants are observed; most occur within non-coding regions or do not result in an amino acid substitution

Pathologic allelic variants: More than 40 different mutations have been reported

Mostly are non-sense mutations, frame shift deletions and insertions and putative splice site mtations

Mis-sense mutations are ~10 %

Nucleotide mutation

Amino acid mutation

Functional? (known or predicted)

Effects

c.1148delC p.T383IfsX12 NO? Does not traffic to the surface

c.G1006T p.E336X NO?

c.G1208A p.R403Q Yes Increased outward rectification, increased cGMP affinity

c.819_826del p.P273fsX13 NO?

c.29_30insA p.K10fsX9 NO?

c.595delG p.E199SfsX2 NO?

c.1573_1574delinsTT

p.F525N Yes Increased surface expression in oocytes, decreased outward rectification, increased cGMP and cAMP affinity

c.C391T p.Q131X NO?

c.T991-3G Splicing NO?

c.T1635A p.Y545X NO?

c.C926T p.P309L

p.P309L p.R216X NO?

PDE6C Normal allelic variants: PDE6C consists of 22 coding

exons

Several polymorphisms and rare variants are observed; most occur within non-coding regions or do not result in an amino acid substitution

Pathologic allelic variants: To date sixteen different mutations in PDE6C in eight independent families have been described

seven missense and two nonsense mutations, three small indels, and four mutations affecting splicing

PDE6H Normal allelic variants: PDE6CH consists of only three

coding exons

Only few polymorphisms and rare variants are observed

Pathologic allelic variants: To date only a single homozygous nonsense mutation c.35C>G in PDE6H in three affected individuals from two independent families originating from Belgium and the Netherlands have been described

Genetics: pattern of inheritance

2 major types of achromatopsia (rod monochromacy & blue cone monochromatism) have different pattern of inheritance

Rod Monochromacy

Autosomal recessive

Usually this form of achromatopsia occurs

Males and females are equally affected

Persons with this vision disorder have inherited 2 faulty genes, 1 from each parent

Usually found in one generation only

BCM

X-linked recessive

Rare form of achromatopsia

In BCM, cone cells develop normally but the retina is unable to fill them with red or green pigment, thus leaving only blue cones

Almost always, only males are affected by BCM

Genetic analysis of 2 Pakistani families with achromatopsia

Family RP26 Family RP44

CNGA3 Nucleotidemutation

protein type

No mutation detectedc.822G>T p.R274S missense

CNGB3

No mutation detected

Nucleotidemutation

protein type

c.1825delG p.V609WfsX9

frameshift

Genetic analysis of four Pakistani families with achromatopsia

Family 50 Family 55

Family 70

Family 74

CNGA3 nucleotide

protein type No mutation detected



c.827A>G p.N276S substitution

missense

CNGB3 No mutation detected No mutation detected


No mutation detected*

The Island of Colorblinds

The Pingelap Atoll is an island consisting of a circular coral reef surrounding a lagoon in the Pacific Ocean.

In 1775 a huge storm called Typhoon Liengkieki ravaged the island, leaving only 20 inhabitants (90% were killed, meaning the original population was around 200)

One of the survivor was carrier for achromatopsia

Inbreeding was necessary to replenish the population and in the 4th generation of inbreeding Achromatopsia appeared

Today, it has roughly 200-250 residents, roughly 10% of which are affected by total color blindness - known as Achromatopsia and 30% are carriers

References

Azam, M., et al. (2010). "Novel CNGA3 and CNGB3 mutations in two Pakistani families with achromatopsia." Molecular Vision 16: 774.

Sacks, O. (1997). The island of the colour-blind: and, Cycad Island, Pan Macmillan.

Futterman, F. (1998). Understanding and Coping with Achromatopsia, F. Futterman.

Kohl, S., et al. (2004). "CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia." European Journal of Human Genetics 13(3): 302-308.

Achromatopsia GeneReviews™ [Internet] by Kohl S, Jägle H, Wissinger B. 2004 Jun 24 [Updated 2013 Jun 27]

Genetic analysis of four Pakistani families with achromatopsia and a novel S4 motif mutation of CNGA3 by Muhammad Arif Nadeem Saqib, Bilal Malik Awan, Mehwish Sarfraz, Muhammad Nasim Khan, Sajid Rashid, Muhammad Ansar

Achromatopsia

Healthcare

Transcript of Achromatopsia